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Anti-Tumor Necrosis Factor Treatment for Glomerulopathy: Case Report and Review of Literature
Podocytes are terminally differentiated, highly specialized cells located in juxtaposition to the basement membrane over the abluminal surfaces of endothelial cells within the glomerular tuft. This triad structure is the site of the filtration barrier, which forms highly delicate and tightly regulated architecture to carry out the ultrafiltration function of the kidney.1 The filtration barrier is characterized by foot processes that are connected by specialized junctions called slit diaphragms.
Insults to components of the filtration barrier can initiate cascading events and perpetuate structural alterations that may eventually result in sclerotic changes.2 Common causes among children include minimal change disease (MCD) with the collapse of foot processes resulting in proteinuria, Alport syndrome due to mutation of collagen fibers within the basement membrane leading to hematuria and proteinuria, immune complex mediated nephropathy following common infections or autoimmune diseases, and focal segmental glomerulosclerosis (FSGS) that can show variable histopathology toward eventual glomerular scarring.3,4 These children often clinically have minimal, if any, signs of systemic inflammation.3-5 This has been a limiting factor for the commitment to immunomodulatory treatment, except for steroids for the treatment of MCD.6 Although prolonged steroid treatment may be efficacious, adverse effects are significant in a growing child. Alternative treatments, such as tacrolimus and rituximab have been suggested as second-line steroid-sparing agents.7,8 Not uncommonly, however, these cases are managed by supportive measures only during the progression of the natural course of the disease, which may eventually lead to renal failure, requiring transplant for survival.8,9
This case report highlights a child with a variant of uncertain significance (VUS) in genes involved in Alport syndrome and FSGS who developed an abrupt onset of proteinuria and hematuria after a respiratory illness. To our knowledge, he represents the youngest case demonstrating the benefit of targeted treatment against tumor necrosis factor-α (TNF-α) for glomerulopathy using biologic response modifiers.
Case Description
This is currently a 7-year-old male patient who was born at 39 weeks gestation to gravida 3 para 3 following induced labor due to elevated maternal blood pressure. During the first 2 years of life, his growth and development were normal and his immunizations were up to date. The patient's medical history included upper respiratory tract infections (URIs), respiratory syncytial virus, as well as 3 bouts of pneumonia and multiple otitis media that resulted in 18 rounds of antibiotics. The child was also allergic to nuts and milk protein. The patient’s parents are of Northern European and Native American descent. There is no known family history of eye, ear, or kidney diseases.
Renal concerns were first noted at the age of 2 years and 6 months when he presented to an emergency department in Fall 2019 (week 0) for several weeks of intermittent dark-colored urine. His mother reported that the discoloration recently progressed in intensity to cola-colored, along with the onset of persistent vomiting without any fever or diarrhea. On physical examination, the patient had normal vitals: weight 14.8 kg (68th percentile), height 91 cm (24th percentile), and body surface area 0.6 m2. There was no edema, rash, or lymphadenopathy, but he appeared pale.
The patient’s initial laboratory results included: complete blood count with white blood cells (WBC) 10 x 103/L (reference range, 4.5-13.5 x 103/L); differential lymphocytes 69%; neutrophils 21%; hemoglobin 10 g/dL (reference range, 12-16 g/dL); hematocrit, 30%; (reference range, 37%-45%); platelets 437 103/L (reference range, 150-450 x 103/L); serum creatinine 0.46 mg/dL (reference range, 0.5-0.9 mg/dL); and albumin 3.1 g/dL (reference range, 3.5-5.2 g/dL). Serum electrolyte levels and liver enzymes were normal. A urine analysis revealed 3+ protein and 3+ blood with dysmorphic red blood cells (RBC) and RBC casts without WBC. The patient's spot urine protein-to-creatinine ratio was 4.3 and his renal ultrasound was normal. The patient was referred to Nephrology.
During the next 2 weeks, his protein-to-creatinine ratio progressed to 5.9 and serum albumin fell to 2.7 g/dL. His urine remained red colored, and a microscopic examination with RBC > 500 and WBC up to 10 on a high powered field. His workup was negative for antinuclear antibodies, antineutrophil cytoplasmic antibody, antistreptolysin-O (ASO) and anti-DNase B. Serum C3 was low at 81 mg/dL (reference range, 90-180 mg/dL), C4 was 13.3 mg/dL (reference range, 10-40 mg/dL), and immunoglobulin G was low at 452 mg/dL (reference range 719-1475 mg/dL). A baseline audiology test revealed normal hearing.
Percutaneous renal biopsy yielded about 12 glomeruli, all exhibiting mild mesangial matrix expansion and hypercellularity (Figure 1). One glomerulus had prominent parietal epithelial cells without endocapillary hypercellularity or crescent formation. There was no interstitial fibrosis or tubular atrophy. Immunofluorescence studies showed no evidence of immune complex deposition with negative staining for immunoglobulin heavy and light chains, C3 and C1q. Staining for α 2 and α 5 units of collagen was normal. Electron microscopy showed patchy areas of severe basement membrane thinning with frequent foci of mild to moderate lamina densa splitting and associated visceral epithelial cell foot process effacement (Figure 2).
These were reported as concerning findings for possible Alport syndrome by 3 independent pathology teams. The genetic testing was submitted at a commercial laboratory to screen 17 mutations, including COL4A3, COL4A4, and COL4A5. Results showed the presence of a heterozygous VUS in the COL4A4 gene (c.1055C > T; p.Pro352Leu; dbSNP ID: rs371717486; PolyPhen-2: Probably Damaging; SIFT: Deleterious) as well as the presence of a heterozygous VUS in TRPC6 gene (c2463A>T; p.Lys821Asn; dbSNP ID: rs199948731; PolyPhen-2: Benign; SIFT: Tolerated). Further genetic investigation by whole exome sequencing on approximately 20,000 genes through MNG Laboratories showed a new heterozygous VUS in the OSGEP gene [c.328T>C; p.Cys110Arg]. Additional studies ruled out mitochondrial disease, CoQ10 deficiency, and metabolic disorders upon normal findings for mitochondrial DNA, urine amino acids, plasma acylcarnitine profile, orotic acid, ammonia, and homocysteine levels.
Figure 3 summarizes the patient’s treatment response during 170 weeks of follow-up (Fall 2019 to Summer 2023). The patient was started on enalapril 0.6 mg/kg daily at week 3, which continued throughout treatment. Following a rheumatology consult at week 30, the patient was started on prednisolone 3 mg/mL to assess the role of inflammation through the treatment response. An initial dose of 2 mg/kg daily (9 mL) for 1 month was followed by every other day treatment that was tapered off by week 48. To control mild but noticeably increasing proteinuria in the interim, subcutaneous anakinra 50 mg (3 mg/kg daily) was added as a steroid
DISCUSSION
This case describes a child with rapidly progressive proteinuria and hematuria following a URI who was found to have VUS mutations in 3 different genes associated with chronic kidney disease. Serology tests on the patient were negative for streptococcal antibodies and antinuclear antibodies, ruling out poststreptococcal glomerulonephritis, or systemic lupus erythematosus. His renal biopsy findings were concerning for altered podocytes, mesangial cells, and basement membrane without inflammatory infiltrate, immune complex, complements, immunoglobulin A, or vasculopathy. His blood inflammatory markers, erythrocyte sedimentation rate, C-reactive protein, and ferritin were normal when his care team initiated daily steroids.
Overall, the patient’s clinical presentation and histopathology findings were suggestive of Alport syndrome or thin basement membrane nephropathy with a high potential to progress into FSGS.10-12 Alport syndrome affects 1 in 5000 to 10,000 children annually due to S-linked inheritance of COL4A5, or autosomal recessive inheritance of COL4A3 or COL4A4 genes. It presents with hematuria and hearing loss.10 Our patient had a single copy COL4A4 gene mutation that was classified as VUS. He also had 2 additional VUS affecting the TRPC6 and OSGEP genes. TRPC6 gene mutation can be associated with FSGS through autosomal dominant inheritance. Both COL4A4 and TRPC6 gene mutations were paternally inherited. Although the patient’s father not having renal disease argues against the clinical significance of these findings, there is literature on the potential role of heterozygous COL4A4 variant mimicking thin basement membrane nephropathy that can lead to renal impairment upon copresence of superimposed conditions.13 The patient’s rapidly progressing hematuria and changes in the basement membrane were worrisome for emerging FSGS. Furthermore, VUS of TRPC6 has been reported in late onset autosomal dominant FSGS and can be associated with early onset steroid-resistant nephrotic syndrome (NS) in children.14 This concern was voiced by 3 nephrology consultants during the initial evaluation, leading to the consensus that steroid treatment for podocytopathy would not alter the patient’s long-term outcomes (ie, progression to FSGS).
Immunomodulation
Our rationale for immunomodulatory treatment was based on the abrupt onset of renal concerns following a URI, suggesting the importance of an inflammatory trigger causing altered homeostasis in a genetically susceptible host. Preclinical models show that microbial products such as lipopolysaccharides can lead to podocytopathy by several mechanisms through activation of toll-like receptor signaling. It can directly cause apoptosis by downregulation of the intracellular Akt survival pathway.15 Lipopolysaccharide can also activate the NF-αB pathway and upregulate the production of interleukin-1 (IL-1) and TNF-α in mesangial cells.16,17
Both cytokines can promote mesangial cell proliferation.18 Through autocrine and paracrine mechanisms, proinflammatory cytokines can further perpetuate somatic tissue changes and contribute to the development of podocytopathy. For instance, TNF-α can promote podocyte injury and proteinuria by downregulation of the slit diaphragm protein expression (ie, nephrin, ezrin, or podocin), and disruption of podocyte cytoskeleton.19,20 TNF-α promotes the influx and activation of macrophages and inflammatory cells. It is actively involved in chronic alterations within the glomeruli by the upregulation of matrix metalloproteases by integrins, as well as activation of myofibroblast progenitors and extracellular matrix deposition in crosstalk with transforming growth factor and other key mediators.17,21,22
For the patient described in this case report, initial improvement on steroids encouraged the pursuit of additional treatment to downregulate inflammatory pathways within the glomerular milieu. However, within the COVID-19 environment, escalating the patient’s treatment using traditional immunomodulators (ie, calcineurin inhibitors or mycophenolate mofetil) was not favored due to the risk of infection. Initially, anakinra, a recombinant IL-1 receptor antagonist, was preferred as a steroid-sparing agent for its short life and safety profile during the pandemic. At first, the patient responded well to anakinra and was allowed a steroid wean when the dose was titrated up to 6 mg/kg daily. However, anakinra did not prevent the escalation of proteinuria following a URI. After the treatment was changed to adalimumab, a fully humanized monoclonal antibody to TNF-α, the patient continued to improve and reach full remission despite experiencing a cold and the flu in the following months.
Literature Review
There is a paucity of literature on applications of biological response modifiers for idiopathic NS and FSGS.23,24 Angeletti and colleagues reported that 3 patients with severe long-standing FSGS benefited from anakinra 4 mg/kg daily to reduce proteinuria and improve kidney function. All the patients had positive C3 staining in renal biopsy and treatment response, which supported the role of C3a in inducing podocyte injury through upregulated expression of IL-1 and IL-1R.23 Trachtman and colleagues reported on the phase II FONT trial that included 14 of 21 patients aged < 18 years with advanced FSGS who were treated with adalimumab 24 mg/m2, or ≤ 40 mg every other week.24 Although, during a 6-month period, none of the 7 patients met the endpoint of reduced proteinuria by ≥ 50%, and the authors suggested that careful patient selection may improve the treatment response in future trials.24
A recent study involving transcriptomics on renal tissue samples combined with available pathology (fibrosis), urinary markers, and clinical characteristics on 285 patients with MCD or FSGS from 3 different continents identified 3 distinct clusters. Patients with evidence of activated kidney TNF pathway (n = 72, aged > 18 years) were found to have poor clinical outcomes.25 The study identified 2 urine markers associated with the TNF pathway (ie, tissue inhibitor of metalloproteinases-1 and monocyte chemoattractant protein-1), which aligns with the preclinical findings previously mentioned.25
Conclusions
The patient’s condition in this case illustrates the complex nature of biologically predetermined cascading events in the emergence of glomerular disease upon environmental triggers under the influence of genetic factors.
Chronic kidney disease affects 7.7% of veterans annually, illustrating the need for new therapeutics.26 Based on our experience and literature review, upregulation of TNF-α is a root cause of glomerulopathy; further studies are warranted to evaluate the efficacy of anti-TNF biologic response modifiers for the treatment of these patients. Long-term postmarketing safety profile and steroid-sparing properties of adalimumab should allow inclusion of pediatric cases in future trials. Results may also contribute to identifying new predictive biomarkers related to the basement membrane when combined with precision nephrology to further advance patient selection and targeted treatment.25,27
Acknowledgments
The authors thank the patient’s mother for providing consent to allow publication of this case report.
1. Arif E, Nihalani D. Glomerular filtration barrier assembly: an insight. Postdoc J. 2013;1(4):33-45.
2. Garg PA. Review of podocyte biology. Am J Nephrol. 2018;47(suppl 1):3-13. doi:10.1159/000481633SUPPL
3. Warady BA, Agarwal R, Bangalore S, et al. Alport syndrome classification and management. Kidney Med. 2020;2(5):639-649. doi:10.1016/j.xkme.2020.05.014
4. Angioi A, Pani A. FSGS: from pathogenesis to the histological lesion. J Nephrol. 2016;29(4):517-523. doi:10.1007/s40620-016-0333-2
5. Roca N, Martinez C, Jatem E, Madrid A, Lopez M, Segarra A. Activation of the acute inflammatory phase response in idiopathic nephrotic syndrome: association with clinicopathological phenotypes and with response to corticosteroids. Clin Kidney J. 2021;14(4):1207-1215. doi:10.1093/ckj/sfaa247
6. Vivarelli M, Massella L, Ruggiero B, Emma F. Minimal change disease. Clin J Am Soc Nephrol. 2017;12(2):332-345.
7. Medjeral-Thomas NR, Lawrence C, Condon M, et al. Randomized, controlled trial of tacrolimus and prednisolone monotherapy for adults with De Novo minimal change disease: a multicenter, randomized, controlled trial. Clin J Am Soc Nephrol. 2020;15(2):209-218. doi:10.2215/CJN.06290420
8. Ye Q, Lan B, Liu H, Persson PB, Lai EY, Mao J. A critical role of the podocyte cytoskeleton in the pathogenesis of glomerular proteinuria and autoimmune podocytopathies. Acta Physiol (Oxf). 2022;235(4):e13850. doi:10.1111/apha.13850
9. Trautmann A, Schnaidt S, Lipska-Ziμtkiewicz BS, et al. Long-term outcome of steroid-resistant nephrotic syndrome in children. J Am Soc Nephrol. 2017;28:3055-3065. doi:10.1681/ASN.2016101121
10. Kashtan CE, Gross O. Clinical practice recommendations for the diagnosis and management of Alport syndrome in children, adolescents, and young adults-an update for 2020. Pediatr Nephrol. 2021;36(3):711-719. doi:10.1007/s00467-020-04819-6
11. Savige J, Rana K, Tonna S, Buzza M, Dagher H, Wang YY. Thin basement membrane nephropathy. Kidney Int. 2003;64(4):1169-78. doi:10.1046/j.1523-1755.2003.00234.x
12. Rosenberg AZ, Kopp JB. Focal segmental glomerulosclerosis. Clin J Am Soc Nephrol. 2017; 12(3):502-517. doi:10.2215/CJN.05960616
13. Savige J. Should we diagnose autosomal dominant Alport syndrome when there is a pathogenic heterozygous COL4A3 or COL4A4 variant? Kidney Int Rep. 2018;3(6):1239-1241. doi:10.1016/j.ekir.2018.08.002
14. Gigante M, Caridi G, Montemurno E, et al. TRPC6 mutations in children with steroid-resistant nephrotic syndrome and atypical phenotype. Clin J Am Soc Nephrol. 2011;6(7):1626-1634. doi:10.2215/CJN.07830910
15. Saurus P, Kuusela S, Lehtonen E, et al. Podocyte apoptosis is prevented by blocking the toll-like receptor pathway. Cell Death Dis. 2015;6(5):e1752. doi:10.1038/cddis.2015.125
16. Baud L, Oudinet JP, Bens M, et al. Production of tumor necrosis factor by rat mesangial cells in response to bacterial lipopolysaccharide. Kidney Int. 1989;35(5):1111-1118. doi:10.1038/ki.1989.98
17. White S, Lin L, Hu K. NF-κB and tPA signaling in kidney and other diseases. Cells. 2020;9(6):1348. doi:10.3390/cells9061348
18. Tesch GH, Lan HY, Atkins RC, Nikolic-Paterson DJ. Role of interleukin-1 in mesangial cell proliferation and matrix deposition in experimental mesangioproliferative nephritis. Am J Pathol. 1997;151(1):141-150.
19. Lai KN, Leung JCK, Chan LYY, et al. Podocyte injury induced by mesangial-derived cytokines in IgA Nephropathy. Nephrol Dial Transplant. 2009;24(1):62-72. doi:10.1093/ndt/gfn441
20. Saleem MA, Kobayashi Y. Cell biology and genetics of minimal change disease. F1000 Res. 2016;5: F1000 Faculty Rev-412. doi:10.12688/f1000research.7300.1
21. Kim KP, Williams CE, Lemmon CA. Cell-matrix interactions in renal fibrosis. Kidney Dial. 2022;2(4):607-624. doi:10.3390/kidneydial2040055
22. Zvaifler NJ. Relevance of the stroma and epithelial-mesenchymal transition (EMT) for the rheumatic diseases. Arthritis Res Ther. 2006;8(3):210. doi:10.1186/ar1963
23. Angeletti A, Magnasco A, Trivelli A, et al. Refractory minimal change disease and focal segmental glomerular sclerosis treated with Anakinra. Kidney Int Rep. 2021;7(1):121-124. doi:10.1016/j.ekir.2021.10.018
24. Trachtman H, Vento S, Herreshoff E, et al. Efficacy of galactose and adalimumab in patients with resistant focal segmental glomerulosclerosis: report of the font clinical trial group. BMC Nephrol. 2015;16:111. doi:10.1186/s12882-015-0094-5
25. Mariani LH, Eddy S, AlAkwaa FM, et al. Precision nephrology identified tumor necrosis factor activation variability in minimal change disease and focal segmental glomerulosclerosis. Kidney Int. 2023;103(3):565-579. doi:10.1016/j.kint.2022.10.023
26. Korshak L, Washington DL, Powell J, Nylen E, Kokkinos P. Kidney Disease in Veterans. US Dept of Veterans Affairs, Office of Health Equity. Updated May 13, 2020. Accessed June 28, 2024. https://www.va.gov/HEALTHEQUITY/Kidney_Disease_In_Veterans.asp
27. Malone AF, Phelan PJ, Hall G, et al. Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis. Kidney Int. 2014;86(6):1253-1259. doi:10.1038/ki.2014.305
Podocytes are terminally differentiated, highly specialized cells located in juxtaposition to the basement membrane over the abluminal surfaces of endothelial cells within the glomerular tuft. This triad structure is the site of the filtration barrier, which forms highly delicate and tightly regulated architecture to carry out the ultrafiltration function of the kidney.1 The filtration barrier is characterized by foot processes that are connected by specialized junctions called slit diaphragms.
Insults to components of the filtration barrier can initiate cascading events and perpetuate structural alterations that may eventually result in sclerotic changes.2 Common causes among children include minimal change disease (MCD) with the collapse of foot processes resulting in proteinuria, Alport syndrome due to mutation of collagen fibers within the basement membrane leading to hematuria and proteinuria, immune complex mediated nephropathy following common infections or autoimmune diseases, and focal segmental glomerulosclerosis (FSGS) that can show variable histopathology toward eventual glomerular scarring.3,4 These children often clinically have minimal, if any, signs of systemic inflammation.3-5 This has been a limiting factor for the commitment to immunomodulatory treatment, except for steroids for the treatment of MCD.6 Although prolonged steroid treatment may be efficacious, adverse effects are significant in a growing child. Alternative treatments, such as tacrolimus and rituximab have been suggested as second-line steroid-sparing agents.7,8 Not uncommonly, however, these cases are managed by supportive measures only during the progression of the natural course of the disease, which may eventually lead to renal failure, requiring transplant for survival.8,9
This case report highlights a child with a variant of uncertain significance (VUS) in genes involved in Alport syndrome and FSGS who developed an abrupt onset of proteinuria and hematuria after a respiratory illness. To our knowledge, he represents the youngest case demonstrating the benefit of targeted treatment against tumor necrosis factor-α (TNF-α) for glomerulopathy using biologic response modifiers.
Case Description
This is currently a 7-year-old male patient who was born at 39 weeks gestation to gravida 3 para 3 following induced labor due to elevated maternal blood pressure. During the first 2 years of life, his growth and development were normal and his immunizations were up to date. The patient's medical history included upper respiratory tract infections (URIs), respiratory syncytial virus, as well as 3 bouts of pneumonia and multiple otitis media that resulted in 18 rounds of antibiotics. The child was also allergic to nuts and milk protein. The patient’s parents are of Northern European and Native American descent. There is no known family history of eye, ear, or kidney diseases.
Renal concerns were first noted at the age of 2 years and 6 months when he presented to an emergency department in Fall 2019 (week 0) for several weeks of intermittent dark-colored urine. His mother reported that the discoloration recently progressed in intensity to cola-colored, along with the onset of persistent vomiting without any fever or diarrhea. On physical examination, the patient had normal vitals: weight 14.8 kg (68th percentile), height 91 cm (24th percentile), and body surface area 0.6 m2. There was no edema, rash, or lymphadenopathy, but he appeared pale.
The patient’s initial laboratory results included: complete blood count with white blood cells (WBC) 10 x 103/L (reference range, 4.5-13.5 x 103/L); differential lymphocytes 69%; neutrophils 21%; hemoglobin 10 g/dL (reference range, 12-16 g/dL); hematocrit, 30%; (reference range, 37%-45%); platelets 437 103/L (reference range, 150-450 x 103/L); serum creatinine 0.46 mg/dL (reference range, 0.5-0.9 mg/dL); and albumin 3.1 g/dL (reference range, 3.5-5.2 g/dL). Serum electrolyte levels and liver enzymes were normal. A urine analysis revealed 3+ protein and 3+ blood with dysmorphic red blood cells (RBC) and RBC casts without WBC. The patient's spot urine protein-to-creatinine ratio was 4.3 and his renal ultrasound was normal. The patient was referred to Nephrology.
During the next 2 weeks, his protein-to-creatinine ratio progressed to 5.9 and serum albumin fell to 2.7 g/dL. His urine remained red colored, and a microscopic examination with RBC > 500 and WBC up to 10 on a high powered field. His workup was negative for antinuclear antibodies, antineutrophil cytoplasmic antibody, antistreptolysin-O (ASO) and anti-DNase B. Serum C3 was low at 81 mg/dL (reference range, 90-180 mg/dL), C4 was 13.3 mg/dL (reference range, 10-40 mg/dL), and immunoglobulin G was low at 452 mg/dL (reference range 719-1475 mg/dL). A baseline audiology test revealed normal hearing.
Percutaneous renal biopsy yielded about 12 glomeruli, all exhibiting mild mesangial matrix expansion and hypercellularity (Figure 1). One glomerulus had prominent parietal epithelial cells without endocapillary hypercellularity or crescent formation. There was no interstitial fibrosis or tubular atrophy. Immunofluorescence studies showed no evidence of immune complex deposition with negative staining for immunoglobulin heavy and light chains, C3 and C1q. Staining for α 2 and α 5 units of collagen was normal. Electron microscopy showed patchy areas of severe basement membrane thinning with frequent foci of mild to moderate lamina densa splitting and associated visceral epithelial cell foot process effacement (Figure 2).
These were reported as concerning findings for possible Alport syndrome by 3 independent pathology teams. The genetic testing was submitted at a commercial laboratory to screen 17 mutations, including COL4A3, COL4A4, and COL4A5. Results showed the presence of a heterozygous VUS in the COL4A4 gene (c.1055C > T; p.Pro352Leu; dbSNP ID: rs371717486; PolyPhen-2: Probably Damaging; SIFT: Deleterious) as well as the presence of a heterozygous VUS in TRPC6 gene (c2463A>T; p.Lys821Asn; dbSNP ID: rs199948731; PolyPhen-2: Benign; SIFT: Tolerated). Further genetic investigation by whole exome sequencing on approximately 20,000 genes through MNG Laboratories showed a new heterozygous VUS in the OSGEP gene [c.328T>C; p.Cys110Arg]. Additional studies ruled out mitochondrial disease, CoQ10 deficiency, and metabolic disorders upon normal findings for mitochondrial DNA, urine amino acids, plasma acylcarnitine profile, orotic acid, ammonia, and homocysteine levels.
Figure 3 summarizes the patient’s treatment response during 170 weeks of follow-up (Fall 2019 to Summer 2023). The patient was started on enalapril 0.6 mg/kg daily at week 3, which continued throughout treatment. Following a rheumatology consult at week 30, the patient was started on prednisolone 3 mg/mL to assess the role of inflammation through the treatment response. An initial dose of 2 mg/kg daily (9 mL) for 1 month was followed by every other day treatment that was tapered off by week 48. To control mild but noticeably increasing proteinuria in the interim, subcutaneous anakinra 50 mg (3 mg/kg daily) was added as a steroid
DISCUSSION
This case describes a child with rapidly progressive proteinuria and hematuria following a URI who was found to have VUS mutations in 3 different genes associated with chronic kidney disease. Serology tests on the patient were negative for streptococcal antibodies and antinuclear antibodies, ruling out poststreptococcal glomerulonephritis, or systemic lupus erythematosus. His renal biopsy findings were concerning for altered podocytes, mesangial cells, and basement membrane without inflammatory infiltrate, immune complex, complements, immunoglobulin A, or vasculopathy. His blood inflammatory markers, erythrocyte sedimentation rate, C-reactive protein, and ferritin were normal when his care team initiated daily steroids.
Overall, the patient’s clinical presentation and histopathology findings were suggestive of Alport syndrome or thin basement membrane nephropathy with a high potential to progress into FSGS.10-12 Alport syndrome affects 1 in 5000 to 10,000 children annually due to S-linked inheritance of COL4A5, or autosomal recessive inheritance of COL4A3 or COL4A4 genes. It presents with hematuria and hearing loss.10 Our patient had a single copy COL4A4 gene mutation that was classified as VUS. He also had 2 additional VUS affecting the TRPC6 and OSGEP genes. TRPC6 gene mutation can be associated with FSGS through autosomal dominant inheritance. Both COL4A4 and TRPC6 gene mutations were paternally inherited. Although the patient’s father not having renal disease argues against the clinical significance of these findings, there is literature on the potential role of heterozygous COL4A4 variant mimicking thin basement membrane nephropathy that can lead to renal impairment upon copresence of superimposed conditions.13 The patient’s rapidly progressing hematuria and changes in the basement membrane were worrisome for emerging FSGS. Furthermore, VUS of TRPC6 has been reported in late onset autosomal dominant FSGS and can be associated with early onset steroid-resistant nephrotic syndrome (NS) in children.14 This concern was voiced by 3 nephrology consultants during the initial evaluation, leading to the consensus that steroid treatment for podocytopathy would not alter the patient’s long-term outcomes (ie, progression to FSGS).
Immunomodulation
Our rationale for immunomodulatory treatment was based on the abrupt onset of renal concerns following a URI, suggesting the importance of an inflammatory trigger causing altered homeostasis in a genetically susceptible host. Preclinical models show that microbial products such as lipopolysaccharides can lead to podocytopathy by several mechanisms through activation of toll-like receptor signaling. It can directly cause apoptosis by downregulation of the intracellular Akt survival pathway.15 Lipopolysaccharide can also activate the NF-αB pathway and upregulate the production of interleukin-1 (IL-1) and TNF-α in mesangial cells.16,17
Both cytokines can promote mesangial cell proliferation.18 Through autocrine and paracrine mechanisms, proinflammatory cytokines can further perpetuate somatic tissue changes and contribute to the development of podocytopathy. For instance, TNF-α can promote podocyte injury and proteinuria by downregulation of the slit diaphragm protein expression (ie, nephrin, ezrin, or podocin), and disruption of podocyte cytoskeleton.19,20 TNF-α promotes the influx and activation of macrophages and inflammatory cells. It is actively involved in chronic alterations within the glomeruli by the upregulation of matrix metalloproteases by integrins, as well as activation of myofibroblast progenitors and extracellular matrix deposition in crosstalk with transforming growth factor and other key mediators.17,21,22
For the patient described in this case report, initial improvement on steroids encouraged the pursuit of additional treatment to downregulate inflammatory pathways within the glomerular milieu. However, within the COVID-19 environment, escalating the patient’s treatment using traditional immunomodulators (ie, calcineurin inhibitors or mycophenolate mofetil) was not favored due to the risk of infection. Initially, anakinra, a recombinant IL-1 receptor antagonist, was preferred as a steroid-sparing agent for its short life and safety profile during the pandemic. At first, the patient responded well to anakinra and was allowed a steroid wean when the dose was titrated up to 6 mg/kg daily. However, anakinra did not prevent the escalation of proteinuria following a URI. After the treatment was changed to adalimumab, a fully humanized monoclonal antibody to TNF-α, the patient continued to improve and reach full remission despite experiencing a cold and the flu in the following months.
Literature Review
There is a paucity of literature on applications of biological response modifiers for idiopathic NS and FSGS.23,24 Angeletti and colleagues reported that 3 patients with severe long-standing FSGS benefited from anakinra 4 mg/kg daily to reduce proteinuria and improve kidney function. All the patients had positive C3 staining in renal biopsy and treatment response, which supported the role of C3a in inducing podocyte injury through upregulated expression of IL-1 and IL-1R.23 Trachtman and colleagues reported on the phase II FONT trial that included 14 of 21 patients aged < 18 years with advanced FSGS who were treated with adalimumab 24 mg/m2, or ≤ 40 mg every other week.24 Although, during a 6-month period, none of the 7 patients met the endpoint of reduced proteinuria by ≥ 50%, and the authors suggested that careful patient selection may improve the treatment response in future trials.24
A recent study involving transcriptomics on renal tissue samples combined with available pathology (fibrosis), urinary markers, and clinical characteristics on 285 patients with MCD or FSGS from 3 different continents identified 3 distinct clusters. Patients with evidence of activated kidney TNF pathway (n = 72, aged > 18 years) were found to have poor clinical outcomes.25 The study identified 2 urine markers associated with the TNF pathway (ie, tissue inhibitor of metalloproteinases-1 and monocyte chemoattractant protein-1), which aligns with the preclinical findings previously mentioned.25
Conclusions
The patient’s condition in this case illustrates the complex nature of biologically predetermined cascading events in the emergence of glomerular disease upon environmental triggers under the influence of genetic factors.
Chronic kidney disease affects 7.7% of veterans annually, illustrating the need for new therapeutics.26 Based on our experience and literature review, upregulation of TNF-α is a root cause of glomerulopathy; further studies are warranted to evaluate the efficacy of anti-TNF biologic response modifiers for the treatment of these patients. Long-term postmarketing safety profile and steroid-sparing properties of adalimumab should allow inclusion of pediatric cases in future trials. Results may also contribute to identifying new predictive biomarkers related to the basement membrane when combined with precision nephrology to further advance patient selection and targeted treatment.25,27
Acknowledgments
The authors thank the patient’s mother for providing consent to allow publication of this case report.
Podocytes are terminally differentiated, highly specialized cells located in juxtaposition to the basement membrane over the abluminal surfaces of endothelial cells within the glomerular tuft. This triad structure is the site of the filtration barrier, which forms highly delicate and tightly regulated architecture to carry out the ultrafiltration function of the kidney.1 The filtration barrier is characterized by foot processes that are connected by specialized junctions called slit diaphragms.
Insults to components of the filtration barrier can initiate cascading events and perpetuate structural alterations that may eventually result in sclerotic changes.2 Common causes among children include minimal change disease (MCD) with the collapse of foot processes resulting in proteinuria, Alport syndrome due to mutation of collagen fibers within the basement membrane leading to hematuria and proteinuria, immune complex mediated nephropathy following common infections or autoimmune diseases, and focal segmental glomerulosclerosis (FSGS) that can show variable histopathology toward eventual glomerular scarring.3,4 These children often clinically have minimal, if any, signs of systemic inflammation.3-5 This has been a limiting factor for the commitment to immunomodulatory treatment, except for steroids for the treatment of MCD.6 Although prolonged steroid treatment may be efficacious, adverse effects are significant in a growing child. Alternative treatments, such as tacrolimus and rituximab have been suggested as second-line steroid-sparing agents.7,8 Not uncommonly, however, these cases are managed by supportive measures only during the progression of the natural course of the disease, which may eventually lead to renal failure, requiring transplant for survival.8,9
This case report highlights a child with a variant of uncertain significance (VUS) in genes involved in Alport syndrome and FSGS who developed an abrupt onset of proteinuria and hematuria after a respiratory illness. To our knowledge, he represents the youngest case demonstrating the benefit of targeted treatment against tumor necrosis factor-α (TNF-α) for glomerulopathy using biologic response modifiers.
Case Description
This is currently a 7-year-old male patient who was born at 39 weeks gestation to gravida 3 para 3 following induced labor due to elevated maternal blood pressure. During the first 2 years of life, his growth and development were normal and his immunizations were up to date. The patient's medical history included upper respiratory tract infections (URIs), respiratory syncytial virus, as well as 3 bouts of pneumonia and multiple otitis media that resulted in 18 rounds of antibiotics. The child was also allergic to nuts and milk protein. The patient’s parents are of Northern European and Native American descent. There is no known family history of eye, ear, or kidney diseases.
Renal concerns were first noted at the age of 2 years and 6 months when he presented to an emergency department in Fall 2019 (week 0) for several weeks of intermittent dark-colored urine. His mother reported that the discoloration recently progressed in intensity to cola-colored, along with the onset of persistent vomiting without any fever or diarrhea. On physical examination, the patient had normal vitals: weight 14.8 kg (68th percentile), height 91 cm (24th percentile), and body surface area 0.6 m2. There was no edema, rash, or lymphadenopathy, but he appeared pale.
The patient’s initial laboratory results included: complete blood count with white blood cells (WBC) 10 x 103/L (reference range, 4.5-13.5 x 103/L); differential lymphocytes 69%; neutrophils 21%; hemoglobin 10 g/dL (reference range, 12-16 g/dL); hematocrit, 30%; (reference range, 37%-45%); platelets 437 103/L (reference range, 150-450 x 103/L); serum creatinine 0.46 mg/dL (reference range, 0.5-0.9 mg/dL); and albumin 3.1 g/dL (reference range, 3.5-5.2 g/dL). Serum electrolyte levels and liver enzymes were normal. A urine analysis revealed 3+ protein and 3+ blood with dysmorphic red blood cells (RBC) and RBC casts without WBC. The patient's spot urine protein-to-creatinine ratio was 4.3 and his renal ultrasound was normal. The patient was referred to Nephrology.
During the next 2 weeks, his protein-to-creatinine ratio progressed to 5.9 and serum albumin fell to 2.7 g/dL. His urine remained red colored, and a microscopic examination with RBC > 500 and WBC up to 10 on a high powered field. His workup was negative for antinuclear antibodies, antineutrophil cytoplasmic antibody, antistreptolysin-O (ASO) and anti-DNase B. Serum C3 was low at 81 mg/dL (reference range, 90-180 mg/dL), C4 was 13.3 mg/dL (reference range, 10-40 mg/dL), and immunoglobulin G was low at 452 mg/dL (reference range 719-1475 mg/dL). A baseline audiology test revealed normal hearing.
Percutaneous renal biopsy yielded about 12 glomeruli, all exhibiting mild mesangial matrix expansion and hypercellularity (Figure 1). One glomerulus had prominent parietal epithelial cells without endocapillary hypercellularity or crescent formation. There was no interstitial fibrosis or tubular atrophy. Immunofluorescence studies showed no evidence of immune complex deposition with negative staining for immunoglobulin heavy and light chains, C3 and C1q. Staining for α 2 and α 5 units of collagen was normal. Electron microscopy showed patchy areas of severe basement membrane thinning with frequent foci of mild to moderate lamina densa splitting and associated visceral epithelial cell foot process effacement (Figure 2).
These were reported as concerning findings for possible Alport syndrome by 3 independent pathology teams. The genetic testing was submitted at a commercial laboratory to screen 17 mutations, including COL4A3, COL4A4, and COL4A5. Results showed the presence of a heterozygous VUS in the COL4A4 gene (c.1055C > T; p.Pro352Leu; dbSNP ID: rs371717486; PolyPhen-2: Probably Damaging; SIFT: Deleterious) as well as the presence of a heterozygous VUS in TRPC6 gene (c2463A>T; p.Lys821Asn; dbSNP ID: rs199948731; PolyPhen-2: Benign; SIFT: Tolerated). Further genetic investigation by whole exome sequencing on approximately 20,000 genes through MNG Laboratories showed a new heterozygous VUS in the OSGEP gene [c.328T>C; p.Cys110Arg]. Additional studies ruled out mitochondrial disease, CoQ10 deficiency, and metabolic disorders upon normal findings for mitochondrial DNA, urine amino acids, plasma acylcarnitine profile, orotic acid, ammonia, and homocysteine levels.
Figure 3 summarizes the patient’s treatment response during 170 weeks of follow-up (Fall 2019 to Summer 2023). The patient was started on enalapril 0.6 mg/kg daily at week 3, which continued throughout treatment. Following a rheumatology consult at week 30, the patient was started on prednisolone 3 mg/mL to assess the role of inflammation through the treatment response. An initial dose of 2 mg/kg daily (9 mL) for 1 month was followed by every other day treatment that was tapered off by week 48. To control mild but noticeably increasing proteinuria in the interim, subcutaneous anakinra 50 mg (3 mg/kg daily) was added as a steroid
DISCUSSION
This case describes a child with rapidly progressive proteinuria and hematuria following a URI who was found to have VUS mutations in 3 different genes associated with chronic kidney disease. Serology tests on the patient were negative for streptococcal antibodies and antinuclear antibodies, ruling out poststreptococcal glomerulonephritis, or systemic lupus erythematosus. His renal biopsy findings were concerning for altered podocytes, mesangial cells, and basement membrane without inflammatory infiltrate, immune complex, complements, immunoglobulin A, or vasculopathy. His blood inflammatory markers, erythrocyte sedimentation rate, C-reactive protein, and ferritin were normal when his care team initiated daily steroids.
Overall, the patient’s clinical presentation and histopathology findings were suggestive of Alport syndrome or thin basement membrane nephropathy with a high potential to progress into FSGS.10-12 Alport syndrome affects 1 in 5000 to 10,000 children annually due to S-linked inheritance of COL4A5, or autosomal recessive inheritance of COL4A3 or COL4A4 genes. It presents with hematuria and hearing loss.10 Our patient had a single copy COL4A4 gene mutation that was classified as VUS. He also had 2 additional VUS affecting the TRPC6 and OSGEP genes. TRPC6 gene mutation can be associated with FSGS through autosomal dominant inheritance. Both COL4A4 and TRPC6 gene mutations were paternally inherited. Although the patient’s father not having renal disease argues against the clinical significance of these findings, there is literature on the potential role of heterozygous COL4A4 variant mimicking thin basement membrane nephropathy that can lead to renal impairment upon copresence of superimposed conditions.13 The patient’s rapidly progressing hematuria and changes in the basement membrane were worrisome for emerging FSGS. Furthermore, VUS of TRPC6 has been reported in late onset autosomal dominant FSGS and can be associated with early onset steroid-resistant nephrotic syndrome (NS) in children.14 This concern was voiced by 3 nephrology consultants during the initial evaluation, leading to the consensus that steroid treatment for podocytopathy would not alter the patient’s long-term outcomes (ie, progression to FSGS).
Immunomodulation
Our rationale for immunomodulatory treatment was based on the abrupt onset of renal concerns following a URI, suggesting the importance of an inflammatory trigger causing altered homeostasis in a genetically susceptible host. Preclinical models show that microbial products such as lipopolysaccharides can lead to podocytopathy by several mechanisms through activation of toll-like receptor signaling. It can directly cause apoptosis by downregulation of the intracellular Akt survival pathway.15 Lipopolysaccharide can also activate the NF-αB pathway and upregulate the production of interleukin-1 (IL-1) and TNF-α in mesangial cells.16,17
Both cytokines can promote mesangial cell proliferation.18 Through autocrine and paracrine mechanisms, proinflammatory cytokines can further perpetuate somatic tissue changes and contribute to the development of podocytopathy. For instance, TNF-α can promote podocyte injury and proteinuria by downregulation of the slit diaphragm protein expression (ie, nephrin, ezrin, or podocin), and disruption of podocyte cytoskeleton.19,20 TNF-α promotes the influx and activation of macrophages and inflammatory cells. It is actively involved in chronic alterations within the glomeruli by the upregulation of matrix metalloproteases by integrins, as well as activation of myofibroblast progenitors and extracellular matrix deposition in crosstalk with transforming growth factor and other key mediators.17,21,22
For the patient described in this case report, initial improvement on steroids encouraged the pursuit of additional treatment to downregulate inflammatory pathways within the glomerular milieu. However, within the COVID-19 environment, escalating the patient’s treatment using traditional immunomodulators (ie, calcineurin inhibitors or mycophenolate mofetil) was not favored due to the risk of infection. Initially, anakinra, a recombinant IL-1 receptor antagonist, was preferred as a steroid-sparing agent for its short life and safety profile during the pandemic. At first, the patient responded well to anakinra and was allowed a steroid wean when the dose was titrated up to 6 mg/kg daily. However, anakinra did not prevent the escalation of proteinuria following a URI. After the treatment was changed to adalimumab, a fully humanized monoclonal antibody to TNF-α, the patient continued to improve and reach full remission despite experiencing a cold and the flu in the following months.
Literature Review
There is a paucity of literature on applications of biological response modifiers for idiopathic NS and FSGS.23,24 Angeletti and colleagues reported that 3 patients with severe long-standing FSGS benefited from anakinra 4 mg/kg daily to reduce proteinuria and improve kidney function. All the patients had positive C3 staining in renal biopsy and treatment response, which supported the role of C3a in inducing podocyte injury through upregulated expression of IL-1 and IL-1R.23 Trachtman and colleagues reported on the phase II FONT trial that included 14 of 21 patients aged < 18 years with advanced FSGS who were treated with adalimumab 24 mg/m2, or ≤ 40 mg every other week.24 Although, during a 6-month period, none of the 7 patients met the endpoint of reduced proteinuria by ≥ 50%, and the authors suggested that careful patient selection may improve the treatment response in future trials.24
A recent study involving transcriptomics on renal tissue samples combined with available pathology (fibrosis), urinary markers, and clinical characteristics on 285 patients with MCD or FSGS from 3 different continents identified 3 distinct clusters. Patients with evidence of activated kidney TNF pathway (n = 72, aged > 18 years) were found to have poor clinical outcomes.25 The study identified 2 urine markers associated with the TNF pathway (ie, tissue inhibitor of metalloproteinases-1 and monocyte chemoattractant protein-1), which aligns with the preclinical findings previously mentioned.25
Conclusions
The patient’s condition in this case illustrates the complex nature of biologically predetermined cascading events in the emergence of glomerular disease upon environmental triggers under the influence of genetic factors.
Chronic kidney disease affects 7.7% of veterans annually, illustrating the need for new therapeutics.26 Based on our experience and literature review, upregulation of TNF-α is a root cause of glomerulopathy; further studies are warranted to evaluate the efficacy of anti-TNF biologic response modifiers for the treatment of these patients. Long-term postmarketing safety profile and steroid-sparing properties of adalimumab should allow inclusion of pediatric cases in future trials. Results may also contribute to identifying new predictive biomarkers related to the basement membrane when combined with precision nephrology to further advance patient selection and targeted treatment.25,27
Acknowledgments
The authors thank the patient’s mother for providing consent to allow publication of this case report.
1. Arif E, Nihalani D. Glomerular filtration barrier assembly: an insight. Postdoc J. 2013;1(4):33-45.
2. Garg PA. Review of podocyte biology. Am J Nephrol. 2018;47(suppl 1):3-13. doi:10.1159/000481633SUPPL
3. Warady BA, Agarwal R, Bangalore S, et al. Alport syndrome classification and management. Kidney Med. 2020;2(5):639-649. doi:10.1016/j.xkme.2020.05.014
4. Angioi A, Pani A. FSGS: from pathogenesis to the histological lesion. J Nephrol. 2016;29(4):517-523. doi:10.1007/s40620-016-0333-2
5. Roca N, Martinez C, Jatem E, Madrid A, Lopez M, Segarra A. Activation of the acute inflammatory phase response in idiopathic nephrotic syndrome: association with clinicopathological phenotypes and with response to corticosteroids. Clin Kidney J. 2021;14(4):1207-1215. doi:10.1093/ckj/sfaa247
6. Vivarelli M, Massella L, Ruggiero B, Emma F. Minimal change disease. Clin J Am Soc Nephrol. 2017;12(2):332-345.
7. Medjeral-Thomas NR, Lawrence C, Condon M, et al. Randomized, controlled trial of tacrolimus and prednisolone monotherapy for adults with De Novo minimal change disease: a multicenter, randomized, controlled trial. Clin J Am Soc Nephrol. 2020;15(2):209-218. doi:10.2215/CJN.06290420
8. Ye Q, Lan B, Liu H, Persson PB, Lai EY, Mao J. A critical role of the podocyte cytoskeleton in the pathogenesis of glomerular proteinuria and autoimmune podocytopathies. Acta Physiol (Oxf). 2022;235(4):e13850. doi:10.1111/apha.13850
9. Trautmann A, Schnaidt S, Lipska-Ziμtkiewicz BS, et al. Long-term outcome of steroid-resistant nephrotic syndrome in children. J Am Soc Nephrol. 2017;28:3055-3065. doi:10.1681/ASN.2016101121
10. Kashtan CE, Gross O. Clinical practice recommendations for the diagnosis and management of Alport syndrome in children, adolescents, and young adults-an update for 2020. Pediatr Nephrol. 2021;36(3):711-719. doi:10.1007/s00467-020-04819-6
11. Savige J, Rana K, Tonna S, Buzza M, Dagher H, Wang YY. Thin basement membrane nephropathy. Kidney Int. 2003;64(4):1169-78. doi:10.1046/j.1523-1755.2003.00234.x
12. Rosenberg AZ, Kopp JB. Focal segmental glomerulosclerosis. Clin J Am Soc Nephrol. 2017; 12(3):502-517. doi:10.2215/CJN.05960616
13. Savige J. Should we diagnose autosomal dominant Alport syndrome when there is a pathogenic heterozygous COL4A3 or COL4A4 variant? Kidney Int Rep. 2018;3(6):1239-1241. doi:10.1016/j.ekir.2018.08.002
14. Gigante M, Caridi G, Montemurno E, et al. TRPC6 mutations in children with steroid-resistant nephrotic syndrome and atypical phenotype. Clin J Am Soc Nephrol. 2011;6(7):1626-1634. doi:10.2215/CJN.07830910
15. Saurus P, Kuusela S, Lehtonen E, et al. Podocyte apoptosis is prevented by blocking the toll-like receptor pathway. Cell Death Dis. 2015;6(5):e1752. doi:10.1038/cddis.2015.125
16. Baud L, Oudinet JP, Bens M, et al. Production of tumor necrosis factor by rat mesangial cells in response to bacterial lipopolysaccharide. Kidney Int. 1989;35(5):1111-1118. doi:10.1038/ki.1989.98
17. White S, Lin L, Hu K. NF-κB and tPA signaling in kidney and other diseases. Cells. 2020;9(6):1348. doi:10.3390/cells9061348
18. Tesch GH, Lan HY, Atkins RC, Nikolic-Paterson DJ. Role of interleukin-1 in mesangial cell proliferation and matrix deposition in experimental mesangioproliferative nephritis. Am J Pathol. 1997;151(1):141-150.
19. Lai KN, Leung JCK, Chan LYY, et al. Podocyte injury induced by mesangial-derived cytokines in IgA Nephropathy. Nephrol Dial Transplant. 2009;24(1):62-72. doi:10.1093/ndt/gfn441
20. Saleem MA, Kobayashi Y. Cell biology and genetics of minimal change disease. F1000 Res. 2016;5: F1000 Faculty Rev-412. doi:10.12688/f1000research.7300.1
21. Kim KP, Williams CE, Lemmon CA. Cell-matrix interactions in renal fibrosis. Kidney Dial. 2022;2(4):607-624. doi:10.3390/kidneydial2040055
22. Zvaifler NJ. Relevance of the stroma and epithelial-mesenchymal transition (EMT) for the rheumatic diseases. Arthritis Res Ther. 2006;8(3):210. doi:10.1186/ar1963
23. Angeletti A, Magnasco A, Trivelli A, et al. Refractory minimal change disease and focal segmental glomerular sclerosis treated with Anakinra. Kidney Int Rep. 2021;7(1):121-124. doi:10.1016/j.ekir.2021.10.018
24. Trachtman H, Vento S, Herreshoff E, et al. Efficacy of galactose and adalimumab in patients with resistant focal segmental glomerulosclerosis: report of the font clinical trial group. BMC Nephrol. 2015;16:111. doi:10.1186/s12882-015-0094-5
25. Mariani LH, Eddy S, AlAkwaa FM, et al. Precision nephrology identified tumor necrosis factor activation variability in minimal change disease and focal segmental glomerulosclerosis. Kidney Int. 2023;103(3):565-579. doi:10.1016/j.kint.2022.10.023
26. Korshak L, Washington DL, Powell J, Nylen E, Kokkinos P. Kidney Disease in Veterans. US Dept of Veterans Affairs, Office of Health Equity. Updated May 13, 2020. Accessed June 28, 2024. https://www.va.gov/HEALTHEQUITY/Kidney_Disease_In_Veterans.asp
27. Malone AF, Phelan PJ, Hall G, et al. Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis. Kidney Int. 2014;86(6):1253-1259. doi:10.1038/ki.2014.305
1. Arif E, Nihalani D. Glomerular filtration barrier assembly: an insight. Postdoc J. 2013;1(4):33-45.
2. Garg PA. Review of podocyte biology. Am J Nephrol. 2018;47(suppl 1):3-13. doi:10.1159/000481633SUPPL
3. Warady BA, Agarwal R, Bangalore S, et al. Alport syndrome classification and management. Kidney Med. 2020;2(5):639-649. doi:10.1016/j.xkme.2020.05.014
4. Angioi A, Pani A. FSGS: from pathogenesis to the histological lesion. J Nephrol. 2016;29(4):517-523. doi:10.1007/s40620-016-0333-2
5. Roca N, Martinez C, Jatem E, Madrid A, Lopez M, Segarra A. Activation of the acute inflammatory phase response in idiopathic nephrotic syndrome: association with clinicopathological phenotypes and with response to corticosteroids. Clin Kidney J. 2021;14(4):1207-1215. doi:10.1093/ckj/sfaa247
6. Vivarelli M, Massella L, Ruggiero B, Emma F. Minimal change disease. Clin J Am Soc Nephrol. 2017;12(2):332-345.
7. Medjeral-Thomas NR, Lawrence C, Condon M, et al. Randomized, controlled trial of tacrolimus and prednisolone monotherapy for adults with De Novo minimal change disease: a multicenter, randomized, controlled trial. Clin J Am Soc Nephrol. 2020;15(2):209-218. doi:10.2215/CJN.06290420
8. Ye Q, Lan B, Liu H, Persson PB, Lai EY, Mao J. A critical role of the podocyte cytoskeleton in the pathogenesis of glomerular proteinuria and autoimmune podocytopathies. Acta Physiol (Oxf). 2022;235(4):e13850. doi:10.1111/apha.13850
9. Trautmann A, Schnaidt S, Lipska-Ziμtkiewicz BS, et al. Long-term outcome of steroid-resistant nephrotic syndrome in children. J Am Soc Nephrol. 2017;28:3055-3065. doi:10.1681/ASN.2016101121
10. Kashtan CE, Gross O. Clinical practice recommendations for the diagnosis and management of Alport syndrome in children, adolescents, and young adults-an update for 2020. Pediatr Nephrol. 2021;36(3):711-719. doi:10.1007/s00467-020-04819-6
11. Savige J, Rana K, Tonna S, Buzza M, Dagher H, Wang YY. Thin basement membrane nephropathy. Kidney Int. 2003;64(4):1169-78. doi:10.1046/j.1523-1755.2003.00234.x
12. Rosenberg AZ, Kopp JB. Focal segmental glomerulosclerosis. Clin J Am Soc Nephrol. 2017; 12(3):502-517. doi:10.2215/CJN.05960616
13. Savige J. Should we diagnose autosomal dominant Alport syndrome when there is a pathogenic heterozygous COL4A3 or COL4A4 variant? Kidney Int Rep. 2018;3(6):1239-1241. doi:10.1016/j.ekir.2018.08.002
14. Gigante M, Caridi G, Montemurno E, et al. TRPC6 mutations in children with steroid-resistant nephrotic syndrome and atypical phenotype. Clin J Am Soc Nephrol. 2011;6(7):1626-1634. doi:10.2215/CJN.07830910
15. Saurus P, Kuusela S, Lehtonen E, et al. Podocyte apoptosis is prevented by blocking the toll-like receptor pathway. Cell Death Dis. 2015;6(5):e1752. doi:10.1038/cddis.2015.125
16. Baud L, Oudinet JP, Bens M, et al. Production of tumor necrosis factor by rat mesangial cells in response to bacterial lipopolysaccharide. Kidney Int. 1989;35(5):1111-1118. doi:10.1038/ki.1989.98
17. White S, Lin L, Hu K. NF-κB and tPA signaling in kidney and other diseases. Cells. 2020;9(6):1348. doi:10.3390/cells9061348
18. Tesch GH, Lan HY, Atkins RC, Nikolic-Paterson DJ. Role of interleukin-1 in mesangial cell proliferation and matrix deposition in experimental mesangioproliferative nephritis. Am J Pathol. 1997;151(1):141-150.
19. Lai KN, Leung JCK, Chan LYY, et al. Podocyte injury induced by mesangial-derived cytokines in IgA Nephropathy. Nephrol Dial Transplant. 2009;24(1):62-72. doi:10.1093/ndt/gfn441
20. Saleem MA, Kobayashi Y. Cell biology and genetics of minimal change disease. F1000 Res. 2016;5: F1000 Faculty Rev-412. doi:10.12688/f1000research.7300.1
21. Kim KP, Williams CE, Lemmon CA. Cell-matrix interactions in renal fibrosis. Kidney Dial. 2022;2(4):607-624. doi:10.3390/kidneydial2040055
22. Zvaifler NJ. Relevance of the stroma and epithelial-mesenchymal transition (EMT) for the rheumatic diseases. Arthritis Res Ther. 2006;8(3):210. doi:10.1186/ar1963
23. Angeletti A, Magnasco A, Trivelli A, et al. Refractory minimal change disease and focal segmental glomerular sclerosis treated with Anakinra. Kidney Int Rep. 2021;7(1):121-124. doi:10.1016/j.ekir.2021.10.018
24. Trachtman H, Vento S, Herreshoff E, et al. Efficacy of galactose and adalimumab in patients with resistant focal segmental glomerulosclerosis: report of the font clinical trial group. BMC Nephrol. 2015;16:111. doi:10.1186/s12882-015-0094-5
25. Mariani LH, Eddy S, AlAkwaa FM, et al. Precision nephrology identified tumor necrosis factor activation variability in minimal change disease and focal segmental glomerulosclerosis. Kidney Int. 2023;103(3):565-579. doi:10.1016/j.kint.2022.10.023
26. Korshak L, Washington DL, Powell J, Nylen E, Kokkinos P. Kidney Disease in Veterans. US Dept of Veterans Affairs, Office of Health Equity. Updated May 13, 2020. Accessed June 28, 2024. https://www.va.gov/HEALTHEQUITY/Kidney_Disease_In_Veterans.asp
27. Malone AF, Phelan PJ, Hall G, et al. Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis. Kidney Int. 2014;86(6):1253-1259. doi:10.1038/ki.2014.305
Kidney, Cardiovascular Benefits Seen With GLP-1 RA Drugs in SLE, Lupus Nephritis
WASHINGTON — Glucagon-like peptide 1 receptor agonist (GLP-1 RA) medications appear beneficial for people with systemic lupus erythematosus (SLE) and lupus nephritis, two new studies suggest.
“The risk of cardiovascular disease is thought to be at least double that for people with lupus ... and we know the risk of progressing to end-stage renal disease [ESKD] for patients with lupus nephritis can be as high as 10%-30%, so there’s clearly a major unmet need for new treatments and approaches to improve these outcomes, perhaps with adjunctive treatment beyond our typical immunosuppressive therapy,” April Jorge, MD, of Massachusetts General Hospital, Boston, said at the annual meeting of the American College of Rheumatology (ACR).
The GLP-1 RAs are approved for the treatment of type 2 diabetes (T2D) and obesity. They also have proven cardiovascular benefit, along with emerging data suggesting kidney protection independent of glucose lowering. Jorge presented findings from a study using data from the US multicenter electronic health record database TriNetX, showing that, among patients who had both T2D and SLE, those using GLP-1 RAs had lower risks for major adverse cardiac events (MACE), venous thrombosis, kidney disease progression, and all-cause mortality, compared with those using a different class of T2D medication.
A second study using TriNetX, presented at the same ACR meeting session by Anna-Kay Palmer, MD, a third-year internal medicine resident at Jefferson Einstein Hospital, Philadelphia, Pennsylvania, showed that GLP-1 RAs reduced the risk of progression to ESKD in patients with lupus nephritis, possibly caused by reductions in pro-inflammatory mediators.
Asked to comment, session moderator Diane L. Kamen, MD, professor of medicine at the Medical University of South Carolina Division of Rheumatology, Charleston, said in an interview that she definitely supports the use of GLP-1 RAs for patients who have SLE and/or lupus nephritis and also a drug label indication, either T2D or obesity. “[The GLP-1 RA prescriber] will usually run it by rheumatology to make sure that it doesn’t conflict with any of their other medical treatment, and it’s very reassuring to know that they could actually get a win-win.”
But as far as prescribing off-label for those with SLE/lupus nephritis who don’t have other GLP-1 RA indications, Kamen said, “that’s a black hole at this point. We need to do those prospective studies. But if they have another indication, yes.”
Cardiovascular, Kidney Benefits of GLP-1 RAs
Jorge noted that patients with lupus were excluded from the randomized clinical trials of GLP-1 RAs, so the current study was designed to investigate the potential impact of these medications on cardiovascular and kidney outcomes in patients with SLE and lupus nephritis.
From TriNetX data for 46 healthcare organizations nationwide, a total of 96,511 patients with both SLE and T2D but not ESKD had initiated either a GLP-1 RA or another diabetes drug class, dipeptidyl peptidase 4 inhibitors (DPP4i), between October 2006 and August 2021. Of those, 29,177 had lupus nephritis.
Propensity score matching for factors such as demographics, lupus severity, comorbidities, and medication use was used to emulate a randomized trial. This yielded 25,838 with SLE and T2D, of whom 910 initiated a GLP-1 RA and 1004 started a DPP4i, and 12,387 with lupus nephritis and T2D, including 267 on a GLP-1 RA and 324 on a DPP4i. After matching, the mean age was 55 years, more than 90% were women, and just under half were White individuals. About one third had chronic kidney disease stages ≥ 3, and about 15% had heart failure.
Over an average follow-up time of 1.2-1.4 years among those with SLE, the hazard ratio (HR) for MACE (a composite of myocardial infarction, stroke, and heart failure) for those taking a GLP-1 RA vs a DPP4i was 0.66, a significant difference. And for venous thrombosis, the HR was also significant at 0.49.
Kidney disease progression, defined as an estimated glomerular filtration rate decline of 30% or more or new ESKD, was significantly less likely in the GLP-1 RA group, with a HR of 0.77. All-cause mortality also was dramatically reduced (HR, 0.26). As expected, there was no difference in control outcome, genital infections (HR, 1.02).
In the subgroup with lupus nephritis, there were also lower risks for both MACE (HR, 0.64) and for renal progression (HR, 0.70). “The findings suggest similar cardiac and kidney benefits among patients with SLE and lupus nephritis as have been observed in other populations,” Jorge concluded.
Kamen commented that the study design “was pretty brilliant, because you wouldn’t be able to do a placebo-controlled trial since the indication was diabetes ... but the fact is you do see that the GLP-1 RA gets the benefit whereas the other drug does not.”
Next steps, Jorge said, will be mechanistic studies to better understand the effects of GLP-1 RAs in lupus and other rheumatic diseases, prospective studies of GLP-1 RAs in SLE and lupus nephritis without diabetes, and clarification of ideal timing for GLP-1 RA use in SLE and lupus nephritis.
“Ideally, with our prospective studies with these patients we can try to isolate the effect on patients with lupus and also better understand whether there might be an impact on disease activity through the anti-inflammatory effects of these medications, rather than just the cardioprotective and nephroprotective benefits,” she said.
In Those With Lupus Nephritis, Kidney Protection Seen
In her presentation, Palmer noted that, despite immunosuppressive therapies for SLE, 10%-20% of patients who develop lupus nephritis will progress to ESKD within 5 years of diagnosis.
She added that GLP-1 RAs have been shown to reduce albuminuria in people with diabetes and have been hypothesized to reduce inflammation through multiple pathways, thereby potentially reducing kidney disease independently of the presence of diabetes or weight loss. These pathways include modulating immune cell signaling and reducing pro-inflammatory cytokines.
Based on all this, Palmer and colleagues used International Classification of Diseases – 10th edition diagnostic codes in TriNetX to identify 839 patients who had been diagnosed with lupus nephritis between 2014 and 2024 and who were prescribed liraglutide, dulaglutide, semaglutide, or exenatide for any time after the lupus nephritis diagnosis. Another 29,840 patients with lupus nephritis had not used GLP-1 RAs.
After 1:1 propensity score matching for age, sex, race, ethnicity, presence of hypertension, diabetes, use of immunosuppressive and diabetes medication, smoking, obesity, and statin use, there were 735 individuals in each group. About two thirds in each had diabetes, whereas the rest had been prescribed the GLP-1 RAs for other indications.
Patients who were not on GLP-1 RAs were twice as likely to develop ESKD or dialysis (8.88% vs 3.971%; odds ratio, 2.35; P = .001).
Kamen pointed out that not including the use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers was a study flaw. On the other hand, the fact that not everyone in this study had diabetes was an advantage.
Jorge received grant/research support from Bristol-Myers Squibb, Cabaletta Bio, and the Lupus Clinical Investigator Network. Kamen is an adviser/review panel member for Alpine Immune Sciences. Palmer had no disclosures.
A version of this article appeared on Medscape.com.
WASHINGTON — Glucagon-like peptide 1 receptor agonist (GLP-1 RA) medications appear beneficial for people with systemic lupus erythematosus (SLE) and lupus nephritis, two new studies suggest.
“The risk of cardiovascular disease is thought to be at least double that for people with lupus ... and we know the risk of progressing to end-stage renal disease [ESKD] for patients with lupus nephritis can be as high as 10%-30%, so there’s clearly a major unmet need for new treatments and approaches to improve these outcomes, perhaps with adjunctive treatment beyond our typical immunosuppressive therapy,” April Jorge, MD, of Massachusetts General Hospital, Boston, said at the annual meeting of the American College of Rheumatology (ACR).
The GLP-1 RAs are approved for the treatment of type 2 diabetes (T2D) and obesity. They also have proven cardiovascular benefit, along with emerging data suggesting kidney protection independent of glucose lowering. Jorge presented findings from a study using data from the US multicenter electronic health record database TriNetX, showing that, among patients who had both T2D and SLE, those using GLP-1 RAs had lower risks for major adverse cardiac events (MACE), venous thrombosis, kidney disease progression, and all-cause mortality, compared with those using a different class of T2D medication.
A second study using TriNetX, presented at the same ACR meeting session by Anna-Kay Palmer, MD, a third-year internal medicine resident at Jefferson Einstein Hospital, Philadelphia, Pennsylvania, showed that GLP-1 RAs reduced the risk of progression to ESKD in patients with lupus nephritis, possibly caused by reductions in pro-inflammatory mediators.
Asked to comment, session moderator Diane L. Kamen, MD, professor of medicine at the Medical University of South Carolina Division of Rheumatology, Charleston, said in an interview that she definitely supports the use of GLP-1 RAs for patients who have SLE and/or lupus nephritis and also a drug label indication, either T2D or obesity. “[The GLP-1 RA prescriber] will usually run it by rheumatology to make sure that it doesn’t conflict with any of their other medical treatment, and it’s very reassuring to know that they could actually get a win-win.”
But as far as prescribing off-label for those with SLE/lupus nephritis who don’t have other GLP-1 RA indications, Kamen said, “that’s a black hole at this point. We need to do those prospective studies. But if they have another indication, yes.”
Cardiovascular, Kidney Benefits of GLP-1 RAs
Jorge noted that patients with lupus were excluded from the randomized clinical trials of GLP-1 RAs, so the current study was designed to investigate the potential impact of these medications on cardiovascular and kidney outcomes in patients with SLE and lupus nephritis.
From TriNetX data for 46 healthcare organizations nationwide, a total of 96,511 patients with both SLE and T2D but not ESKD had initiated either a GLP-1 RA or another diabetes drug class, dipeptidyl peptidase 4 inhibitors (DPP4i), between October 2006 and August 2021. Of those, 29,177 had lupus nephritis.
Propensity score matching for factors such as demographics, lupus severity, comorbidities, and medication use was used to emulate a randomized trial. This yielded 25,838 with SLE and T2D, of whom 910 initiated a GLP-1 RA and 1004 started a DPP4i, and 12,387 with lupus nephritis and T2D, including 267 on a GLP-1 RA and 324 on a DPP4i. After matching, the mean age was 55 years, more than 90% were women, and just under half were White individuals. About one third had chronic kidney disease stages ≥ 3, and about 15% had heart failure.
Over an average follow-up time of 1.2-1.4 years among those with SLE, the hazard ratio (HR) for MACE (a composite of myocardial infarction, stroke, and heart failure) for those taking a GLP-1 RA vs a DPP4i was 0.66, a significant difference. And for venous thrombosis, the HR was also significant at 0.49.
Kidney disease progression, defined as an estimated glomerular filtration rate decline of 30% or more or new ESKD, was significantly less likely in the GLP-1 RA group, with a HR of 0.77. All-cause mortality also was dramatically reduced (HR, 0.26). As expected, there was no difference in control outcome, genital infections (HR, 1.02).
In the subgroup with lupus nephritis, there were also lower risks for both MACE (HR, 0.64) and for renal progression (HR, 0.70). “The findings suggest similar cardiac and kidney benefits among patients with SLE and lupus nephritis as have been observed in other populations,” Jorge concluded.
Kamen commented that the study design “was pretty brilliant, because you wouldn’t be able to do a placebo-controlled trial since the indication was diabetes ... but the fact is you do see that the GLP-1 RA gets the benefit whereas the other drug does not.”
Next steps, Jorge said, will be mechanistic studies to better understand the effects of GLP-1 RAs in lupus and other rheumatic diseases, prospective studies of GLP-1 RAs in SLE and lupus nephritis without diabetes, and clarification of ideal timing for GLP-1 RA use in SLE and lupus nephritis.
“Ideally, with our prospective studies with these patients we can try to isolate the effect on patients with lupus and also better understand whether there might be an impact on disease activity through the anti-inflammatory effects of these medications, rather than just the cardioprotective and nephroprotective benefits,” she said.
In Those With Lupus Nephritis, Kidney Protection Seen
In her presentation, Palmer noted that, despite immunosuppressive therapies for SLE, 10%-20% of patients who develop lupus nephritis will progress to ESKD within 5 years of diagnosis.
She added that GLP-1 RAs have been shown to reduce albuminuria in people with diabetes and have been hypothesized to reduce inflammation through multiple pathways, thereby potentially reducing kidney disease independently of the presence of diabetes or weight loss. These pathways include modulating immune cell signaling and reducing pro-inflammatory cytokines.
Based on all this, Palmer and colleagues used International Classification of Diseases – 10th edition diagnostic codes in TriNetX to identify 839 patients who had been diagnosed with lupus nephritis between 2014 and 2024 and who were prescribed liraglutide, dulaglutide, semaglutide, or exenatide for any time after the lupus nephritis diagnosis. Another 29,840 patients with lupus nephritis had not used GLP-1 RAs.
After 1:1 propensity score matching for age, sex, race, ethnicity, presence of hypertension, diabetes, use of immunosuppressive and diabetes medication, smoking, obesity, and statin use, there were 735 individuals in each group. About two thirds in each had diabetes, whereas the rest had been prescribed the GLP-1 RAs for other indications.
Patients who were not on GLP-1 RAs were twice as likely to develop ESKD or dialysis (8.88% vs 3.971%; odds ratio, 2.35; P = .001).
Kamen pointed out that not including the use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers was a study flaw. On the other hand, the fact that not everyone in this study had diabetes was an advantage.
Jorge received grant/research support from Bristol-Myers Squibb, Cabaletta Bio, and the Lupus Clinical Investigator Network. Kamen is an adviser/review panel member for Alpine Immune Sciences. Palmer had no disclosures.
A version of this article appeared on Medscape.com.
WASHINGTON — Glucagon-like peptide 1 receptor agonist (GLP-1 RA) medications appear beneficial for people with systemic lupus erythematosus (SLE) and lupus nephritis, two new studies suggest.
“The risk of cardiovascular disease is thought to be at least double that for people with lupus ... and we know the risk of progressing to end-stage renal disease [ESKD] for patients with lupus nephritis can be as high as 10%-30%, so there’s clearly a major unmet need for new treatments and approaches to improve these outcomes, perhaps with adjunctive treatment beyond our typical immunosuppressive therapy,” April Jorge, MD, of Massachusetts General Hospital, Boston, said at the annual meeting of the American College of Rheumatology (ACR).
The GLP-1 RAs are approved for the treatment of type 2 diabetes (T2D) and obesity. They also have proven cardiovascular benefit, along with emerging data suggesting kidney protection independent of glucose lowering. Jorge presented findings from a study using data from the US multicenter electronic health record database TriNetX, showing that, among patients who had both T2D and SLE, those using GLP-1 RAs had lower risks for major adverse cardiac events (MACE), venous thrombosis, kidney disease progression, and all-cause mortality, compared with those using a different class of T2D medication.
A second study using TriNetX, presented at the same ACR meeting session by Anna-Kay Palmer, MD, a third-year internal medicine resident at Jefferson Einstein Hospital, Philadelphia, Pennsylvania, showed that GLP-1 RAs reduced the risk of progression to ESKD in patients with lupus nephritis, possibly caused by reductions in pro-inflammatory mediators.
Asked to comment, session moderator Diane L. Kamen, MD, professor of medicine at the Medical University of South Carolina Division of Rheumatology, Charleston, said in an interview that she definitely supports the use of GLP-1 RAs for patients who have SLE and/or lupus nephritis and also a drug label indication, either T2D or obesity. “[The GLP-1 RA prescriber] will usually run it by rheumatology to make sure that it doesn’t conflict with any of their other medical treatment, and it’s very reassuring to know that they could actually get a win-win.”
But as far as prescribing off-label for those with SLE/lupus nephritis who don’t have other GLP-1 RA indications, Kamen said, “that’s a black hole at this point. We need to do those prospective studies. But if they have another indication, yes.”
Cardiovascular, Kidney Benefits of GLP-1 RAs
Jorge noted that patients with lupus were excluded from the randomized clinical trials of GLP-1 RAs, so the current study was designed to investigate the potential impact of these medications on cardiovascular and kidney outcomes in patients with SLE and lupus nephritis.
From TriNetX data for 46 healthcare organizations nationwide, a total of 96,511 patients with both SLE and T2D but not ESKD had initiated either a GLP-1 RA or another diabetes drug class, dipeptidyl peptidase 4 inhibitors (DPP4i), between October 2006 and August 2021. Of those, 29,177 had lupus nephritis.
Propensity score matching for factors such as demographics, lupus severity, comorbidities, and medication use was used to emulate a randomized trial. This yielded 25,838 with SLE and T2D, of whom 910 initiated a GLP-1 RA and 1004 started a DPP4i, and 12,387 with lupus nephritis and T2D, including 267 on a GLP-1 RA and 324 on a DPP4i. After matching, the mean age was 55 years, more than 90% were women, and just under half were White individuals. About one third had chronic kidney disease stages ≥ 3, and about 15% had heart failure.
Over an average follow-up time of 1.2-1.4 years among those with SLE, the hazard ratio (HR) for MACE (a composite of myocardial infarction, stroke, and heart failure) for those taking a GLP-1 RA vs a DPP4i was 0.66, a significant difference. And for venous thrombosis, the HR was also significant at 0.49.
Kidney disease progression, defined as an estimated glomerular filtration rate decline of 30% or more or new ESKD, was significantly less likely in the GLP-1 RA group, with a HR of 0.77. All-cause mortality also was dramatically reduced (HR, 0.26). As expected, there was no difference in control outcome, genital infections (HR, 1.02).
In the subgroup with lupus nephritis, there were also lower risks for both MACE (HR, 0.64) and for renal progression (HR, 0.70). “The findings suggest similar cardiac and kidney benefits among patients with SLE and lupus nephritis as have been observed in other populations,” Jorge concluded.
Kamen commented that the study design “was pretty brilliant, because you wouldn’t be able to do a placebo-controlled trial since the indication was diabetes ... but the fact is you do see that the GLP-1 RA gets the benefit whereas the other drug does not.”
Next steps, Jorge said, will be mechanistic studies to better understand the effects of GLP-1 RAs in lupus and other rheumatic diseases, prospective studies of GLP-1 RAs in SLE and lupus nephritis without diabetes, and clarification of ideal timing for GLP-1 RA use in SLE and lupus nephritis.
“Ideally, with our prospective studies with these patients we can try to isolate the effect on patients with lupus and also better understand whether there might be an impact on disease activity through the anti-inflammatory effects of these medications, rather than just the cardioprotective and nephroprotective benefits,” she said.
In Those With Lupus Nephritis, Kidney Protection Seen
In her presentation, Palmer noted that, despite immunosuppressive therapies for SLE, 10%-20% of patients who develop lupus nephritis will progress to ESKD within 5 years of diagnosis.
She added that GLP-1 RAs have been shown to reduce albuminuria in people with diabetes and have been hypothesized to reduce inflammation through multiple pathways, thereby potentially reducing kidney disease independently of the presence of diabetes or weight loss. These pathways include modulating immune cell signaling and reducing pro-inflammatory cytokines.
Based on all this, Palmer and colleagues used International Classification of Diseases – 10th edition diagnostic codes in TriNetX to identify 839 patients who had been diagnosed with lupus nephritis between 2014 and 2024 and who were prescribed liraglutide, dulaglutide, semaglutide, or exenatide for any time after the lupus nephritis diagnosis. Another 29,840 patients with lupus nephritis had not used GLP-1 RAs.
After 1:1 propensity score matching for age, sex, race, ethnicity, presence of hypertension, diabetes, use of immunosuppressive and diabetes medication, smoking, obesity, and statin use, there were 735 individuals in each group. About two thirds in each had diabetes, whereas the rest had been prescribed the GLP-1 RAs for other indications.
Patients who were not on GLP-1 RAs were twice as likely to develop ESKD or dialysis (8.88% vs 3.971%; odds ratio, 2.35; P = .001).
Kamen pointed out that not including the use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers was a study flaw. On the other hand, the fact that not everyone in this study had diabetes was an advantage.
Jorge received grant/research support from Bristol-Myers Squibb, Cabaletta Bio, and the Lupus Clinical Investigator Network. Kamen is an adviser/review panel member for Alpine Immune Sciences. Palmer had no disclosures.
A version of this article appeared on Medscape.com.
FROM ACR 2024
Deprescribe Low-Value Meds to Reduce Polypharmacy Harms
VANCOUVER, BRITISH COLUMBIA — While polypharmacy is inevitable for patients with multiple chronic diseases, not all medications improve patient-oriented outcomes, members of the Patients, Experience, Evidence, Research (PEER) team, a group of Canadian primary care professionals who develop evidence-based guidelines, told attendees at the Family Medicine Forum (FMF) 2024.
In a thought-provoking presentation called “Axe the Rx: Deprescribing Chronic Medications with PEER,” the panelists gave examples of medications that may be safely stopped or tapered, particularly for older adults “whose pill bag is heavier than their lunch bag.”
Curbing Cardiovascular Drugs
The 2021 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in Adults call for reaching an LDL-C < 1.8 mmol/L in secondary cardiovascular prevention by potentially adding on medical therapies such as proprotein convertase subtilisin/kexin type 9 inhibitors or ezetimibe or both if that target is not reached with the maximal dosage of a statin.
But family physicians do not need to follow this guidance for their patients who have had a myocardial infarction, said Ontario family physician Jennifer Young, MD, a physician advisor in the Canadian College of Family Physicians’ Knowledge Experts and Tools Program.
Treating to below 1.8 mmol/L “means lab testing for the patients,” Young told this news organization. “It means increasing doses [of a statin] to try and get to that level.” If the patient is already on the highest dose of a statin, it means adding other medications that lower cholesterol.
“If that was translating into better outcomes like [preventing] death and another heart attack, then all of that extra effort would be worth it,” said Young. “But we don’t have evidence that it actually does have a benefit for outcomes like death and repeated heart attacks,” compared with putting them on a high dose of a potent statin.
Tapering Opioids
Before placing patients on an opioid taper, clinicians should first assess them for opioid use disorder (OUD), said Jessica Kirkwood, MD, assistant professor of family medicine at the University of Alberta in Edmonton, Canada. She suggested using the Prescription Opioid Misuse Index questionnaire to do so.
Clinicians should be much more careful in initiating a taper with patients with OUD, said Kirkwood. They must ensure that these patients are motivated to discontinue their opioids. “We’re losing 21 Canadians a day to the opioid crisis. We all know that cutting someone off their opioids and potentially having them seek opioids elsewhere through illicit means can be fatal.”
In addition, clinicians should spend more time counseling patients with OUD than those without, Kirkwood continued. They must explain to these patients how they are being tapered (eg, the intervals and doses) and highlight the benefits of a taper, such as reduced constipation. Opioid agonist therapy (such as methadone or buprenorphine) can be considered in these patients.
Some research has pointed to the importance of patient motivation as a factor in the success of opioid tapers, noted Kirkwood.
Deprescribing Benzodiazepines
Benzodiazepine receptor agonists, too, often can be deprescribed. These drugs should not be prescribed to promote sleep on a long-term basis. Yet clinicians commonly encounter patients who have been taking them for more than a year, said pharmacist Betsy Thomas, assistant adjunct professor of family medicine at the University of Alberta.
The medications “are usually fairly effective for the first couple of weeks to about a month, and then the benefits start to decrease, and we start to see more harms,” she said.
Some of the harms that have been associated with continued use of benzodiazepine receptor agonists include delayed reaction time and impaired cognition, which can affect the ability to drive, the risk for falls, and the risk for hip fractures, she noted. Some research suggests that these drugs are not an option for treating insomnia in patients aged 65 years or older.
Clinicians should encourage tapering the use of benzodiazepine receptor agonists to minimize dependence and transition patients to nonpharmacologic approaches such as cognitive behavioral therapy to manage insomnia, she said. A recent study demonstrated the efficacy of the intervention, and Thomas suggested that family physicians visit the mysleepwell.ca website for more information.
Young, Kirkwood, and Thomas reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
VANCOUVER, BRITISH COLUMBIA — While polypharmacy is inevitable for patients with multiple chronic diseases, not all medications improve patient-oriented outcomes, members of the Patients, Experience, Evidence, Research (PEER) team, a group of Canadian primary care professionals who develop evidence-based guidelines, told attendees at the Family Medicine Forum (FMF) 2024.
In a thought-provoking presentation called “Axe the Rx: Deprescribing Chronic Medications with PEER,” the panelists gave examples of medications that may be safely stopped or tapered, particularly for older adults “whose pill bag is heavier than their lunch bag.”
Curbing Cardiovascular Drugs
The 2021 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in Adults call for reaching an LDL-C < 1.8 mmol/L in secondary cardiovascular prevention by potentially adding on medical therapies such as proprotein convertase subtilisin/kexin type 9 inhibitors or ezetimibe or both if that target is not reached with the maximal dosage of a statin.
But family physicians do not need to follow this guidance for their patients who have had a myocardial infarction, said Ontario family physician Jennifer Young, MD, a physician advisor in the Canadian College of Family Physicians’ Knowledge Experts and Tools Program.
Treating to below 1.8 mmol/L “means lab testing for the patients,” Young told this news organization. “It means increasing doses [of a statin] to try and get to that level.” If the patient is already on the highest dose of a statin, it means adding other medications that lower cholesterol.
“If that was translating into better outcomes like [preventing] death and another heart attack, then all of that extra effort would be worth it,” said Young. “But we don’t have evidence that it actually does have a benefit for outcomes like death and repeated heart attacks,” compared with putting them on a high dose of a potent statin.
Tapering Opioids
Before placing patients on an opioid taper, clinicians should first assess them for opioid use disorder (OUD), said Jessica Kirkwood, MD, assistant professor of family medicine at the University of Alberta in Edmonton, Canada. She suggested using the Prescription Opioid Misuse Index questionnaire to do so.
Clinicians should be much more careful in initiating a taper with patients with OUD, said Kirkwood. They must ensure that these patients are motivated to discontinue their opioids. “We’re losing 21 Canadians a day to the opioid crisis. We all know that cutting someone off their opioids and potentially having them seek opioids elsewhere through illicit means can be fatal.”
In addition, clinicians should spend more time counseling patients with OUD than those without, Kirkwood continued. They must explain to these patients how they are being tapered (eg, the intervals and doses) and highlight the benefits of a taper, such as reduced constipation. Opioid agonist therapy (such as methadone or buprenorphine) can be considered in these patients.
Some research has pointed to the importance of patient motivation as a factor in the success of opioid tapers, noted Kirkwood.
Deprescribing Benzodiazepines
Benzodiazepine receptor agonists, too, often can be deprescribed. These drugs should not be prescribed to promote sleep on a long-term basis. Yet clinicians commonly encounter patients who have been taking them for more than a year, said pharmacist Betsy Thomas, assistant adjunct professor of family medicine at the University of Alberta.
The medications “are usually fairly effective for the first couple of weeks to about a month, and then the benefits start to decrease, and we start to see more harms,” she said.
Some of the harms that have been associated with continued use of benzodiazepine receptor agonists include delayed reaction time and impaired cognition, which can affect the ability to drive, the risk for falls, and the risk for hip fractures, she noted. Some research suggests that these drugs are not an option for treating insomnia in patients aged 65 years or older.
Clinicians should encourage tapering the use of benzodiazepine receptor agonists to minimize dependence and transition patients to nonpharmacologic approaches such as cognitive behavioral therapy to manage insomnia, she said. A recent study demonstrated the efficacy of the intervention, and Thomas suggested that family physicians visit the mysleepwell.ca website for more information.
Young, Kirkwood, and Thomas reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
VANCOUVER, BRITISH COLUMBIA — While polypharmacy is inevitable for patients with multiple chronic diseases, not all medications improve patient-oriented outcomes, members of the Patients, Experience, Evidence, Research (PEER) team, a group of Canadian primary care professionals who develop evidence-based guidelines, told attendees at the Family Medicine Forum (FMF) 2024.
In a thought-provoking presentation called “Axe the Rx: Deprescribing Chronic Medications with PEER,” the panelists gave examples of medications that may be safely stopped or tapered, particularly for older adults “whose pill bag is heavier than their lunch bag.”
Curbing Cardiovascular Drugs
The 2021 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in Adults call for reaching an LDL-C < 1.8 mmol/L in secondary cardiovascular prevention by potentially adding on medical therapies such as proprotein convertase subtilisin/kexin type 9 inhibitors or ezetimibe or both if that target is not reached with the maximal dosage of a statin.
But family physicians do not need to follow this guidance for their patients who have had a myocardial infarction, said Ontario family physician Jennifer Young, MD, a physician advisor in the Canadian College of Family Physicians’ Knowledge Experts and Tools Program.
Treating to below 1.8 mmol/L “means lab testing for the patients,” Young told this news organization. “It means increasing doses [of a statin] to try and get to that level.” If the patient is already on the highest dose of a statin, it means adding other medications that lower cholesterol.
“If that was translating into better outcomes like [preventing] death and another heart attack, then all of that extra effort would be worth it,” said Young. “But we don’t have evidence that it actually does have a benefit for outcomes like death and repeated heart attacks,” compared with putting them on a high dose of a potent statin.
Tapering Opioids
Before placing patients on an opioid taper, clinicians should first assess them for opioid use disorder (OUD), said Jessica Kirkwood, MD, assistant professor of family medicine at the University of Alberta in Edmonton, Canada. She suggested using the Prescription Opioid Misuse Index questionnaire to do so.
Clinicians should be much more careful in initiating a taper with patients with OUD, said Kirkwood. They must ensure that these patients are motivated to discontinue their opioids. “We’re losing 21 Canadians a day to the opioid crisis. We all know that cutting someone off their opioids and potentially having them seek opioids elsewhere through illicit means can be fatal.”
In addition, clinicians should spend more time counseling patients with OUD than those without, Kirkwood continued. They must explain to these patients how they are being tapered (eg, the intervals and doses) and highlight the benefits of a taper, such as reduced constipation. Opioid agonist therapy (such as methadone or buprenorphine) can be considered in these patients.
Some research has pointed to the importance of patient motivation as a factor in the success of opioid tapers, noted Kirkwood.
Deprescribing Benzodiazepines
Benzodiazepine receptor agonists, too, often can be deprescribed. These drugs should not be prescribed to promote sleep on a long-term basis. Yet clinicians commonly encounter patients who have been taking them for more than a year, said pharmacist Betsy Thomas, assistant adjunct professor of family medicine at the University of Alberta.
The medications “are usually fairly effective for the first couple of weeks to about a month, and then the benefits start to decrease, and we start to see more harms,” she said.
Some of the harms that have been associated with continued use of benzodiazepine receptor agonists include delayed reaction time and impaired cognition, which can affect the ability to drive, the risk for falls, and the risk for hip fractures, she noted. Some research suggests that these drugs are not an option for treating insomnia in patients aged 65 years or older.
Clinicians should encourage tapering the use of benzodiazepine receptor agonists to minimize dependence and transition patients to nonpharmacologic approaches such as cognitive behavioral therapy to manage insomnia, she said. A recent study demonstrated the efficacy of the intervention, and Thomas suggested that family physicians visit the mysleepwell.ca website for more information.
Young, Kirkwood, and Thomas reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM FMF 2024
Gout and SGLT2 Inhibitors: Evidence Points to Reduced Need for ULT, Flare Drugs
WASHINGTON — Use of sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduced the need for urate-lowering therapy (ULT) and gout flare therapies in people who had both type 2 diabetes (T2D) and gout, new research has found.
Data from a large US claims database showed that SGLT2i use was associated with a 31% lower rate of initiation of ULT. “This provides further support for the use of SLGT2i therapy in patients with gout, particularly those with high-risk multimorbidity and polypharmacy,” Greg Challener, MD, a postdoctoral fellow at the Rheumatology and Allergy Clinical Epidemiology Research Center, Massachusetts General Hospital, Boston, said in his presentation of the data at the annual meeting of the American College of Rheumatology.
The first agent of the SGLT2i class, dapagliflozin, was initially approved in the United States a decade ago for treating T2D. Since then, several other “flozins” have become available, and some have also received additional indications for heart failure and albuminuric chronic kidney disease. Several prior studies have linked SGLT2i use with lower rates of gout flares as well as lower likelihood of developing gout in the first place, although not all studies have found this benefit.
Asked about the clinical implications of the new data, Challener said in an interview that “I don’t think we’re quite at the point where this is changing gout management per se, but this just helps us understand that [SGT2is] may have a role at some point, maybe as a combination on top of another agent. Or, in some patients, it really may be enough if they’re already on an SGLT2i where we don’t need to jump to adding allopurinol. Maybe they have tophi, but they were just started on an SGLT2i and they’re not flaring. Typically, you would start those patients on allopurinol, but you could potentially just monitor them if they were just started on one of those [SGLT2i] agents.”
Asked to comment, session moderator J. Antonio Aviña-Zubieta, MD, PhD, head of the Division of Rheumatology at the University of British Columbia, Vancouver, Canada, and senior scientist at Arthritis Research Canada, said in an interview: “What I can see possibly happening when there’s more evidence is that SGLT2is may be used or even become standard of care as an adjuvant therapy to decrease flares, and by that, decrease the risk of complications.”
Reductions in ULT, Flares, and Healthcare Visits
The new study used administrative health data from the multicenter TriNetX Diamond network of electronic medical record and claims data from 92 healthcare sites with 212 million patients. Among those with both T2D and gout who were not taking ULT at baseline, a total of 16,104 initiated SGLT2is and 16,046 initiated glucagon-like peptide 1 receptor agonists (GLP-1 RA).
Propensity score matching was conducted for demographics including age, race, and sex; comorbidities; use of emergency, inpatient, and critical care services; medications; labs; and body mass index. That yielded 11,800 individuals each in the SGLT2i and GLP-1 RA groups.
Over 5 years, 9.9% of the SGLT2i group vs 13.4% of those using GLP-1 RA had initiated ULT, a significant difference with a hazard ratio (HR) of 0.69 (95% CI, 0.64-0.75). The risk for initiation of colchicine for gout flares was 4.7% with SGLT2i vs 6.0% for GLP-1 RA — also a significant difference with an HR of 0.74 (0.65-0.83).
Medical visits for gout occurred in 28.0% vs 28.4% of patients, which also reached statistical significance (HR, 0.94; 95% CI, 0.89-0.99).
Aviña-Zubieta, an author of one of the previous studies finding a reduction in gout flares with SGLT2i, said, “many patients do not want to start gout therapy until they start having more acute attacks. ... So, for a lot of people, it’s a burden taking another pill to prevent one attack. But, if you don’t treat it over time, the attacks come more often. So, can we still delay the initiation of therapy? If you’re not having that many flares, you’re decreasing the burden of the disease and polypharmacy, which I think is the potential benefit in the long run if you already have an indication for the therapy for diabetes. ... These data are supporting that.”
Indeed, Challener said these data can help in counseling patients. “Taking your SGLT2i for your heart failure and your diabetes is also providing some benefit for your gout, and we know that there is also cardiac benefit when gout is controlled.”
Challener and Aviña-Zubieta had no disclosures.
A version of this article first appeared on Medscape.com.
WASHINGTON — Use of sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduced the need for urate-lowering therapy (ULT) and gout flare therapies in people who had both type 2 diabetes (T2D) and gout, new research has found.
Data from a large US claims database showed that SGLT2i use was associated with a 31% lower rate of initiation of ULT. “This provides further support for the use of SLGT2i therapy in patients with gout, particularly those with high-risk multimorbidity and polypharmacy,” Greg Challener, MD, a postdoctoral fellow at the Rheumatology and Allergy Clinical Epidemiology Research Center, Massachusetts General Hospital, Boston, said in his presentation of the data at the annual meeting of the American College of Rheumatology.
The first agent of the SGLT2i class, dapagliflozin, was initially approved in the United States a decade ago for treating T2D. Since then, several other “flozins” have become available, and some have also received additional indications for heart failure and albuminuric chronic kidney disease. Several prior studies have linked SGLT2i use with lower rates of gout flares as well as lower likelihood of developing gout in the first place, although not all studies have found this benefit.
Asked about the clinical implications of the new data, Challener said in an interview that “I don’t think we’re quite at the point where this is changing gout management per se, but this just helps us understand that [SGT2is] may have a role at some point, maybe as a combination on top of another agent. Or, in some patients, it really may be enough if they’re already on an SGLT2i where we don’t need to jump to adding allopurinol. Maybe they have tophi, but they were just started on an SGLT2i and they’re not flaring. Typically, you would start those patients on allopurinol, but you could potentially just monitor them if they were just started on one of those [SGLT2i] agents.”
Asked to comment, session moderator J. Antonio Aviña-Zubieta, MD, PhD, head of the Division of Rheumatology at the University of British Columbia, Vancouver, Canada, and senior scientist at Arthritis Research Canada, said in an interview: “What I can see possibly happening when there’s more evidence is that SGLT2is may be used or even become standard of care as an adjuvant therapy to decrease flares, and by that, decrease the risk of complications.”
Reductions in ULT, Flares, and Healthcare Visits
The new study used administrative health data from the multicenter TriNetX Diamond network of electronic medical record and claims data from 92 healthcare sites with 212 million patients. Among those with both T2D and gout who were not taking ULT at baseline, a total of 16,104 initiated SGLT2is and 16,046 initiated glucagon-like peptide 1 receptor agonists (GLP-1 RA).
Propensity score matching was conducted for demographics including age, race, and sex; comorbidities; use of emergency, inpatient, and critical care services; medications; labs; and body mass index. That yielded 11,800 individuals each in the SGLT2i and GLP-1 RA groups.
Over 5 years, 9.9% of the SGLT2i group vs 13.4% of those using GLP-1 RA had initiated ULT, a significant difference with a hazard ratio (HR) of 0.69 (95% CI, 0.64-0.75). The risk for initiation of colchicine for gout flares was 4.7% with SGLT2i vs 6.0% for GLP-1 RA — also a significant difference with an HR of 0.74 (0.65-0.83).
Medical visits for gout occurred in 28.0% vs 28.4% of patients, which also reached statistical significance (HR, 0.94; 95% CI, 0.89-0.99).
Aviña-Zubieta, an author of one of the previous studies finding a reduction in gout flares with SGLT2i, said, “many patients do not want to start gout therapy until they start having more acute attacks. ... So, for a lot of people, it’s a burden taking another pill to prevent one attack. But, if you don’t treat it over time, the attacks come more often. So, can we still delay the initiation of therapy? If you’re not having that many flares, you’re decreasing the burden of the disease and polypharmacy, which I think is the potential benefit in the long run if you already have an indication for the therapy for diabetes. ... These data are supporting that.”
Indeed, Challener said these data can help in counseling patients. “Taking your SGLT2i for your heart failure and your diabetes is also providing some benefit for your gout, and we know that there is also cardiac benefit when gout is controlled.”
Challener and Aviña-Zubieta had no disclosures.
A version of this article first appeared on Medscape.com.
WASHINGTON — Use of sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduced the need for urate-lowering therapy (ULT) and gout flare therapies in people who had both type 2 diabetes (T2D) and gout, new research has found.
Data from a large US claims database showed that SGLT2i use was associated with a 31% lower rate of initiation of ULT. “This provides further support for the use of SLGT2i therapy in patients with gout, particularly those with high-risk multimorbidity and polypharmacy,” Greg Challener, MD, a postdoctoral fellow at the Rheumatology and Allergy Clinical Epidemiology Research Center, Massachusetts General Hospital, Boston, said in his presentation of the data at the annual meeting of the American College of Rheumatology.
The first agent of the SGLT2i class, dapagliflozin, was initially approved in the United States a decade ago for treating T2D. Since then, several other “flozins” have become available, and some have also received additional indications for heart failure and albuminuric chronic kidney disease. Several prior studies have linked SGLT2i use with lower rates of gout flares as well as lower likelihood of developing gout in the first place, although not all studies have found this benefit.
Asked about the clinical implications of the new data, Challener said in an interview that “I don’t think we’re quite at the point where this is changing gout management per se, but this just helps us understand that [SGT2is] may have a role at some point, maybe as a combination on top of another agent. Or, in some patients, it really may be enough if they’re already on an SGLT2i where we don’t need to jump to adding allopurinol. Maybe they have tophi, but they were just started on an SGLT2i and they’re not flaring. Typically, you would start those patients on allopurinol, but you could potentially just monitor them if they were just started on one of those [SGLT2i] agents.”
Asked to comment, session moderator J. Antonio Aviña-Zubieta, MD, PhD, head of the Division of Rheumatology at the University of British Columbia, Vancouver, Canada, and senior scientist at Arthritis Research Canada, said in an interview: “What I can see possibly happening when there’s more evidence is that SGLT2is may be used or even become standard of care as an adjuvant therapy to decrease flares, and by that, decrease the risk of complications.”
Reductions in ULT, Flares, and Healthcare Visits
The new study used administrative health data from the multicenter TriNetX Diamond network of electronic medical record and claims data from 92 healthcare sites with 212 million patients. Among those with both T2D and gout who were not taking ULT at baseline, a total of 16,104 initiated SGLT2is and 16,046 initiated glucagon-like peptide 1 receptor agonists (GLP-1 RA).
Propensity score matching was conducted for demographics including age, race, and sex; comorbidities; use of emergency, inpatient, and critical care services; medications; labs; and body mass index. That yielded 11,800 individuals each in the SGLT2i and GLP-1 RA groups.
Over 5 years, 9.9% of the SGLT2i group vs 13.4% of those using GLP-1 RA had initiated ULT, a significant difference with a hazard ratio (HR) of 0.69 (95% CI, 0.64-0.75). The risk for initiation of colchicine for gout flares was 4.7% with SGLT2i vs 6.0% for GLP-1 RA — also a significant difference with an HR of 0.74 (0.65-0.83).
Medical visits for gout occurred in 28.0% vs 28.4% of patients, which also reached statistical significance (HR, 0.94; 95% CI, 0.89-0.99).
Aviña-Zubieta, an author of one of the previous studies finding a reduction in gout flares with SGLT2i, said, “many patients do not want to start gout therapy until they start having more acute attacks. ... So, for a lot of people, it’s a burden taking another pill to prevent one attack. But, if you don’t treat it over time, the attacks come more often. So, can we still delay the initiation of therapy? If you’re not having that many flares, you’re decreasing the burden of the disease and polypharmacy, which I think is the potential benefit in the long run if you already have an indication for the therapy for diabetes. ... These data are supporting that.”
Indeed, Challener said these data can help in counseling patients. “Taking your SGLT2i for your heart failure and your diabetes is also providing some benefit for your gout, and we know that there is also cardiac benefit when gout is controlled.”
Challener and Aviña-Zubieta had no disclosures.
A version of this article first appeared on Medscape.com.
FROM ACR 2024
Need for Low-Dose Steroids to Prevent Relapse in GPA Vasculitis Depends on Treatment Regimen
WASHINGTON — Patients with granulomatosis with polyangiitis (GPA) completely tapered off prednisone have a more than fourfold risk of relapse by 6 months, compared with those tapered to 5 mg/day of prednisone; however, this benefit was only seen in patients not on rituximab, according to new research presented at the annual meeting of the American College of Rheumatology (ACR).
“For patients treated with rituximab, fully tapering off glucocorticoids is reasonable to consider as the first approach,” said Peter Merkel, MD, MPH, chief of the division of rheumatology at the University of Pennsylvania, Philadelphia, during his presentation of the findings.
Although a low dose of glucocorticoids can prevent some minor relapses in patients on other treatment regimens such as methotrexate or azathioprine, “fully tapering off prednisone presents relatively little risk of major relapse, and that major relapse can be treated rather quickly,” Merkel added.
The Assessment of Prednisone in Remission (TAPIR) trial enrolled 143 patients with GPA who were in remission (defined as a Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis [BVAS/WG] of 0) within 1 year of treatment to induce remission for active disease and who were taking 5-10 mg of prednisone per day. After all patients tapered to 5 mg/day of prednisone, 71 patients completely tapered off prednisone over 4 weeks and remained off glucocorticoids until month 6. The remaining patients maintained a 5-mg/day dose over the study period. Placement in either treatment group was randomized, and patients continued other immunosuppressive therapy during the study.
Researchers evaluated the rate of relapse by 6 months, defined as a physician’s decision to increase the dose of glucocorticoids to treat GPA, in both groups.
Across all participants, the median age was 58 years, and 52% of patients were male. Most patients were White, and 47% of all patients were prescribed rituximab.
At 6 months, 15.5% of participants who completely tapered off prednisone experienced a relapse of GPA, compared with 4.2% of those taking low-dose prednisone. Time to relapse was also shorter in the 0-mg prednisone group (P = .026), and relapses occurred continually over 6 months, Merkel said.
When stratified by rituximab use, relapse rates at 6 months between the 5-mg and 0-mg prednisone groups in patients taking rituximab showed no difference. Among patients not taking rituximab, those who completely stopped prednisone were nine and a half times as likely to experience relapse as those in the low-dose group.
Despite these differences in relapse rates, “surprisingly, there were no differences in patient-reported outcomes [such as pain interference, physical function, and fatigue],” Merkel said.
Across all patients, all but one relapse was characterized as minor. There were five serious adverse events and 10 infections in the 0-mg group versus one adverse event and 4 infections in the 5-mg group, but these differences were not statistically significant.
In patients who relapsed, musculoskeletal and ear, nose, and throat manifestations of GPA were most common, and these are “the kind of stuff we see that is helped by low-dose glucocorticoids,” Merkel said.
It’s a good sign that for patients who were completely weaned off glucocorticoids, nearly all relapses were minor, Galina Marder, MD, a rheumatologist and associate professor of medicine at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, said in an interview. She was not involved with the research.
The study “can reinforce the message [of] trying to get them off steroids completely [when possible],” she said.
The findings also provide insight for future clinical trials, Merkel noted. For patients taking non–rituximab-based regimens, completely tapering off glucocorticoids or maintaining a low dose can affect study outcomes.
“[These data are] even more important for clinical trials because they are [reinforcing] the fact that you can have a diminishing signal if you allow some patients to stay on 5 mg prednisone” when GPA flares are the primary outcome, Marder added.
The Vasculitis Clinical Research Consortium received funding for this research through grants from the National Institutes of Health. Merkel has disclosed financial relationships with AbbVie/Abbott, Amgen, argenx, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Cabaletta, ChemoCentryx, CSL Behring, Dynacure, Eicos, Electra, EMD Serono, Forbius, Genentech/Roche, Genzyme/Sanofi, GSK, HI-Bio, Inmagene, InflaRx, Janssen, Kiniksa, Kyverna, Magenta, MiroBio, Neutrolis, Novartis, NS Pharma, Pfizer, Regeneron, Sanofi, Sparrow, Takeda, Talaris, UpToDate, and Visterra. Marder consults for Amgen and Boehringer Ingelheim.
A version of this article first appeared on Medscape.com.
WASHINGTON — Patients with granulomatosis with polyangiitis (GPA) completely tapered off prednisone have a more than fourfold risk of relapse by 6 months, compared with those tapered to 5 mg/day of prednisone; however, this benefit was only seen in patients not on rituximab, according to new research presented at the annual meeting of the American College of Rheumatology (ACR).
“For patients treated with rituximab, fully tapering off glucocorticoids is reasonable to consider as the first approach,” said Peter Merkel, MD, MPH, chief of the division of rheumatology at the University of Pennsylvania, Philadelphia, during his presentation of the findings.
Although a low dose of glucocorticoids can prevent some minor relapses in patients on other treatment regimens such as methotrexate or azathioprine, “fully tapering off prednisone presents relatively little risk of major relapse, and that major relapse can be treated rather quickly,” Merkel added.
The Assessment of Prednisone in Remission (TAPIR) trial enrolled 143 patients with GPA who were in remission (defined as a Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis [BVAS/WG] of 0) within 1 year of treatment to induce remission for active disease and who were taking 5-10 mg of prednisone per day. After all patients tapered to 5 mg/day of prednisone, 71 patients completely tapered off prednisone over 4 weeks and remained off glucocorticoids until month 6. The remaining patients maintained a 5-mg/day dose over the study period. Placement in either treatment group was randomized, and patients continued other immunosuppressive therapy during the study.
Researchers evaluated the rate of relapse by 6 months, defined as a physician’s decision to increase the dose of glucocorticoids to treat GPA, in both groups.
Across all participants, the median age was 58 years, and 52% of patients were male. Most patients were White, and 47% of all patients were prescribed rituximab.
At 6 months, 15.5% of participants who completely tapered off prednisone experienced a relapse of GPA, compared with 4.2% of those taking low-dose prednisone. Time to relapse was also shorter in the 0-mg prednisone group (P = .026), and relapses occurred continually over 6 months, Merkel said.
When stratified by rituximab use, relapse rates at 6 months between the 5-mg and 0-mg prednisone groups in patients taking rituximab showed no difference. Among patients not taking rituximab, those who completely stopped prednisone were nine and a half times as likely to experience relapse as those in the low-dose group.
Despite these differences in relapse rates, “surprisingly, there were no differences in patient-reported outcomes [such as pain interference, physical function, and fatigue],” Merkel said.
Across all patients, all but one relapse was characterized as minor. There were five serious adverse events and 10 infections in the 0-mg group versus one adverse event and 4 infections in the 5-mg group, but these differences were not statistically significant.
In patients who relapsed, musculoskeletal and ear, nose, and throat manifestations of GPA were most common, and these are “the kind of stuff we see that is helped by low-dose glucocorticoids,” Merkel said.
It’s a good sign that for patients who were completely weaned off glucocorticoids, nearly all relapses were minor, Galina Marder, MD, a rheumatologist and associate professor of medicine at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, said in an interview. She was not involved with the research.
The study “can reinforce the message [of] trying to get them off steroids completely [when possible],” she said.
The findings also provide insight for future clinical trials, Merkel noted. For patients taking non–rituximab-based regimens, completely tapering off glucocorticoids or maintaining a low dose can affect study outcomes.
“[These data are] even more important for clinical trials because they are [reinforcing] the fact that you can have a diminishing signal if you allow some patients to stay on 5 mg prednisone” when GPA flares are the primary outcome, Marder added.
The Vasculitis Clinical Research Consortium received funding for this research through grants from the National Institutes of Health. Merkel has disclosed financial relationships with AbbVie/Abbott, Amgen, argenx, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Cabaletta, ChemoCentryx, CSL Behring, Dynacure, Eicos, Electra, EMD Serono, Forbius, Genentech/Roche, Genzyme/Sanofi, GSK, HI-Bio, Inmagene, InflaRx, Janssen, Kiniksa, Kyverna, Magenta, MiroBio, Neutrolis, Novartis, NS Pharma, Pfizer, Regeneron, Sanofi, Sparrow, Takeda, Talaris, UpToDate, and Visterra. Marder consults for Amgen and Boehringer Ingelheim.
A version of this article first appeared on Medscape.com.
WASHINGTON — Patients with granulomatosis with polyangiitis (GPA) completely tapered off prednisone have a more than fourfold risk of relapse by 6 months, compared with those tapered to 5 mg/day of prednisone; however, this benefit was only seen in patients not on rituximab, according to new research presented at the annual meeting of the American College of Rheumatology (ACR).
“For patients treated with rituximab, fully tapering off glucocorticoids is reasonable to consider as the first approach,” said Peter Merkel, MD, MPH, chief of the division of rheumatology at the University of Pennsylvania, Philadelphia, during his presentation of the findings.
Although a low dose of glucocorticoids can prevent some minor relapses in patients on other treatment regimens such as methotrexate or azathioprine, “fully tapering off prednisone presents relatively little risk of major relapse, and that major relapse can be treated rather quickly,” Merkel added.
The Assessment of Prednisone in Remission (TAPIR) trial enrolled 143 patients with GPA who were in remission (defined as a Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis [BVAS/WG] of 0) within 1 year of treatment to induce remission for active disease and who were taking 5-10 mg of prednisone per day. After all patients tapered to 5 mg/day of prednisone, 71 patients completely tapered off prednisone over 4 weeks and remained off glucocorticoids until month 6. The remaining patients maintained a 5-mg/day dose over the study period. Placement in either treatment group was randomized, and patients continued other immunosuppressive therapy during the study.
Researchers evaluated the rate of relapse by 6 months, defined as a physician’s decision to increase the dose of glucocorticoids to treat GPA, in both groups.
Across all participants, the median age was 58 years, and 52% of patients were male. Most patients were White, and 47% of all patients were prescribed rituximab.
At 6 months, 15.5% of participants who completely tapered off prednisone experienced a relapse of GPA, compared with 4.2% of those taking low-dose prednisone. Time to relapse was also shorter in the 0-mg prednisone group (P = .026), and relapses occurred continually over 6 months, Merkel said.
When stratified by rituximab use, relapse rates at 6 months between the 5-mg and 0-mg prednisone groups in patients taking rituximab showed no difference. Among patients not taking rituximab, those who completely stopped prednisone were nine and a half times as likely to experience relapse as those in the low-dose group.
Despite these differences in relapse rates, “surprisingly, there were no differences in patient-reported outcomes [such as pain interference, physical function, and fatigue],” Merkel said.
Across all patients, all but one relapse was characterized as minor. There were five serious adverse events and 10 infections in the 0-mg group versus one adverse event and 4 infections in the 5-mg group, but these differences were not statistically significant.
In patients who relapsed, musculoskeletal and ear, nose, and throat manifestations of GPA were most common, and these are “the kind of stuff we see that is helped by low-dose glucocorticoids,” Merkel said.
It’s a good sign that for patients who were completely weaned off glucocorticoids, nearly all relapses were minor, Galina Marder, MD, a rheumatologist and associate professor of medicine at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, said in an interview. She was not involved with the research.
The study “can reinforce the message [of] trying to get them off steroids completely [when possible],” she said.
The findings also provide insight for future clinical trials, Merkel noted. For patients taking non–rituximab-based regimens, completely tapering off glucocorticoids or maintaining a low dose can affect study outcomes.
“[These data are] even more important for clinical trials because they are [reinforcing] the fact that you can have a diminishing signal if you allow some patients to stay on 5 mg prednisone” when GPA flares are the primary outcome, Marder added.
The Vasculitis Clinical Research Consortium received funding for this research through grants from the National Institutes of Health. Merkel has disclosed financial relationships with AbbVie/Abbott, Amgen, argenx, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Cabaletta, ChemoCentryx, CSL Behring, Dynacure, Eicos, Electra, EMD Serono, Forbius, Genentech/Roche, Genzyme/Sanofi, GSK, HI-Bio, Inmagene, InflaRx, Janssen, Kiniksa, Kyverna, Magenta, MiroBio, Neutrolis, Novartis, NS Pharma, Pfizer, Regeneron, Sanofi, Sparrow, Takeda, Talaris, UpToDate, and Visterra. Marder consults for Amgen and Boehringer Ingelheim.
A version of this article first appeared on Medscape.com.
FROM ACR 2024
First Phase 3 Drug Trial in IgG4-Related Disease Has Success
WASHINGTON — The B cell–depleting agent inebilizumab (Uplizna) dramatically reduced the risk of flares and increased year-long remission of IgG4-related disease (RD), new research has found.
In a phase 3, multicenter, double-blind, randomized, placebo-controlled trial of 135 adults with active IgG4-RD, treatment with inebilizumab resulted in a significant 87% reduction in flare risk and nearly fivefold greater likelihood of flare-free remission at 1 year. The results were published online November 14 in The New England Journal of Medicine and were presented at the annual meeting of the American College of Rheumatology (ACR).
The drug’s manufacturer, Amgen, released top-line results of the trial, called MITIGATE, in June 2024.
Until now, the mainstay of management for the chronic multiorgan disease IgG4-RD has been glucocorticoids, which can cause numerous adverse effects. “It is hoped that inebilizumab can be used as an important steroid-sparing medication in this disease to reduce steroid toxicity,” lead author John H. Stone, MD, professor of medicine at Harvard Medical School, Boston, Massachusetts, said in an interview, noting that it may not entirely eliminate the need for steroid treatment, but for many, it appears to work after the remission induction period as a monotherapy without steroids.
Asked to comment, Leonard H. Calabrese, DO, head of the Section of Clinical Immunology and manager of the Clinical Immunology Clinic at the Cleveland Clinic, Ohio, said: “There has been anecdotal or observational evidence for some effect with other immunosuppressive agents, including rituximab, but no robust clinical trial until this study. This clearly has demonstrated efficacy by reducing the risk of flares. And most importantly, putting people into remission means no active disease in any given organ. ... This gives us another tool in the toolbox to attack B cell–directed diseases, and I think it really makes a lot of sense.”
Calabrese cautioned, though, that “this is a disease that extends over many years. This is just a 1-year study. Label extensions will be important.”
And several questions remain, Calabrese noted: “How long do patients need to remain on drug? What will happen when the drug is stopped? Can they be retreated? These are the natural questions that arise in any sentinel study like this. But this is extremely encouraging. And I think it’s great for patients. I also think it’s a clarion call to increase awareness about this disease since there’s now strong evidence of effective treatment.”
Underrecognized, Often Misdiagnosed as Cancer
Indeed, IgG4-RD, a chronic, relapsing, autoimmune, fibro-inflammatory multiorgan disease, was only first described in Japan in 2003. Since then, it has been reported all over the world yet remains vastly underrecognized. It is often misdiagnosed as cancer because it produces lesions in multiple organs. It received an ICD-10 code only about a year ago. A previous study estimated a prevalence of about 5.3 persons per 100,000 but that is likely to be a three- to fourfold underestimate, said Stone, who is also executive chairman of the IgG4ward! Foundation.
“Nobody had heard of the disease until about 20 years ago. ... And there are many people in the world who have still not heard of it despite the fact that it is a multiorgan autoimmune disease and is probably as common, or more common, than many other diseases that rheumatologists spend a lot of time thinking about, such as scleroderma.”
While knowledge about the disease is increasing in rheumatology circles, it’s less well-recognized among many of the specialties where patients present, depending on the location of their lesions. These include gastroenterology, ophthalmology, pulmonary medicine, neurology, and nephrology. “All would be likely to see this disease,” Stone said.
The disease can be mistaken for tumors in many of those locations and even as metastatic cancer, he noted, adding that “any time a patient has a mass lesion in a typical organ, the pancreas, the major salivary glands, the lungs, or the kidneys, this should be on the differential diagnosis.”
The diagnosis of IgG4-RD is a clinical one, involving “quadrangulation between clinical features, serological findings, IgG4 levels in the blood, radiology studies, and then pathology biopsies when those are available,” Stone said.
Calabrese characterized the current situation as “we’re all blind men on the elephant. To the neurologist or the neurosurgeon, it’s a mass in the brain. It could present to the ophthalmologist as an [eye] tumor. It can be thyroid gland failure, pulmonary disease, retroperitoneal fibrosis, hepatobiliary disease, and beyond. So, whoever sees that patient, there’s often a long lag time in recognizing it.”
And interestingly, Stone noted that unlike other autoimmune diseases, IgG4-RD primarily affects middle-aged men rather than younger-to-middle-aged women. And when IgG4-RD is diagnosed, glucocorticoid treatment can be particularly toxic when the pancreas is involved, heightening the risk for hyperglycemia and potentially causing diabetes.
Dramatic Improvement in Flares, Remission Achievement
MITIGATE is a phase 3, multicenter, double-blind, randomized, placebo-controlled trial in which 135 adults (mean age 58.2 years, 88 men) with active IgG4-RD were randomized 1:1 to receive 300-mg intravenous infusions of inebilizumab or placebo on days 1 and 15, and again at week 26. At baseline, 62 (45.9%) participants had newly diagnosed IgG4-RD and 73 (54.1%) had recurrent disease.
Both groups received identical glucocorticoid tapers. Overall, 127 (94.1%) completed the 52 weeks of treatment.
By 52 weeks, only seven patients in the inebilizumab group (10%) had experienced disease flares vs 40 (60%) in the placebo group, a significant difference with a hazard ratio of 0.13 (P < .001).
The percentage of participants achieving flare-free, treatment-free complete remission was 59 with inebilizumab (57%), compared with just 15 (22%) in the placebo group (odds ratio [OR], 4.68; P < .001). And for flare-free, glucocorticoid-free complete remission, those proportions were 40 (59%) vs 15 (22%), respectively (OR, 4.96; P < .001).
Excluding the 8-week glucocorticoid taper period, mean total glucocorticoid use was 1264.2 mg less in the inebilizumab than the placebo group, a significant reduction. Overall, 61 participants (90%) were able to entirely discontinue glucocorticoids during the trial, compared with just 25 (37%) in the placebo group.
Adverse events of grade 3 or higher occurred in 12 participants (18%) in the inebilizumab group and 8 (12%) in the placebo group; serious adverse events occurred in 12 (18%) and 6 (9%), respectively. However, no serious adverse event occurred in more than one participant, and there were no deaths. Adverse events led to withdrawal from the trial in six patients (9%) in the inebilizumab group and three patients (4%) in the placebo group.
Adverse events that occurred in more than 10% of participants in the inebilizumab group were COVID-19 in 16 participants (24%), lymphopenia in 11 (16%), and urinary tract infection in 8 (12%).
Importantly, Stone noted, B-cell depletion can reduce responses to vaccines, so patients should receive all recommended vaccinations, including COVID-19, influenza, respiratory syncytial virus, and others, prior to initiating therapy.
Uplizna (inebilizumab-cdon) was approved by the Food and Drug Administration (FDA) for the treatment of neuromyelitis optica spectrum disorder in 2020. In October 2024, the FDA granted Amgen breakthrough therapy designation for use in IgG4-RD. The company is also developing the drug for use in myasthenia gravis.
The study was funded by Amgen. Stone has reported being a consultant for Amgen, Zenas, Argenx, Bristol Myers Squibb, Novartis, Sanofi, and Horizon Pharma. Calabrese has reported being a consultant and/or speaker for Amgen, AstraZeneca, Jansen, Sanofi, and UCB.
A version of this article first appeared on Medscape.com.
WASHINGTON — The B cell–depleting agent inebilizumab (Uplizna) dramatically reduced the risk of flares and increased year-long remission of IgG4-related disease (RD), new research has found.
In a phase 3, multicenter, double-blind, randomized, placebo-controlled trial of 135 adults with active IgG4-RD, treatment with inebilizumab resulted in a significant 87% reduction in flare risk and nearly fivefold greater likelihood of flare-free remission at 1 year. The results were published online November 14 in The New England Journal of Medicine and were presented at the annual meeting of the American College of Rheumatology (ACR).
The drug’s manufacturer, Amgen, released top-line results of the trial, called MITIGATE, in June 2024.
Until now, the mainstay of management for the chronic multiorgan disease IgG4-RD has been glucocorticoids, which can cause numerous adverse effects. “It is hoped that inebilizumab can be used as an important steroid-sparing medication in this disease to reduce steroid toxicity,” lead author John H. Stone, MD, professor of medicine at Harvard Medical School, Boston, Massachusetts, said in an interview, noting that it may not entirely eliminate the need for steroid treatment, but for many, it appears to work after the remission induction period as a monotherapy without steroids.
Asked to comment, Leonard H. Calabrese, DO, head of the Section of Clinical Immunology and manager of the Clinical Immunology Clinic at the Cleveland Clinic, Ohio, said: “There has been anecdotal or observational evidence for some effect with other immunosuppressive agents, including rituximab, but no robust clinical trial until this study. This clearly has demonstrated efficacy by reducing the risk of flares. And most importantly, putting people into remission means no active disease in any given organ. ... This gives us another tool in the toolbox to attack B cell–directed diseases, and I think it really makes a lot of sense.”
Calabrese cautioned, though, that “this is a disease that extends over many years. This is just a 1-year study. Label extensions will be important.”
And several questions remain, Calabrese noted: “How long do patients need to remain on drug? What will happen when the drug is stopped? Can they be retreated? These are the natural questions that arise in any sentinel study like this. But this is extremely encouraging. And I think it’s great for patients. I also think it’s a clarion call to increase awareness about this disease since there’s now strong evidence of effective treatment.”
Underrecognized, Often Misdiagnosed as Cancer
Indeed, IgG4-RD, a chronic, relapsing, autoimmune, fibro-inflammatory multiorgan disease, was only first described in Japan in 2003. Since then, it has been reported all over the world yet remains vastly underrecognized. It is often misdiagnosed as cancer because it produces lesions in multiple organs. It received an ICD-10 code only about a year ago. A previous study estimated a prevalence of about 5.3 persons per 100,000 but that is likely to be a three- to fourfold underestimate, said Stone, who is also executive chairman of the IgG4ward! Foundation.
“Nobody had heard of the disease until about 20 years ago. ... And there are many people in the world who have still not heard of it despite the fact that it is a multiorgan autoimmune disease and is probably as common, or more common, than many other diseases that rheumatologists spend a lot of time thinking about, such as scleroderma.”
While knowledge about the disease is increasing in rheumatology circles, it’s less well-recognized among many of the specialties where patients present, depending on the location of their lesions. These include gastroenterology, ophthalmology, pulmonary medicine, neurology, and nephrology. “All would be likely to see this disease,” Stone said.
The disease can be mistaken for tumors in many of those locations and even as metastatic cancer, he noted, adding that “any time a patient has a mass lesion in a typical organ, the pancreas, the major salivary glands, the lungs, or the kidneys, this should be on the differential diagnosis.”
The diagnosis of IgG4-RD is a clinical one, involving “quadrangulation between clinical features, serological findings, IgG4 levels in the blood, radiology studies, and then pathology biopsies when those are available,” Stone said.
Calabrese characterized the current situation as “we’re all blind men on the elephant. To the neurologist or the neurosurgeon, it’s a mass in the brain. It could present to the ophthalmologist as an [eye] tumor. It can be thyroid gland failure, pulmonary disease, retroperitoneal fibrosis, hepatobiliary disease, and beyond. So, whoever sees that patient, there’s often a long lag time in recognizing it.”
And interestingly, Stone noted that unlike other autoimmune diseases, IgG4-RD primarily affects middle-aged men rather than younger-to-middle-aged women. And when IgG4-RD is diagnosed, glucocorticoid treatment can be particularly toxic when the pancreas is involved, heightening the risk for hyperglycemia and potentially causing diabetes.
Dramatic Improvement in Flares, Remission Achievement
MITIGATE is a phase 3, multicenter, double-blind, randomized, placebo-controlled trial in which 135 adults (mean age 58.2 years, 88 men) with active IgG4-RD were randomized 1:1 to receive 300-mg intravenous infusions of inebilizumab or placebo on days 1 and 15, and again at week 26. At baseline, 62 (45.9%) participants had newly diagnosed IgG4-RD and 73 (54.1%) had recurrent disease.
Both groups received identical glucocorticoid tapers. Overall, 127 (94.1%) completed the 52 weeks of treatment.
By 52 weeks, only seven patients in the inebilizumab group (10%) had experienced disease flares vs 40 (60%) in the placebo group, a significant difference with a hazard ratio of 0.13 (P < .001).
The percentage of participants achieving flare-free, treatment-free complete remission was 59 with inebilizumab (57%), compared with just 15 (22%) in the placebo group (odds ratio [OR], 4.68; P < .001). And for flare-free, glucocorticoid-free complete remission, those proportions were 40 (59%) vs 15 (22%), respectively (OR, 4.96; P < .001).
Excluding the 8-week glucocorticoid taper period, mean total glucocorticoid use was 1264.2 mg less in the inebilizumab than the placebo group, a significant reduction. Overall, 61 participants (90%) were able to entirely discontinue glucocorticoids during the trial, compared with just 25 (37%) in the placebo group.
Adverse events of grade 3 or higher occurred in 12 participants (18%) in the inebilizumab group and 8 (12%) in the placebo group; serious adverse events occurred in 12 (18%) and 6 (9%), respectively. However, no serious adverse event occurred in more than one participant, and there were no deaths. Adverse events led to withdrawal from the trial in six patients (9%) in the inebilizumab group and three patients (4%) in the placebo group.
Adverse events that occurred in more than 10% of participants in the inebilizumab group were COVID-19 in 16 participants (24%), lymphopenia in 11 (16%), and urinary tract infection in 8 (12%).
Importantly, Stone noted, B-cell depletion can reduce responses to vaccines, so patients should receive all recommended vaccinations, including COVID-19, influenza, respiratory syncytial virus, and others, prior to initiating therapy.
Uplizna (inebilizumab-cdon) was approved by the Food and Drug Administration (FDA) for the treatment of neuromyelitis optica spectrum disorder in 2020. In October 2024, the FDA granted Amgen breakthrough therapy designation for use in IgG4-RD. The company is also developing the drug for use in myasthenia gravis.
The study was funded by Amgen. Stone has reported being a consultant for Amgen, Zenas, Argenx, Bristol Myers Squibb, Novartis, Sanofi, and Horizon Pharma. Calabrese has reported being a consultant and/or speaker for Amgen, AstraZeneca, Jansen, Sanofi, and UCB.
A version of this article first appeared on Medscape.com.
WASHINGTON — The B cell–depleting agent inebilizumab (Uplizna) dramatically reduced the risk of flares and increased year-long remission of IgG4-related disease (RD), new research has found.
In a phase 3, multicenter, double-blind, randomized, placebo-controlled trial of 135 adults with active IgG4-RD, treatment with inebilizumab resulted in a significant 87% reduction in flare risk and nearly fivefold greater likelihood of flare-free remission at 1 year. The results were published online November 14 in The New England Journal of Medicine and were presented at the annual meeting of the American College of Rheumatology (ACR).
The drug’s manufacturer, Amgen, released top-line results of the trial, called MITIGATE, in June 2024.
Until now, the mainstay of management for the chronic multiorgan disease IgG4-RD has been glucocorticoids, which can cause numerous adverse effects. “It is hoped that inebilizumab can be used as an important steroid-sparing medication in this disease to reduce steroid toxicity,” lead author John H. Stone, MD, professor of medicine at Harvard Medical School, Boston, Massachusetts, said in an interview, noting that it may not entirely eliminate the need for steroid treatment, but for many, it appears to work after the remission induction period as a monotherapy without steroids.
Asked to comment, Leonard H. Calabrese, DO, head of the Section of Clinical Immunology and manager of the Clinical Immunology Clinic at the Cleveland Clinic, Ohio, said: “There has been anecdotal or observational evidence for some effect with other immunosuppressive agents, including rituximab, but no robust clinical trial until this study. This clearly has demonstrated efficacy by reducing the risk of flares. And most importantly, putting people into remission means no active disease in any given organ. ... This gives us another tool in the toolbox to attack B cell–directed diseases, and I think it really makes a lot of sense.”
Calabrese cautioned, though, that “this is a disease that extends over many years. This is just a 1-year study. Label extensions will be important.”
And several questions remain, Calabrese noted: “How long do patients need to remain on drug? What will happen when the drug is stopped? Can they be retreated? These are the natural questions that arise in any sentinel study like this. But this is extremely encouraging. And I think it’s great for patients. I also think it’s a clarion call to increase awareness about this disease since there’s now strong evidence of effective treatment.”
Underrecognized, Often Misdiagnosed as Cancer
Indeed, IgG4-RD, a chronic, relapsing, autoimmune, fibro-inflammatory multiorgan disease, was only first described in Japan in 2003. Since then, it has been reported all over the world yet remains vastly underrecognized. It is often misdiagnosed as cancer because it produces lesions in multiple organs. It received an ICD-10 code only about a year ago. A previous study estimated a prevalence of about 5.3 persons per 100,000 but that is likely to be a three- to fourfold underestimate, said Stone, who is also executive chairman of the IgG4ward! Foundation.
“Nobody had heard of the disease until about 20 years ago. ... And there are many people in the world who have still not heard of it despite the fact that it is a multiorgan autoimmune disease and is probably as common, or more common, than many other diseases that rheumatologists spend a lot of time thinking about, such as scleroderma.”
While knowledge about the disease is increasing in rheumatology circles, it’s less well-recognized among many of the specialties where patients present, depending on the location of their lesions. These include gastroenterology, ophthalmology, pulmonary medicine, neurology, and nephrology. “All would be likely to see this disease,” Stone said.
The disease can be mistaken for tumors in many of those locations and even as metastatic cancer, he noted, adding that “any time a patient has a mass lesion in a typical organ, the pancreas, the major salivary glands, the lungs, or the kidneys, this should be on the differential diagnosis.”
The diagnosis of IgG4-RD is a clinical one, involving “quadrangulation between clinical features, serological findings, IgG4 levels in the blood, radiology studies, and then pathology biopsies when those are available,” Stone said.
Calabrese characterized the current situation as “we’re all blind men on the elephant. To the neurologist or the neurosurgeon, it’s a mass in the brain. It could present to the ophthalmologist as an [eye] tumor. It can be thyroid gland failure, pulmonary disease, retroperitoneal fibrosis, hepatobiliary disease, and beyond. So, whoever sees that patient, there’s often a long lag time in recognizing it.”
And interestingly, Stone noted that unlike other autoimmune diseases, IgG4-RD primarily affects middle-aged men rather than younger-to-middle-aged women. And when IgG4-RD is diagnosed, glucocorticoid treatment can be particularly toxic when the pancreas is involved, heightening the risk for hyperglycemia and potentially causing diabetes.
Dramatic Improvement in Flares, Remission Achievement
MITIGATE is a phase 3, multicenter, double-blind, randomized, placebo-controlled trial in which 135 adults (mean age 58.2 years, 88 men) with active IgG4-RD were randomized 1:1 to receive 300-mg intravenous infusions of inebilizumab or placebo on days 1 and 15, and again at week 26. At baseline, 62 (45.9%) participants had newly diagnosed IgG4-RD and 73 (54.1%) had recurrent disease.
Both groups received identical glucocorticoid tapers. Overall, 127 (94.1%) completed the 52 weeks of treatment.
By 52 weeks, only seven patients in the inebilizumab group (10%) had experienced disease flares vs 40 (60%) in the placebo group, a significant difference with a hazard ratio of 0.13 (P < .001).
The percentage of participants achieving flare-free, treatment-free complete remission was 59 with inebilizumab (57%), compared with just 15 (22%) in the placebo group (odds ratio [OR], 4.68; P < .001). And for flare-free, glucocorticoid-free complete remission, those proportions were 40 (59%) vs 15 (22%), respectively (OR, 4.96; P < .001).
Excluding the 8-week glucocorticoid taper period, mean total glucocorticoid use was 1264.2 mg less in the inebilizumab than the placebo group, a significant reduction. Overall, 61 participants (90%) were able to entirely discontinue glucocorticoids during the trial, compared with just 25 (37%) in the placebo group.
Adverse events of grade 3 or higher occurred in 12 participants (18%) in the inebilizumab group and 8 (12%) in the placebo group; serious adverse events occurred in 12 (18%) and 6 (9%), respectively. However, no serious adverse event occurred in more than one participant, and there were no deaths. Adverse events led to withdrawal from the trial in six patients (9%) in the inebilizumab group and three patients (4%) in the placebo group.
Adverse events that occurred in more than 10% of participants in the inebilizumab group were COVID-19 in 16 participants (24%), lymphopenia in 11 (16%), and urinary tract infection in 8 (12%).
Importantly, Stone noted, B-cell depletion can reduce responses to vaccines, so patients should receive all recommended vaccinations, including COVID-19, influenza, respiratory syncytial virus, and others, prior to initiating therapy.
Uplizna (inebilizumab-cdon) was approved by the Food and Drug Administration (FDA) for the treatment of neuromyelitis optica spectrum disorder in 2020. In October 2024, the FDA granted Amgen breakthrough therapy designation for use in IgG4-RD. The company is also developing the drug for use in myasthenia gravis.
The study was funded by Amgen. Stone has reported being a consultant for Amgen, Zenas, Argenx, Bristol Myers Squibb, Novartis, Sanofi, and Horizon Pharma. Calabrese has reported being a consultant and/or speaker for Amgen, AstraZeneca, Jansen, Sanofi, and UCB.
A version of this article first appeared on Medscape.com.
FROM ACR 2024
New UTI Guideline Offers Treatment Clarity, Reveals Gaps in Knowledge
New recommendations from the WikiGuidelines Group offer strategies for the prevention, diagnosis, and management of urinary tract infections (UTIs) in children and adults.
While the guideline covers a range of clinical topics, including prophylaxis and antimicrobial stewardship, many key clinical questions remain unanswered because of a lack of high-quality evidence, according to lead author Zachary Nelson, PharmD, MPH, of HealthPartners and Park Nicollet Health Services, St. Louis Park, Minnesota, and colleagues.
“This guideline fills a critical gap by providing pragmatic, broadly applicable recommendations tailored for generalist care and systems-based practice,” Nelson and colleagues wrote in JAMA Network Open. “Our guidance is rooted in the best available evidence and is designed for clinicians from various backgrounds and healthcare environments. It emphasizes a patient-centered approach to the diagnosis, prevention, and treatment of UTIs and related genitourinary infections.”
The guideline panelists, including 54 experts from 12 countries, developed the document in accordance with Standards for Quality Improvement Reporting Excellence and the WikiGuidelines charter. The latter requires that “clear recommendations” are based on data from at least two concordant randomized clinical trials (RCTs), or one RCT plus one concordant prospective observational study.
This approach allowed the panel to provide clear recommendations for 6 out of 37 unique questions, while 3 other questions were partially answered. In other words, 75% of the questions lacked sufficient evidence for answers.
“These guidelines are important because they illuminate the clinical data and lack of data we have for approaching diagnosis and treatment of this common infection that leads to a wide array of morbidity and sometimes mortality, as well as significant cost burden to the healthcare system,” said coauthor Sarah Kurz, MD, clinical assistant professor of internal medicine at Michigan Medicine, Ann Arbor, in a written comment.
Jessica Hammett, MD, a urologist at Emory Healthcare, Atlanta, Georgia, who was not an author of the study, suggested that the guideline is additionally impactful because of the panel’s geographic diversity.
“It is an international collaboration that takes into account regional and international practice patterns and differences,” Hammett said in a written comment.
The key guideline recommendations are briefly summarized below.
Preventive Strategies for UTI
The guideline endorses cranberry products as preventive for UTI-prone women, children, and post-intervention patients, though data are insufficient to recommend them for older adults, those with bladder issues, or pregnant women.
Topical estrogen is recommended for postmenopausal women with recurrent UTIs, as it helps restore the vaginal microbiome with minimal systemic absorption. It may also benefit patients with breast cancer when nonhormonal alternatives fail.
For those with intact bladder anatomy, methenamine hippurate is suggested as a noninferior alternative to low-dose antibiotics for preventing recurrent UTIs.
“These findings confirm the best practice of starting postmenopausal women on vaginal estrogen to prevent UTIs, which is a treatment option that should be implemented more commonly,” Hammett said. “Interestingly as compared to the AUA guidelines, this paper recommends the use of cranberry supplementation and methenamine as antibiotic alternatives for preventing UTIs.”
Empirical Treatment Recommendations
According to the guideline, empirical treatment for UTIs should focus on antimicrobials with high urinary tract concentration and local pathogen efficacy.
Nitrofurantoin is recommended for uncomplicated cystitis, while trimethoprim/sulfamethoxazole (TMP/SMX) and first-generation cephalosporins are advised for pyelonephritis.
For intravenous therapy, ceftriaxone is preferred unless there are risk factors for multidrug resistance.
Recommended treatment durations include 5 days for nitrofurantoin, 3 days for TMP/SMX and fluoroquinolones, and a single dose for fosfomycin in acute cystitis cases. For acute pyelonephritis, fluoroquinolones are advised for 5-7 days, with dose-optimized beta-lactams for 7 days. Gram-negative bacteremia from urinary sources warrants a 7-day course.
Stewardship and Clinical Management
The guideline emphasizes antimicrobial stewardship, with support for antibiotic de-escalation and oral regimens where feasible, to reduce adverse effects and hospital stays. Although evidence is limited, the authors suggest thorough allergy assessment and selective reporting of susceptibility results to enhance antibiotic selection.
While data were insufficient to make clear recommendations about the treatment of asymptomatic bacteriuria, Nelson and colleagues suggested that this practice “risks side effects without benefit” while threatening antimicrobial sustainability.
Hammett agreed, noting that “[this] serves as an important reminder not to treat asymptomatic bacteriuria, as it increases side effects and bacterial resistance without any improvement as compared to placebo.”
Special Considerations for Urologic Procedures
Finally, patients undergoing urologic procedures, routine cystoscopy, and urodynamic studies generally do not require prophylactic antibiotics, according to the guideline. Single-dose antibiotic prophylaxis is recommended for low-risk nephrolithotomy patients, though high-risk individuals, such as those who are pregnant or post kidney transplant, may require extended prophylaxis.
Kurz suggested that the guideline consolidates and supports the foundation of evidence driving common practices.
“I don’t think these guidelines offer any strikingly new strategies, which is unsurprising, as they were created after a deep dive into existing literature,” Kurz said. “But more importantly, what I think they do is to highlight where and what the evidence is for many of the clinical strategies that are commonly employed. For example, in terms of prevention, it is common for primary care physicians, urologists, and infectious diseases doctors to recommend cranberry and hydration and to use methenamine. These guidelines highlight that there is sufficient quality and quantity of evidence to support these interventions.”
She also noted how the guidelines emphasize the need for symptoms to make a UTI diagnosis and advise against routine testing of asymptomatic individuals.
“Despite this not being new information, typical clinical practice is often out of step here, and this [guideline] reemphasizes the important factors when considering UTI diagnosis,” Kurz said.
Finally, she expressed frustration for the numerous knowledge gaps remaining in this area, which may be traced back to barriers ranging from the semantic to the more systemic.
“Some of the difficulty is lack of clear definitions and precise terminology regarding UTIs,” Kurz said, noting the unclear distinction between complicated and uncomplicated UTIs. “I would also argue that UTIs are a disease that predominantly affects women, and like many other diseases where this is the case, [they] tend to be less studied. Hopefully, this guideline’s spotlight on all that we do not know can inspire high-quality research to address these gaps, leading to optimal patient care along with decreased burden on the system as a whole in terms of cost and antimicrobial resistance.”
The study was funded by Merck. The WikiGuidelines Group that established this guideline is entirely voluntary and unpaid; the group intends to establish a nonprofit organization to support the development of other guidelines using this novel methodology and eventually intends to trademark the name WikiGuidelines. The authors disclosed relationships with Pfizer, Eumedica, GSK, and others.
A version of this article first appeared on Medscape.com.
New recommendations from the WikiGuidelines Group offer strategies for the prevention, diagnosis, and management of urinary tract infections (UTIs) in children and adults.
While the guideline covers a range of clinical topics, including prophylaxis and antimicrobial stewardship, many key clinical questions remain unanswered because of a lack of high-quality evidence, according to lead author Zachary Nelson, PharmD, MPH, of HealthPartners and Park Nicollet Health Services, St. Louis Park, Minnesota, and colleagues.
“This guideline fills a critical gap by providing pragmatic, broadly applicable recommendations tailored for generalist care and systems-based practice,” Nelson and colleagues wrote in JAMA Network Open. “Our guidance is rooted in the best available evidence and is designed for clinicians from various backgrounds and healthcare environments. It emphasizes a patient-centered approach to the diagnosis, prevention, and treatment of UTIs and related genitourinary infections.”
The guideline panelists, including 54 experts from 12 countries, developed the document in accordance with Standards for Quality Improvement Reporting Excellence and the WikiGuidelines charter. The latter requires that “clear recommendations” are based on data from at least two concordant randomized clinical trials (RCTs), or one RCT plus one concordant prospective observational study.
This approach allowed the panel to provide clear recommendations for 6 out of 37 unique questions, while 3 other questions were partially answered. In other words, 75% of the questions lacked sufficient evidence for answers.
“These guidelines are important because they illuminate the clinical data and lack of data we have for approaching diagnosis and treatment of this common infection that leads to a wide array of morbidity and sometimes mortality, as well as significant cost burden to the healthcare system,” said coauthor Sarah Kurz, MD, clinical assistant professor of internal medicine at Michigan Medicine, Ann Arbor, in a written comment.
Jessica Hammett, MD, a urologist at Emory Healthcare, Atlanta, Georgia, who was not an author of the study, suggested that the guideline is additionally impactful because of the panel’s geographic diversity.
“It is an international collaboration that takes into account regional and international practice patterns and differences,” Hammett said in a written comment.
The key guideline recommendations are briefly summarized below.
Preventive Strategies for UTI
The guideline endorses cranberry products as preventive for UTI-prone women, children, and post-intervention patients, though data are insufficient to recommend them for older adults, those with bladder issues, or pregnant women.
Topical estrogen is recommended for postmenopausal women with recurrent UTIs, as it helps restore the vaginal microbiome with minimal systemic absorption. It may also benefit patients with breast cancer when nonhormonal alternatives fail.
For those with intact bladder anatomy, methenamine hippurate is suggested as a noninferior alternative to low-dose antibiotics for preventing recurrent UTIs.
“These findings confirm the best practice of starting postmenopausal women on vaginal estrogen to prevent UTIs, which is a treatment option that should be implemented more commonly,” Hammett said. “Interestingly as compared to the AUA guidelines, this paper recommends the use of cranberry supplementation and methenamine as antibiotic alternatives for preventing UTIs.”
Empirical Treatment Recommendations
According to the guideline, empirical treatment for UTIs should focus on antimicrobials with high urinary tract concentration and local pathogen efficacy.
Nitrofurantoin is recommended for uncomplicated cystitis, while trimethoprim/sulfamethoxazole (TMP/SMX) and first-generation cephalosporins are advised for pyelonephritis.
For intravenous therapy, ceftriaxone is preferred unless there are risk factors for multidrug resistance.
Recommended treatment durations include 5 days for nitrofurantoin, 3 days for TMP/SMX and fluoroquinolones, and a single dose for fosfomycin in acute cystitis cases. For acute pyelonephritis, fluoroquinolones are advised for 5-7 days, with dose-optimized beta-lactams for 7 days. Gram-negative bacteremia from urinary sources warrants a 7-day course.
Stewardship and Clinical Management
The guideline emphasizes antimicrobial stewardship, with support for antibiotic de-escalation and oral regimens where feasible, to reduce adverse effects and hospital stays. Although evidence is limited, the authors suggest thorough allergy assessment and selective reporting of susceptibility results to enhance antibiotic selection.
While data were insufficient to make clear recommendations about the treatment of asymptomatic bacteriuria, Nelson and colleagues suggested that this practice “risks side effects without benefit” while threatening antimicrobial sustainability.
Hammett agreed, noting that “[this] serves as an important reminder not to treat asymptomatic bacteriuria, as it increases side effects and bacterial resistance without any improvement as compared to placebo.”
Special Considerations for Urologic Procedures
Finally, patients undergoing urologic procedures, routine cystoscopy, and urodynamic studies generally do not require prophylactic antibiotics, according to the guideline. Single-dose antibiotic prophylaxis is recommended for low-risk nephrolithotomy patients, though high-risk individuals, such as those who are pregnant or post kidney transplant, may require extended prophylaxis.
Kurz suggested that the guideline consolidates and supports the foundation of evidence driving common practices.
“I don’t think these guidelines offer any strikingly new strategies, which is unsurprising, as they were created after a deep dive into existing literature,” Kurz said. “But more importantly, what I think they do is to highlight where and what the evidence is for many of the clinical strategies that are commonly employed. For example, in terms of prevention, it is common for primary care physicians, urologists, and infectious diseases doctors to recommend cranberry and hydration and to use methenamine. These guidelines highlight that there is sufficient quality and quantity of evidence to support these interventions.”
She also noted how the guidelines emphasize the need for symptoms to make a UTI diagnosis and advise against routine testing of asymptomatic individuals.
“Despite this not being new information, typical clinical practice is often out of step here, and this [guideline] reemphasizes the important factors when considering UTI diagnosis,” Kurz said.
Finally, she expressed frustration for the numerous knowledge gaps remaining in this area, which may be traced back to barriers ranging from the semantic to the more systemic.
“Some of the difficulty is lack of clear definitions and precise terminology regarding UTIs,” Kurz said, noting the unclear distinction between complicated and uncomplicated UTIs. “I would also argue that UTIs are a disease that predominantly affects women, and like many other diseases where this is the case, [they] tend to be less studied. Hopefully, this guideline’s spotlight on all that we do not know can inspire high-quality research to address these gaps, leading to optimal patient care along with decreased burden on the system as a whole in terms of cost and antimicrobial resistance.”
The study was funded by Merck. The WikiGuidelines Group that established this guideline is entirely voluntary and unpaid; the group intends to establish a nonprofit organization to support the development of other guidelines using this novel methodology and eventually intends to trademark the name WikiGuidelines. The authors disclosed relationships with Pfizer, Eumedica, GSK, and others.
A version of this article first appeared on Medscape.com.
New recommendations from the WikiGuidelines Group offer strategies for the prevention, diagnosis, and management of urinary tract infections (UTIs) in children and adults.
While the guideline covers a range of clinical topics, including prophylaxis and antimicrobial stewardship, many key clinical questions remain unanswered because of a lack of high-quality evidence, according to lead author Zachary Nelson, PharmD, MPH, of HealthPartners and Park Nicollet Health Services, St. Louis Park, Minnesota, and colleagues.
“This guideline fills a critical gap by providing pragmatic, broadly applicable recommendations tailored for generalist care and systems-based practice,” Nelson and colleagues wrote in JAMA Network Open. “Our guidance is rooted in the best available evidence and is designed for clinicians from various backgrounds and healthcare environments. It emphasizes a patient-centered approach to the diagnosis, prevention, and treatment of UTIs and related genitourinary infections.”
The guideline panelists, including 54 experts from 12 countries, developed the document in accordance with Standards for Quality Improvement Reporting Excellence and the WikiGuidelines charter. The latter requires that “clear recommendations” are based on data from at least two concordant randomized clinical trials (RCTs), or one RCT plus one concordant prospective observational study.
This approach allowed the panel to provide clear recommendations for 6 out of 37 unique questions, while 3 other questions were partially answered. In other words, 75% of the questions lacked sufficient evidence for answers.
“These guidelines are important because they illuminate the clinical data and lack of data we have for approaching diagnosis and treatment of this common infection that leads to a wide array of morbidity and sometimes mortality, as well as significant cost burden to the healthcare system,” said coauthor Sarah Kurz, MD, clinical assistant professor of internal medicine at Michigan Medicine, Ann Arbor, in a written comment.
Jessica Hammett, MD, a urologist at Emory Healthcare, Atlanta, Georgia, who was not an author of the study, suggested that the guideline is additionally impactful because of the panel’s geographic diversity.
“It is an international collaboration that takes into account regional and international practice patterns and differences,” Hammett said in a written comment.
The key guideline recommendations are briefly summarized below.
Preventive Strategies for UTI
The guideline endorses cranberry products as preventive for UTI-prone women, children, and post-intervention patients, though data are insufficient to recommend them for older adults, those with bladder issues, or pregnant women.
Topical estrogen is recommended for postmenopausal women with recurrent UTIs, as it helps restore the vaginal microbiome with minimal systemic absorption. It may also benefit patients with breast cancer when nonhormonal alternatives fail.
For those with intact bladder anatomy, methenamine hippurate is suggested as a noninferior alternative to low-dose antibiotics for preventing recurrent UTIs.
“These findings confirm the best practice of starting postmenopausal women on vaginal estrogen to prevent UTIs, which is a treatment option that should be implemented more commonly,” Hammett said. “Interestingly as compared to the AUA guidelines, this paper recommends the use of cranberry supplementation and methenamine as antibiotic alternatives for preventing UTIs.”
Empirical Treatment Recommendations
According to the guideline, empirical treatment for UTIs should focus on antimicrobials with high urinary tract concentration and local pathogen efficacy.
Nitrofurantoin is recommended for uncomplicated cystitis, while trimethoprim/sulfamethoxazole (TMP/SMX) and first-generation cephalosporins are advised for pyelonephritis.
For intravenous therapy, ceftriaxone is preferred unless there are risk factors for multidrug resistance.
Recommended treatment durations include 5 days for nitrofurantoin, 3 days for TMP/SMX and fluoroquinolones, and a single dose for fosfomycin in acute cystitis cases. For acute pyelonephritis, fluoroquinolones are advised for 5-7 days, with dose-optimized beta-lactams for 7 days. Gram-negative bacteremia from urinary sources warrants a 7-day course.
Stewardship and Clinical Management
The guideline emphasizes antimicrobial stewardship, with support for antibiotic de-escalation and oral regimens where feasible, to reduce adverse effects and hospital stays. Although evidence is limited, the authors suggest thorough allergy assessment and selective reporting of susceptibility results to enhance antibiotic selection.
While data were insufficient to make clear recommendations about the treatment of asymptomatic bacteriuria, Nelson and colleagues suggested that this practice “risks side effects without benefit” while threatening antimicrobial sustainability.
Hammett agreed, noting that “[this] serves as an important reminder not to treat asymptomatic bacteriuria, as it increases side effects and bacterial resistance without any improvement as compared to placebo.”
Special Considerations for Urologic Procedures
Finally, patients undergoing urologic procedures, routine cystoscopy, and urodynamic studies generally do not require prophylactic antibiotics, according to the guideline. Single-dose antibiotic prophylaxis is recommended for low-risk nephrolithotomy patients, though high-risk individuals, such as those who are pregnant or post kidney transplant, may require extended prophylaxis.
Kurz suggested that the guideline consolidates and supports the foundation of evidence driving common practices.
“I don’t think these guidelines offer any strikingly new strategies, which is unsurprising, as they were created after a deep dive into existing literature,” Kurz said. “But more importantly, what I think they do is to highlight where and what the evidence is for many of the clinical strategies that are commonly employed. For example, in terms of prevention, it is common for primary care physicians, urologists, and infectious diseases doctors to recommend cranberry and hydration and to use methenamine. These guidelines highlight that there is sufficient quality and quantity of evidence to support these interventions.”
She also noted how the guidelines emphasize the need for symptoms to make a UTI diagnosis and advise against routine testing of asymptomatic individuals.
“Despite this not being new information, typical clinical practice is often out of step here, and this [guideline] reemphasizes the important factors when considering UTI diagnosis,” Kurz said.
Finally, she expressed frustration for the numerous knowledge gaps remaining in this area, which may be traced back to barriers ranging from the semantic to the more systemic.
“Some of the difficulty is lack of clear definitions and precise terminology regarding UTIs,” Kurz said, noting the unclear distinction between complicated and uncomplicated UTIs. “I would also argue that UTIs are a disease that predominantly affects women, and like many other diseases where this is the case, [they] tend to be less studied. Hopefully, this guideline’s spotlight on all that we do not know can inspire high-quality research to address these gaps, leading to optimal patient care along with decreased burden on the system as a whole in terms of cost and antimicrobial resistance.”
The study was funded by Merck. The WikiGuidelines Group that established this guideline is entirely voluntary and unpaid; the group intends to establish a nonprofit organization to support the development of other guidelines using this novel methodology and eventually intends to trademark the name WikiGuidelines. The authors disclosed relationships with Pfizer, Eumedica, GSK, and others.
A version of this article first appeared on Medscape.com.
FROM JAMA NETWORK OPEN
Is Acute Kidney Injury Really a Single Disease?
The search for a better biomarker than creatine for acute kidney injury (AKI) has been “long and elusive.” However, could researchers be on the right path now?
“The thinking is moving away from trying to find one biomarker that can be used for different types of kidney injury to a recognition that AKI is not just a single disease that a patient has or doesn’t have,” Rob D. Nerenz, PhD, an associate professor in the Department of Pathology and Laboratory Medicine at the Medical College of Wisconsin, Milwaukee, told this news organization. “It’s lots of different diseases that all affect the kidney in different ways.”
AKI is actually a “loose collection” of hepatorenal, cardiorenal, nephrotoxic, and sepsis-associated syndromes, as well as acute interstitial nephritis (AIN), he said. “So the question is not: ‘Is AKI present — yes or no?’ It’s: ‘What kind of AKI is present, and how do I treat it?’ ”
‘Mediocre Markers’
AKI affects about 10%-30% of hospitalized patients, according to Nerenz. It’s associated with an increased risk for adverse outcomes, including post-AKI chronic kidney disease and a mortality rate of approximately 24%.
Currently, AKI is defined by a rapid increase in serum creatinine, a decrease in urine output, or both.
“Those are mediocre markers,” Nerenz said, as serum creatinine is not very sensitive to acute change, and the increase is often detected after the therapeutic window of intervention has passed. In addition, “it only tells us that the kidneys are unhappy; it doesn’t say anything about the cause.”
Urine output is limited as a marker because many conditions affect it. “If you’re dehydrated, urine output is going to decrease,” he said. “And in some forms of AKI, urine output actually goes up.”
What’s needed, he said, is a more sensitive biomarker that’s detectable within a shorter timeframe of 2-6 hours following injury.
“Right now, we’re looking at 48 hours before a change becomes apparent, and that’s just too long. Plus, it should be kidney specific. One of the major limitations of the biomarkers that have been evaluated to this point is that, yes, they’re released by the kidney, but they’re also released by other tissue types within the body, and that hinders their effectiveness as a marker.”
Neutrophil Gelatinase-Associated Lipocalin (NGAL)
Although research on better biomarkers is ongoing, “there’s also a recognition that some of the protein markers that have been around for a while, if used appropriately, can provide value,” Nerenz said. These include, among others, NGAL.
NGAL works well in pediatric patients without other comorbidities, but it has been less useful in adult patients because it is also released by other cell types. However, recent research suggests it shows promise in patients with both cirrhosis and AKI.
There are three main causes of AKI in cirrhosis, Nerenz explained. The first is prerenal and can be primarily addressed through rehydration.
“When these patients come in, clinicians won’t do anything right away other than provide fluids. If creatinine improves over the 48-hour period of fluid replenishment, then the patient is sent home because there really isn’t extensive damage to the kidneys.”
If improvement isn’t seen after those 48 hours, then it could be one of two things: Hepatorenal syndrome or acute tubular necrosis. Patients with hepatorenal syndrome are candidates for terlipressin, which the Food and Drug Administration (FDA) approved for this indication in 2022 after it displayed notable efficacy in a double-blind study.
“You don’t want to give terlipressin to just anybody because if the issue is not a diminished blood supply to the kidney, it’s not going to help, and comes with some serious side effects, such as respiratory failure,” Nerenz explained. “Having a biomarker that can distinguish between hepatorenal syndrome and acute tubular necrosis really helps clinicians confidently identify which patients are good candidates for this drug. Right now, we’re flying blind to a certain extent, basically using clinical intuition.”
Currently, the determination of NGAL is FDA cleared only for pediatric use. One way hospitals have dealt with that is by making the test in their own labs, using appropriate reagents, validation, and so forth. These tests are then safe for use in adults but haven’t gone through the FDA approval process.
However, the FDA’s recent announcement stating that the agency should oversee lab-developed tests has made this situation unclear, Nerenz said.
“At this point, we don’t know if there’s still an opportunity to take the NGAL test (or any other cleared biomarker) and validate it for use in a different patient population. Many hospital labs simply don’t have the resources to take these tests through the whole FDA approval process.”
A New Biomarker for AIN?
Meanwhile, research is also moving forward on a better biomarker for AIN, which is also under the AKI umbrella.
“It’s important to diagnose AIN because it has a very specific treatment,” Dennis G. Moledina, MD, PhD, Yale School of Medicine in New Haven, Connecticut, told this news organization.
“AIN is caused by a bunch of different medications, such as proton pump inhibitors, cancer drugs, nonsteroidal anti-inflammatory drugs, and antibiotics, so when someone has this condition, you have to stop potentially life-saving medications and give unnecessary and potentially toxic immunosuppressive drugs, like prednisone,” he said. “If you get the diagnosis wrong, you’re stopping vital drugs and giving immunosuppression for no reason. And if you miss the diagnosis, AIN can lead to permanent chronic kidney disease.”
“Right now, the only way to diagnose AIN is to do a kidney biopsy, which is risky because it can often lead to significant bleeding,” he said. “Some people can’t undergo a biopsy because they’re on medications that increase the risk of bleeding, and they can’t be stopped.”
Furthermore, he noted, “the longer a patient takes a drug that’s causing AIN without getting a diagnosis, the less the chances of recovery because the longer you let this kidney inflammation go on, the more fibrosis and permanent damage develops. So it is important to diagnose it as early as possible, and that’s again why we have a real need for a noninvasive biomarker that can be tested rapidly.”
Moledina and colleagues have been working on identifying a suitable biomarker for close to 10 years, the latest example of which is their 2023 study validating urinary CXCL9 as just such a marker.
“We’re most excited about CXCL9 because it’s already used to diagnose some other diseases in plasma,” Moledina said. “We think that we can convince labs to test it in urine.”
In an accompanying editorial, Mark Canney, PhD, and colleagues at the University of Ottawa and The Ottawa Hospital in Ontario, Canada, wrote that the CXCL9 study findings “are exciting because they provide a road map of where diagnostics can get to for this common, yet poorly identified and treated, cause of kidney damage. The need for a different approach can be readily identified from the fact that clinicians’ gestalt for diagnosing AIN was almost tantamount to tossing a coin (AUC, 0.57). CXCL9 alone outperformed not only the clinician’s prebiopsy suspicion but also an existing diagnostic model and other candidate biomarkers both in the discovery and external validation cohorts.”
Like NGAL, CXCL9 will have to go through the FDA approval process before it can be used for AIN. Therefore, it may be a few years before it can become routinely available, Moledina said.
Nevertheless, Nerenz added, “I think the next steps for AKI are probably continuing on this path of context-dependent, selective biomarker use. I anticipate that we’ll see ongoing development in this space, just expanding to a wider variety of clinical scenarios.”
Nerenz declared receiving research funding from Abbott Labs for evaluation of an AKI biomarker. Moledina is a co-inventor on a pending patent, “Methods and Systems for Diagnosis of Acute Interstitial Nephritis”; a cofounder of the diagnostics company Predict AIN; and a consultant for Biohaven.
A version of this article first appeared on Medscape.com.
The search for a better biomarker than creatine for acute kidney injury (AKI) has been “long and elusive.” However, could researchers be on the right path now?
“The thinking is moving away from trying to find one biomarker that can be used for different types of kidney injury to a recognition that AKI is not just a single disease that a patient has or doesn’t have,” Rob D. Nerenz, PhD, an associate professor in the Department of Pathology and Laboratory Medicine at the Medical College of Wisconsin, Milwaukee, told this news organization. “It’s lots of different diseases that all affect the kidney in different ways.”
AKI is actually a “loose collection” of hepatorenal, cardiorenal, nephrotoxic, and sepsis-associated syndromes, as well as acute interstitial nephritis (AIN), he said. “So the question is not: ‘Is AKI present — yes or no?’ It’s: ‘What kind of AKI is present, and how do I treat it?’ ”
‘Mediocre Markers’
AKI affects about 10%-30% of hospitalized patients, according to Nerenz. It’s associated with an increased risk for adverse outcomes, including post-AKI chronic kidney disease and a mortality rate of approximately 24%.
Currently, AKI is defined by a rapid increase in serum creatinine, a decrease in urine output, or both.
“Those are mediocre markers,” Nerenz said, as serum creatinine is not very sensitive to acute change, and the increase is often detected after the therapeutic window of intervention has passed. In addition, “it only tells us that the kidneys are unhappy; it doesn’t say anything about the cause.”
Urine output is limited as a marker because many conditions affect it. “If you’re dehydrated, urine output is going to decrease,” he said. “And in some forms of AKI, urine output actually goes up.”
What’s needed, he said, is a more sensitive biomarker that’s detectable within a shorter timeframe of 2-6 hours following injury.
“Right now, we’re looking at 48 hours before a change becomes apparent, and that’s just too long. Plus, it should be kidney specific. One of the major limitations of the biomarkers that have been evaluated to this point is that, yes, they’re released by the kidney, but they’re also released by other tissue types within the body, and that hinders their effectiveness as a marker.”
Neutrophil Gelatinase-Associated Lipocalin (NGAL)
Although research on better biomarkers is ongoing, “there’s also a recognition that some of the protein markers that have been around for a while, if used appropriately, can provide value,” Nerenz said. These include, among others, NGAL.
NGAL works well in pediatric patients without other comorbidities, but it has been less useful in adult patients because it is also released by other cell types. However, recent research suggests it shows promise in patients with both cirrhosis and AKI.
There are three main causes of AKI in cirrhosis, Nerenz explained. The first is prerenal and can be primarily addressed through rehydration.
“When these patients come in, clinicians won’t do anything right away other than provide fluids. If creatinine improves over the 48-hour period of fluid replenishment, then the patient is sent home because there really isn’t extensive damage to the kidneys.”
If improvement isn’t seen after those 48 hours, then it could be one of two things: Hepatorenal syndrome or acute tubular necrosis. Patients with hepatorenal syndrome are candidates for terlipressin, which the Food and Drug Administration (FDA) approved for this indication in 2022 after it displayed notable efficacy in a double-blind study.
“You don’t want to give terlipressin to just anybody because if the issue is not a diminished blood supply to the kidney, it’s not going to help, and comes with some serious side effects, such as respiratory failure,” Nerenz explained. “Having a biomarker that can distinguish between hepatorenal syndrome and acute tubular necrosis really helps clinicians confidently identify which patients are good candidates for this drug. Right now, we’re flying blind to a certain extent, basically using clinical intuition.”
Currently, the determination of NGAL is FDA cleared only for pediatric use. One way hospitals have dealt with that is by making the test in their own labs, using appropriate reagents, validation, and so forth. These tests are then safe for use in adults but haven’t gone through the FDA approval process.
However, the FDA’s recent announcement stating that the agency should oversee lab-developed tests has made this situation unclear, Nerenz said.
“At this point, we don’t know if there’s still an opportunity to take the NGAL test (or any other cleared biomarker) and validate it for use in a different patient population. Many hospital labs simply don’t have the resources to take these tests through the whole FDA approval process.”
A New Biomarker for AIN?
Meanwhile, research is also moving forward on a better biomarker for AIN, which is also under the AKI umbrella.
“It’s important to diagnose AIN because it has a very specific treatment,” Dennis G. Moledina, MD, PhD, Yale School of Medicine in New Haven, Connecticut, told this news organization.
“AIN is caused by a bunch of different medications, such as proton pump inhibitors, cancer drugs, nonsteroidal anti-inflammatory drugs, and antibiotics, so when someone has this condition, you have to stop potentially life-saving medications and give unnecessary and potentially toxic immunosuppressive drugs, like prednisone,” he said. “If you get the diagnosis wrong, you’re stopping vital drugs and giving immunosuppression for no reason. And if you miss the diagnosis, AIN can lead to permanent chronic kidney disease.”
“Right now, the only way to diagnose AIN is to do a kidney biopsy, which is risky because it can often lead to significant bleeding,” he said. “Some people can’t undergo a biopsy because they’re on medications that increase the risk of bleeding, and they can’t be stopped.”
Furthermore, he noted, “the longer a patient takes a drug that’s causing AIN without getting a diagnosis, the less the chances of recovery because the longer you let this kidney inflammation go on, the more fibrosis and permanent damage develops. So it is important to diagnose it as early as possible, and that’s again why we have a real need for a noninvasive biomarker that can be tested rapidly.”
Moledina and colleagues have been working on identifying a suitable biomarker for close to 10 years, the latest example of which is their 2023 study validating urinary CXCL9 as just such a marker.
“We’re most excited about CXCL9 because it’s already used to diagnose some other diseases in plasma,” Moledina said. “We think that we can convince labs to test it in urine.”
In an accompanying editorial, Mark Canney, PhD, and colleagues at the University of Ottawa and The Ottawa Hospital in Ontario, Canada, wrote that the CXCL9 study findings “are exciting because they provide a road map of where diagnostics can get to for this common, yet poorly identified and treated, cause of kidney damage. The need for a different approach can be readily identified from the fact that clinicians’ gestalt for diagnosing AIN was almost tantamount to tossing a coin (AUC, 0.57). CXCL9 alone outperformed not only the clinician’s prebiopsy suspicion but also an existing diagnostic model and other candidate biomarkers both in the discovery and external validation cohorts.”
Like NGAL, CXCL9 will have to go through the FDA approval process before it can be used for AIN. Therefore, it may be a few years before it can become routinely available, Moledina said.
Nevertheless, Nerenz added, “I think the next steps for AKI are probably continuing on this path of context-dependent, selective biomarker use. I anticipate that we’ll see ongoing development in this space, just expanding to a wider variety of clinical scenarios.”
Nerenz declared receiving research funding from Abbott Labs for evaluation of an AKI biomarker. Moledina is a co-inventor on a pending patent, “Methods and Systems for Diagnosis of Acute Interstitial Nephritis”; a cofounder of the diagnostics company Predict AIN; and a consultant for Biohaven.
A version of this article first appeared on Medscape.com.
The search for a better biomarker than creatine for acute kidney injury (AKI) has been “long and elusive.” However, could researchers be on the right path now?
“The thinking is moving away from trying to find one biomarker that can be used for different types of kidney injury to a recognition that AKI is not just a single disease that a patient has or doesn’t have,” Rob D. Nerenz, PhD, an associate professor in the Department of Pathology and Laboratory Medicine at the Medical College of Wisconsin, Milwaukee, told this news organization. “It’s lots of different diseases that all affect the kidney in different ways.”
AKI is actually a “loose collection” of hepatorenal, cardiorenal, nephrotoxic, and sepsis-associated syndromes, as well as acute interstitial nephritis (AIN), he said. “So the question is not: ‘Is AKI present — yes or no?’ It’s: ‘What kind of AKI is present, and how do I treat it?’ ”
‘Mediocre Markers’
AKI affects about 10%-30% of hospitalized patients, according to Nerenz. It’s associated with an increased risk for adverse outcomes, including post-AKI chronic kidney disease and a mortality rate of approximately 24%.
Currently, AKI is defined by a rapid increase in serum creatinine, a decrease in urine output, or both.
“Those are mediocre markers,” Nerenz said, as serum creatinine is not very sensitive to acute change, and the increase is often detected after the therapeutic window of intervention has passed. In addition, “it only tells us that the kidneys are unhappy; it doesn’t say anything about the cause.”
Urine output is limited as a marker because many conditions affect it. “If you’re dehydrated, urine output is going to decrease,” he said. “And in some forms of AKI, urine output actually goes up.”
What’s needed, he said, is a more sensitive biomarker that’s detectable within a shorter timeframe of 2-6 hours following injury.
“Right now, we’re looking at 48 hours before a change becomes apparent, and that’s just too long. Plus, it should be kidney specific. One of the major limitations of the biomarkers that have been evaluated to this point is that, yes, they’re released by the kidney, but they’re also released by other tissue types within the body, and that hinders their effectiveness as a marker.”
Neutrophil Gelatinase-Associated Lipocalin (NGAL)
Although research on better biomarkers is ongoing, “there’s also a recognition that some of the protein markers that have been around for a while, if used appropriately, can provide value,” Nerenz said. These include, among others, NGAL.
NGAL works well in pediatric patients without other comorbidities, but it has been less useful in adult patients because it is also released by other cell types. However, recent research suggests it shows promise in patients with both cirrhosis and AKI.
There are three main causes of AKI in cirrhosis, Nerenz explained. The first is prerenal and can be primarily addressed through rehydration.
“When these patients come in, clinicians won’t do anything right away other than provide fluids. If creatinine improves over the 48-hour period of fluid replenishment, then the patient is sent home because there really isn’t extensive damage to the kidneys.”
If improvement isn’t seen after those 48 hours, then it could be one of two things: Hepatorenal syndrome or acute tubular necrosis. Patients with hepatorenal syndrome are candidates for terlipressin, which the Food and Drug Administration (FDA) approved for this indication in 2022 after it displayed notable efficacy in a double-blind study.
“You don’t want to give terlipressin to just anybody because if the issue is not a diminished blood supply to the kidney, it’s not going to help, and comes with some serious side effects, such as respiratory failure,” Nerenz explained. “Having a biomarker that can distinguish between hepatorenal syndrome and acute tubular necrosis really helps clinicians confidently identify which patients are good candidates for this drug. Right now, we’re flying blind to a certain extent, basically using clinical intuition.”
Currently, the determination of NGAL is FDA cleared only for pediatric use. One way hospitals have dealt with that is by making the test in their own labs, using appropriate reagents, validation, and so forth. These tests are then safe for use in adults but haven’t gone through the FDA approval process.
However, the FDA’s recent announcement stating that the agency should oversee lab-developed tests has made this situation unclear, Nerenz said.
“At this point, we don’t know if there’s still an opportunity to take the NGAL test (or any other cleared biomarker) and validate it for use in a different patient population. Many hospital labs simply don’t have the resources to take these tests through the whole FDA approval process.”
A New Biomarker for AIN?
Meanwhile, research is also moving forward on a better biomarker for AIN, which is also under the AKI umbrella.
“It’s important to diagnose AIN because it has a very specific treatment,” Dennis G. Moledina, MD, PhD, Yale School of Medicine in New Haven, Connecticut, told this news organization.
“AIN is caused by a bunch of different medications, such as proton pump inhibitors, cancer drugs, nonsteroidal anti-inflammatory drugs, and antibiotics, so when someone has this condition, you have to stop potentially life-saving medications and give unnecessary and potentially toxic immunosuppressive drugs, like prednisone,” he said. “If you get the diagnosis wrong, you’re stopping vital drugs and giving immunosuppression for no reason. And if you miss the diagnosis, AIN can lead to permanent chronic kidney disease.”
“Right now, the only way to diagnose AIN is to do a kidney biopsy, which is risky because it can often lead to significant bleeding,” he said. “Some people can’t undergo a biopsy because they’re on medications that increase the risk of bleeding, and they can’t be stopped.”
Furthermore, he noted, “the longer a patient takes a drug that’s causing AIN without getting a diagnosis, the less the chances of recovery because the longer you let this kidney inflammation go on, the more fibrosis and permanent damage develops. So it is important to diagnose it as early as possible, and that’s again why we have a real need for a noninvasive biomarker that can be tested rapidly.”
Moledina and colleagues have been working on identifying a suitable biomarker for close to 10 years, the latest example of which is their 2023 study validating urinary CXCL9 as just such a marker.
“We’re most excited about CXCL9 because it’s already used to diagnose some other diseases in plasma,” Moledina said. “We think that we can convince labs to test it in urine.”
In an accompanying editorial, Mark Canney, PhD, and colleagues at the University of Ottawa and The Ottawa Hospital in Ontario, Canada, wrote that the CXCL9 study findings “are exciting because they provide a road map of where diagnostics can get to for this common, yet poorly identified and treated, cause of kidney damage. The need for a different approach can be readily identified from the fact that clinicians’ gestalt for diagnosing AIN was almost tantamount to tossing a coin (AUC, 0.57). CXCL9 alone outperformed not only the clinician’s prebiopsy suspicion but also an existing diagnostic model and other candidate biomarkers both in the discovery and external validation cohorts.”
Like NGAL, CXCL9 will have to go through the FDA approval process before it can be used for AIN. Therefore, it may be a few years before it can become routinely available, Moledina said.
Nevertheless, Nerenz added, “I think the next steps for AKI are probably continuing on this path of context-dependent, selective biomarker use. I anticipate that we’ll see ongoing development in this space, just expanding to a wider variety of clinical scenarios.”
Nerenz declared receiving research funding from Abbott Labs for evaluation of an AKI biomarker. Moledina is a co-inventor on a pending patent, “Methods and Systems for Diagnosis of Acute Interstitial Nephritis”; a cofounder of the diagnostics company Predict AIN; and a consultant for Biohaven.
A version of this article first appeared on Medscape.com.
Plastic Pollution’s Next Victim: The Human Urinary Tract
Although a 2019 World Health Organization (WHO) report concluded that microplastics in drinking water posed no risk to human health, accumulating evidence is beginning to challenge these findings.
Since plastics became widely used in the mid-20th century, they have evolved from a novel substance to an essential component in countless applications, with global production reaching 368 million tons in 2019 and expected to double by 2039. The production and degradation of plastics involve physical, chemical, and biological processes, leading to the formation of tiny fragments known as microplastics (MPs) and nanoplastics (NPs), which accumulate in the environment. Beyond the well-documented environmental harms of MPs and NPs, growing evidence of their presence within the human body raises concerns about their potential to trigger various harmful biological processes. Their detection in the urinary tract and their potential links to kidney and bladder diseases, as shown in animal studies, are particularly alarming.
Impacts Becoming Apparent
As the impact of plastic pollution becomes increasingly apparent, the need for standardized international definitions of MPs and NPs is pressing. Government publications reveal notable discrepancies between organizations in defining these fragmented plastics. The lack of consensus among regulatory bodies highlights the challenges in mitigating the environmental and health impacts of MPs and NPs. The International Organization for Standardization offers the most precise classification, defining MPs as solid, insoluble plastic particles ranging from 1 µm to 1 mm and NPs as particles smaller than 1 µm.
The intrusion of MPs and NPs into the human body, whether through inhalation, ingestion, or skin exposure (via wounds, hair follicles, or sweat glands), has been linked to harmful biological effects, including inflammation, alterations in cellular metabolism, physical cellular damage, and reduced cell viability.
Urinary Tract Plastics
The detection of MPs and NPs in the human urinary tract, combined with limited understanding of their effects, is a growing concern. An exploratory study published earlier this year aimed to systematically summarize the existing literature regarding the presence of MPs and NPs in the urinary tract and their potential consequences, guided by these research questions:
- What are the characteristics of the plastics detected in the human urinary tract?
- How are MPs and NPs defined in the current literature?
- What methodologies are used to explore the presence and effects of MPs and NPs?
- What are the pathophysiologic consequences of the presence of MPs and NPs in the human urinary tract?
For this study, the “urinary tract” included the kidneys, bladder, ureter, urethra, and urine. By focusing on the urinary tract, the study aimed to consolidate current understanding of MPs and NPs, raise awareness of this emerging issue, and lay the groundwork for further research that could contribute to public health policies and clinical practice guidelines.
The researchers conducted a scoping literature review following the recommendations of the JBI [formerly known as the Joanna Briggs Institute). They systematically searched five databases — PubMed, Scopus, CINAHL, Web of Science, and Embase — as well as gray literature sources.
Concerning Study Results
Eighteen articles were identified. The authors represent seven countries: Pakistan (n = 1), the Netherlands (n = 1), the US (n = 1), Taiwan (n = 1), Germany (n = 3), China (n = 5), and Italy (n = 6). Among these studies, six investigated and characterized the presence of MPs and NPs in the human urinary tract. MPs and NPs were detected in urine samples (n = 5), kidney cancer samples (n = 2), and bladder cancer samples (n = 1).
Additionally, 12 studies examined the effects of MPs and NPs on human urinary tract cell lines. Their findings suggest that MPs and NPs have cytotoxic effects, increase inflammation, reduce cell viability, and alter mitogen-activated protein kinase signaling pathways.
Raman spectroscopy was the primary method used to detect and characterize MPs and NPs in human samples (five out of six studies; 83%). Alternatively, pyrolysis-gas chromatography-mass spectrometry combined with direct laser infrared spectroscopy was used in one study.
Further Research Needed
This exploratory study underscores the urgent need for further research and policy development to address the challenges posed by microplastic contamination. It highlights the rapidly emerging threat of human urinary tract contamination by microplastics, questioning the WHO’s claim that microplastics pose no public health risk. The documented cytotoxic effects of microplastics, and their ability to induce inflammation, reduce cell viability, and disrupt signaling pathways, raise significant public health concerns related to bladder cancer, chronic kidney disease, chronic urinary infections, and incontinence.
Bernard-Alex Gauzere, retired physician formerly with the national health system in France (intensive care unit, tropical medicine), has disclosed no relevant financial relationships.
This story was translated from JIM using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
Although a 2019 World Health Organization (WHO) report concluded that microplastics in drinking water posed no risk to human health, accumulating evidence is beginning to challenge these findings.
Since plastics became widely used in the mid-20th century, they have evolved from a novel substance to an essential component in countless applications, with global production reaching 368 million tons in 2019 and expected to double by 2039. The production and degradation of plastics involve physical, chemical, and biological processes, leading to the formation of tiny fragments known as microplastics (MPs) and nanoplastics (NPs), which accumulate in the environment. Beyond the well-documented environmental harms of MPs and NPs, growing evidence of their presence within the human body raises concerns about their potential to trigger various harmful biological processes. Their detection in the urinary tract and their potential links to kidney and bladder diseases, as shown in animal studies, are particularly alarming.
Impacts Becoming Apparent
As the impact of plastic pollution becomes increasingly apparent, the need for standardized international definitions of MPs and NPs is pressing. Government publications reveal notable discrepancies between organizations in defining these fragmented plastics. The lack of consensus among regulatory bodies highlights the challenges in mitigating the environmental and health impacts of MPs and NPs. The International Organization for Standardization offers the most precise classification, defining MPs as solid, insoluble plastic particles ranging from 1 µm to 1 mm and NPs as particles smaller than 1 µm.
The intrusion of MPs and NPs into the human body, whether through inhalation, ingestion, or skin exposure (via wounds, hair follicles, or sweat glands), has been linked to harmful biological effects, including inflammation, alterations in cellular metabolism, physical cellular damage, and reduced cell viability.
Urinary Tract Plastics
The detection of MPs and NPs in the human urinary tract, combined with limited understanding of their effects, is a growing concern. An exploratory study published earlier this year aimed to systematically summarize the existing literature regarding the presence of MPs and NPs in the urinary tract and their potential consequences, guided by these research questions:
- What are the characteristics of the plastics detected in the human urinary tract?
- How are MPs and NPs defined in the current literature?
- What methodologies are used to explore the presence and effects of MPs and NPs?
- What are the pathophysiologic consequences of the presence of MPs and NPs in the human urinary tract?
For this study, the “urinary tract” included the kidneys, bladder, ureter, urethra, and urine. By focusing on the urinary tract, the study aimed to consolidate current understanding of MPs and NPs, raise awareness of this emerging issue, and lay the groundwork for further research that could contribute to public health policies and clinical practice guidelines.
The researchers conducted a scoping literature review following the recommendations of the JBI [formerly known as the Joanna Briggs Institute). They systematically searched five databases — PubMed, Scopus, CINAHL, Web of Science, and Embase — as well as gray literature sources.
Concerning Study Results
Eighteen articles were identified. The authors represent seven countries: Pakistan (n = 1), the Netherlands (n = 1), the US (n = 1), Taiwan (n = 1), Germany (n = 3), China (n = 5), and Italy (n = 6). Among these studies, six investigated and characterized the presence of MPs and NPs in the human urinary tract. MPs and NPs were detected in urine samples (n = 5), kidney cancer samples (n = 2), and bladder cancer samples (n = 1).
Additionally, 12 studies examined the effects of MPs and NPs on human urinary tract cell lines. Their findings suggest that MPs and NPs have cytotoxic effects, increase inflammation, reduce cell viability, and alter mitogen-activated protein kinase signaling pathways.
Raman spectroscopy was the primary method used to detect and characterize MPs and NPs in human samples (five out of six studies; 83%). Alternatively, pyrolysis-gas chromatography-mass spectrometry combined with direct laser infrared spectroscopy was used in one study.
Further Research Needed
This exploratory study underscores the urgent need for further research and policy development to address the challenges posed by microplastic contamination. It highlights the rapidly emerging threat of human urinary tract contamination by microplastics, questioning the WHO’s claim that microplastics pose no public health risk. The documented cytotoxic effects of microplastics, and their ability to induce inflammation, reduce cell viability, and disrupt signaling pathways, raise significant public health concerns related to bladder cancer, chronic kidney disease, chronic urinary infections, and incontinence.
Bernard-Alex Gauzere, retired physician formerly with the national health system in France (intensive care unit, tropical medicine), has disclosed no relevant financial relationships.
This story was translated from JIM using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
Although a 2019 World Health Organization (WHO) report concluded that microplastics in drinking water posed no risk to human health, accumulating evidence is beginning to challenge these findings.
Since plastics became widely used in the mid-20th century, they have evolved from a novel substance to an essential component in countless applications, with global production reaching 368 million tons in 2019 and expected to double by 2039. The production and degradation of plastics involve physical, chemical, and biological processes, leading to the formation of tiny fragments known as microplastics (MPs) and nanoplastics (NPs), which accumulate in the environment. Beyond the well-documented environmental harms of MPs and NPs, growing evidence of their presence within the human body raises concerns about their potential to trigger various harmful biological processes. Their detection in the urinary tract and their potential links to kidney and bladder diseases, as shown in animal studies, are particularly alarming.
Impacts Becoming Apparent
As the impact of plastic pollution becomes increasingly apparent, the need for standardized international definitions of MPs and NPs is pressing. Government publications reveal notable discrepancies between organizations in defining these fragmented plastics. The lack of consensus among regulatory bodies highlights the challenges in mitigating the environmental and health impacts of MPs and NPs. The International Organization for Standardization offers the most precise classification, defining MPs as solid, insoluble plastic particles ranging from 1 µm to 1 mm and NPs as particles smaller than 1 µm.
The intrusion of MPs and NPs into the human body, whether through inhalation, ingestion, or skin exposure (via wounds, hair follicles, or sweat glands), has been linked to harmful biological effects, including inflammation, alterations in cellular metabolism, physical cellular damage, and reduced cell viability.
Urinary Tract Plastics
The detection of MPs and NPs in the human urinary tract, combined with limited understanding of their effects, is a growing concern. An exploratory study published earlier this year aimed to systematically summarize the existing literature regarding the presence of MPs and NPs in the urinary tract and their potential consequences, guided by these research questions:
- What are the characteristics of the plastics detected in the human urinary tract?
- How are MPs and NPs defined in the current literature?
- What methodologies are used to explore the presence and effects of MPs and NPs?
- What are the pathophysiologic consequences of the presence of MPs and NPs in the human urinary tract?
For this study, the “urinary tract” included the kidneys, bladder, ureter, urethra, and urine. By focusing on the urinary tract, the study aimed to consolidate current understanding of MPs and NPs, raise awareness of this emerging issue, and lay the groundwork for further research that could contribute to public health policies and clinical practice guidelines.
The researchers conducted a scoping literature review following the recommendations of the JBI [formerly known as the Joanna Briggs Institute). They systematically searched five databases — PubMed, Scopus, CINAHL, Web of Science, and Embase — as well as gray literature sources.
Concerning Study Results
Eighteen articles were identified. The authors represent seven countries: Pakistan (n = 1), the Netherlands (n = 1), the US (n = 1), Taiwan (n = 1), Germany (n = 3), China (n = 5), and Italy (n = 6). Among these studies, six investigated and characterized the presence of MPs and NPs in the human urinary tract. MPs and NPs were detected in urine samples (n = 5), kidney cancer samples (n = 2), and bladder cancer samples (n = 1).
Additionally, 12 studies examined the effects of MPs and NPs on human urinary tract cell lines. Their findings suggest that MPs and NPs have cytotoxic effects, increase inflammation, reduce cell viability, and alter mitogen-activated protein kinase signaling pathways.
Raman spectroscopy was the primary method used to detect and characterize MPs and NPs in human samples (five out of six studies; 83%). Alternatively, pyrolysis-gas chromatography-mass spectrometry combined with direct laser infrared spectroscopy was used in one study.
Further Research Needed
This exploratory study underscores the urgent need for further research and policy development to address the challenges posed by microplastic contamination. It highlights the rapidly emerging threat of human urinary tract contamination by microplastics, questioning the WHO’s claim that microplastics pose no public health risk. The documented cytotoxic effects of microplastics, and their ability to induce inflammation, reduce cell viability, and disrupt signaling pathways, raise significant public health concerns related to bladder cancer, chronic kidney disease, chronic urinary infections, and incontinence.
Bernard-Alex Gauzere, retired physician formerly with the national health system in France (intensive care unit, tropical medicine), has disclosed no relevant financial relationships.
This story was translated from JIM using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
Evaluating Use of Empagliflozin for Diabetes Management in Veterans With Chronic Kidney Disease
More than 37 million Americans have diabetes mellitus (DM), and approximately 90% have type 2 DM (T2DM), including about 25% of veterans.1,2 The current guidelines suggest that therapy depends on a patient's comorbidities, management needs, and patient-centered treatment factors.3 About 1 in 3 adults with DM have chronic kidney disease (CKD), defined as the presence of kidney damage or an estimated glomerular filtration rate (eGFR) < 60 mL/min per 1.73 m2, persisting for ≥ 3 months.4
Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are a class of antihyperglycemic agents acting on the SGLT-2 proteins expressed in the renal proximal convoluted tubules. They exert their effects by preventing the reabsorption of filtered glucose from the tubular lumen. There are 4 SGLT-2 inhibitors approved by the US Food and Drug Administration: canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin. Empagliflozin is currently the preferred SGLT-2 inhibitor on the US Department of Veterans Affairs (VA) formulary.
According to the American Diabetes Association guidelines, empagliflozin is considered when an individual has or is at risk for atherosclerotic cardiovascular disease, heart failure, and CKD.3 SGLT-2 inhibitors are a favorable option due to their low risk for hypoglycemia while also promoting weight loss. The EMPEROR-Reduced trial demonstrated that, in addition to benefits for patients with heart failure, empagliflozin also slowed the progressive decline in kidney function in those with and without DM.5 The purpose of this study was to evaluate the effectiveness of empagliflozin on hemoglobin A1c (HbA1c) levels in patients with CKD at the Hershel “Woody” Williams VA Medical Center (HWWVAMC) in Huntington, West Virginia, along with other laboratory test markers.
Methods
The Marshall University Institutional Review Board #1 (Medical) and the HWWVAMC institutional review board and research and development committee each reviewed and approved this study. A retrospective chart review was conducted on patients diagnosed with T2DM and stage 3 CKD who were prescribed empagliflozin for DM management between January 1, 2015, and October 1, 2022, yielding 1771 patients. Data were obtained through the VHA Corporate Data Warehouse (CDW) and stored on the VA Informatics and Computing Infrastructure (VINCI) research server.
Patients were included if they were aged 18 to 89 years, prescribed empagliflozin by a VA clinician for the treatment of T2DM, had an eGFR between 30 and 59 mL/min/1.73 m2, and had an initial HbA1c between 7% and 10%. Using further random sampling, patients were either excluded or divided into, those with stage 3a CKD and those with stage 3b CKD. The primary endpoint of this study was the change in HbA1c levels in patients with stage 3b CKD (eGFR 30-44 mL/min/1.73 m2) compared with stage 3a (eGFR 45-59 mL/min/1.73 m2) after 12 months. The secondary endpoints included effects on renal function, weight, blood pressure, incidence of adverse drug events, and cardiovascular events. Of the excluded, 38 had HbA1c < 7%, 30 had HbA1c ≥ 10%, 21 did not have data at 1-year mark, 15 had the medication discontinued due to decline in renal function, 14 discontinued their medication without documented reason, 10 discontinued their medication due to adverse drug reactions (ADRs), 12 had eGFR > 60 mL/ min/1.73 m2, 9 died within 1 year of initiation, 4 had eGFR < 30 mL/min/1.73 m2, 1 had no baseline eGFR, and 1 was the spouse of a veteran.
Statistical Analysis
All statistical analyses were performed using STATA v.15. We used t tests to examine changes within each group, along with paired t tests to compare the 2 groups. Two-sample t tests were used to analyze the continuous data at both the primary and secondary endpoints.
Results
Of the 1771 patients included in the initial data set, a randomized sample of 255 charts were reviewed, 155 were excluded, and 100 were included. Fifty patients, had stage 3a CKD and 50 had stage 3b CKD. Baseline demographics were similar between the stage 3a and 3b groups (Table 1). Both groups were predominantly White and male, with mean age > 70 years.
The primary endpoint was the differences in HbA1c levels over time and between groups for patients with stage 3a and stage 3b CKD 1 year after initiation of empagliflozin. The starting doses of empagliflozin were either 12.5 mg or 25.0 mg. For both groups, the changes in HbA1c levels were statistically significant (Table 2). HbA1c levels dropped 0.65% for the stage 3a group and 0.48% for the 3b group. When compared to one another, the results were not statistically significant (P = .51).
Secondary Endpoint
There was no statistically significant difference in serum creatinine levels within each group between baselines and 1 year later for the stage 3a (P = .21) and stage 3b (P = .22) groups, or when compared to each other (P = .67). There were statistically significant changes in weight for patients in the stage 3a group (P < .05), but not for stage 3b group (P = .06) or when compared to each other (P = .41). A statistically significant change in systolic blood pressure was observed for the stage 3a group (P = .003), but not the stage 3b group (P = .16) or when compared to each other (P = .27). There were statistically significant changes in diastolic blood pressure within the stage 3a group (P = .04), but not within the stage 3b group (P = .61) or when compared to each other (P = .31).
Ten patients discontinued empagliflozin before the 1-year mark due to ADRs, including dizziness, increased incidence of urinary tract infections, rash, and tachycardia (Table 3). Additionally, 3 ADRs resulted in the empagliflozin discontinuation after 1 year (Table 3).
Discussion
This study showed a statistically significant change in HbA1c levels for patients with stage 3a and stage 3b CKD. With eGFR levels in these 2 groups > 30 mL/min/1.73 m2, patients were able to achieve glycemic benefits. There were no significant changes to the serum creatinine levels. Both groups saw statistically significant changes in weight loss within their own group; however, there were no statistically significant changes when compared to each other. With both systolic and diastolic blood pressure, the stage 3a group had statistically significant changes.
The EMPA-REG BP study demonstrated that empagliflozin was associated with significant and clinically meaningful reductions in blood pressure and HbA1c levels compared with placebo and was well tolerated in patients with T2DM and hypertension.6,7,8
Limitations
This study had a retrospective study design, which resulted in missing information for many patients and higher rates of exclusion. The population was predominantly older, White, and male and may not reflect other populations. The starting doses of empagliflozin varied between the groups. The VA employs tablet splitting for some patients, and the available doses were either 10.0 mg, 12.5 mg, or 25.0 mg. Some prescribers start veterans at lower doses and gradually increase to the higher dose of 25.0 mg, adding to the variability in starting doses.
Patients with eGFR < 30 mL/min/1.73 m2 make it difficult to determine any potential benefit in this population. The EMPA-KIDNEY trial demonstrated that the benefits of empagliflozin treatment were consistent among patients with or without DM and regardless of eGFR at randomization.9 Furthermore, many veterans had an initial HbA1c levels outside the inclusion criteria range, which was a factor in the smaller sample size.
Conclusions
While the reduction in HbA1c levels was less in patients with stage 3b CKD compared to patients stage 3a CKD, all patients experienced a benefit. The overall incidence of ADRs was low in the study population, showing empagliflozin as a favorable choice for those with T2DM and CKD. Based on the findings of this study, empagliflozin is a potentially beneficial option for reducing HbA1c levels in patients with CKD.
- Centers for Disease Control and Prevention. Type 2 diabetes. Updated May 25, 2024. Accessed September 27, 2024. https://www.cdc.gov/diabetes/about/about-type-2-diabetes.html?CDC_AAref_Val
- US Department of Veterans Affairs, VA research on diabetes. Updated September 2019. Accessed September 27, 2024. https://www.research.va.gov/pubs/docs/va_factsheets/Diabetes.pdf
- American Diabetes Association. Standards of Medical Care in Diabetes-2022 Abridged for Primary Care Providers. Clin Diabetes. 2022;40(1):10-38. doi:10.2337/cd22-as01
- Centers for Disease Control and Prevention. Diabetes, chronic kidney disease. Updated May 15, 2024. Accessed September 27, 2024. https://www.cdc.gov/diabetes/diabetes-complications/diabetes-and-chronic-kidney-disease.html
- Packer M, Anker SD, Butler J, et al. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N Engl J Med. 2020;383(15):1413-1424. doi:10.1056/NEJMoa2022190
- Tikkanen I, Narko K, Zeller C, et al. Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension. Diabetes Care. 2015;38(3):420-428. doi:10.2337/dc14-1096
- Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128. doi:10.1056/NEJMoa1504720
- Chilton R, Tikkanen I, Cannon CP, et al. Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes. Diabetes Obes Metab. 2015;17(12):1180-1193. doi:10.1111/dom.12572
- The EMPA-KIDNEY Collaborative Group, Herrington WG, Staplin N, et al. Empagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2023;388(2):117-127. doi:10.1056/NEJMoa2204233
More than 37 million Americans have diabetes mellitus (DM), and approximately 90% have type 2 DM (T2DM), including about 25% of veterans.1,2 The current guidelines suggest that therapy depends on a patient's comorbidities, management needs, and patient-centered treatment factors.3 About 1 in 3 adults with DM have chronic kidney disease (CKD), defined as the presence of kidney damage or an estimated glomerular filtration rate (eGFR) < 60 mL/min per 1.73 m2, persisting for ≥ 3 months.4
Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are a class of antihyperglycemic agents acting on the SGLT-2 proteins expressed in the renal proximal convoluted tubules. They exert their effects by preventing the reabsorption of filtered glucose from the tubular lumen. There are 4 SGLT-2 inhibitors approved by the US Food and Drug Administration: canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin. Empagliflozin is currently the preferred SGLT-2 inhibitor on the US Department of Veterans Affairs (VA) formulary.
According to the American Diabetes Association guidelines, empagliflozin is considered when an individual has or is at risk for atherosclerotic cardiovascular disease, heart failure, and CKD.3 SGLT-2 inhibitors are a favorable option due to their low risk for hypoglycemia while also promoting weight loss. The EMPEROR-Reduced trial demonstrated that, in addition to benefits for patients with heart failure, empagliflozin also slowed the progressive decline in kidney function in those with and without DM.5 The purpose of this study was to evaluate the effectiveness of empagliflozin on hemoglobin A1c (HbA1c) levels in patients with CKD at the Hershel “Woody” Williams VA Medical Center (HWWVAMC) in Huntington, West Virginia, along with other laboratory test markers.
Methods
The Marshall University Institutional Review Board #1 (Medical) and the HWWVAMC institutional review board and research and development committee each reviewed and approved this study. A retrospective chart review was conducted on patients diagnosed with T2DM and stage 3 CKD who were prescribed empagliflozin for DM management between January 1, 2015, and October 1, 2022, yielding 1771 patients. Data were obtained through the VHA Corporate Data Warehouse (CDW) and stored on the VA Informatics and Computing Infrastructure (VINCI) research server.
Patients were included if they were aged 18 to 89 years, prescribed empagliflozin by a VA clinician for the treatment of T2DM, had an eGFR between 30 and 59 mL/min/1.73 m2, and had an initial HbA1c between 7% and 10%. Using further random sampling, patients were either excluded or divided into, those with stage 3a CKD and those with stage 3b CKD. The primary endpoint of this study was the change in HbA1c levels in patients with stage 3b CKD (eGFR 30-44 mL/min/1.73 m2) compared with stage 3a (eGFR 45-59 mL/min/1.73 m2) after 12 months. The secondary endpoints included effects on renal function, weight, blood pressure, incidence of adverse drug events, and cardiovascular events. Of the excluded, 38 had HbA1c < 7%, 30 had HbA1c ≥ 10%, 21 did not have data at 1-year mark, 15 had the medication discontinued due to decline in renal function, 14 discontinued their medication without documented reason, 10 discontinued their medication due to adverse drug reactions (ADRs), 12 had eGFR > 60 mL/ min/1.73 m2, 9 died within 1 year of initiation, 4 had eGFR < 30 mL/min/1.73 m2, 1 had no baseline eGFR, and 1 was the spouse of a veteran.
Statistical Analysis
All statistical analyses were performed using STATA v.15. We used t tests to examine changes within each group, along with paired t tests to compare the 2 groups. Two-sample t tests were used to analyze the continuous data at both the primary and secondary endpoints.
Results
Of the 1771 patients included in the initial data set, a randomized sample of 255 charts were reviewed, 155 were excluded, and 100 were included. Fifty patients, had stage 3a CKD and 50 had stage 3b CKD. Baseline demographics were similar between the stage 3a and 3b groups (Table 1). Both groups were predominantly White and male, with mean age > 70 years.
The primary endpoint was the differences in HbA1c levels over time and between groups for patients with stage 3a and stage 3b CKD 1 year after initiation of empagliflozin. The starting doses of empagliflozin were either 12.5 mg or 25.0 mg. For both groups, the changes in HbA1c levels were statistically significant (Table 2). HbA1c levels dropped 0.65% for the stage 3a group and 0.48% for the 3b group. When compared to one another, the results were not statistically significant (P = .51).
Secondary Endpoint
There was no statistically significant difference in serum creatinine levels within each group between baselines and 1 year later for the stage 3a (P = .21) and stage 3b (P = .22) groups, or when compared to each other (P = .67). There were statistically significant changes in weight for patients in the stage 3a group (P < .05), but not for stage 3b group (P = .06) or when compared to each other (P = .41). A statistically significant change in systolic blood pressure was observed for the stage 3a group (P = .003), but not the stage 3b group (P = .16) or when compared to each other (P = .27). There were statistically significant changes in diastolic blood pressure within the stage 3a group (P = .04), but not within the stage 3b group (P = .61) or when compared to each other (P = .31).
Ten patients discontinued empagliflozin before the 1-year mark due to ADRs, including dizziness, increased incidence of urinary tract infections, rash, and tachycardia (Table 3). Additionally, 3 ADRs resulted in the empagliflozin discontinuation after 1 year (Table 3).
Discussion
This study showed a statistically significant change in HbA1c levels for patients with stage 3a and stage 3b CKD. With eGFR levels in these 2 groups > 30 mL/min/1.73 m2, patients were able to achieve glycemic benefits. There were no significant changes to the serum creatinine levels. Both groups saw statistically significant changes in weight loss within their own group; however, there were no statistically significant changes when compared to each other. With both systolic and diastolic blood pressure, the stage 3a group had statistically significant changes.
The EMPA-REG BP study demonstrated that empagliflozin was associated with significant and clinically meaningful reductions in blood pressure and HbA1c levels compared with placebo and was well tolerated in patients with T2DM and hypertension.6,7,8
Limitations
This study had a retrospective study design, which resulted in missing information for many patients and higher rates of exclusion. The population was predominantly older, White, and male and may not reflect other populations. The starting doses of empagliflozin varied between the groups. The VA employs tablet splitting for some patients, and the available doses were either 10.0 mg, 12.5 mg, or 25.0 mg. Some prescribers start veterans at lower doses and gradually increase to the higher dose of 25.0 mg, adding to the variability in starting doses.
Patients with eGFR < 30 mL/min/1.73 m2 make it difficult to determine any potential benefit in this population. The EMPA-KIDNEY trial demonstrated that the benefits of empagliflozin treatment were consistent among patients with or without DM and regardless of eGFR at randomization.9 Furthermore, many veterans had an initial HbA1c levels outside the inclusion criteria range, which was a factor in the smaller sample size.
Conclusions
While the reduction in HbA1c levels was less in patients with stage 3b CKD compared to patients stage 3a CKD, all patients experienced a benefit. The overall incidence of ADRs was low in the study population, showing empagliflozin as a favorable choice for those with T2DM and CKD. Based on the findings of this study, empagliflozin is a potentially beneficial option for reducing HbA1c levels in patients with CKD.
More than 37 million Americans have diabetes mellitus (DM), and approximately 90% have type 2 DM (T2DM), including about 25% of veterans.1,2 The current guidelines suggest that therapy depends on a patient's comorbidities, management needs, and patient-centered treatment factors.3 About 1 in 3 adults with DM have chronic kidney disease (CKD), defined as the presence of kidney damage or an estimated glomerular filtration rate (eGFR) < 60 mL/min per 1.73 m2, persisting for ≥ 3 months.4
Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are a class of antihyperglycemic agents acting on the SGLT-2 proteins expressed in the renal proximal convoluted tubules. They exert their effects by preventing the reabsorption of filtered glucose from the tubular lumen. There are 4 SGLT-2 inhibitors approved by the US Food and Drug Administration: canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin. Empagliflozin is currently the preferred SGLT-2 inhibitor on the US Department of Veterans Affairs (VA) formulary.
According to the American Diabetes Association guidelines, empagliflozin is considered when an individual has or is at risk for atherosclerotic cardiovascular disease, heart failure, and CKD.3 SGLT-2 inhibitors are a favorable option due to their low risk for hypoglycemia while also promoting weight loss. The EMPEROR-Reduced trial demonstrated that, in addition to benefits for patients with heart failure, empagliflozin also slowed the progressive decline in kidney function in those with and without DM.5 The purpose of this study was to evaluate the effectiveness of empagliflozin on hemoglobin A1c (HbA1c) levels in patients with CKD at the Hershel “Woody” Williams VA Medical Center (HWWVAMC) in Huntington, West Virginia, along with other laboratory test markers.
Methods
The Marshall University Institutional Review Board #1 (Medical) and the HWWVAMC institutional review board and research and development committee each reviewed and approved this study. A retrospective chart review was conducted on patients diagnosed with T2DM and stage 3 CKD who were prescribed empagliflozin for DM management between January 1, 2015, and October 1, 2022, yielding 1771 patients. Data were obtained through the VHA Corporate Data Warehouse (CDW) and stored on the VA Informatics and Computing Infrastructure (VINCI) research server.
Patients were included if they were aged 18 to 89 years, prescribed empagliflozin by a VA clinician for the treatment of T2DM, had an eGFR between 30 and 59 mL/min/1.73 m2, and had an initial HbA1c between 7% and 10%. Using further random sampling, patients were either excluded or divided into, those with stage 3a CKD and those with stage 3b CKD. The primary endpoint of this study was the change in HbA1c levels in patients with stage 3b CKD (eGFR 30-44 mL/min/1.73 m2) compared with stage 3a (eGFR 45-59 mL/min/1.73 m2) after 12 months. The secondary endpoints included effects on renal function, weight, blood pressure, incidence of adverse drug events, and cardiovascular events. Of the excluded, 38 had HbA1c < 7%, 30 had HbA1c ≥ 10%, 21 did not have data at 1-year mark, 15 had the medication discontinued due to decline in renal function, 14 discontinued their medication without documented reason, 10 discontinued their medication due to adverse drug reactions (ADRs), 12 had eGFR > 60 mL/ min/1.73 m2, 9 died within 1 year of initiation, 4 had eGFR < 30 mL/min/1.73 m2, 1 had no baseline eGFR, and 1 was the spouse of a veteran.
Statistical Analysis
All statistical analyses were performed using STATA v.15. We used t tests to examine changes within each group, along with paired t tests to compare the 2 groups. Two-sample t tests were used to analyze the continuous data at both the primary and secondary endpoints.
Results
Of the 1771 patients included in the initial data set, a randomized sample of 255 charts were reviewed, 155 were excluded, and 100 were included. Fifty patients, had stage 3a CKD and 50 had stage 3b CKD. Baseline demographics were similar between the stage 3a and 3b groups (Table 1). Both groups were predominantly White and male, with mean age > 70 years.
The primary endpoint was the differences in HbA1c levels over time and between groups for patients with stage 3a and stage 3b CKD 1 year after initiation of empagliflozin. The starting doses of empagliflozin were either 12.5 mg or 25.0 mg. For both groups, the changes in HbA1c levels were statistically significant (Table 2). HbA1c levels dropped 0.65% for the stage 3a group and 0.48% for the 3b group. When compared to one another, the results were not statistically significant (P = .51).
Secondary Endpoint
There was no statistically significant difference in serum creatinine levels within each group between baselines and 1 year later for the stage 3a (P = .21) and stage 3b (P = .22) groups, or when compared to each other (P = .67). There were statistically significant changes in weight for patients in the stage 3a group (P < .05), but not for stage 3b group (P = .06) or when compared to each other (P = .41). A statistically significant change in systolic blood pressure was observed for the stage 3a group (P = .003), but not the stage 3b group (P = .16) or when compared to each other (P = .27). There were statistically significant changes in diastolic blood pressure within the stage 3a group (P = .04), but not within the stage 3b group (P = .61) or when compared to each other (P = .31).
Ten patients discontinued empagliflozin before the 1-year mark due to ADRs, including dizziness, increased incidence of urinary tract infections, rash, and tachycardia (Table 3). Additionally, 3 ADRs resulted in the empagliflozin discontinuation after 1 year (Table 3).
Discussion
This study showed a statistically significant change in HbA1c levels for patients with stage 3a and stage 3b CKD. With eGFR levels in these 2 groups > 30 mL/min/1.73 m2, patients were able to achieve glycemic benefits. There were no significant changes to the serum creatinine levels. Both groups saw statistically significant changes in weight loss within their own group; however, there were no statistically significant changes when compared to each other. With both systolic and diastolic blood pressure, the stage 3a group had statistically significant changes.
The EMPA-REG BP study demonstrated that empagliflozin was associated with significant and clinically meaningful reductions in blood pressure and HbA1c levels compared with placebo and was well tolerated in patients with T2DM and hypertension.6,7,8
Limitations
This study had a retrospective study design, which resulted in missing information for many patients and higher rates of exclusion. The population was predominantly older, White, and male and may not reflect other populations. The starting doses of empagliflozin varied between the groups. The VA employs tablet splitting for some patients, and the available doses were either 10.0 mg, 12.5 mg, or 25.0 mg. Some prescribers start veterans at lower doses and gradually increase to the higher dose of 25.0 mg, adding to the variability in starting doses.
Patients with eGFR < 30 mL/min/1.73 m2 make it difficult to determine any potential benefit in this population. The EMPA-KIDNEY trial demonstrated that the benefits of empagliflozin treatment were consistent among patients with or without DM and regardless of eGFR at randomization.9 Furthermore, many veterans had an initial HbA1c levels outside the inclusion criteria range, which was a factor in the smaller sample size.
Conclusions
While the reduction in HbA1c levels was less in patients with stage 3b CKD compared to patients stage 3a CKD, all patients experienced a benefit. The overall incidence of ADRs was low in the study population, showing empagliflozin as a favorable choice for those with T2DM and CKD. Based on the findings of this study, empagliflozin is a potentially beneficial option for reducing HbA1c levels in patients with CKD.
- Centers for Disease Control and Prevention. Type 2 diabetes. Updated May 25, 2024. Accessed September 27, 2024. https://www.cdc.gov/diabetes/about/about-type-2-diabetes.html?CDC_AAref_Val
- US Department of Veterans Affairs, VA research on diabetes. Updated September 2019. Accessed September 27, 2024. https://www.research.va.gov/pubs/docs/va_factsheets/Diabetes.pdf
- American Diabetes Association. Standards of Medical Care in Diabetes-2022 Abridged for Primary Care Providers. Clin Diabetes. 2022;40(1):10-38. doi:10.2337/cd22-as01
- Centers for Disease Control and Prevention. Diabetes, chronic kidney disease. Updated May 15, 2024. Accessed September 27, 2024. https://www.cdc.gov/diabetes/diabetes-complications/diabetes-and-chronic-kidney-disease.html
- Packer M, Anker SD, Butler J, et al. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N Engl J Med. 2020;383(15):1413-1424. doi:10.1056/NEJMoa2022190
- Tikkanen I, Narko K, Zeller C, et al. Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension. Diabetes Care. 2015;38(3):420-428. doi:10.2337/dc14-1096
- Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128. doi:10.1056/NEJMoa1504720
- Chilton R, Tikkanen I, Cannon CP, et al. Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes. Diabetes Obes Metab. 2015;17(12):1180-1193. doi:10.1111/dom.12572
- The EMPA-KIDNEY Collaborative Group, Herrington WG, Staplin N, et al. Empagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2023;388(2):117-127. doi:10.1056/NEJMoa2204233
- Centers for Disease Control and Prevention. Type 2 diabetes. Updated May 25, 2024. Accessed September 27, 2024. https://www.cdc.gov/diabetes/about/about-type-2-diabetes.html?CDC_AAref_Val
- US Department of Veterans Affairs, VA research on diabetes. Updated September 2019. Accessed September 27, 2024. https://www.research.va.gov/pubs/docs/va_factsheets/Diabetes.pdf
- American Diabetes Association. Standards of Medical Care in Diabetes-2022 Abridged for Primary Care Providers. Clin Diabetes. 2022;40(1):10-38. doi:10.2337/cd22-as01
- Centers for Disease Control and Prevention. Diabetes, chronic kidney disease. Updated May 15, 2024. Accessed September 27, 2024. https://www.cdc.gov/diabetes/diabetes-complications/diabetes-and-chronic-kidney-disease.html
- Packer M, Anker SD, Butler J, et al. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N Engl J Med. 2020;383(15):1413-1424. doi:10.1056/NEJMoa2022190
- Tikkanen I, Narko K, Zeller C, et al. Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension. Diabetes Care. 2015;38(3):420-428. doi:10.2337/dc14-1096
- Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128. doi:10.1056/NEJMoa1504720
- Chilton R, Tikkanen I, Cannon CP, et al. Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes. Diabetes Obes Metab. 2015;17(12):1180-1193. doi:10.1111/dom.12572
- The EMPA-KIDNEY Collaborative Group, Herrington WG, Staplin N, et al. Empagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2023;388(2):117-127. doi:10.1056/NEJMoa2204233