Addressing Disparities in Health Care

Some diseases are either more serious or more frequent in US Hispanics, and systemic lupus erythematosus is one of them. This fact has not yet diffused to all providers, many of whom will be the ones dealing with these individuals when the disease first emerges.

In order to raise physicians’ awareness of this situation, we will briefly review here the salient features of lupus in US Hispanics and its short-term and long-term impact.

HISPANICS ARE THE LARGEST MINORITY IN THE UNITED STATES

Over the last 30 years, the Hispanic population in the United States has increased to the point that it is now the largest US minority group, and the fastest-growing. In the 2010 US census, Hispanics surpassed the 50 million mark.¹ Physicians and health care providers are becoming familiar with this growing population and its ailments, but more needs to be done to familiarize them with specific conditions that are more frequent and more serious in US Hispanics.

No population-based study has yet defined the prevalence and incidence of lupus in US Hispanics. However, on the basis of hospital and outpatient visits in regions in which Hispanics make up a large part of the population, it has been inferred that this group has a higher frequency of lupus, probably as high as in African Americans.

Likewise, clinicians taking care of these patients have suspected that lupus is more severe in US Hispanics than in non-Hispanic Caucasians, but this was documented and brought to general attention only with the publication of reports from the Lupus in Minorities: Nature versus Nurture (LUMINA) study.²

LUMINA, a longitudinal study

LUMINA is a longitudinal study of 640 patients with lupus from four populations: Hispanic from Texas, Hispanic from Puerto Rico, African American, and Caucasian non-Hispanic (Table 1). At the time of recruitment, patients were at least 16 years old and had had lupus for 5 years or less. They come in for periodic visits to the University of Alabama at Birmingham, the University of Texas Health Science Center at Houston, and the University of Puerto Rico Medical Sciences Campus. Recruitment began in 1994 and finished in 2007. Follow-up ranges from 1 to 14 years, with a mean of 4.5 years.

LUMINA is supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Institutes of Health General Clinical Research Centers program, the National Center for Research Resources Clinical Research Infrastructure Initiative, the Mary Kirkland Center for Lupus Research Scholars Program, and Rheuminations Inc (New York, NY).

The purpose of the study is to shed light on the interplay of genetics and environment in this disease and, in the process, to raise awareness about the problem of lupus in Hispanics. In fact, much of the information in the following sections is from the LUMINA study.

HISPANICS ARE NOT A HOMOGENEOUS GROUP

In the United States, the term Hispanic describes anyone whose origin goes back to a Spanish-speaking country. However, US Hispanics are not a homogeneous racial group: they differ in genetics, culture, and problems.

The largest US Hispanic subgroup and the one more likely to be seen by US physicians is Hispanics of Mexican origin, who account for 66% of all US Hispanics. This group has a higher percentage of Amerindian genes than those of Puerto Rican ancestry.³ LUMINA researchers analyzed the DNA of 492 patients and found the following mixtures of genes³:

• Hispanics in Texas (mostly of Mexican origin): 48% Amerindian, 18% African, 34% European
• Hispanics from Puerto Rico: 20% Amerindian, 45% African, 35% European
• African Americans: 0% Amerindian, 79% African, 21% European
• Non-Hispanic Caucasians: 10% Amerindian, 18% African, 72% European.

Latin Americans of mixed European and Amerindian ancestry (which includes Aztec, Mayan, Quechuan, Aymaran, and other Central and South American groups) are called mestizos. Not all people in Latin America are mestizos: some are of European, African, or Asian ancestry, but in the United States they are all called Hispanics.

LUPUS DIFFERS AMONG SUBGROUPS

LUMINA research has revealed that lupus is heterogeneous also among US Hispanic subgroups. When people from Puerto Rico get lupus, it is generally less serious and devastating than in those from Mexico or Central America. Since US Hispanics of Mexican or Central American origin possess more Amerindian genes, this observation supports the notion that these genes are important contributors to the occurrence and expression of the disease.

Amerindian genes contribute to a greater susceptibility to lupus,^4,5 although there is an interplay between genetic and nongenetic factors in the etiology and expression.⁶ Lupus starts at a younger age in Hispanics of predominantly Amerindian ancestry than in non-Hispanic Caucasians, and the onset is more likely to be acute.⁷

Renal involvement in these patients⁸ and mestizos from Latin America is rather common, probably as common as it is in US African Americans, and it tends to develop earlier than in non-Hispanic Caucasians.⁹ Amerindian ancestral genes, like African genes, contribute to the occurrence of renal disease in lupus patients.⁴ Furthermore, once nephritis ensues, end-stage renal disease occurs more often in US Hispanic and African American than in non-Hispanic Caucasian children, as demonstrated by Hiraki et al¹⁰ using national databases, and the same is true in adults, as shown in the LUMINA cohort.¹¹

Other potentially serious manifestations of the disease are also more common, including hematologic and central nervous system manifestations. Not surprisingly, then, these patients show a higher degree of disease activity, both early in the course of the disease^12,13 and over time.¹⁴

Table 1 compares the demographic and clinical features of LUMINA patients according to ethnicity. By and large, Hispanics from Texas have lower levels of education and income (comparable with levels in African Americans), and this can adversely affect the disease course by limiting these patients’ access to adequate care.¹⁵

DISEASE ACTIVITY AND ORGAN DAMAGE ARE GREATER IN HISPANICS

Disease activity in lupus reflects the ongoing immune-mediated inflammatory process. In LUMINA patients, regardless of the time at which disease activity was ascertained, it was higher in Hispanics from Texas and in African Americans than in non-Hispanic Caucasians and in Hispanics from Puerto Rico.^7,12,16–18 Similar findings were seen in the Grupo Latinoamericano de Estudio de Lupus (GLADEL) cohort,¹³ in which mestizos and Hispanics of mixed African and European ancestry had higher maximum disease activity scores than non-Hispanic Caucasians.¹³

In addition, organ damage in lupus—the irreversible changes that occur in organ systems as a consequence of the disease or its treatments (eg, glucocorticoids, immunosuppressive drugs)—is more severe and develops sooner in Hispanics from Texas than in other groups.^6,18,19 Using multivariate analysis, LUMINA investigators¹⁹ estimated the hazard ratio for the time until organ damage appeared for various risk factors, with values of 1 or greater indicating a shorter time and lower values indicating a longer time. Being a Hispanic from Texas carried a hazard ratio of 2.11 (95% confidence interval 1.15–3.88).

Because organ damage is an important and independent predictor of further damage²⁰ and death,²¹ physicians need to take this disease quite seriously and try to prevent damage early in people at risk. To achieve that, the need to control disease activity must be balanced against the risk of overtreatment, as the important contribution of glucocorticoids to organ damage is well recognized.²²

HISPANICS HAVE MORE COMORBIDITIES

Obesity, hypertension, diabetes, and metabolic syndrome are more common in US Hispanics, particularly those of Amerindian ancestry, than in the majority population of non-Hispanic Caucasians.^23,24 The potential deleterious effects of glucocorticoids in patients already predisposed to these conditions need to be considered, balancing adequate disease control against the potential adverse effects.²²

QUALITY OF LIFE IS WORSE WITH LUPUS

Whether it is measured with a generic instrument such as the Short Form 36 (SF-36), as it was in LUMINA,²⁵ or with a disease-specific tool such as the Lupus-Pro, quality of life is significantly worsened by lupus. Furthermore, Fernandez et al²⁶ found that a low level of health-related quality of life, as measured by the SF-6D version of the SF-36, was predictive of poor outcomes in LUMINA patients.

POVERTY, NOT ETHNICITY, ACCOUNTS FOR HIGHER MORTALITY RATE

As yet, we have no population-based data comparing survival in US Hispanic patients with lupus vs that of other population groups.

At first inspection, data from LUMINA indicate that Hispanics of primarily Amerindian ancestry have a lower survival rate than patients in other ethnic groups (Figure 1).⁶ However, when all other factors are taken into consideration, poverty, not ethnicity, is the major contributing factor (Table 2).^6,27

This finding illustrates the important interplay between genetic and nongenetic factors in the course and final outcome of lupus, as already alluded to, although the exact relationship between them is not clear. It remains to be determined whether poverty is only a proxy for other population characteristics such as illiteracy, limited access to specialized care, limited access to medications, or cultural beliefs that may interfere with proper care.

ANTIMALARIAL DRUGS INCREASE SURVIVAL

Using statistical analysis that adjusts for confounding by indication, we and others^28–30 have shown that antimalarial drugs exert an independent and important protective effect on survival in lupus (Figure 2).

Important also is the protective effect of antimalarials on organ damage and the possibility of using them from disease outset in Hispanic patients at risk of early and rapid damage accrual,¹¹ renal damage, and even lupus nephritis.^31,32 This has very practical implications for the adequate and prompt management of these Hispanic patients.

PRACTICAL IMPLICATIONS

Lupus in US Hispanics is a serious disease with devastating consequences. Prompt diagnosis is paramount to prevent early organ damage and to prolong survival.

The disease may present in many different and unexpected ways, but joint pain, sun-sensitive rashes, renal involvement, cytopenias, and other manifestations should prompt the clinician to consider lupus in the differential diagnosis. Patients are often dismissed as having “arthritis” without being asked about other manifestations that may suggest a systemic connective tissue disease such as lupus. The same goes for skin rashes or unusual central nervous system manifestations.

The diagnosis of lupus is clinical, but some laboratory studies are essential to rule in or rule out renal or hematologic abnormalities and determine the level of disease activity. Tests usually ordered in patients suspected of having lupus include antinuclear antibody, complement levels, a complete blood cell count and differential, and a urinalysis. The need for additional tests depends on the results of the tests listed.

Once the disease is diagnosed, treatment should be tailored to the severity and type of clinical manifestations present. In general, glucocorticoids should be used at the smallest possible dose, antimalarials should be prescribed from the outset to all patients (following current guidelines in order to avoid ocular toxicity),³³ and immunosuppressants and other treatments should be considered in certain instances. In parallel, consideration should be given to sun protection, adequate exercise, tobacco avoidance, osteoporosis and atherosclerosis prevention, planned conception, and compliance.

The goal in these people at risk is to control their lupus manifestations without causing undue damage, to preserve their quality of life, and to prevent an early demise.

Some diseases are either more serious or more frequent in US Hispanics, and systemic lupus erythematosus is one of them. This fact has not yet diffused to all providers, many of whom will be the ones dealing with these individuals when the disease first emerges.

In order to raise physicians’ awareness of this situation, we will briefly review here the salient features of lupus in US Hispanics and its short-term and long-term impact.

HISPANICS ARE THE LARGEST MINORITY IN THE UNITED STATES

Over the last 30 years, the Hispanic population in the United States has increased to the point that it is now the largest US minority group, and the fastest-growing. In the 2010 US census, Hispanics surpassed the 50 million mark.¹ Physicians and health care providers are becoming familiar with this growing population and its ailments, but more needs to be done to familiarize them with specific conditions that are more frequent and more serious in US Hispanics.

No population-based study has yet defined the prevalence and incidence of lupus in US Hispanics. However, on the basis of hospital and outpatient visits in regions in which Hispanics make up a large part of the population, it has been inferred that this group has a higher frequency of lupus, probably as high as in African Americans.

Likewise, clinicians taking care of these patients have suspected that lupus is more severe in US Hispanics than in non-Hispanic Caucasians, but this was documented and brought to general attention only with the publication of reports from the Lupus in Minorities: Nature versus Nurture (LUMINA) study.²

LUMINA, a longitudinal study

LUMINA is a longitudinal study of 640 patients with lupus from four populations: Hispanic from Texas, Hispanic from Puerto Rico, African American, and Caucasian non-Hispanic (Table 1). At the time of recruitment, patients were at least 16 years old and had had lupus for 5 years or less. They come in for periodic visits to the University of Alabama at Birmingham, the University of Texas Health Science Center at Houston, and the University of Puerto Rico Medical Sciences Campus. Recruitment began in 1994 and finished in 2007. Follow-up ranges from 1 to 14 years, with a mean of 4.5 years.

LUMINA is supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Institutes of Health General Clinical Research Centers program, the National Center for Research Resources Clinical Research Infrastructure Initiative, the Mary Kirkland Center for Lupus Research Scholars Program, and Rheuminations Inc (New York, NY).

The purpose of the study is to shed light on the interplay of genetics and environment in this disease and, in the process, to raise awareness about the problem of lupus in Hispanics. In fact, much of the information in the following sections is from the LUMINA study.

HISPANICS ARE NOT A HOMOGENEOUS GROUP

In the United States, the term Hispanic describes anyone whose origin goes back to a Spanish-speaking country. However, US Hispanics are not a homogeneous racial group: they differ in genetics, culture, and problems.

The largest US Hispanic subgroup and the one more likely to be seen by US physicians is Hispanics of Mexican origin, who account for 66% of all US Hispanics. This group has a higher percentage of Amerindian genes than those of Puerto Rican ancestry.³ LUMINA researchers analyzed the DNA of 492 patients and found the following mixtures of genes³:

• Hispanics in Texas (mostly of Mexican origin): 48% Amerindian, 18% African, 34% European
• Hispanics from Puerto Rico: 20% Amerindian, 45% African, 35% European
• African Americans: 0% Amerindian, 79% African, 21% European
• Non-Hispanic Caucasians: 10% Amerindian, 18% African, 72% European.

Latin Americans of mixed European and Amerindian ancestry (which includes Aztec, Mayan, Quechuan, Aymaran, and other Central and South American groups) are called mestizos. Not all people in Latin America are mestizos: some are of European, African, or Asian ancestry, but in the United States they are all called Hispanics.

LUPUS DIFFERS AMONG SUBGROUPS

LUMINA research has revealed that lupus is heterogeneous also among US Hispanic subgroups. When people from Puerto Rico get lupus, it is generally less serious and devastating than in those from Mexico or Central America. Since US Hispanics of Mexican or Central American origin possess more Amerindian genes, this observation supports the notion that these genes are important contributors to the occurrence and expression of the disease.

Amerindian genes contribute to a greater susceptibility to lupus,^4,5 although there is an interplay between genetic and nongenetic factors in the etiology and expression.⁶ Lupus starts at a younger age in Hispanics of predominantly Amerindian ancestry than in non-Hispanic Caucasians, and the onset is more likely to be acute.⁷

Renal involvement in these patients⁸ and mestizos from Latin America is rather common, probably as common as it is in US African Americans, and it tends to develop earlier than in non-Hispanic Caucasians.⁹ Amerindian ancestral genes, like African genes, contribute to the occurrence of renal disease in lupus patients.⁴ Furthermore, once nephritis ensues, end-stage renal disease occurs more often in US Hispanic and African American than in non-Hispanic Caucasian children, as demonstrated by Hiraki et al¹⁰ using national databases, and the same is true in adults, as shown in the LUMINA cohort.¹¹

Other potentially serious manifestations of the disease are also more common, including hematologic and central nervous system manifestations. Not surprisingly, then, these patients show a higher degree of disease activity, both early in the course of the disease^12,13 and over time.¹⁴

Table 1 compares the demographic and clinical features of LUMINA patients according to ethnicity. By and large, Hispanics from Texas have lower levels of education and income (comparable with levels in African Americans), and this can adversely affect the disease course by limiting these patients’ access to adequate care.¹⁵

DISEASE ACTIVITY AND ORGAN DAMAGE ARE GREATER IN HISPANICS

Disease activity in lupus reflects the ongoing immune-mediated inflammatory process. In LUMINA patients, regardless of the time at which disease activity was ascertained, it was higher in Hispanics from Texas and in African Americans than in non-Hispanic Caucasians and in Hispanics from Puerto Rico.^7,12,16–18 Similar findings were seen in the Grupo Latinoamericano de Estudio de Lupus (GLADEL) cohort,¹³ in which mestizos and Hispanics of mixed African and European ancestry had higher maximum disease activity scores than non-Hispanic Caucasians.¹³

In addition, organ damage in lupus—the irreversible changes that occur in organ systems as a consequence of the disease or its treatments (eg, glucocorticoids, immunosuppressive drugs)—is more severe and develops sooner in Hispanics from Texas than in other groups.^6,18,19 Using multivariate analysis, LUMINA investigators¹⁹ estimated the hazard ratio for the time until organ damage appeared for various risk factors, with values of 1 or greater indicating a shorter time and lower values indicating a longer time. Being a Hispanic from Texas carried a hazard ratio of 2.11 (95% confidence interval 1.15–3.88).

Because organ damage is an important and independent predictor of further damage²⁰ and death,²¹ physicians need to take this disease quite seriously and try to prevent damage early in people at risk. To achieve that, the need to control disease activity must be balanced against the risk of overtreatment, as the important contribution of glucocorticoids to organ damage is well recognized.²²

HISPANICS HAVE MORE COMORBIDITIES

Obesity, hypertension, diabetes, and metabolic syndrome are more common in US Hispanics, particularly those of Amerindian ancestry, than in the majority population of non-Hispanic Caucasians.^23,24 The potential deleterious effects of glucocorticoids in patients already predisposed to these conditions need to be considered, balancing adequate disease control against the potential adverse effects.²²

QUALITY OF LIFE IS WORSE WITH LUPUS

Whether it is measured with a generic instrument such as the Short Form 36 (SF-36), as it was in LUMINA,²⁵ or with a disease-specific tool such as the Lupus-Pro, quality of life is significantly worsened by lupus. Furthermore, Fernandez et al²⁶ found that a low level of health-related quality of life, as measured by the SF-6D version of the SF-36, was predictive of poor outcomes in LUMINA patients.

POVERTY, NOT ETHNICITY, ACCOUNTS FOR HIGHER MORTALITY RATE

As yet, we have no population-based data comparing survival in US Hispanic patients with lupus vs that of other population groups.

At first inspection, data from LUMINA indicate that Hispanics of primarily Amerindian ancestry have a lower survival rate than patients in other ethnic groups (Figure 1).⁶ However, when all other factors are taken into consideration, poverty, not ethnicity, is the major contributing factor (Table 2).^6,27

This finding illustrates the important interplay between genetic and nongenetic factors in the course and final outcome of lupus, as already alluded to, although the exact relationship between them is not clear. It remains to be determined whether poverty is only a proxy for other population characteristics such as illiteracy, limited access to specialized care, limited access to medications, or cultural beliefs that may interfere with proper care.

ANTIMALARIAL DRUGS INCREASE SURVIVAL

Using statistical analysis that adjusts for confounding by indication, we and others^28–30 have shown that antimalarial drugs exert an independent and important protective effect on survival in lupus (Figure 2).

Important also is the protective effect of antimalarials on organ damage and the possibility of using them from disease outset in Hispanic patients at risk of early and rapid damage accrual,¹¹ renal damage, and even lupus nephritis.^31,32 This has very practical implications for the adequate and prompt management of these Hispanic patients.

PRACTICAL IMPLICATIONS

Lupus in US Hispanics is a serious disease with devastating consequences. Prompt diagnosis is paramount to prevent early organ damage and to prolong survival.

The disease may present in many different and unexpected ways, but joint pain, sun-sensitive rashes, renal involvement, cytopenias, and other manifestations should prompt the clinician to consider lupus in the differential diagnosis. Patients are often dismissed as having “arthritis” without being asked about other manifestations that may suggest a systemic connective tissue disease such as lupus. The same goes for skin rashes or unusual central nervous system manifestations.

The diagnosis of lupus is clinical, but some laboratory studies are essential to rule in or rule out renal or hematologic abnormalities and determine the level of disease activity. Tests usually ordered in patients suspected of having lupus include antinuclear antibody, complement levels, a complete blood cell count and differential, and a urinalysis. The need for additional tests depends on the results of the tests listed.

Once the disease is diagnosed, treatment should be tailored to the severity and type of clinical manifestations present. In general, glucocorticoids should be used at the smallest possible dose, antimalarials should be prescribed from the outset to all patients (following current guidelines in order to avoid ocular toxicity),³³ and immunosuppressants and other treatments should be considered in certain instances. In parallel, consideration should be given to sun protection, adequate exercise, tobacco avoidance, osteoporosis and atherosclerosis prevention, planned conception, and compliance.

The goal in these people at risk is to control their lupus manifestations without causing undue damage, to preserve their quality of life, and to prevent an early demise.

Some diseases are either more serious or more frequent in US Hispanics, and systemic lupus erythematosus is one of them. This fact has not yet diffused to all providers, many of whom will be the ones dealing with these individuals when the disease first emerges.

In order to raise physicians’ awareness of this situation, we will briefly review here the salient features of lupus in US Hispanics and its short-term and long-term impact.

HISPANICS ARE THE LARGEST MINORITY IN THE UNITED STATES

Over the last 30 years, the Hispanic population in the United States has increased to the point that it is now the largest US minority group, and the fastest-growing. In the 2010 US census, Hispanics surpassed the 50 million mark.¹ Physicians and health care providers are becoming familiar with this growing population and its ailments, but more needs to be done to familiarize them with specific conditions that are more frequent and more serious in US Hispanics.

No population-based study has yet defined the prevalence and incidence of lupus in US Hispanics. However, on the basis of hospital and outpatient visits in regions in which Hispanics make up a large part of the population, it has been inferred that this group has a higher frequency of lupus, probably as high as in African Americans.

Likewise, clinicians taking care of these patients have suspected that lupus is more severe in US Hispanics than in non-Hispanic Caucasians, but this was documented and brought to general attention only with the publication of reports from the Lupus in Minorities: Nature versus Nurture (LUMINA) study.²

LUMINA, a longitudinal study

LUMINA is a longitudinal study of 640 patients with lupus from four populations: Hispanic from Texas, Hispanic from Puerto Rico, African American, and Caucasian non-Hispanic (Table 1). At the time of recruitment, patients were at least 16 years old and had had lupus for 5 years or less. They come in for periodic visits to the University of Alabama at Birmingham, the University of Texas Health Science Center at Houston, and the University of Puerto Rico Medical Sciences Campus. Recruitment began in 1994 and finished in 2007. Follow-up ranges from 1 to 14 years, with a mean of 4.5 years.

LUMINA is supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Institutes of Health General Clinical Research Centers program, the National Center for Research Resources Clinical Research Infrastructure Initiative, the Mary Kirkland Center for Lupus Research Scholars Program, and Rheuminations Inc (New York, NY).

The purpose of the study is to shed light on the interplay of genetics and environment in this disease and, in the process, to raise awareness about the problem of lupus in Hispanics. In fact, much of the information in the following sections is from the LUMINA study.

HISPANICS ARE NOT A HOMOGENEOUS GROUP

In the United States, the term Hispanic describes anyone whose origin goes back to a Spanish-speaking country. However, US Hispanics are not a homogeneous racial group: they differ in genetics, culture, and problems.

The largest US Hispanic subgroup and the one more likely to be seen by US physicians is Hispanics of Mexican origin, who account for 66% of all US Hispanics. This group has a higher percentage of Amerindian genes than those of Puerto Rican ancestry.³ LUMINA researchers analyzed the DNA of 492 patients and found the following mixtures of genes³:

• Hispanics in Texas (mostly of Mexican origin): 48% Amerindian, 18% African, 34% European
• Hispanics from Puerto Rico: 20% Amerindian, 45% African, 35% European
• African Americans: 0% Amerindian, 79% African, 21% European
• Non-Hispanic Caucasians: 10% Amerindian, 18% African, 72% European.

Latin Americans of mixed European and Amerindian ancestry (which includes Aztec, Mayan, Quechuan, Aymaran, and other Central and South American groups) are called mestizos. Not all people in Latin America are mestizos: some are of European, African, or Asian ancestry, but in the United States they are all called Hispanics.

LUPUS DIFFERS AMONG SUBGROUPS

LUMINA research has revealed that lupus is heterogeneous also among US Hispanic subgroups. When people from Puerto Rico get lupus, it is generally less serious and devastating than in those from Mexico or Central America. Since US Hispanics of Mexican or Central American origin possess more Amerindian genes, this observation supports the notion that these genes are important contributors to the occurrence and expression of the disease.

Amerindian genes contribute to a greater susceptibility to lupus,^4,5 although there is an interplay between genetic and nongenetic factors in the etiology and expression.⁶ Lupus starts at a younger age in Hispanics of predominantly Amerindian ancestry than in non-Hispanic Caucasians, and the onset is more likely to be acute.⁷

Renal involvement in these patients⁸ and mestizos from Latin America is rather common, probably as common as it is in US African Americans, and it tends to develop earlier than in non-Hispanic Caucasians.⁹ Amerindian ancestral genes, like African genes, contribute to the occurrence of renal disease in lupus patients.⁴ Furthermore, once nephritis ensues, end-stage renal disease occurs more often in US Hispanic and African American than in non-Hispanic Caucasian children, as demonstrated by Hiraki et al¹⁰ using national databases, and the same is true in adults, as shown in the LUMINA cohort.¹¹

Other potentially serious manifestations of the disease are also more common, including hematologic and central nervous system manifestations. Not surprisingly, then, these patients show a higher degree of disease activity, both early in the course of the disease^12,13 and over time.¹⁴

Table 1 compares the demographic and clinical features of LUMINA patients according to ethnicity. By and large, Hispanics from Texas have lower levels of education and income (comparable with levels in African Americans), and this can adversely affect the disease course by limiting these patients’ access to adequate care.¹⁵

DISEASE ACTIVITY AND ORGAN DAMAGE ARE GREATER IN HISPANICS

Disease activity in lupus reflects the ongoing immune-mediated inflammatory process. In LUMINA patients, regardless of the time at which disease activity was ascertained, it was higher in Hispanics from Texas and in African Americans than in non-Hispanic Caucasians and in Hispanics from Puerto Rico.^7,12,16–18 Similar findings were seen in the Grupo Latinoamericano de Estudio de Lupus (GLADEL) cohort,¹³ in which mestizos and Hispanics of mixed African and European ancestry had higher maximum disease activity scores than non-Hispanic Caucasians.¹³

In addition, organ damage in lupus—the irreversible changes that occur in organ systems as a consequence of the disease or its treatments (eg, glucocorticoids, immunosuppressive drugs)—is more severe and develops sooner in Hispanics from Texas than in other groups.^6,18,19 Using multivariate analysis, LUMINA investigators¹⁹ estimated the hazard ratio for the time until organ damage appeared for various risk factors, with values of 1 or greater indicating a shorter time and lower values indicating a longer time. Being a Hispanic from Texas carried a hazard ratio of 2.11 (95% confidence interval 1.15–3.88).

Because organ damage is an important and independent predictor of further damage²⁰ and death,²¹ physicians need to take this disease quite seriously and try to prevent damage early in people at risk. To achieve that, the need to control disease activity must be balanced against the risk of overtreatment, as the important contribution of glucocorticoids to organ damage is well recognized.²²

HISPANICS HAVE MORE COMORBIDITIES

Obesity, hypertension, diabetes, and metabolic syndrome are more common in US Hispanics, particularly those of Amerindian ancestry, than in the majority population of non-Hispanic Caucasians.^23,24 The potential deleterious effects of glucocorticoids in patients already predisposed to these conditions need to be considered, balancing adequate disease control against the potential adverse effects.²²

QUALITY OF LIFE IS WORSE WITH LUPUS

Whether it is measured with a generic instrument such as the Short Form 36 (SF-36), as it was in LUMINA,²⁵ or with a disease-specific tool such as the Lupus-Pro, quality of life is significantly worsened by lupus. Furthermore, Fernandez et al²⁶ found that a low level of health-related quality of life, as measured by the SF-6D version of the SF-36, was predictive of poor outcomes in LUMINA patients.

POVERTY, NOT ETHNICITY, ACCOUNTS FOR HIGHER MORTALITY RATE

As yet, we have no population-based data comparing survival in US Hispanic patients with lupus vs that of other population groups.

At first inspection, data from LUMINA indicate that Hispanics of primarily Amerindian ancestry have a lower survival rate than patients in other ethnic groups (Figure 1).⁶ However, when all other factors are taken into consideration, poverty, not ethnicity, is the major contributing factor (Table 2).^6,27

This finding illustrates the important interplay between genetic and nongenetic factors in the course and final outcome of lupus, as already alluded to, although the exact relationship between them is not clear. It remains to be determined whether poverty is only a proxy for other population characteristics such as illiteracy, limited access to specialized care, limited access to medications, or cultural beliefs that may interfere with proper care.

ANTIMALARIAL DRUGS INCREASE SURVIVAL

Using statistical analysis that adjusts for confounding by indication, we and others^28–30 have shown that antimalarial drugs exert an independent and important protective effect on survival in lupus (Figure 2).

Important also is the protective effect of antimalarials on organ damage and the possibility of using them from disease outset in Hispanic patients at risk of early and rapid damage accrual,¹¹ renal damage, and even lupus nephritis.^31,32 This has very practical implications for the adequate and prompt management of these Hispanic patients.

PRACTICAL IMPLICATIONS

Lupus in US Hispanics is a serious disease with devastating consequences. Prompt diagnosis is paramount to prevent early organ damage and to prolong survival.

The disease may present in many different and unexpected ways, but joint pain, sun-sensitive rashes, renal involvement, cytopenias, and other manifestations should prompt the clinician to consider lupus in the differential diagnosis. Patients are often dismissed as having “arthritis” without being asked about other manifestations that may suggest a systemic connective tissue disease such as lupus. The same goes for skin rashes or unusual central nervous system manifestations.

The diagnosis of lupus is clinical, but some laboratory studies are essential to rule in or rule out renal or hematologic abnormalities and determine the level of disease activity. Tests usually ordered in patients suspected of having lupus include antinuclear antibody, complement levels, a complete blood cell count and differential, and a urinalysis. The need for additional tests depends on the results of the tests listed.

Once the disease is diagnosed, treatment should be tailored to the severity and type of clinical manifestations present. In general, glucocorticoids should be used at the smallest possible dose, antimalarials should be prescribed from the outset to all patients (following current guidelines in order to avoid ocular toxicity),³³ and immunosuppressants and other treatments should be considered in certain instances. In parallel, consideration should be given to sun protection, adequate exercise, tobacco avoidance, osteoporosis and atherosclerosis prevention, planned conception, and compliance.

The goal in these people at risk is to control their lupus manifestations without causing undue damage, to preserve their quality of life, and to prevent an early demise.

“Healthy citizens are the greatest asset any country can have.”

—Winston Churchill

Diabetes and high blood pressure take a toll on the kidneys, especially in African Americans. To prevent chronic kidney disease (CKD) and to slow or stop its progression, the same principles apply in African Americans as in other patients—ie, vigilance for the onset of proteinuria, aggressive control of blood pressure, drug treatment to block the renin-angiotensin system, and attention to lifestyle factors (Table 1). However, we need to try to do better in the care of African Americans.

The purpose of this article is to review recent evidence- and consensus-based recommendations and to present a practical approach for the evaluation and treatment of CKD in African Americans.

CKD DEFINED

In 2002, the National Kidney Foundation¹ defined CKD as either:

• Kidney damage for 3 or more months, as defined by structural or functional abnormalities of the kidney, with or without a decreased glomerular filtration rate (GFR), manifested either by pathologic abnormalities or by markers of kidney damage, including abnormalities in the composition of the blood or urine (eg, proteinuria), or abnormalities in imaging tests; or
• A GFR less than 60 mL/min/1.73 m² for 3 or more months, with or without kidney damage.

The definition divides CKD into five progressive stages according to the GFR:

• Stage 1 (kidney damage with normal or increased GFR): GFR ≥ 90 mL/min/1.73m²
• Stage 2 (kidney damage with mildly decreased GFR): GFR 60–89
• Stage 3 (moderately decreased GFR): GFR 30–59
• Stage 4 (severely decreased GFR): GFR 15–29
• Stage 5 (kidney failure): GFR < 15 or dialysis.

Because the definition includes markers of kidney damage such as albuminuria, it allows CKD to be detected in its earliest stages, when the estimated GFR might still be well within normal limits.

CKD APPEARS EARLIER, PROGRESSES FASTER IN AFRICAN AMERICANS

“Not everything that counts can be counted, and not everything that can be counted counts.”

—Albert Einstein

CKD with or without a sustained reduction in the estimated GFR affects about one in every nine American adults.2 Its course varies depending on the cause and also from patient to patient, even in those with the same cause of CKD.

In general, the prevalence of early CKD is comparable across racial and ethnic groups in the United States, but CKD progresses to end-stage renal disease far more rapidly in minority populations, with rates nearly four times higher in black Americans than in white Americans.³ Also, the onset of CKD is earlier in African Americans.

HYPERTENSION AND DIABETES AS REASONS FOR THE DISPARITIES

Part of the reason for these differences is that minority populations have higher rates of diabetes and hypertension, and these diseases tend to be more severe in these groups. Poverty, less access to health care, exposure to environmental toxins, and genetic variation may also contribute.^4–7

Compared with whites, blacks have higher rates of diabetes and hypertension and earlier onset of these diseases, poorer control, and higher rates of complications such as CKD, stroke, and heart disease.^8,9 The higher rate of hypertension and the lower rate of blood pressure control in African Americans with CKD may contribute to the more rapid progression of CKD to end-stage renal disease.

In the Chronic Renal Insufficiency Cohort, ¹⁰ a racially and ethnically diverse group of 3,612 adults with a broad spectrum of renal disease severity, 93% of African Americans had hypertension at baseline compared with 80% of whites. In addition, African Americans were 18% less likely to have their blood pressure controlled to 140/90 mm Hg (the rates of control were 76% vs 60%), and 28% were less likely to have it controlled to 130/80 mm Hg (56% vs 38%).¹⁰ These factors may partially explain the faster progression to end-stage renal disease in African Americans with CKD.

Despite the potential efficacy of strict control of serum glucose levels and blood pressure,¹¹ the high rate of poor blood pressure control has contributed to the epidemic of diabetic nephropathy, especially among African Americans. Fortunately, hypertension control in the general population, while still not ideal, has improved from 27% in 1988–1994 to 50% in 2007–2008 and is now similar across racial and ethnic groups.¹² This, hopefully, is a preface for improved hypertension-related outcomes for all Americans over the next decade.

OTHER REASONS FOR THE DISPARITIES

“There are no unnatural or supernatural phenomena, only a very large gap in our knowledge of what is natural.”

—Edgar Mitchell, Apollo 14 astronaut

Proteinuria

Proteinuria is another key cardiorenal risk factor prevalent in African Americans.

Knight et al,¹³ analyzing data from the Third National Health and Nutrition Examination Survey, found that people with high-normal blood pressure (systolic pressure 130–139 mm Hg or diastolic pressure 85–89 mm Hg) were twice as likely to have microalbuminuria (odds ratio 2.13, 95% confidence interval [CI] 1.51–3.01) compared with people with optimal blood pressure (systolic pressure < 120 mm Hg and diastolic pressure < 80 mm Hg). Compared with whites as the reference group, Mexican Americans had slightly but not statistically significantly higher odds of microalbuminuria (odds ratio 1.16; 95% CI 0.90–1.51), and African Americans had significantly higher odds (odds ratio 1.30; 95% CI 1.04–1.64).

The incidence of hypertension-related end-stage renal disease is nearly five times higher in African Americans than in whites, and the rate of hypertension-related end-stage renal disease is 15 times higher in African American men ages 24 to 44 than in whites of the same ages.³ The greater risk of proteinuria in African Americans at any given level of higher blood pressure is thought to contribute in part to these disparate rates.

The renin-angiotensin system

The renin-angiotensin system plays a role in modulating hypertension and mediating hypertension-related complications. Hypertensive African Americans are more likely than hypertensive whites to have low-renin, salt-sensitive hypertension. Therein lies a paradox.

Since the renin-angiotensin system promotes the progression of CKD, we would expect patients with low-renin hypertension to have a lower risk of hypertension-related endorgan damage than patients with high-renin hypertension. However, many African Americans (who as a group have high rates of sodium sensitivity and low plasma renin levels) experience more severe hypertension-related end-organ complications such as proteinuria and cardiorenal disease.¹⁴

A reason for this paradox may be that the circulating renin-angiotensin system is separate from the intrarenal one. Supporting this theory is the observation that up-regulation of the intrarenal renin-angiotensin system accompanies renal interstitial inflammation and oxidative stress in the kidneys and cardiovascular tissues of salt-sensitive rats fed a high-salt diet.¹⁵ In other experiments in salt-sensitive rats, renin-angiotensin system blockade reversed endothelial dysfunction, attenuated proteinuria, and reduced renal injury independent of blood pressure changes even though the animals had low circulating renin levels.¹⁶

These findings imply that drugs that block the renin-angiotensin system, ie, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, could still be a rational therapy for CKD patients with low-renin hypertension, particularly African Americans, in whom local up-regulation of the renin-angiotensin system in the kidney could exacerbate both diabetic and hypertensive CKD.¹⁷ Although these drugs may not lower blood pressure as much in low-renin hypertension as in high-renin hypertension, they may still afford the same cardiorenal protection.

Genetic factors

Variations in the MYH9 and APOL1 genes on chromosome 22 have recently been found in genome-wide admixture mapping studies and may explain as much as 70% of the differences in the rates of nondiabetic end-stage renal disease between white and black Americans.^7,18,19 In addition, genetic variations may modulate differences in blood-pressure response to antihypertensive medications across racial and ethnic groups,²⁰ complicating treatment recommendations and clinical outcomes in our increasingly diverse nation.

Comment. The pathophysiologic basis for the variability in the course of CKD is probably multifactorial and is still poorly understood. Nevertheless, we may be able to delay the progression of CKD and prevent its complications with specific therapeutic and life-style interventions.

Race and ethnicity are associated with sociocultural and biologic variations that influence the risk and progression of CKD. Understanding these factors for minority populations can help in targeting interventions to attenuate the disproportionately high rates of CKD progression and complications.

The pathophysiologic reason African Americans have a greater prevalence of end-stage renal disease and a more rapid progression of CKD is complex and probably involves the interplay of biological, behavioral, and environmental factors such as salt intake, stress levels, and exposure to heavy metals.²¹

TRIALS OF ANTIHYPERTENSIVE THERAPY IN AFRICAN AMERICANS WITH CKD

“If we knew what we were doing, it wouldn’t be called research.”

—Albert Einstein

Until recently, trials of antihypertensive therapy in patients with CKD did not include adequate numbers of African American participants, but the following clinical trials have added to our knowledge (Table 2).^22–26

African American Study of Kidney Disease and Hypertension (AASK)

The African American Study of Kidney Disease and Hypertension (AASK),^22,23 with 1,094 patients, was the largest prospective study of CKD to date designed to focus on African Americans.

AASK examined the effects of two levels of blood-pressure control:

• Standard, with a goal blood pressure of 135–140/85–90 mm Hg (mean arterial pressure 102–107 mm Hg)
• Intensive, with a goal of 120/80 mm Hg or less (mean arterial pressure ≤ 92 mm Hg).

In a two-by two factorial design, patients were also randomized to receive one of three antihypertensive drugs as initial therapy:

• The ACE inhibitor ramipril (Altace)
• The sustained-release beta-blocker metoprolol succinate (Toprol XL)
• The calcium channel blocker amlodipine (Norvasc).

To enter the study, patients had to be African American, have at least one diastolic pressure reading of 95 mm Hg or greater during the screening period, and have a measured GFR between 20 and 65 mL/min/1.83 m². They could not have diabetes, substantial proteinuria (> 2.5 g/day), or other causes of CKD.²²

AASK was distinct from many of the larger hypertension trials in which secondary analyses of outcomes in patients with CKD were performed in that it was implicit in the design that most, if not all, study participants had substantial GFR reduction and would need diuretic therapy.

At baseline, after blood pressure medications had been tapered to define eligibility and then reintroduced before randomization, 20.0% of the patients in the intensive blood pressure goal group had pressure lower than 140/90 mm Hg, and this increased to 78.9% by 14 months after randomization. In the standard goal group, the numbers were 21.5% at baseline but only 41.8% at 14 months.²³ In spite of this difference, the rate of decline in GFR (the main clinical outcome measure) was the same in both groups.

However, the class of drug did make a difference. Secondary clinical outcomes, including the composite end point of development of end-stage renal disease, doubling of serum creatinine, or death, were less frequent in the ACE inhibitor group than in the beta-blocker and calcium channel blocker groups. As anticipated and consistent with real world practice, nearly 90% of all participants received concomitant diuretic therapy to achieve target blood pressure levels.

Comments. AASK showed that blood pressure can be controlled in African Americans who have CKD and that clinical cardiorenal outcomes can be improved by using an ACE inhibitor as initial therapy rather than a beta-blocker or calcium channel blocker, with diuretics and other agents added as needed.

AASK cohort phase

After completing the trial phase, patients were invited to enroll in a cohort phase in which the blood pressure target was less than 130/80 mm Hg. The combined follow-up period was 8.8 to 12.2 years.²⁴

During the trial phase, the mean blood pressure was 130/78 mm Hg in the intensive group and 141/86 mm Hg in the standard group. During the cohort phase, the mean blood pressures were 131/78 mm Hg and 134/78 mm Hg, respectively, in these groups.

In both phases, there was no significant difference between groups in clinical outcomes (hazard ratio in the intensive-control group 0.91, P = .27). However, the groups differed when stratified by baseline level of proteinuria (P = .02 for the interaction), with a potential benefit of a blood pressure target lower than 130/80 mm Hg in patients with a protein-to-creatinine ratio of more than 0.22 (hazard ratio 0.73, P = .01).²⁴

Comment. Given that many African Americans with hypertension and CKD have a protein-to-creatinine ratio of more than 0.22, these findings support a practical approach in clinical practice for a target blood pressure less than 130/80 mm Hg, using a first-line combination of a renin-angiotensin system inhibitor and a diuretic.

RENAAL study

The Reduction of Endpoints in NIDDM With the Angiotensin II Antagonist Losartan (RENAAL) study²⁵ included 1,513 patients, of whom 15% were African American and 18% were Hispanic; all had type 2 diabetes mellitus and nephropathy. They were randomized to receive the angiotensin II receptor antagonist losartan (Cozaar) or placebo in addition to other antihypertensive drugs.

At 3.4 years, the blood pressure was about 141/74 mm Hg in both groups. A post hoc analysis found lower rates of albuminuria and end-stage renal disease in the group treated with losartan,²⁵ with no racial or ethnic differences in its renoprotective effect.

Comments. While these findings support the recommendation of inhibiting the renin-angiotensin system for improving clinical outcomes in diabetic nephropathy in racial and ethnic minorities, the AASK study also proved a second important point. These patients required intense blood pressure management for several years in a clinical trial environment, which may be difficult to do in many clinical practice models.

To be cost-effective in today’s health care environment, such care will likely be limited to larger group practices or health care plans with large comprehensive covered populations. Payers and providers need to be willing to invest in intense early care in such high-risk subgroups with the understanding that they could recognize downstream gains from long-term improved outcomes. However, even in these settings, the ability to provide effective care to high-risk subgroups without generating significant financial losses remains a concern.

ALLHAT

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)²⁶ enrolled more than 33,000 hypertensive patients at high risk, of whom 32% were black, 16% were Hispanic, and 36% had diabetes. Their mean serum creatinine level was 1 mg/dL. Follow-up was for up to 8 years. At year 5, the mean blood pressure was 135/75 mm Hg.

In a secondary analysis, patients were stratified by GFR:

• Normal (> 90 mL/min/1.73 m²; n = 8,126)
• Mild reduction (60–89 mL/min/1.73 m²; n = 18,109)
• Moderate-severe reduction (< 60 mL/min/1.73 m²; n = 5,662).

In all three groups, amlodipine, lisinopril (Zestril), and chlorthalidone were equivalent as initial monotherapy in reducing the rate of the composite end point of end-stage renal disease or 50% or greater decrement in GFR.

Comments. The combined AASK, RENAAL, and ALLHAT findings are consistent with the practical recommendation of a diuretic, renin-angiotensin system inhibitor, or both, as initial therapy for blood pressure control in African American patients who have CKD, with a target blood pressure of less than 130/80 mm Hg.

A COMPREHENSIVE APPROACH TO CHRONIC KIDNEY DISEASE CARE

“It is much more important to know what sort of a patient has a disease, than what sort of disease a patient has.”

—William Osler

Many of the risk factors for cardiovascular disease in African Americans are behavioral and modifiable. These include too much salt and fat in the diet, too little physical activity, excessive alcohol intake, and smoking.

Education is key, to identify and communicate the risk attributable to health beliefs and behaviors, particularly in patients with known cardiovascular disease, and to encourage the patient to be proactive in risk-reduction strategies (Table 1). However, effective communication depends on compassion and concern by the health care provider to engender a sense of trust.²⁷ Other health care professionals such as dietitians, pharmacists, and social workers as well as family members can reinforce messages and improve communication with the patient to optimize outcomes.

The International Society on Hypertension in Blacks recommends a blood pressure target of less than 130/80 mm Hg in blacks with elevated blood pressure and target-organ damage. The authors suggest monotherapy with a diuretic or calcium channel blocker if the blood pressure is 10 mm Hg or less above target levels. When blood pressure is more than 15/10 mm Hg above target, two-drug therapy is recommended, either with a calcium channel blocker plus a renin-angiotensin system blocker or, alternatively, in edematous or volume-overload states, with a thiazide diuretic plus a renin-angiotensin system blocker.^28,29

The Clinical Practice Guidelines on Hypertension and Antihypertensive Agents in Chronic Kidney Disease of the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative recommend starting anti-hypertensive therapy with an ACE inhibitor or an angiotensin receptor blocker for most patients with CKD, regardless of ethnicity, recognizing that many will require combination therapy.³⁰ Evaluation of the response to therapy should include not only checking that the blood pressure is at or below the recommended target of 130/80 mm Hg, but also assessing for complications and monitoring the change in the level of proteinuria, which is a powerful predictor of progression of hypertensive kidney disease in all patients at any given GFR.³¹

OUR RECOMMENDATIONS

African Americans with hypertension and kidney disease require an aggressive and comprehensive approach to slow the progression of kidney disease and its complications, often necessitating aggressive care of the primary cause and the use of two or more antihypertensive agents to control blood pressure, proteinuria, or both (Figure 1).³²

We recommend that the initial evaluation of patients with hypertension include a screening for albuminuria and that the initial therapy for hypertension or proteinuria in all patients with CKD include renin-angiotensin system inhibition with a diuretic, because this combination appears most effective to achieve blood pressure control and to confer additional cardiorenal protection beyond that offered by blood-pressure control alone. Although some studies have reported that African Americans have lower blood-pressure response rates than whites to renin-angiotensin system inhibition, 18 it is nevertheless beneficial for clinical outcomes in this group, especially in the presence of proteinuria, a hallmark of hypertension-related CKD in African Americans. Thus, until more data are available, ethnicity should not be the primary criterion for selecting a given class of antihypertensive therapy, especially in patients with hypertensive nephropathy.

The overall treatment decision should be guided by individual response, coexisting risk factors, and potential cultural and socioeconomic considerations such as cost of medications and insurance coverage, which affect adherence to both pharmacologic and nonpharmacologic interventions.³³

Future studies should strive for adequate representation of racial and ethnic minority populations in order to enhance the evidence base for CKD treatment as we move toward using personalized medicine approaches in an increasingly diverse society.³⁴
 

Acknowledgment: Support for this paper was provided in part by NIH grants RR026138 and MD000182.

“Healthy citizens are the greatest asset any country can have.”

—Winston Churchill

Diabetes and high blood pressure take a toll on the kidneys, especially in African Americans. To prevent chronic kidney disease (CKD) and to slow or stop its progression, the same principles apply in African Americans as in other patients—ie, vigilance for the onset of proteinuria, aggressive control of blood pressure, drug treatment to block the renin-angiotensin system, and attention to lifestyle factors (Table 1). However, we need to try to do better in the care of African Americans.

The purpose of this article is to review recent evidence- and consensus-based recommendations and to present a practical approach for the evaluation and treatment of CKD in African Americans.

CKD DEFINED

In 2002, the National Kidney Foundation¹ defined CKD as either:

• Kidney damage for 3 or more months, as defined by structural or functional abnormalities of the kidney, with or without a decreased glomerular filtration rate (GFR), manifested either by pathologic abnormalities or by markers of kidney damage, including abnormalities in the composition of the blood or urine (eg, proteinuria), or abnormalities in imaging tests; or
• A GFR less than 60 mL/min/1.73 m² for 3 or more months, with or without kidney damage.

The definition divides CKD into five progressive stages according to the GFR:

• Stage 1 (kidney damage with normal or increased GFR): GFR ≥ 90 mL/min/1.73m²
• Stage 2 (kidney damage with mildly decreased GFR): GFR 60–89
• Stage 3 (moderately decreased GFR): GFR 30–59
• Stage 4 (severely decreased GFR): GFR 15–29
• Stage 5 (kidney failure): GFR < 15 or dialysis.

Because the definition includes markers of kidney damage such as albuminuria, it allows CKD to be detected in its earliest stages, when the estimated GFR might still be well within normal limits.

CKD APPEARS EARLIER, PROGRESSES FASTER IN AFRICAN AMERICANS

“Not everything that counts can be counted, and not everything that can be counted counts.”

—Albert Einstein

CKD with or without a sustained reduction in the estimated GFR affects about one in every nine American adults.2 Its course varies depending on the cause and also from patient to patient, even in those with the same cause of CKD.

In general, the prevalence of early CKD is comparable across racial and ethnic groups in the United States, but CKD progresses to end-stage renal disease far more rapidly in minority populations, with rates nearly four times higher in black Americans than in white Americans.³ Also, the onset of CKD is earlier in African Americans.

HYPERTENSION AND DIABETES AS REASONS FOR THE DISPARITIES

Part of the reason for these differences is that minority populations have higher rates of diabetes and hypertension, and these diseases tend to be more severe in these groups. Poverty, less access to health care, exposure to environmental toxins, and genetic variation may also contribute.^4–7

Compared with whites, blacks have higher rates of diabetes and hypertension and earlier onset of these diseases, poorer control, and higher rates of complications such as CKD, stroke, and heart disease.^8,9 The higher rate of hypertension and the lower rate of blood pressure control in African Americans with CKD may contribute to the more rapid progression of CKD to end-stage renal disease.

In the Chronic Renal Insufficiency Cohort, ¹⁰ a racially and ethnically diverse group of 3,612 adults with a broad spectrum of renal disease severity, 93% of African Americans had hypertension at baseline compared with 80% of whites. In addition, African Americans were 18% less likely to have their blood pressure controlled to 140/90 mm Hg (the rates of control were 76% vs 60%), and 28% were less likely to have it controlled to 130/80 mm Hg (56% vs 38%).¹⁰ These factors may partially explain the faster progression to end-stage renal disease in African Americans with CKD.

Despite the potential efficacy of strict control of serum glucose levels and blood pressure,¹¹ the high rate of poor blood pressure control has contributed to the epidemic of diabetic nephropathy, especially among African Americans. Fortunately, hypertension control in the general population, while still not ideal, has improved from 27% in 1988–1994 to 50% in 2007–2008 and is now similar across racial and ethnic groups.¹² This, hopefully, is a preface for improved hypertension-related outcomes for all Americans over the next decade.

OTHER REASONS FOR THE DISPARITIES

“There are no unnatural or supernatural phenomena, only a very large gap in our knowledge of what is natural.”

—Edgar Mitchell, Apollo 14 astronaut

Proteinuria

Proteinuria is another key cardiorenal risk factor prevalent in African Americans.

Knight et al,¹³ analyzing data from the Third National Health and Nutrition Examination Survey, found that people with high-normal blood pressure (systolic pressure 130–139 mm Hg or diastolic pressure 85–89 mm Hg) were twice as likely to have microalbuminuria (odds ratio 2.13, 95% confidence interval [CI] 1.51–3.01) compared with people with optimal blood pressure (systolic pressure < 120 mm Hg and diastolic pressure < 80 mm Hg). Compared with whites as the reference group, Mexican Americans had slightly but not statistically significantly higher odds of microalbuminuria (odds ratio 1.16; 95% CI 0.90–1.51), and African Americans had significantly higher odds (odds ratio 1.30; 95% CI 1.04–1.64).

The incidence of hypertension-related end-stage renal disease is nearly five times higher in African Americans than in whites, and the rate of hypertension-related end-stage renal disease is 15 times higher in African American men ages 24 to 44 than in whites of the same ages.³ The greater risk of proteinuria in African Americans at any given level of higher blood pressure is thought to contribute in part to these disparate rates.

The renin-angiotensin system

The renin-angiotensin system plays a role in modulating hypertension and mediating hypertension-related complications. Hypertensive African Americans are more likely than hypertensive whites to have low-renin, salt-sensitive hypertension. Therein lies a paradox.

Since the renin-angiotensin system promotes the progression of CKD, we would expect patients with low-renin hypertension to have a lower risk of hypertension-related endorgan damage than patients with high-renin hypertension. However, many African Americans (who as a group have high rates of sodium sensitivity and low plasma renin levels) experience more severe hypertension-related end-organ complications such as proteinuria and cardiorenal disease.¹⁴

A reason for this paradox may be that the circulating renin-angiotensin system is separate from the intrarenal one. Supporting this theory is the observation that up-regulation of the intrarenal renin-angiotensin system accompanies renal interstitial inflammation and oxidative stress in the kidneys and cardiovascular tissues of salt-sensitive rats fed a high-salt diet.¹⁵ In other experiments in salt-sensitive rats, renin-angiotensin system blockade reversed endothelial dysfunction, attenuated proteinuria, and reduced renal injury independent of blood pressure changes even though the animals had low circulating renin levels.¹⁶

These findings imply that drugs that block the renin-angiotensin system, ie, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, could still be a rational therapy for CKD patients with low-renin hypertension, particularly African Americans, in whom local up-regulation of the renin-angiotensin system in the kidney could exacerbate both diabetic and hypertensive CKD.¹⁷ Although these drugs may not lower blood pressure as much in low-renin hypertension as in high-renin hypertension, they may still afford the same cardiorenal protection.

Genetic factors

Variations in the MYH9 and APOL1 genes on chromosome 22 have recently been found in genome-wide admixture mapping studies and may explain as much as 70% of the differences in the rates of nondiabetic end-stage renal disease between white and black Americans.^7,18,19 In addition, genetic variations may modulate differences in blood-pressure response to antihypertensive medications across racial and ethnic groups,²⁰ complicating treatment recommendations and clinical outcomes in our increasingly diverse nation.

Comment. The pathophysiologic basis for the variability in the course of CKD is probably multifactorial and is still poorly understood. Nevertheless, we may be able to delay the progression of CKD and prevent its complications with specific therapeutic and life-style interventions.

Race and ethnicity are associated with sociocultural and biologic variations that influence the risk and progression of CKD. Understanding these factors for minority populations can help in targeting interventions to attenuate the disproportionately high rates of CKD progression and complications.

The pathophysiologic reason African Americans have a greater prevalence of end-stage renal disease and a more rapid progression of CKD is complex and probably involves the interplay of biological, behavioral, and environmental factors such as salt intake, stress levels, and exposure to heavy metals.²¹

TRIALS OF ANTIHYPERTENSIVE THERAPY IN AFRICAN AMERICANS WITH CKD

“If we knew what we were doing, it wouldn’t be called research.”

—Albert Einstein

Until recently, trials of antihypertensive therapy in patients with CKD did not include adequate numbers of African American participants, but the following clinical trials have added to our knowledge (Table 2).^22–26

African American Study of Kidney Disease and Hypertension (AASK)

The African American Study of Kidney Disease and Hypertension (AASK),^22,23 with 1,094 patients, was the largest prospective study of CKD to date designed to focus on African Americans.

AASK examined the effects of two levels of blood-pressure control:

• Standard, with a goal blood pressure of 135–140/85–90 mm Hg (mean arterial pressure 102–107 mm Hg)
• Intensive, with a goal of 120/80 mm Hg or less (mean arterial pressure ≤ 92 mm Hg).

In a two-by two factorial design, patients were also randomized to receive one of three antihypertensive drugs as initial therapy:

• The ACE inhibitor ramipril (Altace)
• The sustained-release beta-blocker metoprolol succinate (Toprol XL)
• The calcium channel blocker amlodipine (Norvasc).

To enter the study, patients had to be African American, have at least one diastolic pressure reading of 95 mm Hg or greater during the screening period, and have a measured GFR between 20 and 65 mL/min/1.83 m². They could not have diabetes, substantial proteinuria (> 2.5 g/day), or other causes of CKD.²²

AASK was distinct from many of the larger hypertension trials in which secondary analyses of outcomes in patients with CKD were performed in that it was implicit in the design that most, if not all, study participants had substantial GFR reduction and would need diuretic therapy.

At baseline, after blood pressure medications had been tapered to define eligibility and then reintroduced before randomization, 20.0% of the patients in the intensive blood pressure goal group had pressure lower than 140/90 mm Hg, and this increased to 78.9% by 14 months after randomization. In the standard goal group, the numbers were 21.5% at baseline but only 41.8% at 14 months.²³ In spite of this difference, the rate of decline in GFR (the main clinical outcome measure) was the same in both groups.

However, the class of drug did make a difference. Secondary clinical outcomes, including the composite end point of development of end-stage renal disease, doubling of serum creatinine, or death, were less frequent in the ACE inhibitor group than in the beta-blocker and calcium channel blocker groups. As anticipated and consistent with real world practice, nearly 90% of all participants received concomitant diuretic therapy to achieve target blood pressure levels.

Comments. AASK showed that blood pressure can be controlled in African Americans who have CKD and that clinical cardiorenal outcomes can be improved by using an ACE inhibitor as initial therapy rather than a beta-blocker or calcium channel blocker, with diuretics and other agents added as needed.

AASK cohort phase

After completing the trial phase, patients were invited to enroll in a cohort phase in which the blood pressure target was less than 130/80 mm Hg. The combined follow-up period was 8.8 to 12.2 years.²⁴

During the trial phase, the mean blood pressure was 130/78 mm Hg in the intensive group and 141/86 mm Hg in the standard group. During the cohort phase, the mean blood pressures were 131/78 mm Hg and 134/78 mm Hg, respectively, in these groups.

In both phases, there was no significant difference between groups in clinical outcomes (hazard ratio in the intensive-control group 0.91, P = .27). However, the groups differed when stratified by baseline level of proteinuria (P = .02 for the interaction), with a potential benefit of a blood pressure target lower than 130/80 mm Hg in patients with a protein-to-creatinine ratio of more than 0.22 (hazard ratio 0.73, P = .01).²⁴

Comment. Given that many African Americans with hypertension and CKD have a protein-to-creatinine ratio of more than 0.22, these findings support a practical approach in clinical practice for a target blood pressure less than 130/80 mm Hg, using a first-line combination of a renin-angiotensin system inhibitor and a diuretic.

RENAAL study

The Reduction of Endpoints in NIDDM With the Angiotensin II Antagonist Losartan (RENAAL) study²⁵ included 1,513 patients, of whom 15% were African American and 18% were Hispanic; all had type 2 diabetes mellitus and nephropathy. They were randomized to receive the angiotensin II receptor antagonist losartan (Cozaar) or placebo in addition to other antihypertensive drugs.

At 3.4 years, the blood pressure was about 141/74 mm Hg in both groups. A post hoc analysis found lower rates of albuminuria and end-stage renal disease in the group treated with losartan,²⁵ with no racial or ethnic differences in its renoprotective effect.

Comments. While these findings support the recommendation of inhibiting the renin-angiotensin system for improving clinical outcomes in diabetic nephropathy in racial and ethnic minorities, the AASK study also proved a second important point. These patients required intense blood pressure management for several years in a clinical trial environment, which may be difficult to do in many clinical practice models.

To be cost-effective in today’s health care environment, such care will likely be limited to larger group practices or health care plans with large comprehensive covered populations. Payers and providers need to be willing to invest in intense early care in such high-risk subgroups with the understanding that they could recognize downstream gains from long-term improved outcomes. However, even in these settings, the ability to provide effective care to high-risk subgroups without generating significant financial losses remains a concern.

ALLHAT

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)²⁶ enrolled more than 33,000 hypertensive patients at high risk, of whom 32% were black, 16% were Hispanic, and 36% had diabetes. Their mean serum creatinine level was 1 mg/dL. Follow-up was for up to 8 years. At year 5, the mean blood pressure was 135/75 mm Hg.

In a secondary analysis, patients were stratified by GFR:

• Normal (> 90 mL/min/1.73 m²; n = 8,126)
• Mild reduction (60–89 mL/min/1.73 m²; n = 18,109)
• Moderate-severe reduction (< 60 mL/min/1.73 m²; n = 5,662).

In all three groups, amlodipine, lisinopril (Zestril), and chlorthalidone were equivalent as initial monotherapy in reducing the rate of the composite end point of end-stage renal disease or 50% or greater decrement in GFR.

Comments. The combined AASK, RENAAL, and ALLHAT findings are consistent with the practical recommendation of a diuretic, renin-angiotensin system inhibitor, or both, as initial therapy for blood pressure control in African American patients who have CKD, with a target blood pressure of less than 130/80 mm Hg.

A COMPREHENSIVE APPROACH TO CHRONIC KIDNEY DISEASE CARE

“It is much more important to know what sort of a patient has a disease, than what sort of disease a patient has.”

—William Osler

Many of the risk factors for cardiovascular disease in African Americans are behavioral and modifiable. These include too much salt and fat in the diet, too little physical activity, excessive alcohol intake, and smoking.

Education is key, to identify and communicate the risk attributable to health beliefs and behaviors, particularly in patients with known cardiovascular disease, and to encourage the patient to be proactive in risk-reduction strategies (Table 1). However, effective communication depends on compassion and concern by the health care provider to engender a sense of trust.²⁷ Other health care professionals such as dietitians, pharmacists, and social workers as well as family members can reinforce messages and improve communication with the patient to optimize outcomes.

The International Society on Hypertension in Blacks recommends a blood pressure target of less than 130/80 mm Hg in blacks with elevated blood pressure and target-organ damage. The authors suggest monotherapy with a diuretic or calcium channel blocker if the blood pressure is 10 mm Hg or less above target levels. When blood pressure is more than 15/10 mm Hg above target, two-drug therapy is recommended, either with a calcium channel blocker plus a renin-angiotensin system blocker or, alternatively, in edematous or volume-overload states, with a thiazide diuretic plus a renin-angiotensin system blocker.^28,29

The Clinical Practice Guidelines on Hypertension and Antihypertensive Agents in Chronic Kidney Disease of the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative recommend starting anti-hypertensive therapy with an ACE inhibitor or an angiotensin receptor blocker for most patients with CKD, regardless of ethnicity, recognizing that many will require combination therapy.³⁰ Evaluation of the response to therapy should include not only checking that the blood pressure is at or below the recommended target of 130/80 mm Hg, but also assessing for complications and monitoring the change in the level of proteinuria, which is a powerful predictor of progression of hypertensive kidney disease in all patients at any given GFR.³¹

OUR RECOMMENDATIONS

African Americans with hypertension and kidney disease require an aggressive and comprehensive approach to slow the progression of kidney disease and its complications, often necessitating aggressive care of the primary cause and the use of two or more antihypertensive agents to control blood pressure, proteinuria, or both (Figure 1).³²

We recommend that the initial evaluation of patients with hypertension include a screening for albuminuria and that the initial therapy for hypertension or proteinuria in all patients with CKD include renin-angiotensin system inhibition with a diuretic, because this combination appears most effective to achieve blood pressure control and to confer additional cardiorenal protection beyond that offered by blood-pressure control alone. Although some studies have reported that African Americans have lower blood-pressure response rates than whites to renin-angiotensin system inhibition, 18 it is nevertheless beneficial for clinical outcomes in this group, especially in the presence of proteinuria, a hallmark of hypertension-related CKD in African Americans. Thus, until more data are available, ethnicity should not be the primary criterion for selecting a given class of antihypertensive therapy, especially in patients with hypertensive nephropathy.

The overall treatment decision should be guided by individual response, coexisting risk factors, and potential cultural and socioeconomic considerations such as cost of medications and insurance coverage, which affect adherence to both pharmacologic and nonpharmacologic interventions.³³

Future studies should strive for adequate representation of racial and ethnic minority populations in order to enhance the evidence base for CKD treatment as we move toward using personalized medicine approaches in an increasingly diverse society.³⁴
 

Acknowledgment: Support for this paper was provided in part by NIH grants RR026138 and MD000182.

“Healthy citizens are the greatest asset any country can have.”

—Winston Churchill

Diabetes and high blood pressure take a toll on the kidneys, especially in African Americans. To prevent chronic kidney disease (CKD) and to slow or stop its progression, the same principles apply in African Americans as in other patients—ie, vigilance for the onset of proteinuria, aggressive control of blood pressure, drug treatment to block the renin-angiotensin system, and attention to lifestyle factors (Table 1). However, we need to try to do better in the care of African Americans.

The purpose of this article is to review recent evidence- and consensus-based recommendations and to present a practical approach for the evaluation and treatment of CKD in African Americans.

CKD DEFINED

In 2002, the National Kidney Foundation¹ defined CKD as either:

• Kidney damage for 3 or more months, as defined by structural or functional abnormalities of the kidney, with or without a decreased glomerular filtration rate (GFR), manifested either by pathologic abnormalities or by markers of kidney damage, including abnormalities in the composition of the blood or urine (eg, proteinuria), or abnormalities in imaging tests; or
• A GFR less than 60 mL/min/1.73 m² for 3 or more months, with or without kidney damage.

The definition divides CKD into five progressive stages according to the GFR:

• Stage 1 (kidney damage with normal or increased GFR): GFR ≥ 90 mL/min/1.73m²
• Stage 2 (kidney damage with mildly decreased GFR): GFR 60–89
• Stage 3 (moderately decreased GFR): GFR 30–59
• Stage 4 (severely decreased GFR): GFR 15–29
• Stage 5 (kidney failure): GFR < 15 or dialysis.

Because the definition includes markers of kidney damage such as albuminuria, it allows CKD to be detected in its earliest stages, when the estimated GFR might still be well within normal limits.

CKD APPEARS EARLIER, PROGRESSES FASTER IN AFRICAN AMERICANS

“Not everything that counts can be counted, and not everything that can be counted counts.”

—Albert Einstein

CKD with or without a sustained reduction in the estimated GFR affects about one in every nine American adults.2 Its course varies depending on the cause and also from patient to patient, even in those with the same cause of CKD.

In general, the prevalence of early CKD is comparable across racial and ethnic groups in the United States, but CKD progresses to end-stage renal disease far more rapidly in minority populations, with rates nearly four times higher in black Americans than in white Americans.³ Also, the onset of CKD is earlier in African Americans.

HYPERTENSION AND DIABETES AS REASONS FOR THE DISPARITIES

Part of the reason for these differences is that minority populations have higher rates of diabetes and hypertension, and these diseases tend to be more severe in these groups. Poverty, less access to health care, exposure to environmental toxins, and genetic variation may also contribute.^4–7

Compared with whites, blacks have higher rates of diabetes and hypertension and earlier onset of these diseases, poorer control, and higher rates of complications such as CKD, stroke, and heart disease.^8,9 The higher rate of hypertension and the lower rate of blood pressure control in African Americans with CKD may contribute to the more rapid progression of CKD to end-stage renal disease.

In the Chronic Renal Insufficiency Cohort, ¹⁰ a racially and ethnically diverse group of 3,612 adults with a broad spectrum of renal disease severity, 93% of African Americans had hypertension at baseline compared with 80% of whites. In addition, African Americans were 18% less likely to have their blood pressure controlled to 140/90 mm Hg (the rates of control were 76% vs 60%), and 28% were less likely to have it controlled to 130/80 mm Hg (56% vs 38%).¹⁰ These factors may partially explain the faster progression to end-stage renal disease in African Americans with CKD.

Despite the potential efficacy of strict control of serum glucose levels and blood pressure,¹¹ the high rate of poor blood pressure control has contributed to the epidemic of diabetic nephropathy, especially among African Americans. Fortunately, hypertension control in the general population, while still not ideal, has improved from 27% in 1988–1994 to 50% in 2007–2008 and is now similar across racial and ethnic groups.¹² This, hopefully, is a preface for improved hypertension-related outcomes for all Americans over the next decade.

OTHER REASONS FOR THE DISPARITIES

“There are no unnatural or supernatural phenomena, only a very large gap in our knowledge of what is natural.”

—Edgar Mitchell, Apollo 14 astronaut

Proteinuria

Proteinuria is another key cardiorenal risk factor prevalent in African Americans.

Knight et al,¹³ analyzing data from the Third National Health and Nutrition Examination Survey, found that people with high-normal blood pressure (systolic pressure 130–139 mm Hg or diastolic pressure 85–89 mm Hg) were twice as likely to have microalbuminuria (odds ratio 2.13, 95% confidence interval [CI] 1.51–3.01) compared with people with optimal blood pressure (systolic pressure < 120 mm Hg and diastolic pressure < 80 mm Hg). Compared with whites as the reference group, Mexican Americans had slightly but not statistically significantly higher odds of microalbuminuria (odds ratio 1.16; 95% CI 0.90–1.51), and African Americans had significantly higher odds (odds ratio 1.30; 95% CI 1.04–1.64).

The incidence of hypertension-related end-stage renal disease is nearly five times higher in African Americans than in whites, and the rate of hypertension-related end-stage renal disease is 15 times higher in African American men ages 24 to 44 than in whites of the same ages.³ The greater risk of proteinuria in African Americans at any given level of higher blood pressure is thought to contribute in part to these disparate rates.

The renin-angiotensin system

The renin-angiotensin system plays a role in modulating hypertension and mediating hypertension-related complications. Hypertensive African Americans are more likely than hypertensive whites to have low-renin, salt-sensitive hypertension. Therein lies a paradox.

Since the renin-angiotensin system promotes the progression of CKD, we would expect patients with low-renin hypertension to have a lower risk of hypertension-related endorgan damage than patients with high-renin hypertension. However, many African Americans (who as a group have high rates of sodium sensitivity and low plasma renin levels) experience more severe hypertension-related end-organ complications such as proteinuria and cardiorenal disease.¹⁴

A reason for this paradox may be that the circulating renin-angiotensin system is separate from the intrarenal one. Supporting this theory is the observation that up-regulation of the intrarenal renin-angiotensin system accompanies renal interstitial inflammation and oxidative stress in the kidneys and cardiovascular tissues of salt-sensitive rats fed a high-salt diet.¹⁵ In other experiments in salt-sensitive rats, renin-angiotensin system blockade reversed endothelial dysfunction, attenuated proteinuria, and reduced renal injury independent of blood pressure changes even though the animals had low circulating renin levels.¹⁶

These findings imply that drugs that block the renin-angiotensin system, ie, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, could still be a rational therapy for CKD patients with low-renin hypertension, particularly African Americans, in whom local up-regulation of the renin-angiotensin system in the kidney could exacerbate both diabetic and hypertensive CKD.¹⁷ Although these drugs may not lower blood pressure as much in low-renin hypertension as in high-renin hypertension, they may still afford the same cardiorenal protection.

Genetic factors

Variations in the MYH9 and APOL1 genes on chromosome 22 have recently been found in genome-wide admixture mapping studies and may explain as much as 70% of the differences in the rates of nondiabetic end-stage renal disease between white and black Americans.^7,18,19 In addition, genetic variations may modulate differences in blood-pressure response to antihypertensive medications across racial and ethnic groups,²⁰ complicating treatment recommendations and clinical outcomes in our increasingly diverse nation.

Comment. The pathophysiologic basis for the variability in the course of CKD is probably multifactorial and is still poorly understood. Nevertheless, we may be able to delay the progression of CKD and prevent its complications with specific therapeutic and life-style interventions.

Race and ethnicity are associated with sociocultural and biologic variations that influence the risk and progression of CKD. Understanding these factors for minority populations can help in targeting interventions to attenuate the disproportionately high rates of CKD progression and complications.

The pathophysiologic reason African Americans have a greater prevalence of end-stage renal disease and a more rapid progression of CKD is complex and probably involves the interplay of biological, behavioral, and environmental factors such as salt intake, stress levels, and exposure to heavy metals.²¹

TRIALS OF ANTIHYPERTENSIVE THERAPY IN AFRICAN AMERICANS WITH CKD

“If we knew what we were doing, it wouldn’t be called research.”

—Albert Einstein

Until recently, trials of antihypertensive therapy in patients with CKD did not include adequate numbers of African American participants, but the following clinical trials have added to our knowledge (Table 2).^22–26

African American Study of Kidney Disease and Hypertension (AASK)

The African American Study of Kidney Disease and Hypertension (AASK),^22,23 with 1,094 patients, was the largest prospective study of CKD to date designed to focus on African Americans.

AASK examined the effects of two levels of blood-pressure control:

• Standard, with a goal blood pressure of 135–140/85–90 mm Hg (mean arterial pressure 102–107 mm Hg)
• Intensive, with a goal of 120/80 mm Hg or less (mean arterial pressure ≤ 92 mm Hg).

In a two-by two factorial design, patients were also randomized to receive one of three antihypertensive drugs as initial therapy:

• The ACE inhibitor ramipril (Altace)
• The sustained-release beta-blocker metoprolol succinate (Toprol XL)
• The calcium channel blocker amlodipine (Norvasc).

To enter the study, patients had to be African American, have at least one diastolic pressure reading of 95 mm Hg or greater during the screening period, and have a measured GFR between 20 and 65 mL/min/1.83 m². They could not have diabetes, substantial proteinuria (> 2.5 g/day), or other causes of CKD.²²

AASK was distinct from many of the larger hypertension trials in which secondary analyses of outcomes in patients with CKD were performed in that it was implicit in the design that most, if not all, study participants had substantial GFR reduction and would need diuretic therapy.

At baseline, after blood pressure medications had been tapered to define eligibility and then reintroduced before randomization, 20.0% of the patients in the intensive blood pressure goal group had pressure lower than 140/90 mm Hg, and this increased to 78.9% by 14 months after randomization. In the standard goal group, the numbers were 21.5% at baseline but only 41.8% at 14 months.²³ In spite of this difference, the rate of decline in GFR (the main clinical outcome measure) was the same in both groups.

However, the class of drug did make a difference. Secondary clinical outcomes, including the composite end point of development of end-stage renal disease, doubling of serum creatinine, or death, were less frequent in the ACE inhibitor group than in the beta-blocker and calcium channel blocker groups. As anticipated and consistent with real world practice, nearly 90% of all participants received concomitant diuretic therapy to achieve target blood pressure levels.

Comments. AASK showed that blood pressure can be controlled in African Americans who have CKD and that clinical cardiorenal outcomes can be improved by using an ACE inhibitor as initial therapy rather than a beta-blocker or calcium channel blocker, with diuretics and other agents added as needed.

AASK cohort phase

After completing the trial phase, patients were invited to enroll in a cohort phase in which the blood pressure target was less than 130/80 mm Hg. The combined follow-up period was 8.8 to 12.2 years.²⁴

During the trial phase, the mean blood pressure was 130/78 mm Hg in the intensive group and 141/86 mm Hg in the standard group. During the cohort phase, the mean blood pressures were 131/78 mm Hg and 134/78 mm Hg, respectively, in these groups.

In both phases, there was no significant difference between groups in clinical outcomes (hazard ratio in the intensive-control group 0.91, P = .27). However, the groups differed when stratified by baseline level of proteinuria (P = .02 for the interaction), with a potential benefit of a blood pressure target lower than 130/80 mm Hg in patients with a protein-to-creatinine ratio of more than 0.22 (hazard ratio 0.73, P = .01).²⁴

Comment. Given that many African Americans with hypertension and CKD have a protein-to-creatinine ratio of more than 0.22, these findings support a practical approach in clinical practice for a target blood pressure less than 130/80 mm Hg, using a first-line combination of a renin-angiotensin system inhibitor and a diuretic.

RENAAL study

The Reduction of Endpoints in NIDDM With the Angiotensin II Antagonist Losartan (RENAAL) study²⁵ included 1,513 patients, of whom 15% were African American and 18% were Hispanic; all had type 2 diabetes mellitus and nephropathy. They were randomized to receive the angiotensin II receptor antagonist losartan (Cozaar) or placebo in addition to other antihypertensive drugs.

At 3.4 years, the blood pressure was about 141/74 mm Hg in both groups. A post hoc analysis found lower rates of albuminuria and end-stage renal disease in the group treated with losartan,²⁵ with no racial or ethnic differences in its renoprotective effect.

Comments. While these findings support the recommendation of inhibiting the renin-angiotensin system for improving clinical outcomes in diabetic nephropathy in racial and ethnic minorities, the AASK study also proved a second important point. These patients required intense blood pressure management for several years in a clinical trial environment, which may be difficult to do in many clinical practice models.

To be cost-effective in today’s health care environment, such care will likely be limited to larger group practices or health care plans with large comprehensive covered populations. Payers and providers need to be willing to invest in intense early care in such high-risk subgroups with the understanding that they could recognize downstream gains from long-term improved outcomes. However, even in these settings, the ability to provide effective care to high-risk subgroups without generating significant financial losses remains a concern.

ALLHAT

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)²⁶ enrolled more than 33,000 hypertensive patients at high risk, of whom 32% were black, 16% were Hispanic, and 36% had diabetes. Their mean serum creatinine level was 1 mg/dL. Follow-up was for up to 8 years. At year 5, the mean blood pressure was 135/75 mm Hg.

In a secondary analysis, patients were stratified by GFR:

• Normal (> 90 mL/min/1.73 m²; n = 8,126)
• Mild reduction (60–89 mL/min/1.73 m²; n = 18,109)
• Moderate-severe reduction (< 60 mL/min/1.73 m²; n = 5,662).

In all three groups, amlodipine, lisinopril (Zestril), and chlorthalidone were equivalent as initial monotherapy in reducing the rate of the composite end point of end-stage renal disease or 50% or greater decrement in GFR.

Comments. The combined AASK, RENAAL, and ALLHAT findings are consistent with the practical recommendation of a diuretic, renin-angiotensin system inhibitor, or both, as initial therapy for blood pressure control in African American patients who have CKD, with a target blood pressure of less than 130/80 mm Hg.

A COMPREHENSIVE APPROACH TO CHRONIC KIDNEY DISEASE CARE

“It is much more important to know what sort of a patient has a disease, than what sort of disease a patient has.”

—William Osler

Many of the risk factors for cardiovascular disease in African Americans are behavioral and modifiable. These include too much salt and fat in the diet, too little physical activity, excessive alcohol intake, and smoking.

Education is key, to identify and communicate the risk attributable to health beliefs and behaviors, particularly in patients with known cardiovascular disease, and to encourage the patient to be proactive in risk-reduction strategies (Table 1). However, effective communication depends on compassion and concern by the health care provider to engender a sense of trust.²⁷ Other health care professionals such as dietitians, pharmacists, and social workers as well as family members can reinforce messages and improve communication with the patient to optimize outcomes.

The International Society on Hypertension in Blacks recommends a blood pressure target of less than 130/80 mm Hg in blacks with elevated blood pressure and target-organ damage. The authors suggest monotherapy with a diuretic or calcium channel blocker if the blood pressure is 10 mm Hg or less above target levels. When blood pressure is more than 15/10 mm Hg above target, two-drug therapy is recommended, either with a calcium channel blocker plus a renin-angiotensin system blocker or, alternatively, in edematous or volume-overload states, with a thiazide diuretic plus a renin-angiotensin system blocker.^28,29

The Clinical Practice Guidelines on Hypertension and Antihypertensive Agents in Chronic Kidney Disease of the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative recommend starting anti-hypertensive therapy with an ACE inhibitor or an angiotensin receptor blocker for most patients with CKD, regardless of ethnicity, recognizing that many will require combination therapy.³⁰ Evaluation of the response to therapy should include not only checking that the blood pressure is at or below the recommended target of 130/80 mm Hg, but also assessing for complications and monitoring the change in the level of proteinuria, which is a powerful predictor of progression of hypertensive kidney disease in all patients at any given GFR.³¹

OUR RECOMMENDATIONS

African Americans with hypertension and kidney disease require an aggressive and comprehensive approach to slow the progression of kidney disease and its complications, often necessitating aggressive care of the primary cause and the use of two or more antihypertensive agents to control blood pressure, proteinuria, or both (Figure 1).³²

We recommend that the initial evaluation of patients with hypertension include a screening for albuminuria and that the initial therapy for hypertension or proteinuria in all patients with CKD include renin-angiotensin system inhibition with a diuretic, because this combination appears most effective to achieve blood pressure control and to confer additional cardiorenal protection beyond that offered by blood-pressure control alone. Although some studies have reported that African Americans have lower blood-pressure response rates than whites to renin-angiotensin system inhibition, 18 it is nevertheless beneficial for clinical outcomes in this group, especially in the presence of proteinuria, a hallmark of hypertension-related CKD in African Americans. Thus, until more data are available, ethnicity should not be the primary criterion for selecting a given class of antihypertensive therapy, especially in patients with hypertensive nephropathy.

The overall treatment decision should be guided by individual response, coexisting risk factors, and potential cultural and socioeconomic considerations such as cost of medications and insurance coverage, which affect adherence to both pharmacologic and nonpharmacologic interventions.³³

Future studies should strive for adequate representation of racial and ethnic minority populations in order to enhance the evidence base for CKD treatment as we move toward using personalized medicine approaches in an increasingly diverse society.³⁴
 

Acknowledgment: Support for this paper was provided in part by NIH grants RR026138 and MD000182.

Prostate cancer is the most common cancer affecting American men. In 2010, an estimated 217,730 men were diagnosed with it and 32,050 died of it.¹ African American men are disproportionately affected, with a prostate cancer incidence two-thirds higher than whites and a mortality rate twice as high.¹ Owing to such disparities, the life expectancy of African Americans is several years shorter than that of non-Hispanic whites.²

For the primary care provider, who is often the first access point for health care in the United States, it is important to understand what mechanisms may underlie these differences and what can be done to narrow the gap.³

WHAT IS THE CAUSE OF THESE DIFFERENCES?

Many studies have looked into the causes of the higher incidence of prostate cancer in African American men and their higher mortality rate from it. The disparity may be due to a variety of factors, some socioeconomic and some biologic.

Poorer access to care, or lower-quality care?

A study of US servicemen who had equal access to care showed that African American men had a higher rate of prostate cancer regardless of access to care and socioeconomic status.⁴

However, the 2002 Institute of Medicine report, Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care, found evidence that racial and ethnic minorities tend to receive lower-quality health care than whites, “even when access-related factors, such as patients’ insurance status and income, are controlled.”⁵

Genetic predisposition?

Some have proposed that the disparity may be a function of genetic predisposition.

Evidence of a genetic component to the high incidence and mortality rate in African American men comes from epidemiologic studies of men with similar genetic backgrounds. For example, men in Nigeria and Ghana also have a high incidence of prostate cancer, as do men of African descent in the Caribbean islands and in the United Kingdom.⁶

Chromosome 8q24 variants have been shown in several studies to be associated with prostate cancer risk and are more common in African American men.^7–10 Some studies have also shown a higher rate of variations in cell apoptosis genes such as BCL2¹¹ and tumor-suppression genes such as EphB2 in African American men.¹²

These findings suggest that genetic differences may contribute to the higher prostate cancer incidence and mortality rate seen in African American men.

More-aggressive cancer, or later detection?

Not only do African American men tend to have a higher incidence of prostate cancer, they also tend to have more-aggressive disease (ie, a higher pathologic grade) at the time of diagnosis, which may contribute to the disparity in mortality rates.^13–19

Initially, there was some controversy as to whether this observation is a result of genetic and biologic factors that may predispose African American men to more-aggressive disease, or if it is due to inadequate screening and delayed presentation. However, a body of evidence supports the contention that prostate cancer is more aggressive in African American men.

For example, a study of autopsy data from men who died of prostate cancer at ages 20 to 49 showed that the age of onset of prostate cancer was similar between African American and white men.²⁰ The Surveillance Epidemiology and End Results (SEER) database showed that African American men had a higher incidence of metastatic disease across all age groups.²⁰ A similar study conducted 10 years later confirmed that rates of subclinical prostate cancer in African American and white men do not differ by race at the early ages, but that advanced or metastatic disease occurred nearly four times as frequently in African American men.²¹

Another study examined prostate biopsies from African American men and found that their tumors expressed higher levels of biomarkers, suggesting they had more-aggressive disease.²²

SCREENING FOR PROSTATE CANCER

Serum prostate-specific antigen (PSA) testing has become the method of choice for prostate cancer screening. However, PSA screening in asymptomatic men is under debate, because it can lead to overdetection and subsequent overtreatment of indolent disease.²³

Several recent studies showed differing results from prostate cancer screening.

The US Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial found that the mortality rate was no lower with combined PSA screening and digital rectal examination during a median follow-up of 11 years than in a control group that had a lower rate of screening.²⁴ However, further analysis of these data, with stratifying by comorbidities, showed that PSA screening in young and healthy men reduces the risk of death from prostate cancer, with minimal overtreatment.²⁵

The European Randomized Study of Screening for Prostate Cancer found a statistically significant 20% reduction in deaths from prostate cancer with PSA screening, but that it was necessary to treat 48 men in order to save one life.²⁶

Another study, published in 2010, showed that regular PSA screening reduced the rate of prostate cancer mortality by half over 14 years.²⁷

African American men generally present with disease that is more advanced than in white men.²⁸ This historically has been attributed to the fact that African Americans have been less likely to be screened for prostate cancer, though recent data indicate the gap is lessening.^29–31 A cross-sectional study from the Texas Medical Center showed that 54.4% of African American men had received PSA screening, compared with 63.2% of white men.³²

Another study showed that African Americans were more likely to have had a longer interval between PSA screenings before diagnosis, and that a longer PSA screening interval was associated with greater odds of having advanced disease at diagnosis.³³ However, when the researchers controlled for the PSA screening interval, they found that African Americans had the same odds of being diagnosed with advanced prostate cancer as white patients did. They concluded that more frequent or systematic PSA screening may reduce the racial differences in cancer stage at diagnosis and in deaths.

Many reasons have been proposed to explain why African Americans receive less screening, including poor communication between physicians and minority patients due to lack of cultural competency among physicians, lack of health insurance (and poor access to quality care as a result), and deficiency of knowledge about screening. Though awareness is rising, many African Americans are unaware of early detection methods for prostate cancer (eg, PSA testing), and other barriers such as cost and transportation exist that may prevent African American men from being screened.^34,35

As gatekeepers, primary care physicians are in a position to address these shortcomings in patient education and to enhance the physician-patient relationship.³⁶

Black men have higher PSA levels, with or without cancer

Physicians must also be aware of racial differences in PSA levels and realize that the predictive value of PSA in the diagnosis of prostate cancer may differ between African Americans and whites.

Black men, with or without prostate cancer, have been found to have higher PSA levels. Kyle and colleagues³⁷ found that African American men without prostate cancer had significantly higher mean PSA levels than white men across all age groups. Furthermore, Vijayakumar et al³⁸ found that African Americans with newly diagnosed localized prostate cancer had higher serum PSA levels than whites at diagnosis.

Although PSA cutoff levels have not been officially modified according to race, primary care physicians should have a lower threshold for referring African American men who have a suspiciously high PSA level for further urologic evaluation. Close partnership between the internist, family practitioner, and urologist will aid in the optimal use of PSA testing for the early detection of prostate cancer.

When to start PSA screening? How often to screen?

The age at which African American men should begin to have their PSA levels checked (with or without a digital rectal examination) continues to debated. However, the American Cancer Society³⁹ recommends that African American men who have a father or brother who had prostate cancer before age 65 should begin having discussions with their physician on this topic and, with their informed consent, screening at age 45.

The frequency of PSA screening depends on the individual’s PSA level. The National Comprehensive Cancer Network⁴⁰ recommends that men at high risk be offered a baseline PSA measurement and digital rectal examination at age 40 and, if the PSA level is higher than 1 ng/mL, that they be offered annual follow-ups. If the PSA level is less than 1 ng/mL, they recommend screening again at age 45. Risk factors for prostate cancer include family history as well as African American race.⁴¹

How should PSA levels be interpreted?

Interpreting PSA results is important in detecting prostate cancer at early stages.

At first, we believed the normal range of PSA for all men was 4.0 ng/mL or less. However, the American Urological Association now recognizes that the normal PSA range, in addition to varying along racial lines, also is age-dependent.⁴² The Cleveland Clinic Minority Men's Health Center's suggested normal ranges of PSA in African American men are:

• Age 40–49: ≤ 2.5 ng/mL
• Age 50–59: ≤ 3.0 ng/mL
• Age 60–69: ≤ 3.5 ng/mL
• Age 70–79: ≤ 4.5 ng/mL
• Age > 80: ≤ 5.0 ng/mL.

Remember that an elevated PSA does not necessarily signify prostate cancer, and that these are reference ranges only and may vary in individual men.

SURVIVAL AFTER DIAGNOSIS

African American men with prostate cancer have significantly higher mortality rates than white men. The possible causes of worse outcomes are many, and there have been many studies that attempted to address this disparity. The question of a more biologically aggressive cancer was previously discussed, but additional factors such as socioeconomic factors, comorbidities, and treatment received have also been studied, and data are mixed.^43–45

In a large SEER database review, once confounding variables of socioeconomic status, cancer stage, and treatment received were eliminated, African Americans had similar stage-for-stage survival from prostate cancer.⁴⁶ Another study found, in 2,046 men, that differences in socioeconomic status explained the difference in mortality rates between white and black patients.⁴⁷

However, other studies that adjusted for socioeconomic status as well as patient and tumor characteristics found that African American and Hispanic men were more likely to die of prostate cancer than white men.⁴⁸

Do African American men receive less-aggressive care?

Studies have also determined that there may be differences in treatments offered to patients, which in turn negatively affect survival.^28,49–53 Potentially curative local therapies (including radical surgery or radiation) may be recommended less often to black men because of major comorbidities or socioeconomic considerations.^49–52

Additionally, potential metastatic disease may be identified in a less timely and accurate manner, as African American men are less likely to undergo pelvic lymph node dissection. This was associated with worse survival in men with poorly differentiated prostate cancer.⁵³

However, returning to the possibility that prostate cancer is biologically more aggressive in African American men, some studies have shown that even after adjusting for treatment, African Americans continue to have worse survival rates.^54,55 One study in men with stage T1 to T3 prostate cancer who chose brachytherapy for treatment reported that after adjusting for PSA, clinical stage, socioeconomic status, and comorbidities, African American and Hispanic race were associated with higher all-cause mortality rates.⁵⁵

Equal care, equal outcomes?

In total, these results suggest that factors unrelated to tumor biology may be additional reasons for the poorer survival rates in African American men with prostate cancer. More favorable survival outcomes for African Americans with localized disease may be achieved with uniform assignment of treatment.

Fowler and Terrell⁵⁶ reviewed the outcomes of 148 black and 209 white men with localized prostate cancer treated with surgery or radiation therapy over an 11-year period at a Veterans Administration hospital. Not surprisingly, the black men presented more often with advanced disease. However, survival outcomes were equivalent between whites and blacks when treatment was assigned in a uniform manner without regard to race. After a median follow-up of 96 months, there were no significant differences in all-cause, cause-specific, metastasis-free, clinical disease-free, or PSA recurrence-free survival rates in 109 black and 167 white men with low-stage cancer treated with surgery or radiation therapy or in 39 black and 42 white men with high-stage disease treated with radiotherapy.⁵⁶

Similarly, Tewari et al⁵⁷ studied a cohort of 402 African American and 642 white men, all of whom underwent radical prostatectomy for clinically localized prostate cancer. They were followed for PSA recurrence to determine if race-specific differences in PSA doubling time or histopathologic variables might account for the higher mortality rate in black men. While there were race-specific differences in baseline serum PSA and incidence of high-grade prostatic intraepithelial neoplasia, race was not an independent risk factor for biochemical recurrence. Instead, other variables such as the Gleason pathology score, bilateral cancers, and margin positivity were independently associated with biochemical recurrence.

Furthermore, researchers at Louisiana State University⁵⁸ retrospectively analyzed data from 205 men of different races with early-stage prostate cancer. The African American men had a higher serum PSA level, suggesting more advanced disease or greater tumor burden at presentation, but no statistically significant differences were found among the pretreatment biopsy variables, including prostate volume (measured by ultrasonography), Gleason score, millimeters of cancer within the biopsy specimen, and percentage of cancer within the biopsy specimen. After treatment, there were no significant differences in survival outcomes along racial lines, leading the authors to conclude that early detection and treatment of prostate cancer in African Americans would be the best approach to lowering mortality rates.

Taken together, these data suggest that if localized prostate cancer is treated adequately and appropriately, African American patients may have improved survival rates.

DIETARY AND LIFESTYLE FACTORS

The incidence of prostate cancer is increasing in other countries where Western diets and lifestyles have been adopted,^59,60 suggesting that nutritional factors may also contribute partly to prostate carcinogenesis. Culture- and race-specific differences in diet may play an important role in prostate cancer risk in certain racial minorities. Many aspects of diet and nutrition have been studied for their impact on prostate cancer.

Dietary risk factors

Too much red meat and processed meat? Although some have suggested that diets high in red and processed meats may lead to a higher risk of prostate cancer, a meta-analysis showed no association.^61,62

Too much calcium? The European Prospective Investigation Into Cancer and Nutrition study found that high dietary intake of dairy protein and calcium from dairy products was associated with a higher risk of prostate cancer.⁶³ A cohort study in the United States had similar findings with regard to calcium.⁶⁴ However, the higher risk of prostate cancer was associated with consumption of 2,000 mg or more of calcium per day, which was consumed by only 2% of the study’s cohort and, as the study’s authors reported, fewer than 1% of US men. As such, only a small population of American men seem to be exposing themselves to a higher risk of prostate cancer by high calcium consumption.

High fat intake? Certain fatty acids have been implicated in general tumor genesis, and that risk has been extrapolated to prostate cancer.⁶⁵ For example, high fat intake and obesity are associated with increased levels of insulin-like growth factor 1, which in turn has been shown to correlate with a significantly elevated risk of prostate cancer.^63,65

Obesity has been shown to increase the risk of more-aggressive prostate cancer, but not of less-aggressive tumors.⁶⁶ Moreover, men who lost weight had a lower risk of prostate cancer than those who maintained their weight over 10 years.⁶⁶ Obesity may be particularly risky for African American men, in whom it was found to be associated with shorter biochemical relapse-free survival, whereas it was not an independent risk factor in white men.⁶⁷

Preventive dietary agents have been elusive

Unfortunately, despite attempts to identify preventive dietary agents, none has yet been confirmed.

No benefit from selenium or vitamin E. The Selenium and Vitamin E Cancer Prevention Trial was discontinued, as there was no evidence that either agent prevented prostate cancer in relatively healthy men.⁶⁸

Vitamin D? It has been suggested that lower levels of vitamin D could contribute to the higher rates of prostate cancer in African Americans, as vitamin D deficiency is more common in African Americans.⁶⁹ However, several meta-analyses have shown no association between vitamin D and prostate cancer.^70–72

Soy? Attempts at correlating the relatively low incidence of prostate cancer in Asians have revealed that high soy intake may be protective. Asians consume more soy than Americans do (100 vs 3 mg/day), and soy isoflavones such as genistein, glycitein, and daidzein lower the incidence of prostate cancer in laboratory mice.⁷³

Other lifestyle factors

Other lifestyle factors have also been analyzed to see if they contribute to prostate cancer.

Pollution. Some studies have suggested that the etiology of prostate cancer may lie in environmental exposures to pesticides,⁷⁴ metal industrial facilities,⁷⁵ and urban living.⁷⁶

Smoking. Watters et al⁷⁷ found that current and former cigarette smokers were actually at a lower risk of being diagnosed with non-advanced prostate cancer, but current smokers were at higher risk of dying from prostate cancer.

Physical activity. A prospective study of lifetime physical activity of more than 45,000 men found that men who were not sedentary during work and who walked or bicycled more than 30 minutes per day during adult life had an approximately 20% lower incidence of prostate cancer.⁷⁸

In sum, primary care providers who are generally promoting healthy lifestyles can point to a reduction in risk for prostate cancer as yet another benefit to a low-fat diet, a healthy body mass index, and daily exercise.

HOW PRIMARY CARE PHYSICIANS CAN HELP CLOSE THE GAP

Primary care physicians serve as the first point of health access for many in the United States today.

The diagnosis of prostate cancer is made more frequently in African American men than in other American men, often at a higher pathological grade, and with a worse mortality rate. Primary care physicians can help improve these statistics. Interventions targeting overall health, such as promotion of a healthy diet, could be established at primary care visits and could also reduce the incidence of prostate cancer in African American men. Patient education regarding prostate cancer screening, the impact of family history, and the rate of PSA screening could be improved.

Primary care physicians serve a vital role in health education and prostate cancer screening, and therefore they begin the process in potentially reducing the impact of prostate cancer in African American men. The racial disparity seen in prostate cancer may begin to be minimized with primary care physicians and specialists working together to ensure that all men receive appropriate treatment.

Prostate cancer is the most common cancer affecting American men. In 2010, an estimated 217,730 men were diagnosed with it and 32,050 died of it.¹ African American men are disproportionately affected, with a prostate cancer incidence two-thirds higher than whites and a mortality rate twice as high.¹ Owing to such disparities, the life expectancy of African Americans is several years shorter than that of non-Hispanic whites.²

For the primary care provider, who is often the first access point for health care in the United States, it is important to understand what mechanisms may underlie these differences and what can be done to narrow the gap.³

WHAT IS THE CAUSE OF THESE DIFFERENCES?

Many studies have looked into the causes of the higher incidence of prostate cancer in African American men and their higher mortality rate from it. The disparity may be due to a variety of factors, some socioeconomic and some biologic.

Poorer access to care, or lower-quality care?

A study of US servicemen who had equal access to care showed that African American men had a higher rate of prostate cancer regardless of access to care and socioeconomic status.⁴

However, the 2002 Institute of Medicine report, Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care, found evidence that racial and ethnic minorities tend to receive lower-quality health care than whites, “even when access-related factors, such as patients’ insurance status and income, are controlled.”⁵

Genetic predisposition?

Some have proposed that the disparity may be a function of genetic predisposition.

Evidence of a genetic component to the high incidence and mortality rate in African American men comes from epidemiologic studies of men with similar genetic backgrounds. For example, men in Nigeria and Ghana also have a high incidence of prostate cancer, as do men of African descent in the Caribbean islands and in the United Kingdom.⁶

Chromosome 8q24 variants have been shown in several studies to be associated with prostate cancer risk and are more common in African American men.^7–10 Some studies have also shown a higher rate of variations in cell apoptosis genes such as BCL2¹¹ and tumor-suppression genes such as EphB2 in African American men.¹²

These findings suggest that genetic differences may contribute to the higher prostate cancer incidence and mortality rate seen in African American men.

More-aggressive cancer, or later detection?

Not only do African American men tend to have a higher incidence of prostate cancer, they also tend to have more-aggressive disease (ie, a higher pathologic grade) at the time of diagnosis, which may contribute to the disparity in mortality rates.^13–19

Initially, there was some controversy as to whether this observation is a result of genetic and biologic factors that may predispose African American men to more-aggressive disease, or if it is due to inadequate screening and delayed presentation. However, a body of evidence supports the contention that prostate cancer is more aggressive in African American men.

For example, a study of autopsy data from men who died of prostate cancer at ages 20 to 49 showed that the age of onset of prostate cancer was similar between African American and white men.²⁰ The Surveillance Epidemiology and End Results (SEER) database showed that African American men had a higher incidence of metastatic disease across all age groups.²⁰ A similar study conducted 10 years later confirmed that rates of subclinical prostate cancer in African American and white men do not differ by race at the early ages, but that advanced or metastatic disease occurred nearly four times as frequently in African American men.²¹

Another study examined prostate biopsies from African American men and found that their tumors expressed higher levels of biomarkers, suggesting they had more-aggressive disease.²²

SCREENING FOR PROSTATE CANCER

Serum prostate-specific antigen (PSA) testing has become the method of choice for prostate cancer screening. However, PSA screening in asymptomatic men is under debate, because it can lead to overdetection and subsequent overtreatment of indolent disease.²³

Several recent studies showed differing results from prostate cancer screening.

The US Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial found that the mortality rate was no lower with combined PSA screening and digital rectal examination during a median follow-up of 11 years than in a control group that had a lower rate of screening.²⁴ However, further analysis of these data, with stratifying by comorbidities, showed that PSA screening in young and healthy men reduces the risk of death from prostate cancer, with minimal overtreatment.²⁵

The European Randomized Study of Screening for Prostate Cancer found a statistically significant 20% reduction in deaths from prostate cancer with PSA screening, but that it was necessary to treat 48 men in order to save one life.²⁶

Another study, published in 2010, showed that regular PSA screening reduced the rate of prostate cancer mortality by half over 14 years.²⁷

African American men generally present with disease that is more advanced than in white men.²⁸ This historically has been attributed to the fact that African Americans have been less likely to be screened for prostate cancer, though recent data indicate the gap is lessening.^29–31 A cross-sectional study from the Texas Medical Center showed that 54.4% of African American men had received PSA screening, compared with 63.2% of white men.³²

Another study showed that African Americans were more likely to have had a longer interval between PSA screenings before diagnosis, and that a longer PSA screening interval was associated with greater odds of having advanced disease at diagnosis.³³ However, when the researchers controlled for the PSA screening interval, they found that African Americans had the same odds of being diagnosed with advanced prostate cancer as white patients did. They concluded that more frequent or systematic PSA screening may reduce the racial differences in cancer stage at diagnosis and in deaths.

Many reasons have been proposed to explain why African Americans receive less screening, including poor communication between physicians and minority patients due to lack of cultural competency among physicians, lack of health insurance (and poor access to quality care as a result), and deficiency of knowledge about screening. Though awareness is rising, many African Americans are unaware of early detection methods for prostate cancer (eg, PSA testing), and other barriers such as cost and transportation exist that may prevent African American men from being screened.^34,35

As gatekeepers, primary care physicians are in a position to address these shortcomings in patient education and to enhance the physician-patient relationship.³⁶

Black men have higher PSA levels, with or without cancer

Physicians must also be aware of racial differences in PSA levels and realize that the predictive value of PSA in the diagnosis of prostate cancer may differ between African Americans and whites.

Black men, with or without prostate cancer, have been found to have higher PSA levels. Kyle and colleagues³⁷ found that African American men without prostate cancer had significantly higher mean PSA levels than white men across all age groups. Furthermore, Vijayakumar et al³⁸ found that African Americans with newly diagnosed localized prostate cancer had higher serum PSA levels than whites at diagnosis.

Although PSA cutoff levels have not been officially modified according to race, primary care physicians should have a lower threshold for referring African American men who have a suspiciously high PSA level for further urologic evaluation. Close partnership between the internist, family practitioner, and urologist will aid in the optimal use of PSA testing for the early detection of prostate cancer.

When to start PSA screening? How often to screen?

The age at which African American men should begin to have their PSA levels checked (with or without a digital rectal examination) continues to debated. However, the American Cancer Society³⁹ recommends that African American men who have a father or brother who had prostate cancer before age 65 should begin having discussions with their physician on this topic and, with their informed consent, screening at age 45.

The frequency of PSA screening depends on the individual’s PSA level. The National Comprehensive Cancer Network⁴⁰ recommends that men at high risk be offered a baseline PSA measurement and digital rectal examination at age 40 and, if the PSA level is higher than 1 ng/mL, that they be offered annual follow-ups. If the PSA level is less than 1 ng/mL, they recommend screening again at age 45. Risk factors for prostate cancer include family history as well as African American race.⁴¹

How should PSA levels be interpreted?

Interpreting PSA results is important in detecting prostate cancer at early stages.

At first, we believed the normal range of PSA for all men was 4.0 ng/mL or less. However, the American Urological Association now recognizes that the normal PSA range, in addition to varying along racial lines, also is age-dependent.⁴² The Cleveland Clinic Minority Men's Health Center's suggested normal ranges of PSA in African American men are:

• Age 40–49: ≤ 2.5 ng/mL
• Age 50–59: ≤ 3.0 ng/mL
• Age 60–69: ≤ 3.5 ng/mL
• Age 70–79: ≤ 4.5 ng/mL
• Age > 80: ≤ 5.0 ng/mL.

Remember that an elevated PSA does not necessarily signify prostate cancer, and that these are reference ranges only and may vary in individual men.

SURVIVAL AFTER DIAGNOSIS

African American men with prostate cancer have significantly higher mortality rates than white men. The possible causes of worse outcomes are many, and there have been many studies that attempted to address this disparity. The question of a more biologically aggressive cancer was previously discussed, but additional factors such as socioeconomic factors, comorbidities, and treatment received have also been studied, and data are mixed.^43–45

In a large SEER database review, once confounding variables of socioeconomic status, cancer stage, and treatment received were eliminated, African Americans had similar stage-for-stage survival from prostate cancer.⁴⁶ Another study found, in 2,046 men, that differences in socioeconomic status explained the difference in mortality rates between white and black patients.⁴⁷

However, other studies that adjusted for socioeconomic status as well as patient and tumor characteristics found that African American and Hispanic men were more likely to die of prostate cancer than white men.⁴⁸

Do African American men receive less-aggressive care?

Studies have also determined that there may be differences in treatments offered to patients, which in turn negatively affect survival.^28,49–53 Potentially curative local therapies (including radical surgery or radiation) may be recommended less often to black men because of major comorbidities or socioeconomic considerations.^49–52

Additionally, potential metastatic disease may be identified in a less timely and accurate manner, as African American men are less likely to undergo pelvic lymph node dissection. This was associated with worse survival in men with poorly differentiated prostate cancer.⁵³

However, returning to the possibility that prostate cancer is biologically more aggressive in African American men, some studies have shown that even after adjusting for treatment, African Americans continue to have worse survival rates.^54,55 One study in men with stage T1 to T3 prostate cancer who chose brachytherapy for treatment reported that after adjusting for PSA, clinical stage, socioeconomic status, and comorbidities, African American and Hispanic race were associated with higher all-cause mortality rates.⁵⁵

Equal care, equal outcomes?

In total, these results suggest that factors unrelated to tumor biology may be additional reasons for the poorer survival rates in African American men with prostate cancer. More favorable survival outcomes for African Americans with localized disease may be achieved with uniform assignment of treatment.

Fowler and Terrell⁵⁶ reviewed the outcomes of 148 black and 209 white men with localized prostate cancer treated with surgery or radiation therapy over an 11-year period at a Veterans Administration hospital. Not surprisingly, the black men presented more often with advanced disease. However, survival outcomes were equivalent between whites and blacks when treatment was assigned in a uniform manner without regard to race. After a median follow-up of 96 months, there were no significant differences in all-cause, cause-specific, metastasis-free, clinical disease-free, or PSA recurrence-free survival rates in 109 black and 167 white men with low-stage cancer treated with surgery or radiation therapy or in 39 black and 42 white men with high-stage disease treated with radiotherapy.⁵⁶

Similarly, Tewari et al⁵⁷ studied a cohort of 402 African American and 642 white men, all of whom underwent radical prostatectomy for clinically localized prostate cancer. They were followed for PSA recurrence to determine if race-specific differences in PSA doubling time or histopathologic variables might account for the higher mortality rate in black men. While there were race-specific differences in baseline serum PSA and incidence of high-grade prostatic intraepithelial neoplasia, race was not an independent risk factor for biochemical recurrence. Instead, other variables such as the Gleason pathology score, bilateral cancers, and margin positivity were independently associated with biochemical recurrence.

Furthermore, researchers at Louisiana State University⁵⁸ retrospectively analyzed data from 205 men of different races with early-stage prostate cancer. The African American men had a higher serum PSA level, suggesting more advanced disease or greater tumor burden at presentation, but no statistically significant differences were found among the pretreatment biopsy variables, including prostate volume (measured by ultrasonography), Gleason score, millimeters of cancer within the biopsy specimen, and percentage of cancer within the biopsy specimen. After treatment, there were no significant differences in survival outcomes along racial lines, leading the authors to conclude that early detection and treatment of prostate cancer in African Americans would be the best approach to lowering mortality rates.

Taken together, these data suggest that if localized prostate cancer is treated adequately and appropriately, African American patients may have improved survival rates.

DIETARY AND LIFESTYLE FACTORS

The incidence of prostate cancer is increasing in other countries where Western diets and lifestyles have been adopted,^59,60 suggesting that nutritional factors may also contribute partly to prostate carcinogenesis. Culture- and race-specific differences in diet may play an important role in prostate cancer risk in certain racial minorities. Many aspects of diet and nutrition have been studied for their impact on prostate cancer.

Dietary risk factors

Too much red meat and processed meat? Although some have suggested that diets high in red and processed meats may lead to a higher risk of prostate cancer, a meta-analysis showed no association.^61,62

Too much calcium? The European Prospective Investigation Into Cancer and Nutrition study found that high dietary intake of dairy protein and calcium from dairy products was associated with a higher risk of prostate cancer.⁶³ A cohort study in the United States had similar findings with regard to calcium.⁶⁴ However, the higher risk of prostate cancer was associated with consumption of 2,000 mg or more of calcium per day, which was consumed by only 2% of the study’s cohort and, as the study’s authors reported, fewer than 1% of US men. As such, only a small population of American men seem to be exposing themselves to a higher risk of prostate cancer by high calcium consumption.

High fat intake? Certain fatty acids have been implicated in general tumor genesis, and that risk has been extrapolated to prostate cancer.⁶⁵ For example, high fat intake and obesity are associated with increased levels of insulin-like growth factor 1, which in turn has been shown to correlate with a significantly elevated risk of prostate cancer.^63,65

Obesity has been shown to increase the risk of more-aggressive prostate cancer, but not of less-aggressive tumors.⁶⁶ Moreover, men who lost weight had a lower risk of prostate cancer than those who maintained their weight over 10 years.⁶⁶ Obesity may be particularly risky for African American men, in whom it was found to be associated with shorter biochemical relapse-free survival, whereas it was not an independent risk factor in white men.⁶⁷

Preventive dietary agents have been elusive

Unfortunately, despite attempts to identify preventive dietary agents, none has yet been confirmed.

No benefit from selenium or vitamin E. The Selenium and Vitamin E Cancer Prevention Trial was discontinued, as there was no evidence that either agent prevented prostate cancer in relatively healthy men.⁶⁸

Vitamin D? It has been suggested that lower levels of vitamin D could contribute to the higher rates of prostate cancer in African Americans, as vitamin D deficiency is more common in African Americans.⁶⁹ However, several meta-analyses have shown no association between vitamin D and prostate cancer.^70–72

Soy? Attempts at correlating the relatively low incidence of prostate cancer in Asians have revealed that high soy intake may be protective. Asians consume more soy than Americans do (100 vs 3 mg/day), and soy isoflavones such as genistein, glycitein, and daidzein lower the incidence of prostate cancer in laboratory mice.⁷³

Other lifestyle factors

Other lifestyle factors have also been analyzed to see if they contribute to prostate cancer.

Pollution. Some studies have suggested that the etiology of prostate cancer may lie in environmental exposures to pesticides,⁷⁴ metal industrial facilities,⁷⁵ and urban living.⁷⁶

Smoking. Watters et al⁷⁷ found that current and former cigarette smokers were actually at a lower risk of being diagnosed with non-advanced prostate cancer, but current smokers were at higher risk of dying from prostate cancer.

Physical activity. A prospective study of lifetime physical activity of more than 45,000 men found that men who were not sedentary during work and who walked or bicycled more than 30 minutes per day during adult life had an approximately 20% lower incidence of prostate cancer.⁷⁸

In sum, primary care providers who are generally promoting healthy lifestyles can point to a reduction in risk for prostate cancer as yet another benefit to a low-fat diet, a healthy body mass index, and daily exercise.

HOW PRIMARY CARE PHYSICIANS CAN HELP CLOSE THE GAP

Primary care physicians serve as the first point of health access for many in the United States today.

The diagnosis of prostate cancer is made more frequently in African American men than in other American men, often at a higher pathological grade, and with a worse mortality rate. Primary care physicians can help improve these statistics. Interventions targeting overall health, such as promotion of a healthy diet, could be established at primary care visits and could also reduce the incidence of prostate cancer in African American men. Patient education regarding prostate cancer screening, the impact of family history, and the rate of PSA screening could be improved.

Primary care physicians serve a vital role in health education and prostate cancer screening, and therefore they begin the process in potentially reducing the impact of prostate cancer in African American men. The racial disparity seen in prostate cancer may begin to be minimized with primary care physicians and specialists working together to ensure that all men receive appropriate treatment.

Prostate cancer is the most common cancer affecting American men. In 2010, an estimated 217,730 men were diagnosed with it and 32,050 died of it.¹ African American men are disproportionately affected, with a prostate cancer incidence two-thirds higher than whites and a mortality rate twice as high.¹ Owing to such disparities, the life expectancy of African Americans is several years shorter than that of non-Hispanic whites.²

For the primary care provider, who is often the first access point for health care in the United States, it is important to understand what mechanisms may underlie these differences and what can be done to narrow the gap.³

WHAT IS THE CAUSE OF THESE DIFFERENCES?

Many studies have looked into the causes of the higher incidence of prostate cancer in African American men and their higher mortality rate from it. The disparity may be due to a variety of factors, some socioeconomic and some biologic.

Poorer access to care, or lower-quality care?

A study of US servicemen who had equal access to care showed that African American men had a higher rate of prostate cancer regardless of access to care and socioeconomic status.⁴

However, the 2002 Institute of Medicine report, Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care, found evidence that racial and ethnic minorities tend to receive lower-quality health care than whites, “even when access-related factors, such as patients’ insurance status and income, are controlled.”⁵

Genetic predisposition?

Some have proposed that the disparity may be a function of genetic predisposition.

Evidence of a genetic component to the high incidence and mortality rate in African American men comes from epidemiologic studies of men with similar genetic backgrounds. For example, men in Nigeria and Ghana also have a high incidence of prostate cancer, as do men of African descent in the Caribbean islands and in the United Kingdom.⁶

Chromosome 8q24 variants have been shown in several studies to be associated with prostate cancer risk and are more common in African American men.^7–10 Some studies have also shown a higher rate of variations in cell apoptosis genes such as BCL2¹¹ and tumor-suppression genes such as EphB2 in African American men.¹²

These findings suggest that genetic differences may contribute to the higher prostate cancer incidence and mortality rate seen in African American men.

More-aggressive cancer, or later detection?

Not only do African American men tend to have a higher incidence of prostate cancer, they also tend to have more-aggressive disease (ie, a higher pathologic grade) at the time of diagnosis, which may contribute to the disparity in mortality rates.^13–19

Initially, there was some controversy as to whether this observation is a result of genetic and biologic factors that may predispose African American men to more-aggressive disease, or if it is due to inadequate screening and delayed presentation. However, a body of evidence supports the contention that prostate cancer is more aggressive in African American men.

For example, a study of autopsy data from men who died of prostate cancer at ages 20 to 49 showed that the age of onset of prostate cancer was similar between African American and white men.²⁰ The Surveillance Epidemiology and End Results (SEER) database showed that African American men had a higher incidence of metastatic disease across all age groups.²⁰ A similar study conducted 10 years later confirmed that rates of subclinical prostate cancer in African American and white men do not differ by race at the early ages, but that advanced or metastatic disease occurred nearly four times as frequently in African American men.²¹

Another study examined prostate biopsies from African American men and found that their tumors expressed higher levels of biomarkers, suggesting they had more-aggressive disease.²²

SCREENING FOR PROSTATE CANCER

Serum prostate-specific antigen (PSA) testing has become the method of choice for prostate cancer screening. However, PSA screening in asymptomatic men is under debate, because it can lead to overdetection and subsequent overtreatment of indolent disease.²³

Several recent studies showed differing results from prostate cancer screening.

The US Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial found that the mortality rate was no lower with combined PSA screening and digital rectal examination during a median follow-up of 11 years than in a control group that had a lower rate of screening.²⁴ However, further analysis of these data, with stratifying by comorbidities, showed that PSA screening in young and healthy men reduces the risk of death from prostate cancer, with minimal overtreatment.²⁵

The European Randomized Study of Screening for Prostate Cancer found a statistically significant 20% reduction in deaths from prostate cancer with PSA screening, but that it was necessary to treat 48 men in order to save one life.²⁶

Another study, published in 2010, showed that regular PSA screening reduced the rate of prostate cancer mortality by half over 14 years.²⁷

African American men generally present with disease that is more advanced than in white men.²⁸ This historically has been attributed to the fact that African Americans have been less likely to be screened for prostate cancer, though recent data indicate the gap is lessening.^29–31 A cross-sectional study from the Texas Medical Center showed that 54.4% of African American men had received PSA screening, compared with 63.2% of white men.³²

Another study showed that African Americans were more likely to have had a longer interval between PSA screenings before diagnosis, and that a longer PSA screening interval was associated with greater odds of having advanced disease at diagnosis.³³ However, when the researchers controlled for the PSA screening interval, they found that African Americans had the same odds of being diagnosed with advanced prostate cancer as white patients did. They concluded that more frequent or systematic PSA screening may reduce the racial differences in cancer stage at diagnosis and in deaths.

Many reasons have been proposed to explain why African Americans receive less screening, including poor communication between physicians and minority patients due to lack of cultural competency among physicians, lack of health insurance (and poor access to quality care as a result), and deficiency of knowledge about screening. Though awareness is rising, many African Americans are unaware of early detection methods for prostate cancer (eg, PSA testing), and other barriers such as cost and transportation exist that may prevent African American men from being screened.^34,35

As gatekeepers, primary care physicians are in a position to address these shortcomings in patient education and to enhance the physician-patient relationship.³⁶

Black men have higher PSA levels, with or without cancer

Physicians must also be aware of racial differences in PSA levels and realize that the predictive value of PSA in the diagnosis of prostate cancer may differ between African Americans and whites.

Black men, with or without prostate cancer, have been found to have higher PSA levels. Kyle and colleagues³⁷ found that African American men without prostate cancer had significantly higher mean PSA levels than white men across all age groups. Furthermore, Vijayakumar et al³⁸ found that African Americans with newly diagnosed localized prostate cancer had higher serum PSA levels than whites at diagnosis.

Although PSA cutoff levels have not been officially modified according to race, primary care physicians should have a lower threshold for referring African American men who have a suspiciously high PSA level for further urologic evaluation. Close partnership between the internist, family practitioner, and urologist will aid in the optimal use of PSA testing for the early detection of prostate cancer.

When to start PSA screening? How often to screen?

The age at which African American men should begin to have their PSA levels checked (with or without a digital rectal examination) continues to debated. However, the American Cancer Society³⁹ recommends that African American men who have a father or brother who had prostate cancer before age 65 should begin having discussions with their physician on this topic and, with their informed consent, screening at age 45.

The frequency of PSA screening depends on the individual’s PSA level. The National Comprehensive Cancer Network⁴⁰ recommends that men at high risk be offered a baseline PSA measurement and digital rectal examination at age 40 and, if the PSA level is higher than 1 ng/mL, that they be offered annual follow-ups. If the PSA level is less than 1 ng/mL, they recommend screening again at age 45. Risk factors for prostate cancer include family history as well as African American race.⁴¹

How should PSA levels be interpreted?

Interpreting PSA results is important in detecting prostate cancer at early stages.

At first, we believed the normal range of PSA for all men was 4.0 ng/mL or less. However, the American Urological Association now recognizes that the normal PSA range, in addition to varying along racial lines, also is age-dependent.⁴² The Cleveland Clinic Minority Men's Health Center's suggested normal ranges of PSA in African American men are:

• Age 40–49: ≤ 2.5 ng/mL
• Age 50–59: ≤ 3.0 ng/mL
• Age 60–69: ≤ 3.5 ng/mL
• Age 70–79: ≤ 4.5 ng/mL
• Age > 80: ≤ 5.0 ng/mL.

Remember that an elevated PSA does not necessarily signify prostate cancer, and that these are reference ranges only and may vary in individual men.

SURVIVAL AFTER DIAGNOSIS

African American men with prostate cancer have significantly higher mortality rates than white men. The possible causes of worse outcomes are many, and there have been many studies that attempted to address this disparity. The question of a more biologically aggressive cancer was previously discussed, but additional factors such as socioeconomic factors, comorbidities, and treatment received have also been studied, and data are mixed.^43–45

In a large SEER database review, once confounding variables of socioeconomic status, cancer stage, and treatment received were eliminated, African Americans had similar stage-for-stage survival from prostate cancer.⁴⁶ Another study found, in 2,046 men, that differences in socioeconomic status explained the difference in mortality rates between white and black patients.⁴⁷

However, other studies that adjusted for socioeconomic status as well as patient and tumor characteristics found that African American and Hispanic men were more likely to die of prostate cancer than white men.⁴⁸

Do African American men receive less-aggressive care?

Studies have also determined that there may be differences in treatments offered to patients, which in turn negatively affect survival.^28,49–53 Potentially curative local therapies (including radical surgery or radiation) may be recommended less often to black men because of major comorbidities or socioeconomic considerations.^49–52

Additionally, potential metastatic disease may be identified in a less timely and accurate manner, as African American men are less likely to undergo pelvic lymph node dissection. This was associated with worse survival in men with poorly differentiated prostate cancer.⁵³

However, returning to the possibility that prostate cancer is biologically more aggressive in African American men, some studies have shown that even after adjusting for treatment, African Americans continue to have worse survival rates.^54,55 One study in men with stage T1 to T3 prostate cancer who chose brachytherapy for treatment reported that after adjusting for PSA, clinical stage, socioeconomic status, and comorbidities, African American and Hispanic race were associated with higher all-cause mortality rates.⁵⁵

Equal care, equal outcomes?

In total, these results suggest that factors unrelated to tumor biology may be additional reasons for the poorer survival rates in African American men with prostate cancer. More favorable survival outcomes for African Americans with localized disease may be achieved with uniform assignment of treatment.

Fowler and Terrell⁵⁶ reviewed the outcomes of 148 black and 209 white men with localized prostate cancer treated with surgery or radiation therapy over an 11-year period at a Veterans Administration hospital. Not surprisingly, the black men presented more often with advanced disease. However, survival outcomes were equivalent between whites and blacks when treatment was assigned in a uniform manner without regard to race. After a median follow-up of 96 months, there were no significant differences in all-cause, cause-specific, metastasis-free, clinical disease-free, or PSA recurrence-free survival rates in 109 black and 167 white men with low-stage cancer treated with surgery or radiation therapy or in 39 black and 42 white men with high-stage disease treated with radiotherapy.⁵⁶

Similarly, Tewari et al⁵⁷ studied a cohort of 402 African American and 642 white men, all of whom underwent radical prostatectomy for clinically localized prostate cancer. They were followed for PSA recurrence to determine if race-specific differences in PSA doubling time or histopathologic variables might account for the higher mortality rate in black men. While there were race-specific differences in baseline serum PSA and incidence of high-grade prostatic intraepithelial neoplasia, race was not an independent risk factor for biochemical recurrence. Instead, other variables such as the Gleason pathology score, bilateral cancers, and margin positivity were independently associated with biochemical recurrence.

Furthermore, researchers at Louisiana State University⁵⁸ retrospectively analyzed data from 205 men of different races with early-stage prostate cancer. The African American men had a higher serum PSA level, suggesting more advanced disease or greater tumor burden at presentation, but no statistically significant differences were found among the pretreatment biopsy variables, including prostate volume (measured by ultrasonography), Gleason score, millimeters of cancer within the biopsy specimen, and percentage of cancer within the biopsy specimen. After treatment, there were no significant differences in survival outcomes along racial lines, leading the authors to conclude that early detection and treatment of prostate cancer in African Americans would be the best approach to lowering mortality rates.

Taken together, these data suggest that if localized prostate cancer is treated adequately and appropriately, African American patients may have improved survival rates.

DIETARY AND LIFESTYLE FACTORS

The incidence of prostate cancer is increasing in other countries where Western diets and lifestyles have been adopted,^59,60 suggesting that nutritional factors may also contribute partly to prostate carcinogenesis. Culture- and race-specific differences in diet may play an important role in prostate cancer risk in certain racial minorities. Many aspects of diet and nutrition have been studied for their impact on prostate cancer.

Dietary risk factors

Too much red meat and processed meat? Although some have suggested that diets high in red and processed meats may lead to a higher risk of prostate cancer, a meta-analysis showed no association.^61,62

Too much calcium? The European Prospective Investigation Into Cancer and Nutrition study found that high dietary intake of dairy protein and calcium from dairy products was associated with a higher risk of prostate cancer.⁶³ A cohort study in the United States had similar findings with regard to calcium.⁶⁴ However, the higher risk of prostate cancer was associated with consumption of 2,000 mg or more of calcium per day, which was consumed by only 2% of the study’s cohort and, as the study’s authors reported, fewer than 1% of US men. As such, only a small population of American men seem to be exposing themselves to a higher risk of prostate cancer by high calcium consumption.

High fat intake? Certain fatty acids have been implicated in general tumor genesis, and that risk has been extrapolated to prostate cancer.⁶⁵ For example, high fat intake and obesity are associated with increased levels of insulin-like growth factor 1, which in turn has been shown to correlate with a significantly elevated risk of prostate cancer.^63,65

Obesity has been shown to increase the risk of more-aggressive prostate cancer, but not of less-aggressive tumors.⁶⁶ Moreover, men who lost weight had a lower risk of prostate cancer than those who maintained their weight over 10 years.⁶⁶ Obesity may be particularly risky for African American men, in whom it was found to be associated with shorter biochemical relapse-free survival, whereas it was not an independent risk factor in white men.⁶⁷

Preventive dietary agents have been elusive

Unfortunately, despite attempts to identify preventive dietary agents, none has yet been confirmed.

No benefit from selenium or vitamin E. The Selenium and Vitamin E Cancer Prevention Trial was discontinued, as there was no evidence that either agent prevented prostate cancer in relatively healthy men.⁶⁸

Vitamin D? It has been suggested that lower levels of vitamin D could contribute to the higher rates of prostate cancer in African Americans, as vitamin D deficiency is more common in African Americans.⁶⁹ However, several meta-analyses have shown no association between vitamin D and prostate cancer.^70–72

Soy? Attempts at correlating the relatively low incidence of prostate cancer in Asians have revealed that high soy intake may be protective. Asians consume more soy than Americans do (100 vs 3 mg/day), and soy isoflavones such as genistein, glycitein, and daidzein lower the incidence of prostate cancer in laboratory mice.⁷³

Other lifestyle factors

Other lifestyle factors have also been analyzed to see if they contribute to prostate cancer.

Pollution. Some studies have suggested that the etiology of prostate cancer may lie in environmental exposures to pesticides,⁷⁴ metal industrial facilities,⁷⁵ and urban living.⁷⁶

Smoking. Watters et al⁷⁷ found that current and former cigarette smokers were actually at a lower risk of being diagnosed with non-advanced prostate cancer, but current smokers were at higher risk of dying from prostate cancer.

Physical activity. A prospective study of lifetime physical activity of more than 45,000 men found that men who were not sedentary during work and who walked or bicycled more than 30 minutes per day during adult life had an approximately 20% lower incidence of prostate cancer.⁷⁸

In sum, primary care providers who are generally promoting healthy lifestyles can point to a reduction in risk for prostate cancer as yet another benefit to a low-fat diet, a healthy body mass index, and daily exercise.

HOW PRIMARY CARE PHYSICIANS CAN HELP CLOSE THE GAP

Primary care physicians serve as the first point of health access for many in the United States today.

The diagnosis of prostate cancer is made more frequently in African American men than in other American men, often at a higher pathological grade, and with a worse mortality rate. Primary care physicians can help improve these statistics. Interventions targeting overall health, such as promotion of a healthy diet, could be established at primary care visits and could also reduce the incidence of prostate cancer in African American men. Patient education regarding prostate cancer screening, the impact of family history, and the rate of PSA screening could be improved.

Primary care physicians serve a vital role in health education and prostate cancer screening, and therefore they begin the process in potentially reducing the impact of prostate cancer in African American men. The racial disparity seen in prostate cancer may begin to be minimized with primary care physicians and specialists working together to ensure that all men receive appropriate treatment.

The last several decades have seen a dramatic surge in the prevalence of asthma. In 2009, there were an estimated 17.5 million adults and almost 7.1 million children with asthma in the United States,¹ up from 9.5 million adults and slightly more than 5 million children in 1995.²

Multiple factors contribute to these disparities, including genetics, socioeconomic factors, cultural factors, health maintenance behaviors, provider-patient communication, air quality, and obesity.

GENETICS: 70% OF DESTINY?

The trend towards personalized medicine has spurred extensive research into the genetics of asthma. Studies in twins and familial aggregation studies suggest genetics plays a significant role, with estimates of the heritability of asthma as high as 70%.^4,5 More than 100 candidate genes have been shown to be associated with asthma and atopy, 30 of them in five or more independent studies.⁶

Researchers face many challenges when investigating the genetics involved in asthma for a particular race. Race is both a biologic and a social construct and, as such, is a poor substitute for genetics. Race constitutes not only genetic differences in individuals, but also the behaviors, beliefs, and experiences that vary among races.

The clinical disease—the phenotype—is the product of the interaction of genes and these differing behaviors and exposures. Genetics can affect how environmental factors found in association with socioeconomic factors relate to asthma morbidity and mortality.

For example, as we will discuss below, African Americans are more likely than whites to be sensitized to cockroach allergen, even after controlling for socioeconomic variables that may be associated with greater exposure.⁷ High-level exposure to cockroach allergen in sensitized children has been associated with poor asthma outcomes.⁸ This suggests that a genetic difference may exist between African Americans and whites with respect to the potential to develop cockroach sensitization, and this difference may be of particular importance for those African Americans living in areas with higher levels of cockroach exposure.

Two polymorphisms

Two polymorphisms have garnered attention for their influence on African Americans with asthma:

TheADRB2gene. This gene codes for the beta-2 adrenergic receptor and resides at chromosome 5q13.⁹ The receptor is found on several types of cells in the lung, including airway smooth muscle and epithelial cells, and is responsible for the salutary effects of inhaled beta-2 agonists such as albuterol (eg, Proventil).

Allelic polymorphisms of this gene are clinically relevant. The substitution of arginine (Arg) for glycine (Gly) at codon 16 of this gene is responsible for differences in response to short-acting beta-2 agonists. The allelic frequency of Arg16 is lower in white Americans (39.3%) than in African Americans (49.2%), and thus African Americans are more likely to be homozygous for Arg16 (ie, to have the Arg/Arg genotype).¹⁰

People who are homozygous for Arg16 who use albuterol on a regular basis are at higher risk of untoward asthma outcomes.¹¹ This is important, for several reasons. In general, adherence to inhaled corticosteroids is poor (not only in African Americans),¹² and patients who do not take their inhaled corticosteroids as they should may rely on short-acting beta-2 agonists more frequently. Furthermore, African Americans may have a poorer response to the repeated doses of albuterol that are typically given in the emergency department and in the hospital for severe asthma exacerbations.¹³ Additionally, data suggest that Arg/Arg individuals have more frequent exacerbations independent of beta-agonist use,¹⁴ although curiously, patients who are homozygous for Arg16 have a greater benefit from single doses of short-acting beta-2 agonists than those who are Gly16 homozygous.¹⁵

TheCD14gene. An interesting relationship between innate immunity and asthma has recently been described. Polymorphisms of CD14, which codes for a receptor for endotoxin, have been uncovered. The single-nucleotide polymorphism variant thymine (T) at position −260 has been found in greater frequency in whites than in African Americans, who are more likely to have the cytosine (C) allele.¹⁶ An association between the CC genotype and atopy has been reported,¹⁶ although this has not been consistent.¹⁷

A possible explanation for these inconsistencies may lie in complex gene-environment interactions. The amount of endotoxin exposure may play a role in phenotypic expression. Individuals with the CC genotype were at lower risk of developing atopy when exposed to high levels of endotoxin; however, when exposed to lower levels of endotoxin, the CC genotype was associated with a higher risk of atopy.¹⁸ Nonfarm homes in westernized countries tend to have lower levels of endotoxin than farm homes, even in low-income urban areas.¹⁹ This implies that individuals with the CC allele, who are more likely to be African American, would be at greater risk for atopy in the United States. Greater knowledge of these types of gene-environment interactions may lead to improved understanding of the observations that have generated controversy concerning the “hygiene hypothesis.”

The details of how microbial exposure can influence the human immune response to antigen exposure are still being elucidated.²⁰

These examples highlight not only the importance of genetics in the development of asthma, but also the role genes play in variation of treatment response and subsequent risk of morbidity and death. An understanding of these genetic differences among patients is clearly important for moving towards personalized treatment strategies for asthma.

A developing strategy to assess the differences in asthma prevalence, severity, and response to treatment between racial groups is the use of ancestry-informative markers (AIMs).

AIMs are single-nucleotide polymorphisms that occur in varying allelic frequencies between ancestral groups, eg, continental Africans or European whites.²¹ AIMs provide an estimate of an individual’s proportion of ancestry—ie, of how “African” an African American is genetically.

African ancestry, determined using AIMs, was found to be associated with asthma in people living on the Caribbean coast of Colombia.²² However, one study found that AIMs could not predict an individual’s response to inhaled corticosteroids.²³

Further research is necessary to find a technique to determine how groups of individuals can be characterized more precisely and managed more appropriately.

SOCIOECONOMIC FACTORS

African Americans living in low-income urban areas have an even greater prevalence of asthma and a greater risk of asthma-related morbidity and death than African Americans overall.^3,24,25 Urban areas typically have a high proportion of residents living at or below the poverty level, and minorities often constitute a substantial proportion of the population in these areas. Evidence suggests that both African American race and lower socioeconomic status are independent risk factors for asthma prevalence, morbidity, and death.^3,25

To provide better care for African Americans living in low-income urban areas, it is important to understand the factors that may be contributing to the higher morbidity and mortality rates in low-income urban areas.

Inadequate follow-up

Proper and routine follow-up for evaluation of asthma symptoms is essential for appropriate management. The Expert Panel Report 3 (EPR-3) of the National Education and Prevention Program Guidelines for the Diagnosis and Management of Asthma,²⁶ published in 2007, recommends that patients be seen at least every 6 months if they have been experiencing good control. While gaining control, patients should be seen every 2 to 6 weeks.²⁶

Despite these recommendations, numerous studies have suggested that African Americans do not receive adequate follow-up. Children who are poor, are nonwhite or Hispanic, or are underinsured are more likely to lack routine health care²⁷ and, more specifically, routine asthma care.²⁸ Low-income patients are also more likely to receive care in a large hospital-run clinic or neighborhood clinic,^27,28 where continuity of care may be less than ideal.²⁹ Even among patients enrolled in Medicaid or Medicare, African American children with a primary care provider have fewer asthma visits compared with white Medicaid-insured children.³⁰

Insufficient follow-up care contributes to greater asthma morbidity, resulting in, for example, more emergency department visits for asthma in African Americans.^27,31,32

Suboptimal care

Data also suggest that the quality of care that residents of low-income urban areas receive is often suboptimal. Many people living in low-income urban areas are not provided with the knowledge and tools to treat asthma exacerbations at home.³³ African Americans are also less likely to be seen by an asthma specialist^31,34 as recommended for those with moderate or severe asthma.²⁶

The EPR-3 guidelines also stress the importance of inhaled corticosteroids as the preferred therapy for all patients with persistent asthma. Even after controlling for the number of primary care visits, insurance status, and disease severity, African Americans are less likely to receive a prescription for inhaled corticosteroids, or they receive the same dosage of inhaled corticosteroids in the face of more severe disease.^31,33,35,36

The reasons for these differences in treatment are not fully understood but are likely multiple. Lack of access to an asthma specialist and financial or formulary constraints are some of the potential barriers to optimal asthma care outcomes.

Misdiagnosis in the acute setting may also be a source of less-than-ideal care, as patients seen in emergency departments may be misdiagnosed with viral infection or bronchitis.

African Americans may report different symptoms than whites

Intriguing studies suggest that African Americans report different symptoms while describing asthma exacerbations.

In one study, compared with whites, African Americans were less likely to report nocturnal symptoms, dyspnea, or chest pain during exacerbations.³⁷ In another study, when given a methacholine challenge that induced a significant drop in forced expiratory volume in 1 second (FEV₁), African Americans with asthma were more likely to complain of upper airway symptoms as opposed to lower airway symptoms, compared with white patients.³⁸

The symptoms that African Americans describe, such as having a tight throat or voice, are not typically regarded as related to asthma; for this reason, such descriptions may be an obstacle to correct diagnosis, management, and follow-up.

Asthma care providers should be aware of these observations to ensure that their patients are managed appropriately.

Lack of social support

Living in a low-income urban area presents many challenges that can interfere with proper asthma control.

Asthma diagnosis, management, and morbidity are affected by family support.³⁹ Patients with asthma who lack sufficient financial support for treatment, who lack adequate psychological support, and who have more major life stressors are at higher risk of untoward outcomes. Disruption and dysfunction of the family and the supports available have been associated with greater asthma morbidity.^40–42 Unfortunately, these types of stressors are all too common in families living in low-income urban areas.^43–45

Multiple stressors that can occur more often in low-income urban areas, including exposure to violent crime, have also been linked to greater asthma morbidity.^45–47

POOR PHYSICIAN-PATIENT COMMUNICATION

A consistent theme in focus groups of African Americans living in inner-city areas is the perception that health care providers are not effectively communicating and taking the time to listen to their concerns.^48,49 Respondents believed they had better insight into their illness than their providers, and for this reason were better able to manage their disease.

The importance of an optimal provider-patient relationship was highlighted by a prospective cohort study in which Medicaid children receiving care at physician’s offices with the highest cultural competency scores were more adherent with their asthma controller medications.⁵⁰

MEDICATION ADHERENCE RATES ARE DISTURBINGLY LOW

Rates of medication adherence for chronic diseases is disturbingly low, and may be even worse for pulmonary diseases.⁵¹ Reported rates of adherence to asthma medications among all patients range from 50% to 60%.^52,53 Several studies showed that African Americans have a lower rate of adherence than do whites,^53–55 even after adjusting for multiple socioeconomic variables.⁵⁶

Many explanations have been proposed for this discrepancy, and all likely play a role in particular environments. For example, the incidence of crime in the surrounding area was inversely related to medication adherence after adjusting for socioeconomic factors.⁵⁷ African Americans may have more concern about side effects associated with inhaled corticosteroid use and may be less likely to understand how these drugs work.^52,53 A poor provider-patient relationship has also been cited as a barrier to adherence.^55,57 Finally, physicians are more likely to underestimate asthma severity in an African American patient than in a white patient.⁵⁸

Taking the time to ensure that patients truly understand all aspects of their disease and establishing a health care environment that is culturally appropriate may have a significant impact in patients with asthma.

ENVIRONMENTAL EXPOSURES

Air quality contributes to the greater asthma morbidity observed in urban residents, including African Americans. While poor outdoor air quality has not been clearly linked to a higher incidence of asthma, it has been associated with greater asthma morbidity. Poor air quality may affect individuals of all races, but with respect to ambient pollutants such as particulate matter and diesel exhaust, outdoor air quality is worse in urban environments where greater proportions of people of low socioeconomic status reside.^59,60

The most extensively studied components of air pollution are ozone, sulfur dioxide, and particulate matter. These pollutants have been associated with a higher rate of emergency department visits,^61,62 worse asthma symptoms,^63,64 and higher exhaled nitric oxide levels.⁶⁵

Tobacco smoke

Despite the substantial success of smoking cessation efforts nationwide, exposure to tobacco smoke continues to be common and is a significant risk factor for poor asthma control. Recent data suggest that African Americans and whites have a similar prevalence of smoking,⁶⁶ but a study found a very high prevalence in low-income African Americans.⁶⁷

Active smoking has been associated with worse asthma control and a higher risk of death.⁶⁸ People with asthma who smoke are less likely to improve in their lung function and symptom scores when treated with short courses of oral glucocorticoids compared with both nonsmokers and former smokers.⁶⁹

Secondhand smoke hurts too. Many children living in low-income urban areas are exposed to secondhand smoke or environmental tobacco smoke.^70,71 Passive exposure in children has been associated with worse asthma outcomes, and data suggest such exposure may be a cause of asthma.^68,72–74

Environmental tobacco smoke has also been implicated in gene-environment interactions. Patients who are either homozygous or heterozygous for the Arg allele at codon 16 of the ADRB2 gene (discussed above) had significantly lower FEV₁ and forced vital capacity (FVC) values when exposed to passive tobacco smoke. This difference was not seen in people who were not exposed.⁷⁵

Cockroach allergen

The type and condition of a person’s housing also plays a role in asthma-related morbidity and death. Across several socioeconomic levels, it has been suggested that African Americans have poorer-quality housing compared with whites.⁷⁶ Some of the conditions found in low-quality houses, such as interruptions in heat, plumbing leaks, and the presence of rodents, have been associated with a higher prevalence of asthma in the household.⁷⁷

Cockroach allergen exposure and sensitization is a major contributor to asthma morbidity in African Americans, particularly those living in poorer urban areas where cockroach allergen may be the most common indoor allergen.⁸ Living in older housing in urban areas is associated with higher exposure to cockroach allergen, and with subsequent sensitization.^78,79 Exposure to high levels of the major cockroach allergen, Bla g 1, in sensitized individuals has been linked to a greater risk of hospitalization and unscheduled medical visits for asthma. This was not found to be the case for other common indoor allergens, such as dust mite and cat dander.⁸

However, it is not only exposure to high cockroach allergen levels that puts African Americans at risk. African Americans living in low-income urban areas may also be more likely than whites living in low-income urban areas to become sensitized to cockroach allergen.^7,80 This suggests a gene-environment interaction that may be unique to African Americans. Moreover, cockroach sensitization may occur early in life.^81,82

While successful cockroach avoidance measures and environmental control may be challenging, such measures have been shown to decrease rates of asthma morbidity.⁸³

OBESITY

Obesity has been linked to an ever-growing list of diseases, one of which is asthma. Obesity is not a unique challenge for African Americans, but recent data from the US Centers for Disease Control and Prevention show that African Americans have a 51% higher prevalence of obesity compared with whites.⁸⁴

Obesity is a risk factor for greater asthma morbidity and is a significant challenge in the African American community. The rise in obesity rates has paralleled the rise in asthma in recent decades. The higher one’s body mass index, the higher one’s risk of asthma.⁸⁵ This association appears to be stronger in people without concurrent atopic disease.⁸⁶ Obesity has also been associated with a poorer response to inhaled corticosteroids and a higher risk of asthma exacerbations.⁸⁷ Interestingly, significant weight loss has been associated with improvements in both asthma control and lung function.^88,89

The underlying pathogenic mechanisms have not been completely elucidated, and they are likely multiple.

Adipokines (cytokines secreted by adipocytes) have been implicated. Two of the most extensively studied adipokines are leptin and adiponectin. Leptin production is increased in obesity, and it has inflammatory effects on both the innate and adaptive immune systems.⁹⁰ The opposite is true for adiponectin, which may have anti-inflammatory properties and which decreases as the body mass index increases.⁹⁰ The precise role these molecules may have in lung disease is undergoing further investigation.

Mechanical alterations in lung function may also contribute. Obese people have a lower functional residual capacity and expiratory reserve volume. Breathing with a lower-volume functional residual capacity results in decreased airway diameter and contributes to increased airway resistance.⁹⁰ The decreased airway diameter may alter the contractile properties of airway smooth muscle and lead to increased airway responsiveness.⁹⁰ These differences are in addition to the lower mean values of common spirometry indices such as the FEV₁ and FVC, found in nonasthmatic African Americans compared with whites.⁹¹

Data suggest these differences are primarily due to anthropometric factors, with nutritional and environmental factors playing a less significant role.⁹² On this basis, the American Thoracic Society recommends applying race-specific reference standards for use with spirometry in order to accurately gauge lung function in African Americans.

APPROPRIATE CARE AND EDUCATION

The cause of greater asthma prevalence and severity among African Americans is multifactorial. It is likely that a number of factors work together, rather than separately, in influencing the development of asthma and its course.

Some risk factors are avoidable, and it is important to identify and ameliorate them. Others are not preventable, but knowledge of them may provide more specific management strategies and may lead to new therapies in the future.

While more work is needed to further unravel the complex risk factors associated with asthma, ensuring that higher-risk patients are provided the appropriate care and the knowledge to help control their disease is a necessary step in improving the disparities in asthma care outcomes.