Research opportunities for reducing racial disparities in kidney disease

Research Opportunities for Reducing Racial Disparities in Kidney Disease Thomas H. Hostetter Several minority populations in the United States have higher risks for end-stage renal disease than does the white population. This article addresses some areas for research aimed at reducing the disproportionate risks. Four general areas are considered: health services, risk factors and causative agents, clinical trials, and awareness campaigns. © 2004 by the National Kidney Foundation, Inc. Index Words: Chronic kidney disease; research; race; ethnicity: health services.

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lacks and Native Americans bear exceptionally high risks for end-stage renal disease (ESRD). Hispanics and some Asian groups also have somewhat greater risks than the white population in the United States. These facts are well known. This article will attempt to offer some approaches to research that can reduce or eliminate these discrepancies.

Health Services Delivery Preventive measures can avert the development of chronic kidney disease (CKD). Glycemic and blood pressure control are the 2 most modifiable factors, although smoking cessation may also be beneficial to kidney function as it certainly is for cardiovascular health.1 Awareness of hypertension is comparable between blacks and whites, but Mexican Americans have a significantly lower degree of awareness.2 However, among middle-aged hypertensives (age 40-59 years) both blacks and Mexican Americans had lower prevalences of adequate control than whites.2 Glycemic control also lags in black women and Mexican American men.3 The reasons for the discrepancies are likely complex, but further scrutiny of potentially modifiable elements seems merited. For example, do providers accept higher achieved blood pressures in some groups despite uniform guidelines? Are there variable rates of compliance? Do regimens have inconsistent efficacy across groups? Identification of CKD is essential to the secondary preventive strategies noted below. Laboratory testing of patients at risk is critical because CKD is asymptomatic in its earliest stages when it is most amenable to effective intervention. In general, health screening

seems to be poorer in minorities than in the majority population. Schneider and coworkers4 reported that adherence to 4 quality indicators for enrollees in Medicare managed care plans was lower for blacks than whites.4 One of these indicators was eye examination for people with diabetes. Similar surveys for testing for CKD would be informative. The most accepted test for CKD is the annual screening for albuminuria in people with diabetes. Because estimates indicate that only 10% to 20 % of patients receive this testing in the general population, it might be hard to detect differences among racial or ethnic groups.5 CKD can be treated and its progression to ESRD delayed.1 However, solid clinical evidence for this assertion has only appeared over the last decade. In the early 1990s, the Diabetes Control and Complications Trial showed not only that rigorous glycemic control prevented the appearance of early kidney disease, but also it delayed progression in those with established microalbuminuria.6 Around the same time, Lewis and colleagues7 published the results of the first clinical trial showing the efficacy of an angiotensin-converting enzyme (ACE) inhibitor in attenuating the course of established diabetic nephropathy. Subsequently, multiple trials in other kidney diseases, including hypertensive nephroFrom the National Institutes of Health, National Institute of Diabetes, Digestive, and Kidney Diseases, Bethesda, MD. Address correspondence to Thomas H. Hostetter, National Institutes of Health, National Institute of Diabetes, Digestive, and Kidney Diseases, 6707 Democracy Blvd, Room 625, Bethesda, MD 20892. E-mail: [email protected] © 2004 by the National Kidney Foundation, Inc. 1073-4449/04/1101-0008$30.00/0 doi:10.1053/j.arrt.2003.10.009

Advances in Renal Replacement Therapy, Vol 11, No 1 (January), 2004: pp 59-65

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sclerosis in blacks, have attested to the value of ACE inhibitor based hypertension therapy in CKD.1,8,9 In the last several years, angiotensin receptor blockers have been similarly validated at least in diabetic CKD.10,11 Also, in this period, meta-analyses of several trials confirmed that dietary protein restriction could mitigate the course of CKD.12 Given the relative recency of this information, a first question might be whether this knowledge has yet informed practice and in particular has it informed the care of the groups sustaining disproportionate degrees of ESRD. For the general population, data published in 1997 indicated that less than one third of Medicare beneficiaries who had laboratory evidence of CKD on an inpatient test were discharged on an ACE inhibitor. Whether there were racial differences was unreported.13 Racial disparities do exist in the time of referral to a nephrologist of patients destined for ESRD. Kinchen and colleagues14 found that black patients were more likely to receive late referral than white. Because the time of referral can be related to prognosis with ESRD, poorer overall care for CKD may exist. Clearly, studies of discrepancies in delivery of established standards of care could be informative. Late referral may betoken poor provision of glycemic control, blood pressure therapy with ACE, and dietary counseling in earlier stages of CKD among blacks than the majority population. However, studies are needed to test this hypothesis and even more importantly ascertain the bases should it prove true. Thus, at the levels of primary prevention, screening for CKD, and provision of secondary prevention to those with CKD, observational investigations are needed to test in more detail for racial disparities in delivery of effective CKD care. However, for each of these steps in the disease course, evidence suggests that notable racial discrepancies exist. Although large social and political issues such as variation in health care insurance loom, the available data suggest that even within covered populations, such as managed care and/or Medicare beneficiaries, disparities exist. Their causes, likely complex, need further exploration.

Epidemiology and Mechanistic Studies The simple hypothesis that systematic differences in provision of care among different groups contribute to varying prevalences of ESRD seems highly likely but incomplete. Other data suggest that additional factors are also at work. Traditional risk factors classified under socioeconomic (eg, education and income), lifestyle (eg, smoking, activity and obesity), and clinical (eg, hypertension and diabetes) categories in aggregate accounted for about one half of the excess risk for ESRD in blacks compared with whites.15 This analysis of data from the National Health and Nutrition Examination does not strictly test adequacy of care, but it does suggest that modifiable factors, factors that could in principle be influenced by health care, although important, are not alone sufficient to account for ESRD differences between blacks and whites. A more direct assessment of the importance of uneven care was provided by a study of people with diabetes managed within a single private health plan.16 Again adjusting for known risk factors, an increased risk for ESRD was noted in blacks, Latinos, and Asians as compared with whites. Such results call for renewed efforts at discovering unrecognized risk factors. Several ongoing studies may provide new insights. The African American Study of Kidney Disease began as a randomized controlled clinical trial of level of blood pressure control and type of drug in hypertensive nephrosclerosis.9 However, a continuing observational study of this cohort has begun. About 650 to 700 individuals form the original trial are projected to remain with cohort study.17 The subjects will be offered antihypertensive care with the agent proven best in the trial, an ACE inhibitor. In this way, these aspects of progression should be held constant potentially allowing for uncovering new risk factors. The long follow-up comprising both the trial and the subsequent observation will yield a total of 9 to 12 years in which to document the course of disease. The Chronic Renal Insufficiency Cohort will be another observational study supported by the National Institute of Diabetes and Digestive and Kidney Diseases.18 Plans call for

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enrolling 3,000 adult subjects across a wide range of ages with intentional over sampling of blacks and people with diabetes. The course of their kidney disease will be tracked along with selective measurements of cardiovascular disease. Again, biological samples will be stored in addition to testing for currently proposed risk factors. The Kidney Early Evaluation Program sponsored by the National Kidney Foundation constitutes yet another resource from which to test for risk associations in cohorts whose CKD outcomes are to be followed.19 Fifteen centers plan to develop a study population of 6,900 subjects with high risk for CKD and annual surveillance after enrollment. These observational studies will only be successful in providing new insights if the right factors are measured. However, the careful documentation of the course of disease and known predisposing influences together with archiving of samples should allow novel determinants to be tested as they arise in the future. A wide range of risk associations has been proposed for CKD and its progression to ESRD.20 However, in a retrospective examination of the 830 subjects in the Modification of Diet in Renal Disease study, only 6 of 41 hypothesized variables predicted rates of functional decay in multivariate analysis. They were black race, polycystic kidney disease, greater levels of proteinuria and blood pressure, and lower levels of transferrin and HDL cholesterol.21 Several more including Creactive protein, leptin, and homocystine have since been tested in this fairly well-characterized data set and found not to add to the 6 mentioned ones.22,23 Some that seem relatively well supported from other sources such as glycemic control in diabetes and familial aggregation can reasonably adduced as well.6,24,25 Still, at present, we can point with confidence to a fairly modest number of discrete predictors. Specific candidates can only arise from more work and imagination. Given the higher risk for ESRD in certain ethnic groups, analysis of risk factors based on such groups may be fruitful. Indeed, if certain factors are specific to a given group, then such an approach will be necessary. Because larger numbers of various groups accrue in the previously noted

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studies, such an approach should become more feasible. Nevertheless, some groups such as certain Asian Pacific Islanders and even Hispanics may not have sufficient samples sizes. This may not prove to be a significant barrier. Although specific risk factors/ causative agents may, in theory, associate uniquely with ethnic groups at risk, varying levels/exposure to factors that are injurious generally, in all populations, seems much more likely. If so, a risk factor such as a signaling molecule, an environmental toxin, an infectious agent, or a developmental variant should be discernible in the general population of CKD or ESRD but be in greater abundance in higher risk groups. Despite the current paucity of well-substantiated predictors of CKD and its progression, a rather large assortment of possibilities can be assembled. Some of these have not been yet examined, and others may be difficult to appraise even in the emerging cohort studies. A few can be considered. Among the host of cytokines proposed as critical in progressive kidney injury, transforming growth factor ␤ (TGF-␤) has been particularly often incriminated.26 Moreover, blacks with hypertension have higher circulating TGF beta levels than white hypertensives.27 Blacks with ESRD also have higher plasma levels of TGF-␤ than do whites with ESRD.28 Together, with considerable animal and cellular data, these observations raise the possibility that some systematic difference in TGF-␤ protein may contribute to the greater prevalence of kidney injury in blacks. The basis for this difference is not certain, but in blacks higher levels of TGF-␤ RNA were noted in peripheral blood monocytes, as well as a greater prevalence of a polymorphism for TGF-␤.27 Further exploration of this observation seems warranted, as well as extending the question to other high-risk groups. The success of ACE inhibitors and angiotensin receptor blockers (ARBs) in treating CKD focuses attention on the renin-angiotensin-aldosterone system (RAAS) as a possible factor in determining progression of CKD. In the hypertensive population, black patients tend to have lower renin values than whites.29 Also, in the general population of people with CKD, plasma renin activity is not especially

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elevated.30,31 These findings raise the paradoxical situation that drugs specific to the RAAS system are effective in a situation wherein the system is not notably activated. Although intrarenal levels of renin may be high, the levels of angiotensin II are not elevated, at least in animal models of CKD in which they can be measured accurately.32 On the other hand, aldosterone levels are elevated in both animals and humans with CKD.33 In this context, the possibility has arisen that ACE inhibitors and ARBs work in large part through suppression of aldosterone. Further examination of the RAAS in CKD and the aldosterone component may yield a risk factor that can be targeted. Environmental toxins, such as lead and infectious agents, such as human immunodeficiency virus, can engender CKD. Even though discrete etiologic agents such as these are thought to be rare within the whole scope of ESRD, maintaining an open mind to such factors seems prudent. For example, identification of a bacterial cause for a large fraction of peptic ulcer disease was an astonishing and relatively recent discovery. Searches for occult microbial causes or contributors to ESRD should not be dismissed. Likewise, classic toxins such as heavy metals may abet the course of the large categories of CKD such as diabetes and hypertension, even if not the sole cause. In this regard, the recent demonstration that chelation attenuated the decline in kidney function of a selected group of CKD patients suggests that either relatively low levels of known toxins such as lead or unknown but chelatable toxins can provoke or accelerate injury.34 Renal developmental variation, especially variation in nephron number, may underlie CKD. Specifically, several writers have suggested that people with lower nephron numbers are more subject to CKD.35 Some have proposed a chain of events beginning with genetic or intrauterine factors yielding low birth weight and concomitant diminution in nephron population. Indeed, a recent article associates lower nephron numbers with hypertension.36 The distal link to low birth weight is more controversial but also has support.37 Blacks do, as a group, have lower birth weights, but 1 recent article found no racial

disparity in nephron numbers between blacks and whites.37,38 Because major reductions in kidney mass by uninephrectomy lead to little if any hypertension or excess kidney disease, the possibility that hypertension is being caused by a process of accelerated senescence/apoptosis, that simultaneously is also removing nephrons, is also worthy of consideration.39 Enumeration of nephron number is difficult and at present can only be achieved on autopsy material. Unless other approaches can be developed, this area of investigation will remain unsettled even though intriguing. Careful epidemiological investigations of maternal and gestational characteristics of those with CKD and ESRD may yield hints even short of providing clear pathophysiologic or anatomic mechanism and seem worthwhile. Genetic approaches for dissecting racial disparities are often considered and are to some degree controversial.40,41 Because the identification of predisposing/protective genetic variation for complex diseases has been a slow and to date not particularly fruitful endeavor, finding genetic risk factors for racial disparities for CKD seems relatively remote. The familial aggregation of risk for diabetic CKD is nevertheless a strong motivation for these efforts.24,25 The Familial Investigation of Diabetic Nephropathy seeks to discover genetic variants contributing to risk. Both blacks and Hispanic are being studied in high numbers in this trial.42 Proteomic and gene expression approaches to identifying risk factors or markers of CKD progression will surely be projects of the coming years. Again, racially specific patterns may emerge. However, similar patterns associated with risk but with varying prevalence between different racial groups seem a more likely result.

Clinical Trials Trials of therapies would be most reasonably tailored for a specific group if unique modifiable risk factors existed for that group or if especially high prevalence of a common risk factor were found in a group. However, as noted in the foregoing discussion, at present no particular risk factor has been identified for any of the groups at who have known excess

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jeopardy for ESRD. Diabetes and hypertension do afflict blacks disproportionately and diabetes is highly prevalent in Native American and Hispanic groups. However, risk factors or causative pathways more proximal to the CKD, of the types sketched earlier like growth factors or dysregulation of a hormone, are only beginning to emerge in the general population. Thus, firm recognition of specific ethnic risks at this more intimate molecular level of causation is yet more distant. Nevertheless, studies focused on a group could have value. It should be noted that some have raised cautions regarding this approach.43 For various reasons including the low plasma renin activity in black hypertensives, ACE inhibitors had been viewed as poor, ineffective choices for therapy in blacks. The African American Study of Kidney Diseases trial described earlier showed that contrary to this impression blacks with hypertensive CKD did better with this class of drug than with calcium channel blockers or beta-blockers.9 On the other hand, a trial of an ACE inhibitor for left ventricular dysfunction found on a subgroup analysis that blacks did not obtain the benefits that the whites received.44,45 Obviously, subgroup analyses after a trial is completed can be misleading, but this sort of result raises a rationale for race specific trials. Drug trials conducted in a highrisk group are likely to be more efficient than trials in groups with a range of risk as endpoints appear much more quickly. Of course, a positive result in such a high-risk group would imply nothing about the drug’s efficacy or lack thereof in other groups. In addition to traditional pharmaceutical trials, 2 other trials might be of particular interest in addressing racial disparity in ESRD. Preemptive or prophylactic therapy with ACE inhibitors has some theoretical support. The case has been made that for older and/or high-risk patients with diabetes this approach is cost saving largely by delaying ESRD.46,47 Such analyses would be informative using racial risk as a component of the calculation. If reanalysis of this sort still projects favorable outcomes a formal trial, although a formidable undertaking, should be considered. A major advantage of preemptive therapy is that the need for screening and

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interpretation of tests is largely superseded. Another class of trial using race as a component, or perhaps even necessary entry criterion, would be of modes of care delivery. Quite possibly different disease management strategies would work better in different settings. To be sure, fundamental issues such as medical coverage dominate models of delivery but cultural sensitivities and practical implications thereof might profitably be tested in different models of care for CKD and the conditions predisposing to it.

Risk Group Awareness Over the last several years, government, nonprofit groups, and industry have begun to work at raising awareness among people at risk. The National Kidney Disease Education Program of the National Institute of Diabetes and Digestive and Kidney Disease has begun pilot site testing of materials and methods targeted at blacks at risk (diabetes, hypertension, and/or a family member with ESRD) and at primary care providers.48 In the course of this program, an evaluation process is obtaining baseline and control population data. Although, at present, messages for medical therapy and testing do not differ across ethnic groups, culturally more effective and resonant methods of delivering messages appear to be important. Further testing to determine these best channels is needed.

Summary Despite the vagaries of race and its reporting, ESRD does powerfully associate differentially among racial categories. As fraught as any racially directed effort may be, thoughtfully designed research in at least 4 major areas seems justified with the aim of reducing and hopefully eliminating disparities in ESRD. Understanding differences in current delivery of effective therapy is needed. Testing for unique or more likely enrichment of new risk factors and causative agents in high-risk group needs to proceed. Testing variation in effective use of certain drugs and even methods of conveying care are also warranted in some cases. However, we must be cautious that race-based trials are not just conveniences

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for more efficient trial design, but they answer genuine questions of pharmacological variance. Finally, careful scrutiny of the methods for enhancing awareness and education is needed.

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15. Tarver-Carr ME, Powe NR, Eberhardt MS, et al: Excess risk of chronic kidney disease among AfricanAmerican versus white subjects in the United States: A population-based study of potential explanatory factors. J Am Soc Nephrol 13:2363-2370, 2002 16. Karter AJ, Ferrara A, Liu JY, et al: Ethnic disparities in diabetic complications in an insured population. JAMA 287:2519-2527, 2002 17. Appel LJ, Middleton J, Miller ER3rd, et al: The rationale and design of the AASK cohort study. J Am Soc Nephrol 14:S166-172, 2003 18. Feldman HI, Appel LJ, Chertow GM, et al: The Chronic Renal Insufficiency Cohort (CRIC) Study: Design and methods. J Am Soc Nephrol 14:S148-153, 2003 19. Ohmit SE, Flack JM, Peters RM, et al: Longitudinal Study of the National Kidney Foundation’s (NKF) Kidney Early Evaluation Program (KEEP). J Am Soc Nephrol 14:S117-121, 2003 20. McClellan WM, Flanders WD: Risk factors for progressive chronic kidney disease. J Am Soc Nephrol 14:S65-70, 2003 21. Hunsicker LG, Adler S, Caggiula A, et al: Predictors of the progression of renal disease in the Modification of Diet in Renal Disease Study. Kidney Int 51:19081919, 1997 22. Sarnak MJ, Poindexter A, Wang SR, et al: Serum C-reactive protein and leptin as predictors of kidney disease progression in the Modification of Diet in Renal Disease Study. Kidney Int 62:2208-2215, 2002 23. Sarnak MJ, Wang SR, Beck GJ, et al: Homocysteine, cysteine, and B vitamins as predictors of kidney disease progression. Am J Kidney Dis 40:932-939, 2002 24. Freedman BI, Soucie JM, McClellan WM: Family history of end-stage renal disease among incident dialysis patients. J Am Soc Nephrol 8:1942-1945, 1997 25. Jurkovitz C, Franch H, Shoham D, et al: Family members of patients treated for ESRD have high rates of undetected kidney disease. Am J Kidney Dis 40:11731178, 2002 26. Kim S, Ohta K, Hamaguchi A, et al: Role of angiotensin II in renal injury of deoxycorticosterone acetatesalt hypertensive rats. Hypertension 24:195-204, 1994 27. Suthanthiran M, Li B, Song JO, et al: Transforming growth factor-beta 1 hyperexpression in AfricanAmerican hypertensives: A novel mediator of hypertension and/or target organ damage. Proc Natl Acad Sci USA 97:3479-3484, 2000 28. Suthanthiran M, Khanna A, Cukran D, et al: Transforming growth factor-beta 1 hyperexpression in African American end-stage renal disease patients. Kidney Int 53:639-644, 1998 29. Grim CE, Luft FC, Miller JZ, et al: Racial differences in blood pressure in Evans County, Georgia: Relationship to sodium and potassium intake and plasma renin activity. J Chronic Dis 33:87-94, 1980 30. Kahn T, Mohammad G, Bornia ME, et al: Control of plasma renin activity in chronic stable renal disease. J Lab Clin Med 85:637-644, 1975 31. Rosenberg ME, Smith LJ, Correa-Rotter R, et al: The paradox of the renin-angiotensin system in chronic renal disease. Kidney Int 45:403-410, 1994

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32. Mackie FE, Campbell DJ, Meyer TW: Intrarenal angiotensin and bradykinin peptide levels in the remnant kidney model of renal insufficiency. Kidney Int 59:1458-1465, 2001 33. Ibrahim HN, Hostetter TH: Aldosterone in renal disease. Curr Opin Nephrol Hypertens 12:159-164, 2003 34. Lin JL, Lin-Tan DT, Hsu KH, et al: Environmental lead exposure and progression of diabetes in patients without diabetes. N Engl J Med 348:277-286, 2003 35. Brenner BM, Garcia DL, Anderson S: Glomeruli and blood pressure. Less of one, more the other? Am J Hypertens 1:335-347, 1988 36. Keller G, Zimmer G, Mall G, et al: Nephron number in patients with primary hypertension. N Engl J Med 348:101-108, 2003 37. Hughson M, Farris AB, Douglas-Denton R, et al: Glomerular number and size in autopsy kidneys: The relationship to birth weight. Kidney Int 63:2113-2122, 2003 38. David RJ, Collins JW Jr: Differing birth weight among infants of U.S. -born blacks, African-born blacks, and U.S.-born whites. N Engl J Med 337:1209-1214, 1997 39. Narkun-Burgess DM, Nolan CR, Norman JE, et al: Forty-five year follow-up after uninephrectomy. Kidney Int 43:1110-1115, 1993 40. Cooper RS, Kaufman JS, Ward R: Race and genomics. N Engl J Med 348:1166-1170, 2003 41. Burchard EG, Ziv E, Coyle N, et al: The importance of

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race and ethnic background in biomedical research and clinical practice. N Engl J Med 348:1170-1175, 2003 Genetic determinants of diabetic nephropathy: The family investigation of nephropathy and diabetes (FIND). J Am Soc Nephrol 14:S202-204, 2003 Haga SB, Venter JC: Genetics. FDA races in wrong direction. Science 301:466, 2003 Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD Investigators: N Engl J Med 325:293-302, 1991 Exner DV, Dries DL, Domanski MJ, et al: Lesser response to angiotensin-converting-enzyme inhibitor therapy in black as compared with white patients with left ventricular dysfunction. N Engl J Med 344: 1351-1357, 2001 Golan L, Birkmeyer JD, Welch HG: The cost-effectiveness of treating all patients with type 2 diabetes with angiotensin-converting enzyme inhibitors. Ann Intern Med 131:660-667, 1999 Kiberd BA, Jindal KK: Routine treatment of insulindependent diabetic patients with ACE inhibitors to prevent renal failure: an economic evaluation. Am J Kidney Dis 31:49-54, 1998 Hostetter TH, Lising M: National kidney disease education program. J Am Soc Nephrol 14:S114-116, 2003