DIABETES MELLITUS AND HYPERTENSION: KEY RISK FACTORS FOR KIDNEY DISEASE Janice P. Lea, MD, and Susanne B. Nicholas, MD, PhD Atlanta, Georgia, and Los Angeles, California The incidence of end-stage renal disease (ESRD) in the US is rising at an alarming rate, with the largest increase among African-American populations. The key risk factors for kidney disease are hypertension and diabetes, which are both becoming more prevalent in the US, and particu- larly in African Americans. Although African Americans make up 12.6% of the US population, the incidence of diabetes-related ESRD is four times higher than for whites, and the prevalence of ESRD due to hypertension is twice that of white patients. Approximately 30 to 40% of all patients with diabetes will develop nephropathy and many will progress to ESRD, necessitating dialysis or kidney transplantation. Recent studies in patients with type 2 diabetes indicate a significant delay in progression or development of diabetic nephropathy following blockade of the renin- angiotensin-aldosterone system with the use of angiotensin receptor antagonists. Early intervention in patients with hypertension is necessary to prevent kidney damage, and data from the African American Study of Kidney Disease and Hypertension suggest that angiotensin- converting enzyme inhibitors are effective in this population. Although African-American patients receiving hemodialysis appear to have increased survival compared with whites, racial factors and poor access to medical care contribute to the increased risk of kidney disease in minorities. A con- certed effort is necessary to raise awareness in minority populations and provide strategies for prevention and early treatment thereby attenuating the increasing prevalence of kidney failure in these groups. Key words: end-stage renal disease * next 10 years.5 In general, the most common diabetes + hypertension + kidney disease causes of ESRD are diabetes and hypertension (Fig. 1).5 Chronic kidney disease (CKD) and end-stage A major risk factor for the development oftype renal disease (ESRD) affect an increasing pro- 2 diabetes is obesity.6 Therefore, it is thought that portion of the population in the US. 1-3 The Third the dramatic increase in the incidence of ESRD National Health and Nutrition Examination that has been observed over the past 20 years is Survey (NHANES III) recently estimated the attributable to the epidemic of type 2 diabetes that prevalence of CKD (defined as a serum creatinine has occurred during this time. At present, approxi- level of > 1.5 mg/dL) in the US to be approxi- mately 15.6 million Americans have diabetes, pre- mately 6.2 million,4 and the number of patients dominantly type 2 diabetes. A further 13.4 million with ESRD is expected to almost double in the have impaired glucose tolerance,7 and 50 million have hypertension.8 However, the prevalence of © 2002. From Emory University School of Medicine, Atlanta, Georgia; and the University of California School of Medicine, Los diabetes, hypertension, and obesity is significantly Angeles, California. Address correspondence to: Janice R Lea, higher in African Americans than in whites, MD, Assistant Professor of Medicine, Department of Medicine, particularly in the Southeastern region of the US. Emory University School of Medicine, Woodruff Memorial Building, Atlanta, GA 30322; phone (404) 727-2521; fax (404) In fact, the prevalence of hypertension in African 727-3425; or direct e-mail to [email protected]. Americans is among the highest in the world.9 JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL. 94, NO. 8 (SUPPL), AUGUST 2002 7S KEY RISK FACTORS FOR KIDNEY DISEASE (IDNT) studies have reported the effect of 100 angiotensin receptor antagonism on delaying the 90 progression and development of diabetic nephropathy in hypertensive type 2 diabetics. 80 These studies were performed in large populations with representative (A14%) African-American - 70 enrollment.15,16 These studies have demonstrated C 60 that blockade of the RAAS via angiotensin recep- 50.1 tor blockade can also improve BP, and attenuate a g 50 rise in serum creatinine levels and the time to ESRD. However, the lessons learned from these j40. latter studies can only be useful if patients are 30 27 monitored aggressively, not only for BP and blood glucose, but also for early detection of proteinuria 20 and deterioration in kidney function. 10 This review will focus on the two main caus- es of the increase in the prevalence of ESRD, 0 diabetes and hypertension. It will also discuss Diabetes Hypertewon reasons for disparities between populations, highlight risk factors in the post-transplant per- iod, explore factors contributing to suboptimal Figure 1. Primary Causes of ESRD.5 care in these patients, and propose steps to Data from US Renal Data System 2000. address these issues. As a result, the adjusted incidence ofESRD among REASONS FOR RACIAL DISPARITIES African Americans in the Southeastern US has IN KIDNEY DISEASE been estimated to be up to 15-fold greater than Demographic data suggest that those most in whites.10 In addition, even when hypertension susceptible to ESRD are the elderly (> 65 years is well-controlled, there is a tendency for African of age), those of low socioeconomic status, Americans to suffer impairments in kidney and minority groups, particularly African function.1 1,12 Americans.10 In addition, data from the Multiple Recently, the African-American Study of Risk Factor Intervention Trial (MRFIT) and Kidney Disease and Hypertension (AASK) exam- Modification of Diet in Renal Disease (MDRD) ined the role of the renin-angiotensin-aldosterone study suggest a significantly greater rate of loss system (RAAS) and the use of angiotensin- of kidney function in African Americans with converting enzyme (ACE) inhibitors in the hypertension compared with whites. 12,17,18 Taken management of hypertension, specifically in together, these data suggest that African African Americans.13 Preliminary findings have Americans possess a unique susceptibility to demonstrated that ACE inhibitor therapy can effec- kidney disease. tively improve blood pressure (BP) and signifi- A complex interplay of genetic, cultural, cantly reduce the rate of rise of serum creatinine social and environmental influences, as well as levels and time to ESRD. 14 In addition, the healthcare inequities, play a part in the racial Reduction of Endpoints in NIDDM with the disparities associated with kidney disease.1 9-21 Angiotensin II Antagonist Losartan (RENAAL) Diets high in calories, carbohydrates, and and Irbesartan Type II Diabetic Nephropathy Trial sodium, but low in potassium, magnesium, and 8S JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL. 94, NO. 8 (SUPPL), AUGUST 2002 KEY RISK FACTORS FOR KIDNEY DISEASE calcium, are common in minority populations, Pathogenesis of Diabetic and may contribute to the higher prevalence and Kidney Disease severity of hypertension among African Early in the course of diabetic nephropathy, Americans compared with whites.22 African- changes in kidney hemodynamics and hyperfiltra- American patients with hypertension have higher tion lead to an increase in glomerular filtration rate rates of salt sensitivity, and recent evidence sug- (GFR).26 The progression of nephropathy involves gests that this causes higher rates of left ventricu- characteristic pathologic changes, including accu- lar hypertrophy, higher serum creatinine levels, mulation of the extracellular matrix, widening of and increased urinary albumin excretion, as well the glomerular basement membrane, arteriosclero- as retinopathy.23 High sodium diets increase sis, and some degree of interstitial fibrosis.27 To BP,24 and so raise intraglomerular pressure in date, there is no evidence of any significant differ- salt-sensitive patients, which may contribute to ence in the histologic changes that occur in African the propensity for kidney failure in African Americans and whites. Americans. How sodium sensitivity increases the The earliest clinical manifestation of diabetic risk of cardiovascular events remains unknown, nephropathy is microalbuminuria (20 to 200 but it may be due to concurrent microalbumin- ,ug/min), which, if left untreated, can progress to uria. Clustering of several factors with well- overt nephropathy after 10 to 15 years of diabetes, known atherogenic potential, including hyper- and is also a marker for cardiovascular disease.27 insulinemia, hyperlipidemia, and microalbumin- In African Americans, albuminuria may be present in 30 to 40% of with uria, in salt-sensitive hypertensive patients patients diabetic nephro- may pathy.28,29 However, delayed diagnosis and poorer explain, in part, their increased risk of cardiovas- control of plasma glucose and BP among African- cular disease. In fact, this metabolic syndrome, American patients reduce the chances of improve- also termed syndrome X, is associated with ment and resolution of microalbuminuria. Some of obesity and type 2 diabetes, and may be more the clinical features that are characteristic oftype 2 prevalent in African Americans.25 diabetic nephropathy are listed in Table 1. In fact, the increasing racial disparities in Although, poor glycemic control and hyper- diabetic nephropathy in African Americans may tension are the major risk factors in African be directly related to the increased incidence of Americans that contribute to a more rapid pro- obesity, particularly in African-American females gression to ESRD, other putative risk factors who demonstrate the highest prevalence,