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Still, some individuals believe that renal failure due to primary (essential, non-malignant) hypertension does not exist or else that it is overstated as a cause of renal failure (Schlessinger, 1994; Siewart-Delle, 1998). Data from the USRDS (USRDS 1997) and NHANES (Burt 1995) March 25, 2004 4 suggest that the annual rate for developing ESRD in the hypertensive population ranges from 1/500 to 1/1100 depending on whether all hypertensives or just treated hypertensives are examined. Thus, unless a very large population of hypertensives is studied, or a high-risk population, such as hypertensive African Americans, is enrolled, few patients will develop renal failure and therefore ESRD will not be considered an important consequence of hypertension. In contrast, the feasibility study for the study for the AASK Trial, using strict clinical criteria for hypertension-related kidney disease, found only arterio- and/or arteriolonephrosclerosis as the primary lesion in 38/39 renal biopsies performed in these subjects (Fogo, 1997).

The mechanisms by which hypertension might damage the kidney are numerous. Translational and shear forces produced by hypertension damage the vascular endothelium causing vascular growth; vascular hypertrophy; local release of ANG II, TGFß1, inflammatory cytokines;

mesangial cell proliferation; fibroblast transformation; matrix accumulation; and glomerular scarring (O’Callaghan, 2000, Border, 1998). Of interest, TGFß1 has been demonstrated to be over expressed in African Americans with chronic renal failure (Suthanthiran, 1998).

Sustained glomerular hypertension, in part a result of systemic hypertension, may produce glomerular hyperfiltration, increased mesangial cell activity and subsequent scarring by intermediary processes similar to those noted above (Brenner, 1985). In the case of African Americans, the process of glomerular damage may be greater than in whites since data suggest greater hyperfiltration in African Americans in response to a solute load (Parmer, 1994). Also, increased wall:lumen ratios from pre-puberty through adulthood has been reported either because of an intrinsic alteration or a consequence of a more exuberant response to the effects of blood pressure (Tracy, 1990). This may result in increased renal vascular resistance, reduced renal blood flow and renal ischemia (Frolich, 1990). The importance of these molecular effects of hypertension is underscored by the finding that certain antihypertensives, especially ACEI, show renoprotective effects, which might be independent from their antihypertensive effects (Agodoa, 2001).

Management of Hypertension: Despite aggressive blood pressure control and despite use of reno-protective antihypertensive medications, hypertension-related renal disease commonly March 25, 2004 5 progresses. Among participants enrolled in the MRFIT clinical trial, blacks experienced deterioration of renal function (as measured by reciprocal creatinine slope) despite conventional blood pressure control, i.e. an average diastolic BP 95 mmHg (Walker, 1992). In contrast, non-blacks in MRFIT with similarly controlled blood pressure had stable renal function. Initial published results from the AASK trial (Agodoa, 2001) confirm this observation, that is, among the 436 persons assigned to ramipril, all of whom received conventional or aggressive blood pressure control, there were 47 cases of ESRD and 44 instances of substantial GFR decline (either a 50% decline in GFR or reduction of 25 ml/min/1.73 m2 from baseline). Final but as yet unpublished results from AASK confirm that even those patients assigned to the most effective therapy, on average, had substantial declines in GFR (see Section 4). The focus of the AASK Cohort study is to determine the factors that explain this decline in renal function that occurs despite control of blood pressure to recommended levels.

Environmental and Socio-Economic Factors: As a group, African Americans, like other minority groups in the US, often have less education and lower incomes than their white counterparts. They also may live in high stress environments and have less secure employment.

This situation has important health implications and may produce reduced access to medical care, poor understanding of medical problems, less aggressive health seeking behavior and as a result less effective, minimal or no medical care (Feldman, 1992). An ecologic analysis of patients with ESRD has revealed a strong positive association between the percentage of families below the poverty line by each zip code and the number of patients with ESRD (Rostand,1992) suggesting an important role for socioeconomic factors in the genesis of chronic renal failure. In contrast, Byrne and colleagues (1994) found that at all levels of income, African Americans had a significantly greater prevalence of ESRD than whites; this finding suggests that in addition to socioeconomic factors, other factors account for the higher prevalence of ESRD in AfricanAmericans than in non-African-Americans.

It is difficult to tease apart the effects of socio-economic from the effects of environmental factors on the progression of renal disease. In any group of people, social structure and culture have major economic and health consequences, the latter resulting from changes in diet, physical activity, and other exposures, that may cause increased body mass, diabetes, hypertension, March 25, 2004 6 atherosclerosis, and low birth weight. In the case of African Americans, a large percent have a blunted rate of renal sodium excretion and evidence of blood pressure that is salt sensitive (Weinberger, 1986). This has led to an hypothesis (Wilson, 1991) suggesting that as a consequence of the African Diaspora and exposure to Western cultural practices, these people, acclimated for millennia to a low salt intake, became exposed to high salt diets that could not be excreted effectively producing not only high blood pressure but also hyperfiltration, glomerular hypertension and attendant renal damage. A similar construct has been postulated by Brenner et al (1982) for the glomerular sclerosis resulting from high protein diets.

In addition to salt and protein, other dietary factors such as obesity and dyslipidemia may promote renal damage. In this regard, restricting calories has, at least in animal studies, been shown to prevent glomerular sclerosis and may in part explain the glomerular changes associated with obesity (Maeda, 1985; Kasiske, 1990; Verani, 1992). African Americans consume diets low in potassium that have been demonstrated to increase renal vascular wall: lumen ratios thereby contributing to hypertension and renal damage ( Ford, 1998; Tobian, 1984). Because of a high prevalence of milk intolerance African Americans consume diets low in calcium that may also be associated with hypertension (Fruedenheim, 1991; Appel, 1997). Low dietary calcium together with altered vitamin D production, and, perhaps, parathyroid function may also promote vascular growth (Rostand, 1999). Such deficient diets may also contribute to alterations in cellular ion transport (Weder, 1984; Ferrannini, 1989) that may play a role in hypertension and type II diabetes mellitus found at increased frequency in African Americans (Cowie, 1989). A tendency to obesity in African Americans, coupled with low potassium diets, may impair glucose tolerance, produce insulin resistance and may contribute not only to the high prevalence of hypertensive renal disease but also the production of advanced glycation end products that have also damaging effects on the kidney (Tanji, et al. JASN, 2000).

Environmental exposures may be important contributors to progressive deterioration of renal function. Among these are employment as a laborer (Rostand, 1989), occupational exposure to numerous toxic substances (Nuyts, 1995), and high risk behaviors including smoking, excess alcohol consumption and use of illicit substances such as cocaine.

March 25, 2004 7 Genetic Factors: Renal disease (from a variety of causes including hypertension, diabetes, focal glomerulosclerosis and AIDS) is more prevalent in the African American population than in the non-African-American population, suggesting a genetic susceptibility to renal injury (USRDS 2000). Studies have also demonstrated a markedly increased risk of renal dysfunction in relatives of patients with end-stage renal disease (odds ratios for renal disease as high as 9-fold if a first-degree relative has ESRD), that is, findings that lend strong support to the concept of nephropathy susceptibility genes in the African American population (Freedman, 1993;

Freedman, 1997; Klag, 1997). Still, the role of environmental factors cannot be completely excluded, because of residual confounding from geographic location, education, income and socioeconomic status. At present, no susceptibility gene for this increased incidence of nephropathy has been clearly defined, although several candidates exist.

Relationship of Change in Proteinuria to Incident ESRD: Over the past 20 years, there have been hundreds of studies that show a relationship between reductions in proteinuria and slowed declines in either actual or calculated GFR. More recently, a number of clinical trials in people with nondiabetic renal disease, including the AIPRI and REIN trials, have shown that a reduction in proteinuria is associated with a delay in the time to doubling of serum creatinine and decline in GFR. Moreover, data from long term clinical studies as well as clinical trials like AASK and the recently completed IDNT trial (diabetes) demonstrate that failing to reduce proteinuria, in spite of blood pressure reduction, while not directly harmful, does not provide for optimal preservation of renal function. Moreover, the optimal degree of proteinuria reduction that correlates with slowing of kidney disease is not known. Additionally, it is unclear whether antihypertensive agents that do not reduce proteinuria, when used with agents that reduce proteinuria, preserve kidney function to the same degree as other agents all known to reduce proteinuria.

Cardiovascular Disease (CVD) in the Setting of ESRD: Cardiovascular diseases are the leading causes of death in ESRD patients accounting for nearly 50 percent of all deaths. The incidence of CVD may even be 10 times the rate in the general population (Foley, 1998). The increased prevalence of cardiovascular disease in ESRD populations can be related to: 1) demographics; 2) the diseases causing ESRD; 3) factors associated with renal disease; and 4)

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Demographics: The median age of RRT patients now is about 64 years. USRDS data (1999) also show that the number of comorbid cardiovascular conditions, the onset of RRT, and the development of subsequent CVD events rise with increasing age.

Diseases Causing ESRD: The two leading causes of ESRD, diabetes mellitus and hypertension, are strongly associated with the development of cardiovascular disease and its consequences. Patients with progressive renal insufficiency have been shown to be at increased risk for the development of cardiovascular disease. Jungers, et al. (1999) have shown pre-ESRD patients have a 3 fold greater likelihood of a cardiovascular event than those with normal renal function. This observation has been recently confirmed by results from the Hypertension Optimal Treatment (HOT) Study showing that subjects with GFR 60 ml/min were at increased risk for major cardiovascular events and mortality (Ruilope, 2001).

Factors Associated with Renal Disease: Progressive renal dysfunction is associated with the occurrence of traditional and non-established risk factors for CVD.

Dyslipoproteinemia is commonly seen in ESRD and the extent of lipid abnormalities depends on the duration and the severity of renal failure (Attman, 1991). The contribution of hypertension to atherosclerosis and to left ventricular hypertrophy (LVH) is well known. LVH is the most common cardiac structural change seen in ESRD and its prevalence increases as renal function deteriorates. LVH is well known to be an independent risk for sudden cardiac death. The anemia that develops with progressive renal deterioration may also contribute to LVH and increased LVMI which compromise coronary vasodilator reserve and which, together with a mismatch of cardiomyocyte mass and capillaries, contribute to a tendency to myocardial ischemia (Levin, 1999; Amann, 1998). Independent of diabetes mellitus, renal insufficiency is associated with insulin resistance and glucose intolerance that may produce vascular endothelial damage as a result of the production of advanced glycation end products (Schmidt, 1999). Secondary hyperparathyroidism and altered vitamin D metabolism seen with developing renal

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Other factors that may be important include: early menopause in women, hyperhomocysteinemia, and inflammation (Stehman-Breen, 1999; Chaveau, 1993;

Zimmerman, 1999). Attempts to modify these risk factors in ESRD subjects have not been successful in reducing cardiovascular events or mortality. However, a recent study (Meier-Kreische, 2001) reported that during the past decade, CVD mortality in dialysis patients awaiting transplant and in transplant recipients has decreased significantly suggesting that either invasive intervention, risk factor modification, and/or changes in the dialysis prescription may have ameliorated CVD mortality. It remains to be determined which risk factors and treatment interventions are the most important clinically.

Summary of Rationale and Significance: The incidence and prevalence of hypertensionrelated ESRD are relentlessly increasing, despite evidence from national surveys that rates of blood pressure-related cardiovascular disease are declining. In view of the substantial public health burden of hypertensive kidney disease, particularly among African-Americans, and evidence that the condition is progressive, even among persons with well-controlled and appropriately treated hypertension, efforts to understand the determinants of disease progression should be a high national priority. In this setting, the most prudent strategy for determining risk factors for hypertension-related ESRD in African-Americans is to establish a cohort of individuals with early evidence of renal disease but with variable rates of progression.

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