End‐stage renal failure in African Americans: insights in kidney disease susceptibility (original) (raw)

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Section on Nephrology, Wake Forest University School of Medicine, Winston‐Salem, North Carolina, USA

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01 February 2002

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Barry I. Freedman, End‐stage renal failure in African Americans: insights in kidney disease susceptibility, Nephrology Dialysis Transplantation, Volume 17, Issue 2, February 2002, Pages 198–200, https://doi.org/10.1093/ndt/17.2.198
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Epidemiology

The aetiologies of the markedly increased incidence rate of end‐stage renal failure (ESRF) among African‐, Native‐, Hispanic‐, and Asian Americans, relative to European Americans, continue to be debated. Much has been learned about the impact that African American (black) race has on the biologic and sociocultural aspects of systemic diseases predisposing to ESRF. This information may prove useful in determining the causes of the unique susceptibility to kidney disease that is observed in the American black population. In aggregate, blacks have lower socioeconomic status (SES) with poorer access to medical care than do whites. However, well‐designed analyses reveal that lower SES and greater severity of hypertension and hyperglycaemia fail to fully account for their excess rate of ESRF [1–3].

Racial variation in hypertension and diabetes

In the US, hypertension‐associated ESRF (H‐ESRF) exhibits the largest black to white difference in incidence rate among the common aetiologies of kidney disease (the others being diabetes and chronic glomerulonephritis). In 1996, H‐ESRF was reported 20 times more often in blacks residing in the southeastern US [4] and seven times more often nationally [5]. Compared with whites, the entity of essential hypertension is clinically and biochemically different in American blacks. Blacks develop hypertension 10 years earlier, lack a pronounced nocturnal blood pressure decline, and are seven times more likely to have severe elevations in blood pressure, relative to whites (reviewed in [6]). Although sodium intake has repeatedly been reported to be similar between the races, renal sodium handling and plasma volume regulation are markedly different [6]. However, blacks do ingest lesser amounts of potassium.

Hypertensive (and normotensive) blacks demonstrate delayed sodium excretion, plasma volume expansion, lower plasma renin activity, elevated intracellular sodium concentration, and altered numbers/activities of sodium transporters (the Na‐H antiporter, Na‐K ATPase, and Na‐K‐Cl co‐transporter), relative to whites [6]. Despite equivalent age, blood pressure, and serum creatinine concentration, blacks have reduced renal blood flow and urinary kallikrein excretion [6]. Kotchen et al. reported baseline glomerular hyperfiltration in black patients, which is further augmented upon exposure to norepinephrine [7]. Allowing that some patients classified as having H‐ESRF may be misdiagnosed, the variable pathophysiologic causes of blood pressure elevation between the races raises the possibility that the black hypertensive profile may more often predispose to kidney failure.

How could these racial differences in sodium handling have arisen? Grim et al. proposed the theory that the American slave trade may have selected for individuals who were able to aggressively conserve sodium [8]. While this could have improved survival during times of severe salt depletion (starvation, dysentery, profuse sweating), this could now be detrimental in the current environment of high sodium intake. Whether the American slave trade could have caused this pronounced genetic selection remains unknown. The Grim hypothesis may be partially dispelled by a recent report demonstrating similar frequencies of hypertension‐promoting genotypes among African‐born and African American health professionals [9]. This paper suggests that a genetic ‘bottleneck’ resulting from the slave trade did not occur, nor cause a genetic predisposition to elevated blood pressure in American blacks. In fact, presumably due to admixture, the frequency of hypertension‐promoting loci was actually somewhat lower in the African American cohort.

Blacks also appear more likely to become diabetic than whites and at an earlier age [10]. This may relate to their increased rates of obesity; however, obese individuals do not uniformly develop diabetes. The 4‐fold greater incidence rate of diabetic ESRF among blacks is not fully accounted for by poorer glycaemic control, obesity, hypertension, or access to care [2]. It has been proposed that in a hyperglycaemic environment, the kidneys in black individuals react differently than those in white diabetics [2].

Putative renal failure susceptibility genes

A familial aggregation of ESRF/kidney disease has been widely reported. Striking aspects of this aggregation include the consistency of results within races despite differences in geographic region and the multiple kidney diseases that cluster in families (hypertension, diabetes mellitus, systemic lupus erythematosus, human immunodeficiency virus‐associated nephropathy, IgA nephropathy, and focal and segmental glomerulosclerosis) (reviewed in [11–13]). These aspects, along with the clustering of different aetiologies of ESRF within single families [12,13], support the existence of renal failure susceptibility genes.

To date, two chromosomal regions have demonstrated linkage or association with ESRF in the American black population. These are the plasma kallikrein gene and the human homologue of the rodent renal failure 1 gene.

We detected significant evidence for the association between polymorphisms in the plasma kallikrein (KLKB1) gene on human chromosome 4 and non‐diabetic ESRF (primarily H‐ESRF and chronic glomerulonephritis‐associated ESRF) [14]. In contrast, the tissue kallikrein gene demonstrated no evidence of association with non‐diabetic, diabetic, or all‐cause ESRF [15]. We next determined the genomic structure of the KLKB1 gene (30‐kb length with 15 exons and 14 introns) [16]. Association between ESRF and novel polymorphic markers within KLKB1 remained significant. However, polymorphisms in the coding and 5′‐proximal promoter of KLKB1 failed to show a statistically significant association with ESRF in 591 black individuals on dialysis [16]. These observations suggested that other sequences, within or near KLKB1, or a different gene nearby, might contribute to ESRF susceptibility. This may be relevant when viewed in the context of the reduced urinary kallikrein excretion and renal blood flow that is observed in hypertensive blacks. It is tempting to speculate that genetically mediated underproduction of renal kallikrein might be a factor that could promote renal scarring.

The fawn‐hooded rat (FHR) is an inbred strain that develops early focal and segmental glomerulosclerosis (FSGS) with hypertension. Dr Howard Jacob and colleagues determined that the renal failure (Rf) genes (predominantly _Rf_‐1 and _Rf‐_2) promote glomerulosclerosis with resultant proteinuria, independently from the genes that lead to high blood pressure in this strain [17]. His laboratory also determined that the human homologue of the _Rf_‐1 gene was located on chromosome 10q [18]. The group first reported evidence of the association between this region and H‐ESRF in black patients [18]. An initial report from our laboratory, in 129 black sib pairs, failed to detect evidence for linkage between markers on 10q and ESRF [19]. However, a recent analysis in 452 black sib pairs concordant for ESRF detected significant evidence for linkage between the marker D10S667, adjacent to the human homologue of the human _Rf‐_1 gene, and all‐cause ESRF (maximum likelihood ratio _z_‐score [Zlr]=3.33, _P_=0.004, log of the odds ratio [lod]=3.40) [20]. Another marker on 10p, D10S1435, was also significantly linked to non‐diabetic ESRF in this population. Therefore, the identification of renal failure susceptibility genes in animal models of glomerulosclerosis may ultimately lead to advances in understanding the aetiology of human disease.

While initial genetic findings are pursued in the American black population, genes and markers predisposing to the more homogeneous disorders of familial IgA nephropathy and familial FSGS have recently been detected. The alpha‐actinin‐4 gene on chromosome 19q13 has been linked to nephropathy in familial FSGS [21], as have loci on chromosomes 11q21‐22 [22] and 1q25‐31 [23]. An additional locus on chromosome 6q22‐23 has been linked to IgA nephropathy, with an autosomal dominant mode of inheritance [24].

Conclusions

The gene pool from Africa is quite diverse, often unique, and was likely the site of origin of mankind (based upon mitochondrial DNA analysis). Interactions between our modern day environment and the results of the African diaspora are likely to contribute, in part, to the racially diverse disease states that we now observe. A careful analysis of the biological and environmental components leading to renal and cardiovascular disease in the American black population will likely improve our understanding of the aetiology of these disease processes in individuals of other races.

Correspondence and offprint requests to: Barry I. Freedman, MD, Section on Nephrology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston‐Salem, NC 27157‐1053, USA. Email: bfreedma@wfubmc.edu

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European Renal Association–European Dialysis and Transplant Association

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