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A new report suggests that differences in albuminuria might contribute to disparities in susceptibility to nephropathy in African American and white individuals. Interpretation of this finding requires consideration of renal histology, clinical trials and genetic studies. These factors indicate that a far more complex scenario is likely to exist than previously thought.
An interesting report by McClellan et al. assessed relationships between albuminuria, race and risk of end-stage renal disease (ESRD) in participants of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, and linked outcomes with the US Renal Data System.1 Albuminuria and microalbuminuria were significantly more common in African American than in white individuals in this population-based study, and were associated with racial differences in progression to ESRD. This observation would be particularly useful if albuminuria was readily treatable and normalization of albumin levels stabilized renal function in African Americans.
The mechanisms underlying progressive nephropathy in the setting of albuminuria in African Americans could not be determined in the epidemiological report by McClellan and colleagues. However, an analysis of the Dallas Heart Study reveals that genetic variation in apolipoprotein L1 (APOL1) underlies albuminuria and nephropathy progression in this population.2 Results of the REGARDS analysis complement those of the Dallas Heart Study as both studies were population-based. Unfortunately, APOL1 genotypes were not available in REGARDS and albuminuria and glomerular filtration rate (GFR) were used as surrogate intermediate markers of nephropathy progression.
Although albuminuria can be associated with progression of renal disease across races, the underlying pathogenesis may differ between races. Albuminuria exhibits variable relationships with nonrenal phenotypes in African American and white individuals. For example, although albuminuria and microalbuminuria are accepted risk factors for cardiovascular disease, they differentially associate with subclinical atherosclerosis in African American and white individuals with diabetes mellitus.3
In the case of nephropathy, many non-diabetic African Americans with low-level albuminuria, reduced GFR and hypertension have kidney disease ascribed to essential hypertension without confirmation by biopsy.4 However, the histopathology of renal lesions in putative hypertensive nephropathy differs between individuals of different races. Compared with white individuals, African Americans have significantly higher frequencies of solidified glomerulosclerosis, interstitial fibrosis and vascular lesions, which do not correlate with systemic blood pressure despite equivalent proteinuria and hypertension. Essential hypertension is unlikely to be the cause of progressive kidney disease or albuminuria in many of these African Americans.4
Lowering systemic blood pressure and use of angiotensin-converting-enzyme (ACE) inhibitors often reduce albuminuria. However, abundant evidence indicates that these treatments do not reduce nephropathy progression to an equal extent in hypertensive African American and white individuals without diabetic nephropathy or glomerulonephritis. The Hypertension Detection and Follow-Up Program5 and Multiple Risk Factor Intervention Trial6 revealed that blood pressure reduction was less effective in slowing nephropathy progression in African American than in white individuals. The African American Study of Kidney Disease and Hypertension (AASK) evaluated ACE inhibitors and intensive hypertension control.7 AASK demonstrated that ACE inhibition and use of low blood pressure targets led to slight reductions in the rate of renal function loss compared with usual blood pressure control and use of other antihypertensive drug classes. After completing the trial phase, the investigators of AASK administered universal ACE inhibition and applied low blood pressure targets to all participants who did not reach a trial end point. Ultimately, 60% of these individuals reached dialysis initiation, doubling of serum creatinine or death. As such, these interventions were not broadly effective. Strikingly, African Americans in REGARDS were more likely than white participants to receive ACE inhibitors, yet they still had more albuminuria.1 The major question arising from REGARDS is whether reducing albuminuria leads to equal reductions in ESRD among African American and white individuals.
What factors are likely to account for racial differences in nephropathy progression associated with albuminuria? McClellan and colleagues proposed that elevated blood pressure, risk factors for cardiovascular disease, obesity, metabolic syndrome, smoking, vitamin D levels, geographic origin, lower socioeconomic class and low birth weight are potentially related.1 Gene polymorphisms were also included on this list, as evidence supports the major contribution of two coding variants in APOL1 on racially variable risk for development and progression of nondiabetic nephropathy.2,8
“It is now apparent that, APOL1, and not albuminuria, is the major driver of racial disparities in ESRD”
The impact of genetic risk associated with APOL1 is among the most impressive observed in complex disease. The odds ratio for APOL1 association with ‘hypertension-attributed’ ESRD is 7.3, 10.5 in individuals with focal segmental glomerulosclerosis and >30 in those with HIV-associated collapsing glomerulosclerosis.9 Variants in APOL1 associated with nephropathy risk are essentially limited to the African American population, where one copy protects against African sleeping sickness. Approximately 39% of African Americans possess one APOL1 risk haplotype and 12% possess two risk haplotypes and are at high risk of ESRD. These polymorphisms are virtually absent in white individuals.8
Racial differences in the frequencies of APOL1 risk variants explain the observed racial differences in nondiabetic nephropathy.2,8 As such, genetic ancestry was likely the cause of the observations in REGARDS. When the investigators adjusted ESRD risk for the impact of GFR and albuminuria—an effect that attenuated the disparity in risk of ESRD between African American and white individuals—they were essentially adjusting for the effect of APOL1. This concept is exemplified by the observation that donor kidneys from African Americans function for shorter periods after transplantation than donor kidneys from white individuals, an effect also related to APOL1 genotype.10 By contrast, kidneys from African American donors lacking the two APOL1 risk haplotypes function equally well as those from white individuals. Hence, donor APOL1 genotypes, and not race, confer nephropathy risk.10 Future studies should focus on the primary reasons for kidney failure, rather than intermediate outcomes such as albuminuria and GFR. The association of genetic markers with albuminuria will become increasingly important.
Albuminuria should no longer be considered a modifiable risk factor for nephropathy of equivalent significance in African American and white individuals. Generic efforts to reduce albuminuria in African Americans will soon be replaced by approaches that target the primary cause of albuminuria and subsequent nephropathy. ACE inhibitors and intensive blood pressure control do not markedly slow nephropathy progression in African Americans with low levels of albuminuria,7 implying that reduction of albuminuria is insufficient. It is now apparent that APOL1, and not albuminuria, is the major driver of racial disparities in ESRD. As such, novel strategies based on genetic breakthroughs, which include the identification of genes commonly involved in nondiabetic nephropathy such as APOL1, podocin (NPHS2) and inverted formin-2 (INF2), will need to directly target the pathogenesis of kidney disease and the associated albuminuria. In addition, results of epidemiological analyses can be extended by evaluation of causative genes and ancestry informative markers.2
The authors declare no competing interests.
Barry I. Freedman, Department of Internal Medicine, Section on Nephrology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
Donald W. Bowden, Section on Endocrinology and Metabolism, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.