Is It Variants in the Apolipoprotein L1 Gene, or Blood Pressure Control, That Predicts Progression of Nondiabetic Hypertensive Nephropathy in African Americans?

African Americans have a significantly higher burden of hypertension and associated cardiovascular morbidity and mortality.1 Compared with Caucasians, African Americans develop hypertension earlier in life, with much higher average blood pressure (BP) and more target organ damage related to hypertension.2 The mortality rates related to hypertension are much higher for both African American men and women when compared with Caucasians.3 African Americans are also at greater risk for developing progressive chronic kidney disease (CKD) and end-stage renal disease (ESRD) than other racial groups.4 In combined data from the Third Report of the National Health and Nutrition Examination Survey (NHANES III) and United States Renal Data System (USRDS), the prevalence of CKD was similar among African Americans and Caucasians but the risk of CKD progression was 5-fold higher in African Americans.5 African Americans contribute disproportionally to the number of patients reaching ESRD,6 and ESRD has a 4 times higher incidence in African Americans than other races.7 African Americans have been shown to have faster progression of CKD than Caucasians despite similar BP control.8 This study was conducted in an era before the use of angiotensin-converting enzyme (ACE) inhibitors and lower BP goals; however, in the more recent African American Study of Kidney Disease and Hypertension (AASK) trial, African Americans with hypertensive CKD again showed progressive CKD despite use of renin-angiotensin-aldosterone system (RAAS) blockade and achievement of lower BP goals of 130/80 mm Hg.9 In this study, the 10-year cumulative incidence of doubling of serum creatinine, developing ESRD, or death was 54%, and it was similar for patients randomized to the standard or lower BP goal. The genetic contribution to the increased prevalence of hypertension-attributed ESRD is now better understood. A significant association between African ancestry and nondiabetic ESRD has been demonstrated, and this association has not been shown to be present at this time in diabetic ESRD.10, 11 The Genome-Wide Association revealed a region on chromosome 22, which contains the non-muscle myosin heavy chain 9 (MYH9) and several apolipoprotien genes including APOL1. Although initial interest focused on MYH9 as a genetic link to human immunodeficiency virus nephropathy and focal segmental glomerulosclerosis (FSGS),12-14 recent studies emphasize that the association is with particular risk variants in the APOL1 gene with resulting FSGS when biopsied in African Americans. The frequency of risk variants in the APOL1 alleles is extremely low among Caucasians. Freedman and colleagues15 recently published a case-controlled study to evaluate the role of APOL1 and MYH9 genetic variants in hypertensive-attributed CKD using data from the AASK trial. They compared 675 patients who had DNA available from the AASK study with 618 African Americans control patients. The case group from the AASK study had clinically been diagnosed with hypertensive nephropathy with a mean GFR of 47 cc/min and absent or subnephrotic proteinuria 0.6 g/g or a serum creatinine >3 mg/dL during follow-up, the association was strengthened, with odds ratios of 6.29 and 4.61, respectively.15 Patients in the AASK study received ACE inhibitors, dihydropyridine calcium channel blockers, or β-blockers with a low or usual goal BP.9 Then all participants in the continuation AASK cohort study received ACE inhibitors with a low BP goal. Medication class and BP treatment arm did not significantly differ in effect on progression of kidney disease across groups accounting for APOL1-associated genetic risk. This is consistent with the data from the AASK trial, which demonstrated that a lower BP goal did not prevent renal disease progression. These results suggest that the failure of intensive treatment of BP to slow progression of renal disease is associated with APOL1 gene variants. This research sheds some light on why African Americans with nondiabetic renal disease appear to progress despite good BP control. The presence of APOL1 risk variants predicts kidney disease progression in Africans Americans, and BP seems to play a secondary role. However, it is important to remember that the brain and heart are also vital target organs and it remains important to manage BP to protect these other target organs where outcome data have shown that BP control does improve outcomes.