The present results demonstrate that nephropathy risk variants in the APOL1
gene, and to a lesser extent MYH9
, are significantly associated with CKD attributed to essential hypertension in non-diabetic AASK participants compared to controls. Evidence of genetic association was most robust in individuals with progressive renal functional decline and higher baseline levels of proteinuria. It is unlikely that these variants are associated with essential hypertension per se
, as the results were consistent when comparing hypertensive AASK cases to controls with or without high BP. These results strongly suggest that progressive kidney disease attributed to hypertensive nephrosclerosis in AASK participants, particularly in those with higher baseline levels of proteinuria, lie in the spectrum of FSGS-related kidney disease, as in idiopathic FSGS, as well as HIV-related, C1q-related and idiopathic collapsing forms of FSGS. Focal global glomerulosclerosis, arteriolar nephrosclerosis and interstitial scarring are commonly present in the renal biopsies of AASK participants (12
) and appear to reside in this disease-spectrum based on APOL1
Subjects in the AASK trial were randomized to angiotensin converting enzyme (ACE) inhibitor, dihydropyridine calcium channel blocker or beta blockade with low and usual BP targets (e.g.
, a 3 × 2 factorial design). Subsequently, all participants in the continuation study, the AASK Cohort Study, received ACE inhibitors with a low BP goal. Despite this aggressive therapy, 54% of AASK patients experienced the primary outcome (doubling of creatinine, ESKD, or death) (13
). These analyses demonstrate that APOL1
risk (recessive model) predicted the least squares projected slope of iothalamate GFR during the AASK Trial phase. The non-significant heterogeneity p-value reveals that 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 AASK Trial results demonstrating that a lower BP goal did not affect renal disease progression. However, ACE inhibitors did slow the progression of renal disease in AASK relative to beta blockers and calcium channel blockers; the inability to detect this in the current study may be due to the smaller sample size. These results suggest that the failure of intensive treatment of BP to halt the progression of renal disease is associated with the role of APOL1
gene variants. New clinical targets are urgently required to combat this severe genetic form of kidney disease.
It is unclear why ACE inhibition, which often benefits patients with heavy proteinuria, had less of a protective effect in AASK. In this subset of AASK participants, ACE inhibition (regardless of usual or low blood pressure treatment arm) did not significantly impact renal disease progression after accounting for APOL1. Not all AASK Trial or AASK Cohort participants were included in these genetic analyses, hence low power may contribute. In addition, AASK excluded participants with >2.5 grams of proteinuria per day at baseline, most had a far lower level of proteinuria. Therefore, the protective effect of ACE inhibition might have been reduced due to the generally lower levels of proteinuria.
Important clinical and histologic differences exist between African Americans and European Americans in the kidney disease that is labeled hypertensive nephrosclerosis. African Americans develop ESKD attributed to high BP earlier in life than European Americans (2
). In addition, successful treatment of hypertension more effectively slows nephropathy progression in European Americans, relative to African Americans (14
). Despite being labeled with the same clinical diagnosis (hypertensive nephrosclerosis), African Americans exhibit greater degrees of solidified glomerulosclerosis and arteriolonephrosclerosis, whereas European Americans have greater degrees of obsolescent, collapsed glomeruli (12
). These racial differences have long hinted at different causative factors for renal disease progression. APOL1
nephropathy risk variants are present at high frequency in African-derived populations and are virtually absent in European-derived and Asian populations. Therefore, the clinical differences in non-diabetic renal disease may primarily relate to variation in APOL1
, as it has been associated with shorter survivals of African American-donated kidneys in the setting of deceased donor transplantation (17
). Importantly, kidneys from African American donors without APOL1
risk variants demonstrated excellent allograft survival, similar to European American donated kidneys. Thus, APOL1
genotypes, not race, convey risk for nephropathy.
Aggressive treatment of high BP in AASK failed to significantly slow nephropathy progression in non-diabetic African Americans with hypertension and CKD, particularly among those who lacked proteinuria at baseline (11
); use of ACE inhibitors slowed progression compared to beta-blocker or calcium channel blocker (18
), but long term progression rates on ACE inhibitors remain high (13
). Genetic influences that may not be sensitive to ACE inhibitors or BP control have previously been shown to contribute to this propensity for progressive loss of kidney function among AASK participants, including variants in the adrenergic pathway (19
) and the homocysteine pathway (20
). We now show that in this region of chromosome 22, genetic variation in APOL1
, and to a lesser extent MYH9,
is strongly associated with this renal progression and may offer a new perspective on hypertension-attributed renal disease. MYH9
has effects independent of APOL1
on nephropathy risk in those with sickle cell disease (21
) and in individuals of European ancestry (8
). There is now abundant data that current therapies have limited ability to slow progression of kidney disease. It is therefore critical to understand the function of APOL1
in order to develop improved therapeutic options to slow progression of non-diabetic kidney disease.