麻豆传媒

ATLANTA -- A high-risk genetic variant conferred a significantly increased risk of progressive kidney disease in African Americans, at least partly explaining a racial disparity in end-stage renal disease (ESRD), investigators reported here.

Analysis of black and white patients in another trial -- half with diabetes -- showed kidney function declined almost three times as fast in blacks with the high-risk APOL1 profile as compared with whites, researchers reported at the American Society of Nephrology Kidney Week.

"These variants explain, in part, the markedly increased risk of ESRD among black patients, as compared with white patients, regardless of diabetes status," , of Johns Hopkins University, and colleagues simultaneously reported online in the .

"These results also highlight the need to identify other risk factors that can account for residual disparities in ESRD between black patients and white patients. In the context of previous studies, our results suggest that APOL1 high-risk variants increase the risk of progression of chronic kidney disease among black patients, regardless of the cause," they said.

Blacks in the U.S. have almost double the risk of ESRD compared with whites, even after accounting for differences in socioeconomic and clinical factors.

The increased risk of kidney failure emerges despite both races having a similar prevalence of early-stage chronic kidney disease (CKD), which suggests that certain factors accelerate disease progression in blacks, the authors noted.

Previous studies have suggested the racial disparity arises from variants in genes encoding nonmuscle myosin heavy chain 9 and APOL1, both on chromosome 22. Recent evidence has pointed more specifically to the common variants G1 and G2 in the last exon of APOL1.

The G1 and G2 variants have been postulated to account for much of the disparity in ESRD rates between blacks and whites, the authors noted. However, evidence of a link between APOL1 and ESRD in diabetes has been equivocal.

To examine in greater detail the association of APOL1 variants in ESRD, Appel and colleagues analyzed data from two large clinical trials: the African American Study of Kidney Disease and Hypertension (AASK) and the (CRIC) study.

AASK evaluated blood pressure control in blacks with CKD. CRIC enrolled black and white patients with CKD, half of whom had diabetes.

AASK had a composite primary outcome, consisting of a doubling of serum creatinine from baseline or progression to ESRD. Serum creatinine was measured at baseline and then every 6 months. Analyses of interaction between APOL1 variants and trial interventions had a composite outcome of a 50% decline in glomerular filtration rate (GFR) or progression to ESRD.

CRIC had two primary outcomes: decline in kidney function (defined by GFR slope over time) and the composite of ESRD or at least a 50% decline in GFR.

Analysis of AASK data included 693 patients. Of those 160 (23.1%) had two copies of APOL1 variants, which was associated with the lowest baseline mean GFR (44 mL/min/1.73 m2, P=0.01) and the highest prevalence of proteinuria (48%, P<0.001).

During a median follow-up of 9 years, 77 patients in the AASK cohort died before reaching the composite endpoint, 204 progressed to ESRD, and 288 reached the composite endpoint.

APOL1 status was not associated with death before ESRD. Patients with two copies of the variants were twice as likely to reach the composite outcome as compared with patients who had no copies (hazard ratio 2.03, P<0.001). The risk associated with a single copy of a variant did not differ significantly from the reference group (HR 1.15, P=0.34).

Similar results emerged from analyses of associations between APOL1 status and ESRD.

Recessive genetic modeling yielded an HR of 1.88 for the composite renal outcome in the APOL1 high-risk group as compared with the low-risk group (P<0.001).

The CRIC analysis included 2,955 patients with adequate genotyping information, 48% of whom were black and 45.5% of whom had diabetes. White and black patients differed significantly with respect to several baseline characteristics, including mean blood pressure and severity of proteinuria, both of which were higher in blacks.

During a mean follow-up of 4.4 years, 676 composite renal events occurred. Among diabetic and nondiabetic patients, blacks had a steeper decline in GFR and a higher rate of the composite renal outcome as compared with whites.

In the diabetic subgroup, GFR slope was -1.5 mL/min/1.73 m² in whites, -2.7 mL/min/1.73 m² in blacks with low-risk APOL1 profile, and -4.3 mL/min/1.73 m² in blacks with the high-risk APOL1 profile. Among nondiabetic participants, corresponding slopes were -0.7, -1.0, and -2.9 mL/min/1.73 m².

Similar results were observed for the composite renal outcome, as whites had the lowest event rate, followed by blacks with the low-risk APOL1 profile, then blacks with the high-risk profile.

The results may lead to refinement of the conceptual framework of CKD in blacks, , and, of Harvard Medical School in Boston, said in an accompanying editorial.

"First, patient with two copies of a risk allele (homozygotes or compound heterozygotes) were twice as likely to reach the composite endpoint for kidney disease as were those with no or one copy," they wrote. "Second, the progression of CKD did not appear to be related to or explained by the level of blood pressure control, but, rather, was closely linked to APOL1 status.

"In AASK, the use of angiotensin-converting-enzyme inhibitors slowed disease progression, yet nearly all patients had progression to ESRD over a 10-year period. Therefore, CKD that is attributed to hypertension or hypertensive nephrosclerosis may be a misnomer, and the molecular classification of black patients at least partially according to their APOL1 status may eventually supplant such nomenclature."

Because the analysis by Appel and colleagues was limited to patients with CKD, the results probably underestimate the association between APOL1 status and ESRD risk in the general black population, Williams and Pollak added.

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