Nancy A. Melville

November 15, 2013

ATLANTA, Georgia — Apolipoprotein L1 (APOL1) variants increase the risk for chronic kidney and end-stage renal disease (ESRD) in black patients, regardless of blood pressure control, diabetes status, and disease etiology, according to new research.

"The effects of APOL1 risk variants on chronic kidney disease progression are not significantly modified by randomized therapies, such as blood pressure medications or baseline proteinuria," said senior author Afshin Parsa, MD, from the University of Maryland School of Medicine in Baltimore. "This explains, in part, the increased progression of chronic kidney disease and risk for end stage renal disease in black patients compared to white patients, regardless of diabetes status."

Dr. Parsa presented the findings here at Kidney Week 2013 . Results were simultaneously published in the New England Journal of Medicine.

In the United States, black patients reportedly have twice the risk of developing ESRD compared with white patients, despite having similar rates of chronic kidney disease.

Previous studies have suggested that 2 functional variants of the APOL1 gene are associated with an increased risk of ESRD. The specific role of the variants in the progression of chronic kidney disease, particularly in the context of diabetes, however, is unclear.

To investigate the issue, Dr. Parsa and his team examined the effects of the APOL1 variants in 2 large prospective studies: the African American Study of Kidney Disease and the Hypertension and the Chronic Renal Insufficiency Cohort Study.

In both studies, patients had 2 copies of the high-risk APOL1 variants.

First Large Trial

In the African American study, 693 black patients with chronic kidney disease attributed to hypertension were randomly assigned during a trial phase to standard or intensive blood pressure control, as well as to 3 different antihypertensive drug class medications: angiotensin-converting enzyme inhibitors, β-blockers, and calcium-channel blockers.

The trial phase was then followed by a 5-year observational cohort phase.

Fifty-eight percent of patients in the APOL1risk group developed ESRD or a doubling of serum creatinine over the course of the study compared with 37% in the APOL1 nonrisk group (adjusted hazard ratio, 1.88; P < .001).

The results showed no interaction between APOL1 status and the trial's interventions of 3 antihypertensive medications, and the risk variants did not modify the effects of proteinuria on progression of chronic kidney disease.

Second Large Trial

The Chronic Renal Insufficiency Cohort Study, which involved 2955 participants, showed that patients in the black APOL1 risk group who did not have diabetes had a hazard ratio of 2.7 for a composite renal event of ESRD or halving their glomerular filtration rate from baseline, while the hazard ratio among the APOL1 nonrisk group was 1.6.

In patients with diabetes, risk were 2.0 among those in the APOL1 risk group and 1.4 in the APOL1 nonrisk group.

"The black patients in the APOL1 risk group had the most events among patients without diabetes, with a hazard ratio that was nearly 3-fold, compared to white patients," Dr. Parsa said. "While the overall number of events was higher, the relationship in patients with diabetes remained unchanged compared to nondiabetics."

The rate of decline in the estimated glomerular filtration rate in black patients in the APOL1 risk group was greater than in white patients, whether the risk patients had diabetes (change, –1.32 mL/min per 1.73 m2 per year; P < .001) or did not have diabetes (change, –1.11 mL/min per 1.73 m2 per year; P < .001).

"Interestingly, black patients who were in the APOL1 nonrisk group had a similar rate of decline in estimated glomerular filtration rate as white patients," said Dr. Parsa.

In terms of clinical implications, Dr. Parsa noted that screening the general population for the APOL1 risk likely wouldn't be beneficial, at this point.

The black patients in the APOL1 risk group had the most events among patients without diabetes, with a hazard ratio that was nearly 3-fold, compared to white patients. Dr. Afshin Parsa

"Even though we can see that this is a strong risk factor, most people still don't develop the disease and we don't have a different way of managing it if they do," he pointed out. "But I do see an important potential utility of the findings in the context of clinical trials."

Nephrologist Orlando Gutierrez, MD, from the University of Alabama, said the study is a valuable contribution to the understanding of the important role of APOL1 as a genetic risk factor.

"This study adds to the growing body of literature which suggests that a substantial proportion of black patients have genetic risk factors for kidney disease progression," he told Medscape Medical News.

Dr. Gutierrez added that the knowledge of the risk could indeed have implications in the management of patients, notably in transplantation.

"The potential promise for future clinicians is that genotyping individuals may help determine those at highest risk for complications of accelerated kidney failure," explained Dr. Gutierrez. "Particularly in the transplant setting where being able to predict the consequences of transplanting APOL1 high-risk kidneys may improve decision-making in the use of the precious organ supply."

This study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Parsa and Dr. Gutierrez have disclosed no relevant financial relationships.

Kidney Week 2013: The American Society of Nephrology 46th Annual Meeting. Late-breaker abstract. Presented November 9, 2013.

N Engl J Med. Published online November 9, 2013. Abstract


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