Genetic Discovery Shows Pathway of ESRD : Variants in APOL1 gene may explain fourfold higher rate of nondiabetic ESRD in African Americans

To determine how much of nondiabetic kidney disease can be explained by the genetic variants, the investigators reviewed data from the prospective population-based Dallas Heart Study and compared the outcomes of European American and Caucasian patients, in whom the renal risk alleles are essentially nonexistent, with those of African Americans with zero or one risk allele and those with both risk alleles. Looking at urine protein levels, an indicator of renal microvascular disease, “we found that black individuals with zero or one copy of the risk allele had rates more similar to whites than to blacks with two alleles,” Dr. Friedman reported.

The results were even more striking for actual hard measures of renal function, he said. “Rates of chronic kidney disease or impaired renal function, indicated by glomerular filtration rates less than 60 mL/min per 1.73 m

In their preliminary review of the data, they couldn't “tell any difference between African Americans with zero or one copy of the allele and Caucasians, but African Americans with two renal risk alleles have at least 10-fold increase in kidney failure,” Dr. Friedman stated. “To our surprise, this really only applies to nondiabetic kidney disease. The alleles have essentially no effect that we can detect on diabetic renal disease.”

This realization led the investigators to revisit the issue of natural selection. It turns out, according to Dr. Friedman, “APOL1 is the genetic source for the immunity factor that protected people from African sleeping sickness, a parasitic infection caused by Trypanosoma brucei gambiense.” Similar to selection for the gene variants associated with sickle cell anemia, he explained, “inheriting one copy of the APOL1 gene risk variant provides protection from the parasite, while having two copies seems to increase the risk of kidney disease up to 10-fold.” Through natural selection, as more people survived African sleeping sickness, the percentage of the population with kidney disease risk variants increased, he said.

The investigators are currently studying the risk variants intensively to figure out how they work. “We think they may differentially regulate processes such as apoptosis, and cell repair may function as a chloride channel in mammalian systems in the same way it does in lysosomes and may affect biological function,” Dr. Friedman hypothesized.

In addition to exploring the underlying mechanisms, the potential clinical value of the genetic discovery is also being considered. “This may help us improve risk stratification,” Dr. Friedman said. “It's one thing to say that African Americans have a fourfold increased risk of kidney disease. It's better to find the tag SNP [single nucleotide polymorphism] that will tell if an individual might have an increased risk. If you can actually find the causal variant, then you can potentially predict with much higher success who is and is not at risk for kidney failure,” he stated. “The problem is that it works pretty well in Western African populations, such as Nigerians, but not as well in East Africans, such as Ethiopians.”

One of the main questions that Dr. Friedman and his colleagues currently are pursuing is whether hypertension causes kidney disease in these at-risk individuals or whether hypertension is the result of primary renal vascular disease. “To us, the fact that the very same genetic variants cause hypertension-associated ESRD and FSGS, a primary renal microvascular disease, suggests that these may be the same disease process that we are either catching at different stages or that have different modifiers, and that hypertension in these patients may just be a symptom and not a cause of kidney failure,” Dr. Friedman said.

A cure for nondiabetic kidney disease, which accounts for more than $8.2 billion annually in dialysis coasts, may directly result from the APOL1 finding, Dr. Friedman said. “It's that important.”

Dr. Friedman reported no financial conflicts of interested related to his presentation.