Genetic Variants May Serve as Indicator of Kidney Disease in African Americans with Lupus

Genetic Variants May Serve as Indicator of Kidney Disease in African Americans with Lupus

African Americans living with lupus are five times more likely to develop lupus nephritis (LN)—a kidney disorder which can lead to end-stage renal disease—than whites of European descent living with the same disease. It may be possible to identify those who are more likely to develop severe LN by noting the presence of genetic variants, identified by researchers at the University of Alabama at Birmingham, in collaboration with the Lupus Nephritis-ESRD Consortium. The gene variant could serve as a biomarker for patients who might require more intensive treatment and medical management to delay or avoid end-stage disease (ESRD), say the study’s authors. It may also offer clues on the development of therapies to treat the disease.

Lupus is a chronic autoimmune disorder with a markedly higher prevalence in women and in individuals of African ancestry. In lupus, the immune system—meant to fight off infections—instead attacks the body’s own tissues, causing inflammation and damage.

In about half of all lupus patients, this damage leads to the development of lupus nephritis (LN), a form of kidney inflammation. Lupus nephritis can be treated with medication, but, if it progresses, can lead to kidney failure, requiring dialysis. A paper on the study, entitled “End-stage kidney disease in African Americans with lupus nephritis associates with APOL1” was published recently in the journal Arthritis and Rheumatism.

The study looked at two genetic variations within the apolipoprotein L1 (APOL1) gene—common in African Americans and rare in European Americans—and found the variations were present in lupus patients more likely to develop kidney damage resulting from lupus’ attack on the immune system. In other words, when found together in the same person, the two genetic variants could contribute to the likelihood of an African-American lupus patient developing end-stage renal disease.

 “This study found a large attributable risk for the end-stage renal disease phenotype, especially when comparing African Americans versus European Americans,” says study leader Robert Kimberly, M.D., Director of the Center for Clinical and Translational Science and Senior Associate Dean for Research at the University of Alabama at Birmingham. “It offers a biologic explanation for racial disparities, at least in part, and suggests the potential for identification of a biomarker for lupus patients who might require more intense medical treatment and management to delay—or avoid—end stage renal disease.”

“The development could play an important role in understanding ESRD risk in lupus patients,” Kimberly continues. “It could also serve as a guide for clinical trial designs for potential therapies for lupus nephritis.”

The precise mechanism whereby APOL1 contributes to the development of severe LN remains unknown. Further research must be done to identify this mechanism and to determine whether APOL1 genetics influence severity in renal disease, independent of whether a patient’s kidney problems started with lupus or conditions such as HIV infection, diabetes, hypertension.

Further Research Warranted to Tease Out Associations

 

Past studies of African Americans with kidney disease associated with HIV and hypertension have shown strong associations with the altered versions of the APOL1 gene. This study provides the first association between the altered gene and severity in lupus nephritis. Other teams are exploring whether APOL1 variants drive kidney disease severity related to diabetes or hypertension.

“One theory suggests that no matter what causes original damage to the kidney,” Kimberly says, “people with these APOL1 variants have a second mechanism in place that accelerates the damage once under way.”

The study also found that in African Americans with LN possessing both APOL1 mutations, there was an acceleration of the average time from diagnosis of lupus to onset of end-stage kidney disease (four years, rather than six in those without). This two-year gap could represent an opportunity for targeted, more intensive treatment to delay onset of ESRD.

While we’re very excited by our results, it’s important to note that variations in the APOL1 gene explains part of this risk, but far from all of it,” says Kimberly. “There are people with lupus and severe kidney disease, but without an APOL1 risk variant in their gene code.  Nonetheless, these results represent an important piece of the puzzle and will guide near-future studies that tell us more.”

 Funding from the American Recovery and Reinvestment Act, commonly known as the “stimulus act,” enabled the research team to find and analyze the genetic information of 1,400 people with lupus and kidney disease, nationwide. Also pivotal was the expertise and effort of researchers from the more than 20 institutions that partnered with UAB for the study, in particular the UAB Center for Clinical and Translational Science.