HLA Associations in End-Stage Renal Disease Due to Membranous Glomerulonephritis: HLA-DR3 Associations With Progressive Renal Injury Barry I. Freedman, MD, Beverly J. Spray, PhD, Georgia M. Dunston, PhD, and Eugene R. Heise, PhD, in association with the Southeastern Organ Procurement Foundation • Membranous glomerulonephritis (MGN) is the most common cause of idiopathic glomerulonephritis in American adults. African-Americans develop end-stage renal disease (ESRD) due to chronic glomerulonephritis four times more often than whites. To determine whether HLA phenotype associations existed in the subset of MGN patients with ESRD we analyzed HLA frequencies, by race, in patients with MGN entered in the Southeastern Organ Procurement Foundation registry between 1982 and 1992. HLA frequencies from 250 renal transplant patients with MGN (190 whites and 60 African-Americans) were compared with 4,506 race-matched cadaveric kidney donor controls (4,039 whites and 467 African-Americans). Race-specific odds ratios (ORs) were calculated and fitted into a log-linear model to determine associations between MGN and HLA frequencies. The reported values were considered significant (P < 0.05) after Bonferroni correction for multiple comparisons. HLA-DR3 and HLA-DR5 frequencies were increased in cases of both races compared with race-matched controls (race-combined ORs, 2.22 and 1.61, respectively; all P < 0.02). Interracial analyses revealed that HLA-DR7 frequency was decreased solely in whites with MGN (OR, 0.53; P < 0.04). The results of this study indicate that HLA-DR3 and HLA-DR5 are positively associated with ESRD due to MGN in patients of both races and that HLA-DR7 is negatively associated with MGN in whites. These analyses confirm the published reports of HLA-DR3 association with MGN in Chinese, French, British, Chilean, and American white populations. The novel association of HLA-DR5 may reflect the fact that the MGN cases in this study all had ESRD. This phenotype may serve as a marker to identify individuals with MGN who are at risk for developing progressive renal scarring. These results, coupled with those from our previous analyses, suggest that HLA-DR3 may exist in linkage disequilibrium with a gene(s) causing progressive renal scarring in patients with insulin-dependent diabetes mellitus, systemic lupus erythematosus, hypertension, and MGN. © 1994 by the National Kidney Foundation, Inc. INDEX WORDS: Genetics; race; HLA-DR3; membranous glomerulonephritis; end-stage renal disease. M EMBRANOUS glomerulonephritis (MGN) is the most common cause of the nephrotic syndrome in American adults, ac- counting for approximately one third of cases. I African-Americans are at fourfold increased risk for developing end-stage renal disease (ESRD) due to chronic glomerulonephritis compared with whites, 2 but the proportion of this increased risk that is due to the presence ofMGN is unknown. It is difficult to determine the racial distribution of patients with MGN since African-Americans may be seen later in the course of their renal dis- ease and may be less likely to receive a renal bi- opsy compared with whites. 3 Approximately 25% of patients with MGN develop progressive renal scarring and are at risk for future ESRD.4 Previous analyses in diverse ethnic groups have revealed associations between MGN and HLA phenotypes. 5 - 15 HLA-DR3 is positively associated with MGN in all published analyses,5-13 with the exception of those in Japanese populations. 14 ,15 HLA-DR2 is positively associated with MGN in the Japanese. 14 ,15 Sacks et al have identified unique restriction enzyme cleavage sites in HLA- DR3-positive Europeans with MGN, proving the presence of disease-associated DNA polymor- phisms. 16 The role of these polymorphisms in disease susceptibility remains unclear. HLA as- sociations have not been reported in African- Americans with MGN or in individuals with ESRD due to MGN. The present analyses were undertaken to de- termine (1) if HLA phenotype frequency asso- ciations exist in the subset ofMGN patients who progress to ESRD, (2) ifHLA associations in this From the Department 0/ Medicine, Section 0/ Nephrology, and the Departments 0/ Public Health Sciences and Micro- biology/Immunology, Bowman Gray School 0/ Medicine oj Wake Forest University, Winston-Salem, NC; the Department 0/ Microbiology, Howard University School 0/ Medicine, Washington, DC; and the Southeastern Organ Procurement Foundation, Richmond, VA. Received October 25, 1993; accepted in revised/orm January 19, 1994. Supported in part by a grant from Marion Merrill Dow, Inc. Address reprint requests to Barry I. Freedman, MD, De- partment o/Internal Medicine, Section o/Nephrology, Bowman Gray School 0/ Medicine o/Wake Forest University, Medical Center Blvd, Winston-Salem, NC 27157-1053. © 1994 by the National Kidney Foundation, Inc. 0272-6386/94/2306-0005$3.00/0 American Journal of Kidney Diseases, Vol 23, No 6 (June), 1994: pp 797-802 797