Influence of the MYH9 and APOL1 genes polymorphisms in the risk of CKD in lupus nephritis patients

Abstract

Lupus nephritis (LN) is a frequent complication with high morbidity and mortality. Chronic kidney disease (CKD) is observed in 8 to 15% of the patients after 5 years of follow up. LN is an inflammatory disorder related to a systemic autoimmune activation. Once inflammation is shutdown, several renal and nonrenal factors such as residual proteinuria, hypertension and ethnicity of the patient, may emerge and impose an increased risk of chronicity to the kidney (interstitial fibrosis, glomerular adhesions and glomerulosclerosis). Recently, E1 haplotype (rs4821480, rs2032487, rs4821481 and rs3752462 polymorphisms) of the MYH9 gene and polymorphisms of APOL1 gene (rs73885319 and rs71785313) were associated to progressive kidney disease in non-diabetic chronic kidney disease in the african-american and spanic populations. Besides that, these polymorphisms were also related to an increased risk of FSGS (focal segmental glomerulosclerosis) and HIV nephropathy. It is still unclear 1. Which of the 2 genes is biologically involved and the role of ethnicity as a confounding variable; 2. The pathological mechanisms associated with progression and 3. Whether other renal diseases, such as lupus nephritis are also influenced by these genes. Methods. Retrospective analysis of 196 patients with LN followed in our outpatient glomerular disease service from January 1999 to December 2010. Clinical and laboratorial data were retrieved and genotypying of MYH9 (rs4821480, rs2032487, rs4821481 and rs3752462) and APOL1 (rs73885319 and rs71785313) polymorphisms were performed. Primary outcome (PO) was defined as doubling of serum creatinine and/or end stage renal disease (ESRD). Preliminar results. The mean follow-up time was 6.1 years, with an initial mean creatinine of 1.6 g/dL and mean proteinuria 3.9 g/day. Nineteen patients presented already on dialysis and never recovered renal function, and were excluded from analyses of progressive kidney disease. Of the remaining 177 patients, 43 (24%) presented the PO. The four polymorphisms segregate as a haplotype, according to the Hardy-Weinberg model. Analysing each polymorphism, only TT/CT genotype from rs3752462 polymorphism was associated with the PO (p= 0.02). E1 haplotype was associated with PO, OR 1.79 (CI 1.02-3.0). Conclusion. The presence of the E1 haplotype is associated with worse renal prognosis in lupus nephritis. To be performed: APOL1 analysis and ancestrality mapping to evaluate the role of ethnicity as a confounding variable on the relation between MYH9 and APOL1 and CKD progression. (AU)