An Integrative Study of the Genetic, Social and Environmental Determinants of Chronic Kidney Disease Characterized by Tubulointerstitial Damages in the North Central Region of Sri Lanka: Shanika NANAYAKKARA, et al. Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University—Objectives: Previous investigations on chronic kidney disease of unknown etiology characterized by tubulointerstitial damages (CKDu) in the North Central Region (NCR) of Sri Lanka have supported the involvement of social, environmental and genetic factors in its pathogenesis. Methods: We conducted a social‐environmental‐ and‐genetic epidemiology study on a male population in NCR to investigate the genetic and environmental contributors. We recruited 311 case‐series patients and 504 control candidates. Of the 504 control candidates, 218 (43%) were eliminated because of the presence of hypertension, proteinuria, high HbA1c, high serum creatinine or high alpha‐1 microglobulin in urine.Results and Discussion: None of 18 metals measured (μg/l) in urine, including Cd, As and Pb, showed significantly higher concentrations in cases compared with controls. As speciation results showed that 75.80% of total urinary As was in the form of arsenobetaine, which is non‐toxic to humans. None of the metal concentrations in drinking water samples exceeded guideline values. A genome‐wide association study (GWAS) was conducted to determine the genetic contributors. The GWAS yielded a genome‐wide significant association with CKDu for a single nucleotide polymorphism (SNP; rs6066043; p=5.23 ~ 10.9 in quantitative trait locus analysis; p=3.73 ~ 10.8 in dichotomous analysis) in SLC13A3 (sodium‐dependent dicarboxylate transporter member 3). The population attributable fraction and odds ratio for this SNP were 50% and 2.13. Genetic susceptibility was identified as the major risk factor for CKDu. However, 43% of the apparently healthy male population suffers from non‐communicable diseases, suggesting their possible influence on CKDu progression.

Background In the North Central Province of Sri Lanka, chronic kidney disease of uncertain etiology (CKDue) has increased markedly over the past 15–20 years. Methods From around 4,700 patients who were followed up, 106 affected patients who visited two local clinics in the endemic area for CKDue on August 10, 2009 and 10 pedigrees of 10 of these cases with familial clustering of CKDue participated in this study. Urine samples, collected from affected patients (n = 106), unaffected relative controls (n = 81), and Japanese controls (n = 50), were analyzed for two tubular markers: α1-microglobulin and N-acetyl-β-d-glucosaminidase. Urine samples from patients with CKDue stages 1–4 (n = 101) and all the samples from unaffected relatives and Japanese controls were analyzed for urinary cadmium concentration. Results Urinary excretion of α1-microglobulin was elevated even in the earliest stage of CKDue compared with its levels in unaffected relative controls. Urinary excretion of N-acetyl-β-d-glucosaminidase was elevated only in stage 5. In contrast, urinary cadmium excretion was similar in CKDue patients and in the unaffected relative controls, and levels in both these groups were significantly lower than the level in the Japanese controls. All levels were below the threshold level for renal toxicity, indicating the absence of any evidence of cadmium toxicity. Conclusions The present study indicates that renal tubular damage occurs in the very early stage of CKDue and demonstrates the existence of familial clustering, suggesting that CKDue is likely to be the outcome of exposure to an unknown nephrotoxin in susceptible subjects in the endemic region.