Prospective Biopsy-Based Study of CKD of Unknown Etiology in Sri Lanka

Background and objectives A kidney disease of unknown cause is common in Sri Lanka’s lowland (dry) region. Detailed clinical characterizations of patients with biopsy-proven disease are limited, and there is no current consensus on criteria for a noninvasive diagnosis. Design, setting, participants, & measurements We designed a prospective study in a major Sri Lankan hospital servicing endemic areas to ascertain pathologic and clinical characteristics of and assess risk factors for primary tubulointerstitial kidney disease. We used logistic regression to determine whether common clinical characteristics could be used to predict the presence of primary tubulointerstitial kidney disease on kidney biopsy. Results From 600 new patients presenting to a tertiary nephrology clinic over the course of 1 year, 87 underwent kidney biopsy, and 43 (49%) had a biopsy diagnosis of primary tubulointerstitial kidney disease. On detailed biopsy review, 13 (30%) had evidence of moderate to severe active kidney disease, and six (15%) had evidence of moderate to severe chronic tubulointerstitial kidney disease. Patients with tubulointerstitial kidney disease were exclusivelyborn in endemicprovinces; 91%spent amajority of their lifespan there. Theyweremore likelymenand farmers (risk ratio, 2.0; 95% confidence interval, 1.2 to 2.9), and they were more likely to have used tobacco (risk ratio, 1.7; 95% confidence interval, 1.0 to 2.3) and well water (risk ratio, 1.5; 95% confidence interval, 1.1 to 2.0). Three clinical characteristics—age, urine dipstick for protein, and serum albumin—could predict likelihood of tubulointerstitial kidney disease on biopsy (model sensitivity of 79% and specificity of 84%). Patients referred for kidney biopsy despite comorbid diabetes or hypertension did not experience lower odds of tubulointerstitial kidney disease. Conclusions A primary tubulointerstitial kidney disease occurs commonly in specific regions of Sri Lanka with characteristic environmental and lifestyle exposures. Clin J Am Soc Nephrol 14: 224–232, 2019. doi: https://doi.org/10.2215/CJN.07430618 Introduction Residents of Sri Lanka’s dry zone face a high risk for kidney disease characterized predominantly by tubulointersititial kidney disease of as yet unknown etiology (1,2). Termed CKD of unknown etiology (CKDu), this condition has emerged as a leading cause of hospitalization and death, with significant political and economic upheaval in the region (3). Care for this single disease now consumes 5% of the total health care budget in Sri Lanka (4). The demographic features (2,5) and the timeline of CKDu’s emergence in Sri Lanka align with descriptions of Mesoamerican nephropathy (6–8) and Uddanam nephropathy in Andhra Pradesh, India (9). Despite considerable efforts to improve the understanding of CKDu epidemiology and investigate its etiology, several questions remain unanswered, including whether a set of clinical features can inform reliable, noninvasive diagnosis for persons living in recognized “hot spots.” At the current time, the “gold standard” for a diagnosis of CKDu is biopsy-proven primary tubulointerstitial kidney disease with no evident predisposing condition and residence in an area with high prevalence of similar disease. However, kidney biopsies are impractical for large-scale surveillance, geographic mapping, and entry into a patient-control study. Thus, varying approaches have been applied for categorization and study inclusion. For example, the CKDu National Project Team surveyed nearly 5000 persons in a population-based study in three endemic regions and one nonendemic region of Sri Lanka (10). Persons who had albuminuria without a reduction in eGFR were classified as “CKDu cases,” despite numerous studies of CKDu pointing to tubulointerstitial kidney disease (2,6,7,11,12) as unlikely to present as albuminuria without reduced eGFR. Any assessment of exposures was biased (13). Other studies have accepted clinicianor self-reported Division of