Chronic kidney disease of uncertain origin—management proposal

Chronic kidney disease of unknown etiology (CKDu) affects residents of distinct clusters of rural communities in Central America, Sri Lanka, and India. Affected persons may lack conventional metabolic or vascular risk factors for CKD and present with declining kidney function in the absence of significant proteinuria. The precise pathogenesis remains uncertain, with leading hypotheses including recurrent heat stress, agrochemical exposure, silica nanoparticles, contaminated groundwater, infections, and genetic susceptibility. Histopathology demonstrates varying levels of inflammation and fibrosis in the tubulo-interstitial compartment, and glomerulosclerosis without immune-complex deposition. No validated biomarker exists for diagnosis of CKDu, although tubular injury and inflammatory markers are under study. Interventions in CKDu can target the mitigation of disease progression, but also, notably, interventions at a community or occupation level could be preventive, since the list of hypothesized causes are primarily community or occupation-based exposures. In the absence of CKDu-specific trials, to aid management at the individual level, we review the subgroup data from large, randomized control trials and meta-analyses in CKD populations. We selected the non-albuminuric CKD population as the closest relevant phenotype with available individual level data to inform the proposed management standard. Although randomized trials may be feasible for some community-based interventions, available evidence is largely limited to non-randomized evaluations; we therefore review the pre-post data from programs on rest-water-shade and provision of safe drinking water in endemic regions. We also highlight key knowledge gaps and research priorities in CKDu management and prevention, and review ongoing studies that may inform future evidence-based prevention and treatment strategies.