Getting to the cause of Chronic Kidney Disease of unknown cause (CKDu)

There is an epidemic of primarily tubular-interstitial chronic kidney disease (CKD) clustering in agricultural communities in low-and-middle income countries (LMICs). Although it is currently unclear whether there is a common underlying cause, these conditions have been collectively termed CKD of unknown cause (CKDu). CKDu is estimated to have led to the premature deaths of tens to hundreds of thousands of young adults in LMICs over the last two decades. Thus, there is an urgent need to understand the aetiology and pathophysiology of these condition(s) and to develop preventive interventions. We have now established that CKDu exists in Central America (Nicaragua) and South Asia (India, Sri Lanka), but not in some other tropical countries (Malawi, Peru). It is not clear yet whether the epidemics in Central America and South Asia have common causes or different causes, which is why is it important to conduct research using the same protocols and methods in these different regions. Together with colleagues we have established prospective studies in affected communities in Nicaragua, South India, Sri Lanka to investigate the causes of the epidemics of CKDu, and factors which affect prognosis. We already have published striking findings from Nicaragua, where 10% of the community, who were apparently healthy when we started following them, have lost one-third of their kidney function in two years of follow-up - so something very alarming and striking is occurring. The underlying hypothesis is that CKDu is caused by unknown factors to which the populations have become exposed due to the changes in agricultural practice, or other environmental changes (e.g. water supply), over recent decades. The objectives of the proposed Programme Grant research are to investigate the environmental causes of renal decline in these high-risk populations, using both standardised instruments capturing occupational and environmental exposures. We will address four proposed causes of CKDu: (i) metals and metaloids; (ii) agrochemicals; (iii) infections by organisms that affect the kidney; and (iv) heat/dehydration. To achieve these objectives we aim to: (i) extend the follow-up to at least four years in each of the three studies (Nicaragua, India, Sri Lanka); (ii) expand each prospective study to a total of 1000 participants to increase the power of the primary analyses; (iii) use standardized questionnaires to capture self-reported exposures; (iv) directly measure exposures to metals, agrochemicals, infections and heat/dehydration; (v) identify potential biomarkers of early disease; and (vi) identify genetic factors which affect decline in kidney function.