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.

The underlying hypothesis is that CKDu is caused by currently unidentified factors to which the populations have become exposed due to changes in agricultural practice, or other environmental changes.
The objectives are to:
1. Investigate the environmental causes of renal decline in high-risk populations (Nicaragua, India, Sri Lanka), using standardised instruments for four proposed causes of the disease:
a. Metals and metaloids (using direct measurement in biological samples)
b. Agrochemicals (using direct measurement in biological samples)
c. Infection by nephrotropic organisms (using serological evidence and metagenomic analyses)
d. Heat/dehydration (using standardised questionnaires on work history, lifestyle, and climate data, combined with environmental measurements to create a heat-exposure-matrix)
2. Identify early biomarkers of disease and genetic risk loci
3. Provide a bioresource of urine and blood samples from these three robustly characterized prospective studies to allow the exploration of other causal hypotheses going forward.

To achieve these objectives we will:
1. Extend the follow-up to at least four years in each of the three prospective studies (Nicaragua, India, Sri Lanka).
2. Expand each prospective study to a total of 1000 participants to increase the power of the primary analyses.
3. Use standardized questionnaires to capture self-reported exposures
4. Using a nested case-control approach, directly measure urinary metal, agrochemicals and agrochemical metabolites in baseline samples in all three regions.
5. Using a nested case-control approach, to perform serial serology for several known nephrotopic pathogens.
6. Using a nested case-control approach, undertake proteomic studies to identify potential biomarkers of early disease.
7. Perform genome-wide association studies to identify genetic risk loci for decline in eGFR using the same array in the entire study sample from all three regions.