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

在低收入和中等收入国家（LMIC）的农业社区，主要是肾小管间质性慢性肾病（CKD）的流行。虽然目前还不清楚是否有共同的潜在原因，这些条件已被统称为CKD的原因不明（CKDu）。据估计，在过去20年中，CKDu已导致中低收入国家数万至数十万年轻人过早死亡。因此，迫切需要了解这些疾病的病因和病理生理学，并制定预防干预措施。我们现在已经确定CKDu存在于中美洲（尼加拉瓜）和南亚（印度、斯里兰卡），但在其他一些热带国家（马拉维、秘鲁）不存在。目前尚不清楚中美洲和南亚的流行病是否有共同的原因或不同的原因，这就是为什么在这些不同地区使用相同的协议和方法进行研究很重要。我们与同事一起在尼加拉瓜，南印度，斯里兰卡的受影响社区开展了前瞻性研究，以调查CKDu流行的原因以及影响预后的因素。我们已经发表了来自尼加拉瓜的惊人发现，在那里，10%的社区，当我们开始跟踪他们时，他们显然是健康的，在两年的随访中，他们失去了三分之一的肾功能-所以一些非常令人震惊和惊人的事情正在发生。潜在的假设是，CKDu是由未知因素引起的，近几十年来，由于农业实践的变化或其他环境变化（如供水），人口受到了这些因素的影响。 拟议的计划赠款研究的目标是调查这些高危人群肾功能下降的环境原因，使用标准化的仪器捕获职业和环境暴露。我们将讨论CKDu的四个拟议原因：（一）金属和类金属;（二）农用化学品;（三）影响肾脏的生物体感染;（四）热/脱水。为了实现这些目标，我们的目标是：（i）将三项研究的随访时间延长至至少四年（尼加拉瓜、印度、斯里兰卡）;（ii）将每项前瞻性研究的参与者总数扩大到1000人，以提高初步分析的效力;（iii）使用标准化问卷调查表收集自我报告的接触情况;（iv）直接测量对金属、农用化学品、感染和高温/脱水的暴露;（v）确定早期疾病的潜在生物标志物;和（vi）确定影响肾功能下降的遗传因素。

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.