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Chronic kidney disease of uncertain aetiology (CKDu) is an advanced version of chronic kidney disease (CKD) which bears a high burden on the world health economy. More than 200 articles were analysed to understand the disease responsible for more than 30,000 deaths per year. CKDu is a non-communicable occupational disease that has a progressive deterioration of the kidney in the absence of CKD risk factors such as hypertension, diabetes and glomerulonephritis, while the diagnosis is only possible at the later stages when kidney function is no longer effective. Published evidence for the existence of CKDu was found for around 35 countries. This is a growing health issue in Asia, Central America, Africa and Middle East with identified hot spots. Despite many research studies over decades, the exact root causes are still uncertain. Six main suspected causative factors are identified. Those are heat stress, strenuous labour, dehydration, use of agrochemicals, exposure to heavy metals and the use of polluted water and agricultural lands. This review summarizes four key areas which are CKDu and its general medical background, worldwide prevalence, suspected causative factors and potential circumventing steps to mitigate against CKDu. The importance of further studies addressing early detection and surveillance methods, contribution of nephrotoxins in environmental health, soil chemistry on transporting nephrotoxins, geological parameters which influence the prevalence of the disease and other related sectors to overcome the mysterious nature is highlighted. Mitigation steps to lessen the burden of CKDu are also identified., (© 2022. The Author(s).)