Although many factors have been proposed as the cause of MeN, most attention has focused on heat stress due to a combination of strenuous work in a hot climate with insufficient hydration. Additional postulated contributing exposures include agrochemicals, metals, and pathogens. These factors are themselves a result of global and national economic and political systems that have led to poverty and social stratification. Discovery of the causes of MeN has been complicated by the fact that there are likely multiple factors that arise from different sources of exposure and/or different times of life. Until recently, progress has also been slowed by a lack of research funding, although more support has become available as awareness of the disease and its toll on the population has increased. A review published in the New England Journal of Medicine in 2019 summarizes a proposed mechanism in which heat exposure leads to dehydration and volume depletion and/or an increase in core temperature, which may cause kidney injury directly through tissue dysfunction or indirectly through hyperosmolarity or rhabdomyolysis. Similarly, it is possible that chronic sub-clinical undetected AKI leads to eventual CKD. Another proposed mechanism is increased kidney tubular toxin uptake resulting in direct tubular toxicity, which might also be amplified by heat-associated dehydration. Genetic factors are also likely to play a role. Regardless of what mechanisms are eventually proven to be involved, researchers agree that preventive measures should include measures to ensure safe drinking water, adequate hydration, rest, and shade for workers at risk, as well as to reduce exposure to toxins. A review of the state of knowledge on potential causes and mechanisms as of 2019 can be found in a summary of the Third International Workshop on Chronic Kidney Disease of Uncertain/Non-Traditional Etiology in<unk> and Other Regions on Chronic Kidney Disease of Unknown Etiology held in March 2019. Heat stress, dehydration and disturbances in water and mineral balance. Heat strain and dehydration is in the spotlight globally due to emerging evidence of their association with adverse renal health issues including chronic kidney disease, especially in working populations. The probability of heat stress is greater when the temperature of the environment surpasses a persons core temperature, a situation common for outdoor workers in tropical settings where temperatures can easily surpass 37 °C. Although the specific mechanism by which heat, dehydration and workload contribute to the causal pathway for MeN remains to be definitively established, the association with MeN has been shown repeatedly. Epidemiological studies in Central America have reported adverse heat stress impacts in agricultural workers, particularly those in the sugarcane industry. In addition to exposure to high temperatures, evidence exists that high sweat rates and limited fluid intake can lead to functional and sub-clinical acute kidney injuries (AKI), and that repetitive AKI may lead to the development of CKD. A well-conducted study on the relationship between workload and incidence of kidney injury in a fieldworker cohort with different levels of physically demanding work over a sugarcane harvest in Nicaragua was published in October 2019. The results provide evidence of dose-effect as well as dose-response relations between high-heat and high workload exposure and both increased episodes of incident acute kidney injury as well as progressive decline in GFR. The role of heat stress in the etiology of MeN is further supported by intervention studies showing mitigation of kidney function decline with efforts to improve rest, hydration, and access to shade among high-risk agricultural workers. Finally, evidence from animal models suggests a potential mechanism or mechanisms for how heat stress may drive development of MeN. Agrochemicals Agrochemicals and pesticides have been frequently been proposed as a potential cause or contributor to the development of MeN, although the epidemiological and pathophysiologic evidence is somewhat limited and contradictory. The main limitations of both positive and negative studies remain poor specificity and quantification of pesticide exposure, as well as the cross-sectional nature of most studies and issues with confounding and selection bias. No study has directly investigated interactions between pesticides and other concomitant exposures in agricultural occupations, in particular heat stress and dehydration. Thus, existing studies provide scarce evidence for an association between pesticides and regional MeN epidemics, but a role of nephrotoxic agrochemicals nevertheless should not be conclusively discarded. Exposure to metals Exposure to metals such as cadmium, lead, nickel, and mercury has also been proposed as a cause or contributor to MeN, again with limited and contradictory evidence. A number of well conducted studies have shown no association with the development of MeN, although a 2020 case–control study found an association with nickel exposure. There may be regional variation with respect to the role of heavy metals, which appear unlikely to be an important contributor in<unk> but which remain under more active investigation in India and Sri Lanka. Alcohol and self-medication Alcohol consumption, including consumption of home-brewed alcohol, as well as self-medication with NSAIDS and other nephrotoxic medications occurs in populations affected by MeN. To what extent such exposures contribute to the epidemic of MeN is not known, as evidence is again contradictory. Some studies have described an association between NSAID use or consumption of a home-brewed alcohol called "lija" and MeN, whereas others have found limited evidence that either is an important risk factor. Infectious causes The high density of infectious disease vectors and reservoirs, in the context of limited access to clean water, limited resources for detecting and controlling infectious disease outbreaks, and the continued emergence of new pathogens and pathogen variants, is an important consideration when addressing kidney health in tropical and low-resource settings. The presence of these factors in MeN burdened regions lend credence to the hypothesis of an infectious etiology, and there is some evidence in support of infection as a risk factor. However, other published studies investigating infectious agents as a causal factor in MeN have been negative. There may again exist regional variation between<unk> and India / Sri Lanka with respect to the role of infectious causes in CKD development.
Mesoamerican nephropathy
IgA nephropathy
Malarial nephropathy
Balkan endemic nephropathy
Sickle cell nephropathy
Uddanam nephropathy
HIV-associated nephropathy
Analgesic nephropathy