Two decades of chronic kidney disease of unknown aetiology (CKDu) research: Existing evidence and persistent gaps from epidemiological studies in Sri Lanka

Abstract

Background: Chronic Kidney Disease of unknown origin (CKDu) excludes known primary renal conditions or systemic disease (such as diabetes mellitus or hypertension). Prominence of CKDu has been noted for some decades in Sri Lanka, especially among men in particular rural areas, prompting many studies directed towards environmental causation. This article critically reviews relevant primary studies.Methods: Articles for this literature review (n = 86) were found by searching Medline, Embase, Global Health and ProQuest databases over 2000-2020 utilizing a standard algorithm. Articles were critiqued according to criteria for diagnosis of CKDu, aetiological agents investigated, analytic methods employed and findings.Results: Criteria for diagnosis of CKDu varied significantly, including pre-selection by proteinuria, eGFR and biopsy proven interstitial nephritis. Prevalence studies have been largely conducted in the North Central Province, with recent studies demonstrating the presence of CKDu in other regions. Aetiological factors investigated in primary studies included water source, use of agrochemicals, agricultural work, heavy metals, snake bites, ayurvedic medication, heat stress, infectious diseases and usage of tobacco and betel leaf. There is no conclusive evidence for any one aetiological agent despite consistent evidence of distal factors such as male sex, rural residence and farming. Conclusions:The current body of evidence for any aetiological agent as the cause of CKDu in Sri Lanka is limited. Further research with stronger study designs is necessary to increase knowledge of aetiology of CKDu in Sri Lanka to identify and eliminate exposure to possible causative agent(s) prior to concluding that the disease is multifactorial.

Chronic kidney disease with unknown cause across the global spectrum

“…Co-occurrence of elevated fluoride and silica concentrations was associated with CKDu more often than either alone [34]. However, the absence of fluorosis and presence of high fluoride concentrations in nonendemic areas and countries without CKDu cast doubt on a significant role of fluoride [4]. Silica exposure has been reported via groundwater contamination in Sri Lanka and India and by inhaling particulates in Guatemala; however, no concurrent human samples testing for silica levels was performed and the significance is unknown [7 ▪ ].…”

“…Nonsteroidal anti-inflammatory agents (NSAIDs) were commonly taken by up to 77.9% of CKDu patients in some areas of Central America but not others, and infrequently used in Sri Lanka [7 ▪ ,16]. Indigenous and over-the-counter pain medication use was reported frequently in CKDu patients in India while ayurvedic medication is a possible risk factor in Sri Lanka [4]. In Thailand, those considered to have CKDu had significantly more use of painkillers and herbal medicines [13].…”

“…Most individuals presenting with CKDu are young-to-middle-aged men working in economically disadvantaged agricultural communities often, but not always, in elevated temperatures (Table 2). Males dominate over females by 1.2 to more than 3 : 1; rarely female individuals slightly predominate in select geographic regions [4,13]. The age at initial diagnosis is 20–60 years, with Asian patients trending older than those in Central America [3 ▪▪ ,8,13,14].…”

“…CKDu essentially is a diagnosis of exclusion, defined as CKD by KDIGO criteria in the absence of other known causes of kidney disease and associated with occupational determinants and some consistent clinical characteristics [1,2]. Patients with CKDu often progress to end-stage kidney disease (ESKD) or death within 3–5 years of diagnosis, causing more than 40 000 deaths in Central America and Sri Lanka to date, and with a global death toll of more than 30 000 annually [3 ▪▪ ,4]. This is a serious public health crisis, as these communities have insufficient resources to care for patients with ESKD.…”

Chronic kidney disease of unknown aetiology: A comprehensive review of a global public health problem

“…Glyphosate has been banned in several countries and its use has been restricted in others. Other pesticides have been banned in Sri Lanka several times in the past too, the most recent one being in April 2021 [93]. While the impact of these bans on CKDu prevalence is not known, it is possible that they may adversely impact food security and economy [94].…”