Fifty Years of Balkan Endemic Nephropathy: Challenges of Study Using Epidemiological Method

Abstract

Balkan endemic nephropathy (BEN) is a chronic tubulointerstitial disease associated with urothelial cancer, which affects people living in the alluvial plains along the tributaries of the Danube River. Challenges of studying BEN using the epidemiological method are multiple. The natural history from exposure to occurrence of the disease may take many years. The early stages of BEN are not easily detectable clinically, as the disease is asymptomatic until a significant decline in function occurs, and even then symptoms are usually non-specific. The natural history of BEN is complex, possibly with multiple risk factors operating both at the stage of initiation of renal damage and in its progression. In BEN, genetic susceptibility is due to multiple genes of small effects, gene-gene interactions, and gene-environment interactions of complex nature that are difficult to assess with current study designs. BEN is now kidney disease of the old people, and many risk factors for disease such as smoking, alcohol consumption, obesity, and diabetes could contribute to the kidney damage. Evidence is presented that environmental rather than genetic factors play a decisive role in the etiopathogenesis of BEN. Aristolochic acid, described as a culprit of BEN in 1959, is confirmed in 2007 by the molecular biology methods. Mycotoxins and polycyclic aromatic hydrocarbons, leached from lignites and found in the vicinity of endemic settlements, deserve further investigation. Despite advances in understanding the epidemiology of BEN, more research is needed on the patterns of BEN over time and between places, and on identifying the contributions of modifiable risk factors in initiating and hastening progression of BEN in order to improve the scope for preventing BEN. Primary prevention is still at the beginning. Knowledge accumulated in the fifty years of BEN research and new data about prevention and treatment of chronic kidney disease reveal several effective methods in secondary and tertiary prevention of BEN. Genetic epidemiology could establish the relative size of the genetic effect in relation to other sources of variation in disease risk (i.e., environmental effects such as intrauterine environment, physical and chemical effects, as well as behavioral and social aspects). Public health authorities in the several countries having aristolochic acid nephropathy should take immediate measures for reducing dietary exposure of residents to Aristolochia.

Escalating chronic kidney diseases of multi-factorial origin in Sri Lanka: causes, solutions, and recommendations

“…Worldwide, these CKDue epidemics are localised in the dry zones of agricultural societies, where the landscape is flat and the ground conditions are harsh, with little rain and prolonged dry periods and drought. Examples of somewhat similar CKDu conditions reported in other countries include Uddanam, in the agricultural belt of Andhra Pradesh [7]; unusual nephropathy, in China [8] and Nicaragua [9]; and Balkan endemic nephropathy, which affects rural villages in Serbia, Bulgaria, Romania, Croatia, and Bosnia [10,11].…”

“…Worldwide, CKD of unknown/uncertain aetiology has been reported after chronic exposure to certain heavy metals, including arsenic, cadmium, mercury, chromium, uranium, gold, platinum, silver, thallium, and antimony, as well as fluoride [4,19,20] and agrochemicals [7][8][9][10][11]. Despite the epidemiological studies carried out over the past 40 years, other than the reported associations and correlations (except arsenic in ground-water, Bihar, India), no causative factor has been identified for CKDu across the continent.…”

Genetic loci that affect aristolochic acid-induced nephrotoxicity in the mouse

“…AA poisoning (31), ochratoxin, or lignites from coal field runoff, have been proposed as environmental agents that may cause BEN (reviewed in Ref. 54). Several lines of evidence, including the finding of AA-derived aristolactam-DNA adducts in kidney DNA of BEN patients, and fingerprint A:T-ϾT:A transversion mutations in the TP53 gene in urothelial tumors from BEN patients, have solidified the consensus that BEN is a form of AAN (26).…”

A study of chronic kidney disease patients with no known risk factors coming to tertiary care hospital

“…11,12 Similarly, Balkan-endemic nephropathy, which affects people living along the tributaries of the Danube river in Europe, is now considered to be a form of aristolochic acid-related kidney disease. 13 In two studies in India partially funded by the ISN Research and Prevention Committee, no excess of heavy metals was found in the water in the Srikakulam district (MS Ravishankar, Seven hills Hospital, Mumbai, India, personal communication), while contamination of ground water used for drinking purposes with trace elements such as silica was suspected of causing CKD described in rural villages in the state of Andhra Pradesh (G. Taduri, Nizams Institute of Medical Sciences, Hyderabad, India, personal communication).…”