Balkan Nephropathy: Evolution of Our Knowledge

Abstract

Balkan endemic nephropathy (BEN), originally described in the late 1950s as a chronic tubulointerstitial kidney disease, is identified by its unique epidemiological features. The most remarkable characteristic of BEN is the focal topographical nature that characterizes its occurrence at the global, national, and even household level. BEN affects only certain endemic rural foci along tributaries of the Danube River in the Balkan countries of Bosnia, Bulgaria, Croatia, Romania, and Serbia. The spatial distribution has remained astonishingly unchanged with time because the disease affects the same endemic clusters as 50 years ago. The natural course of the disease is characterized by universal development of end-stage renal disease and the frequent development of upper urinary tract tumors, posing a substantial disease burden to the afflicted areas. The greatest challenge in the study of BEN has been the elucidation of its cause. The unique features of the disease, in particular its endemic nature and the long incubation period required for the disease to develop, have led to the proposal that BEN represents a unique environmental disease. The quest for the responsible environmental factor has been long and diverse, and although no definitive answer has been provided to date, converging lines of evidence support the theory that long-term consumption of food contaminated with aristolochic acid underlies the pathogenesis of BEN. The present review describes the evolution of our knowledge of BEN in relation to the development of the main theories for its pathogenesis.

The Central American Epidemic of CKD

“…The limited evidence available to date supporting and opposing several of these hypotheses is reviewed in Table 3. Critically, other potential causes certainly exist, and, as evidenced by the chain of events that led to the recognition of aristolochic acid as a nephrotoxin (16), it is quite possible that the cause of kidney disease may not be among those causes listed in Table 3 or that several of these possibilities may be acting together to result in CKD.…”

Limitations and plausibility of the Pliocene lignite hypothesis in explaining the etiology of Balkan endemic nephropathy

“…44,[52][53][54] However, ochratoxin A contamination has been found in both endemic and nonendemic regions, 22,55,56 nonaffected households, 57 and in Romania, no ochratoxin A or its degradation products were detected in the urine of BEN patients, 58 raising doubts about its role in the etiology of the disease. Likewise, Aristolochia plants are ubiquitous, 24 and Aristolochia contamination has occurred in nonendemic areas of BEN affected countries.…”

“…10 No new endemic areas have emerged, and no known endemic locations have become nonendemic. 57,74 A fixed environmental factor like exposure to Pliocene lignites may best explain the constancy of the disease.…”

“…57 If BEN is caused by organic compounds from such a stationary source, why is it a relatively new disease? Balkan endemic nephropathy is likely not a new disease, but rather a newly recognized and described one.…”

Metabonomics: on the Road to Detect Diagnostic Biomarkers in Endemic (Balkan) Nephropathy. Evaluation in a Retrospective Pilot Project

“…Until the 1990's, ochratoxin A was the most suspected as the environmental cause of EN, a mycotoxin produced by fungi growing in barns and grain crops and favored by the moisture occurring in these areas due to flood. Although it was detected in a variety of foods, its role in EN has never convinced scientists because of the lack of reproducibility in experimental kidney disease models [1,2]. In 2006, the EU Committee on Food Safety concluded that there is no convincing evidence from human epidemiology to confirm the association between ochratoxin an exposure and the prevalence of endemic nephropathy or urothelial cancers [3].…”