Balkan endemic nephropathy (BEN) is a form of

interstitial nephritis Interstitial nephritis, also known as tubulointerstitial nephritis, is inflammation of the area of the kidney known as the renal interstitium, which consists of a collection of cells, extracellular matrix, and fluid surrounding the renal tubules ...

causing

kidney failure Kidney failure, also known as renal failure or end-stage renal disease (ESRD), is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney fa ...

. It was first identified in the 1920s among several small, discrete communities along the

Danube The Danube ( ; see also #Names and etymology, other names) is the List of rivers of Europe#Longest rivers, second-longest river in Europe, after the Volga in Russia. It flows through Central and Southeastern Europe, from the Black Forest sou ...

River and its major tributaries, in the modern countries of

Croatia Croatia, officially the Republic of Croatia, is a country in Central Europe, Central and Southeast Europe, on the coast of the Adriatic Sea. It borders Slovenia to the northwest, Hungary to the northeast, Serbia to the east, Bosnia and Herze ...

Bosnia and Herzegovina Bosnia and Herzegovina, sometimes known as Bosnia-Herzegovina and informally as Bosnia, is a country in Southeast Europe. Situated on the Balkans, Balkan Peninsula, it borders Serbia to the east, Montenegro to the southeast, and Croatia to th ...

Serbia , image_flag = Flag of Serbia.svg , national_motto = , image_coat = Coat of arms of Serbia.svg , national_anthem = () , image_map = , map_caption = Location of Serbia (gree ...

Kosovo Kosovo, officially the Republic of Kosovo, is a landlocked country in Southeast Europe with International recognition of Kosovo, partial diplomatic recognition. It is bordered by Albania to the southwest, Montenegro to the west, Serbia to the ...

Romania Romania is a country located at the crossroads of Central Europe, Central, Eastern Europe, Eastern and Southeast Europe. It borders Ukraine to the north and east, Hungary to the west, Serbia to the southwest, Bulgaria to the south, Moldova to ...

, and

Bulgaria Bulgaria, officially the Republic of Bulgaria, is a country in Southeast Europe. It is situated on the eastern portion of the Balkans directly south of the Danube river and west of the Black Sea. Bulgaria is bordered by Greece and Turkey t ...

. It is caused by small long-term doses of

aristolochic acid Aristolochic acids () are a family of carcinogenic, mutagenic, and nephrotoxic phytochemicals commonly found in the flowering plant family Aristolochiaceae (birthworts). Aristolochic acid (AA) I is the most abundant one. The family Aristolochiace ...

in the diet. The disease primarily affects people 30 to 60 years of age. Doses of the toxin are usually low and people moving to endemic areas typically develop the condition only when they have lived there for 10–20 years. People taking aristolochic acid pills as an

alternative medicine Alternative medicine refers to practices that aim to achieve the healing effects of conventional medicine, but that typically lack biological plausibility, testability, repeatability, or supporting evidence of effectiveness. Such practices are ...

have developed fast-onset kidney failure as part of a syndrome known as "Aristolochic acid nephropathy" or "Chinese herbs nephropathy".Stiborová, M., Arlt, V.M. & Schmeiser, H.H. Balkan endemic nephropathy: an update on its aetiology. Arch Toxicol 90, 2595–2615 (2016). https://doi.org/10.1007/s00204-016-1819-3

Signs and symptoms

The patients are distinguished from those suffering from other causes of end-stage renal disease by showing an absence of high blood pressure, xanthochromia of palms and soles (Tanchev's sign), early hypochromic anemia, absence of

proteinuria Proteinuria is the presence of excess proteins in the urine. In healthy persons, urine contains very little protein, less than 150 mg/day; an excess is suggestive of illness. Excess protein in the urine often causes the urine to become fo ...

, and slow progression of

. There is no specific therapy; BEN causes end-stage renal disease, for which the only effective treatments are dialysis or a

kidney transplant Kidney transplant or renal transplant is the organ transplant of a kidney into a patient with end-stage kidney disease (ESRD). Kidney transplant is typically classified as deceased-donor (formerly known as cadaveric) or living-donor transplantat ...

. In endemic areas BEN is responsible for up to 70% of end-stage renal disease. At least 25,000 individuals are known to have this form of the disease. Patients with BEN have a greatly increased rate of

transitional cell carcinoma Transitional cell carcinoma is a type of cancer that arises from the transitional epithelium, a tissue lining the inner surface of these hollow organs. It typically occurs in the urothelium of the urinary system; in that case, it is also called ...

of the upper urothelial tract, (the

renal pelvis The renal pelvis or pelvis of the kidney is the funnel-like dilated part of the ureter in the kidney. It is formed by the convergence of the major calyces, acting as a funnel for urine flowing from the major calyces to the ureter. It has a mucous ...

and

ureter The ureters are tubes composed of smooth muscle that transport urine from the kidneys to the urinary bladder. In an adult human, the ureters typically measure 20 to 30 centimeters in length and about 3 to 4 millimeters in diameter. They are lin ...

s). (In populations without BEN, most urothelial cancer occurs in the

bladder The bladder () is a hollow organ in humans and other vertebrates that stores urine from the kidneys. In placental mammals, urine enters the bladder via the ureters and exits via the urethra during urination. In humans, the bladder is a distens ...

. )

Causes

Dietary exposure to

is the cause of BEN and its attendant transitional cell cancers. Former hypotheses that included roles for ochratoxin, poisoning by organic compounds leached from lignite or by heavy metals, viruses, and trace-element deficiencies, are not supported by current evidence. Genetic factors may be involved in determining which persons exposed to aristolochic acid suffer from BEN and which do not. In the Balkan region, dietary aristolochic acid exposure may come from the consumption of the seeds of '' Aristolochia clematitis'' (European birthwort), a plant native to the endemic region, which grows among wheat plants and whose seeds mingle with the wheat used for bread. Aristolochic-acid-containing

herbal remedies Herbal medicine (also called herbalism, phytomedicine or phytotherapy) is the study of pharmacognosy and the use of medicinal plants, which are a basis of traditional medicine. Scientific evidence for the effectiveness of many herbal treatments ...

used in

traditional Chinese medicine Traditional Chinese medicine (TCM) is an alternative medicine, alternative medical practice drawn from traditional medicine in China. A large share of its claims are pseudoscientific, with the majority of treatments having no robust evidence ...

are associated with a related—possibly identical—condition known as "Chinese herbs nephropathy". Exposure to aristolochic acid is associated with a high incidence of uroepithelial

tumorigenesis Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abn ...

Diagnosis

Biopsy - For definitive diagnosis

History

The first official published description of the disease was made by the Bulgarian nephrologist Dr. Yoto Tanchev (1917–2000) and his team in 1956 in the Bulgarian Journal ''Savremenna Medizina'',Tanchev Y, Evstatiev Z, Dorossiev D, Pencheva J, Tzvetkova G. Studies on the nephritides in the District of Vratza. ''Savremena Medicina'' 1956; 7: 14–29 (Bulgarian). a priority generally acknowledged by the international nephrological community. The disease was originally called "Vratsa nephritis," and became known as "Balkan endemic nephropathy" later, after people living in

Yugoslavia , common_name = Yugoslavia , life_span = 1918–19921941–1945: World War II in Yugoslavia#Axis invasion and dismemberment of Yugoslavia, Axis occupation , p1 = Kingdom of SerbiaSerbia , flag_p ...

and

were found to be suffering from it as well.

References

External links