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 end-stage kidney disease, 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 failure is classified as eit ...

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

Danube The Danube ( ; ) is a river that was once a long-standing frontier of the Roman Empire and today connects 10 European countries, running through their territories or being a border. Originating in Germany, the Danube flows southeast for , pa ...

River and its major tributaries, in the modern countries of

Croatia , image_flag = Flag of Croatia.svg , image_coat = Coat of arms of Croatia.svg , anthem = "Lijepa naša domovino"("Our Beautiful Homeland") , image_map = , map_caption = , capit ...

Bosnia and Herzegovina Bosnia and Herzegovina ( sh, / , ), abbreviated BiH () or B&H, sometimes called Bosnia–Herzegovina and often known informally as Bosnia, is a country at the crossroads of south and southeast Europe, located in the Balkans. Bosnia and H ...

Serbia Serbia (, ; Serbian language, Serbian: , , ), officially the Republic of Serbia (Serbian language, Serbian: , , ), is a landlocked country in Southeast Europe, Southeastern and Central Europe, situated at the crossroads of the Pannonian Bas ...

Kosovo Kosovo ( sq, Kosova or ; sr-Cyrl, Косово ), officially the Republic of Kosovo ( sq, Republika e Kosovës, links=no; sr, Република Косово, Republika Kosovo, links=no), is a partially recognised state in Southeast Euro ...

Romania Romania ( ; ro, România ) is a country located at the crossroads of Central Europe, Central, Eastern Europe, Eastern, and Southeast Europe, Southeastern Europe. It borders Bulgaria to the south, Ukraine to the north, Hungary to the west, S ...

, and

Bulgaria Bulgaria (; bg, България, Bǎlgariya), officially the Republic of Bulgaria,, ) is a country in Southeast Europe. It is situated on the eastern flank of the Balkans, and is bordered by Romania to the north, Serbia and North Macedon ...

. 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 Aristolochiacea ...

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 higher doses of aristolochic acid (as Chinese herbal supplements) have developed kidney failure after shorter durations of exposure.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 Chronic kidney disease (CKD) is a type of kidney disease in which a gradual loss of kidney function occurs over a period of months to years. Initially generally no symptoms are seen, but later symptoms may include leg swelling, feeling tired, vom ...

by showing an absence of high blood pressure,

xanthochromia Xanthochromia, from the Greek ''xanthos'' (ξανθός) "yellow" and ''chroma'' (χρώμα) "colour", is the yellowish appearance of cerebrospinal fluid that occurs several hours after bleeding into the subarachnoid space caused by certain medic ...

of palms and soles (Tanchev's sign), early

hypochromic anemia Hypochromic anemia is a generic term for any type of anemia in which the red blood cells are paler than normal. (''Hypo''- refers to ''less'', and ''chromic'' means ''colour''.) A normal red blood cell has a biconcave disk shape and will have an a ...

, absence of

proteinuria Proteinuria is the presence of excess proteins in the urine. In healthy persons, urine contains very little protein; an excess is suggestive of illness. Excess protein in the urine often causes the urine to become foamy (although this symptom ma ...

, 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 transplantati ...

. 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, also called urothelial carcinoma, is a type of cancer that typically occurs in the urinary system. It is the most common type of bladder cancer and cancer of the ureter, urethra, and urachus. It accounts for 95% of ...

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 covnvergence 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 made of smooth muscle that propel urine from the kidneys to the urinary bladder. In a human adult, the ureters are usually long and around in diameter. The ureter is lined by urothelial cells, a type of transitional epit ...

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

bladder The urinary bladder, or simply bladder, is a hollow organ in humans and other vertebrates that stores urine from the kidneys before disposal by urination. In humans the bladder is a distensible organ that sits on the pelvic floor. Urine enters ...

. )

Causes

Dietary exposure to

is the cause of BEN and its attendant transitional cell cancers. Former hypotheses that included roles for

ochratoxin Ochratoxins are a group of mycotoxins produced by some ''Aspergillus'' species (mainly ''A. ochraceus'' and A. ''carbonarius'', but also by 33% of ''A. niger'' industrial strains) and some ''Penicillium'' species, especially ''P. verrucosum''. ...

, 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 ''Aristolochia clematitis'', the (European) birthwort, is a twining herbaceous plant in the family Aristolochiaceae, which is native to Europe. The leaves are heart shaped and the flowers are pale yellow and tubular in form. The plant seeks ligh ...

'' (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 herbalism) is the study of pharmacognosy and the use of medicinal plants, which are a basis of traditional medicine. With worldwide research into pharmacology, some herbal medicines have been translated into modern remedie ...

used in

traditional Chinese medicine Traditional Chinese medicine (TCM) is an alternative medical practice drawn from traditional medicine in China. It has been described as "fraught with pseudoscience", with the majority of its treatments having no logical mechanism of action ...

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 Transitional epithelium also known as urothelium is a type of stratified epithelium. Transitional epithelium is a type of tissue that changes shape in response to stretching (stretchable epithelium). The transitional epithelium usually appears ...

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 abno ...

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. Their study was based on a wide screening of inhabitants of the villages around the town of

Vratsa Vratsa ( bg, Враца ) is the largest city in northwestern Bulgaria and the administrative and economic centre of the municipality of Vratsa and Vratsa district. It is located about 112 km north of Sofia, 40 km southeast of Montana. ...

. Their contribution to the understanding of this unusual endemic disease of the kidneys was their description of symptoms which were not typical of common chronic nephritis, i.e., incidence only in adults (no children affected), absence of high blood pressure,

of palms and soles (Tanchev's sign), early

, absence of

, and slow progression of

. A striking feature of the disease is its very localized occurrence. There are approximately ten small areas where it occurs, all of them more or less rural, but nothing seems to connect those areas other than the occurrence of this illness. Tanchev and colleagues suggested that the condition was ''

sui generis ''Sui generis'' ( , ) is a Latin phrase that means "of its/their own kind", "in a class by itself", therefore "unique". A number of disciplines use the term to refer to unique entities. These include: * Biology, for species that do not fit in ...

''. Their initial tentative hypothesis for its cause was intoxication with heavy metals, because the affected villages were supplied with water coming from nearby

Mountain, a

karst Karst is a topography formed from the dissolution of soluble rocks such as limestone, dolomite, and gypsum. It is characterized by underground drainage systems with sinkholes and caves. It has also been documented for more weathering-resistant ro ...

-type mountain. The disease was originally called "Vratsa nephritis," and became known as "Balkan endemic nephropathy" later, after people living in

Yugoslavia Yugoslavia (; sh-Latn-Cyrl, separator=" / ", Jugoslavija, Југославија ; sl, Jugoslavija ; mk, Југославија ;; rup, Iugoslavia; hu, Jugoszlávia; rue, label=Pannonian Rusyn, Югославия, translit=Juhoslavija ...

and

were found to be suffering from it as well. But in Bulgaria and in neighbouring countries, the condition is known as "Tanchev's Nephropathy", in homage to Dr. Tanchev's work.

References

External links