Therapeutic Remedies Based on <i>Aristolochia</i> <i>clematitis</i> in the Main Foci of Balkan Endemic Nephropathy in Romania

Abstract

Balkan endemic nephropathy (BEN) is a disease found in Romania and neighboring countries in the Balkan area. In Romania, BEN is most prevalent in Mehedinti County, located in the South of Romania near the Danube River. The etiology of the disease is as yet unknown. One of the current hypotheses concerning BEN etiology is an involvement of aristolochic acid (AA). BEN bears many similarities to aristolochic nephropathy, which is developed due to the use of Chinese herbs as therapeutic remedies in slimming diets. This paper analyzes the involvement of therapeutic remedies based on AA in the BEN found in Mehedinti County, where these herbs have been traditionally used. The presence of AA in the plasma of BEN patients as well as of other subjects, including healthy relatives of these patients and other persons from the BEN-affected area, has been analyzed. No AA was detected in the plasma of the studied subjects. This proves the absence, at the current time, of an AA contribution in the analyzed subjects. Therapeutic remedies based on AA have been used in the BEN-affected area. We were not able to reveal direct relationships between these remedies and either the development of BEN in dialyzed patients or the development of urinary-tract tumors in dialyzed patients with urothelial tumors. Therapeutic remedies based on Aristolochiaclematitis may play a stimulating role in BEN with regard to its development and the development of urinary-tract tumors. There may be a relationship between BEN and cumulative previous exposure to low doses of AA due to the consumption of contaminated foodstuffs, which could add to any contributions by therapeutic remedies.

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

“…101 The Pliocene lignite hypothesis is consistent with the gender incidence and prevalence difference in BEN, as women are more exposed than men to household factors, 10 and would be more likely to not work outside the home, thereby being exposed nearly exclusively to the endemic water supply. In contrast, husbands are often employed outside the home, 10 and therefore would be expected to be exposed to more heterogeneous water supplies.…”

“…Furthermore, though an epidemiological study showed that exposure to A. clematitis has occurred in endemic areas via other routes, i.e., from teas and baths prepared for therapeutic purposes, the majority of BEN patients had not used such remedies. 61 Finally, the exact mechanism by which aristolochic acid may cause tubulointerstitial nephropathy remains uncertain. 62 Thus, although many characteristics of BEN are consistent with the three environmental hypotheses for which there is the most compelling evidence (i.e., Pliocene lignites, ochratoxin A, and aristolochic acid), the Pliocene lignite hypothesis best accounts for the geographical distribution of the disease, as the lignites are not distributed uniformly among both endemic and nonendemic areas, but are proximal to endemic areas.…”

Aristolochic Acid in the Etiology of Renal Cell Carcinoma

“…Although Romania has long been known to harbor regions of endemic nephropathy, the RCC patients whose tumors were sequenced apparently did not reside in the endemic areas. However, the therapeutic use of Aristolochia herbs is known to occur in Romania (33), and a follow-up study did establish the presence of AL–DNA adducts in Romanian RCC patients (23). …”

Is herbal tea consumption a factor in endemic nephropathy?

“…However, the causative relationship between AA and EN again raised the question whether bread intake is the only route of ingestion or whether AA was ingested also in EN as a part of folkloric medicine. Gluhovschi et al reported that although therapeutic remedies based on AA products are used in the EN affected area, no relationship between these remedies and the development of EN or of tumors was observed [8]. However, they used HPLC for detection of AA in plasma, which is less sensitive than the mass spectrometry we recently used [1,2].…”