Balkan Endemic Nephropathy and the Causative Role of Aristolochic Acid.

Balkan endemic nephropathy is a chronic tubulointerstitial disease with insidious onset, slowly progressing to end-stage renal disease and frequently associated with urothelial carcinoma of the upper urinary tract (UTUC). It was described in South-East Europe at the Balkan peninsula in rural areas around tributaries of the Danube River. After decades of intensive investigation, the causative factor was identified as the environmental phytotoxin aristolochic acid (AA) contained in Aristolochia clematitis, a common plant growing in wheat fields that was ingested through home-baked bread.

[Aristolochic acid nephropathy ("Chinese herb nephropathy")].

Aristolochic acid nephropathy is a renal disease of toxic origin characterized by a progressive interstitial fibrosis and frequently associated with urinary tract cancer. It was initially reported in Belgium after the intake of slimming pills containing root extracts of a Chinese herb, Aristolochia fangchi. In the following decades, numerous cases have been reported worldwide, particularly in Asian countries.

The epidemiology, diagnosis, and management of aristolochic acid nephropathy: a narrative review.

It has been 20 years since the first description of a rapidly progressive renal disease that is associated with the consumption of Chinese herbs containing aristolochic acid (AA) and is now termed aristolochic acid nephropathy (AAN). Recent data have shown that AA is also the primary causative agent in Balkan endemic nephropathy and associated urothelial cancer. Aristolochic acid nephropathy is associated with a high long-term risk for renal failure and urothelial cancer, and the potential worldwide population exposure is enormous.

Aristolochic acid nephropathy revisited: a place for innate and adaptive immunity?

Aims: The histological features of aristolochic acid nephropathy (AAN) consist of paucicellular interstitial fibrosis, severe tubular atrophy, and almost intact glomeruli with media lesions of interlobular arteries. As an early phase of interstitial inflammation preceded peritubular fibrosis in the rat model of AAN, the aim was to investigate the presence of inflammatory cells in human AAN.

Methods And Results: Reports of confirmed cases and case series of AAN were reviewed in terms of interstitial inflammation and found to have very conflicting results.

Cytotoxicity of mononuclear cells as induced by peritoneal dialysis fluids: insight into mechanisms that regulate osmotic stress-related apoptosis.

Objective: High glucose content of peritoneal dialysis fluids (PDFs) has been shown to contribute to loss of peritoneal function during long-term peritoneal dialysis. However, hyperosmolality and hypertonicity of PDF are usually seen as similar stress events inducing osmotic stress-induced programmed cell death. In this study, we examined the impact of various osmotic agents on apoptosis induced by hyperosmolar PDFs, focusing on the mechanisms underlying the lethal effects of PDFs on peripheral blood mononuclear cells (PBMCs).

Aristolochic acid nephropathy: a worldwide problem.

Aristolochic acid nephropathy (AAN), a progressive renal interstitial fibrosis frequently associated with urothelial malignancies, was initially reported in a Belgian cohort of more than 100 patients after the intake of slimming pills containing a Chinese herb, Aristolochia fangchi. Although botanicals known or suspected to contain aristolochic acid (AA) were no longer permitted in many countries, several AAN cases were regularly observed all around the world. The incidence of AAN is probably much higher than initially thought, especially in Asia and the Balkans.

Patterns of interstitial inflammation during the evolution of renal injury in experimental aristolochic acid nephropathy.

Background: Interstitial inflammation is a prominent feature associated with the severity of renal injury and progressive kidney failure. We utilized an animal model of aristolochic acid (AA)-induced nephropathy (AAN) to assess patterns of infiltration and inflammation during the evolution of tubulointerstitial damage and to relate them to the development of fibrosis.

Methods: Male Wistar rats receiving sc daily AA or vehicle were sacrificed between Days 1 and 35.

Late onset of bladder urothelial carcinoma after kidney transplantation for end-stage aristolochic acid nephropathy: a case series with 15-year follow-up.

Background: Aristolochic acids are nephrotoxins and predispose to upper-tract urothelial carcinoma. The risk of bladder urothelial carcinoma after kidney transplantation and its relationship to upper-tract urothelial carcinoma is not well defined.

Study Design: Case series.

Early proximal tubule injury in experimental aristolochic acid nephropathy: functional and histological studies.

Background: Aristolochic acid (AA), the plant extract of Aristolochia species, is involved in the onset of progressive tubulointerstitial renal fibrosis in humans. Clinical and in vitro findings have previously suggested that the proximal tubule was the target of AA.

Methods: Using a rat model of AA nephropathy, the proximal tubular lesions induced by daily subcutaneous injections of AA for 35 or 5 days were characterized biochemically and histologically.

The renin-angiotensin system blockade does not prevent renal interstitial fibrosis induced by aristolochic acids.

Background: Experimental aristolochic acid nephropathy (AAN), characterized by interstitial fibrosis, tubular atrophy, and chronic renal failure, was reported after 35-day injections of aristolochic acids (AA) to salt-depleted male Wistar rats. The link between renal fibrosis and the renin-angiotensin system (RAS) in this model remains unknown.

Methods: We investigated the impact of sodium diets (low and normal), of RAS inhibition with enalapril (ENA) alone, or combined with candesartan (CSN) for 35 days, and ENA + CSN for 65 days on AAN development.

Herbs and the kidney.

The use of herbal therapy has increased dramatically in past years and may lead to renal injury or various toxic insults, especially in renal patients. In most countries, herbal products are not regulated as medicines. Herbal poisoning may be secondary to the presence of undisclosed drugs or heavy metals, interaction with the pharmacokinetic profile of concomitantly administered drugs, or association with a misidentified herbal species.

Effects of dexfenfluramine on aristolochic acid nephrotoxicity in a rat model for Chinese-herb nephropathy.

Chinese-herb nephropathy (CHN) is a progressive renal interstitial fibrosis initially reported after concomitant intake of an anorexigen, (dex)fenfluramine, and a Chinese herb ( Aristolochia fangchi) containing nephrotoxic and carcinogenic aristolochic acid (AA). We thus tested the possible enhancing effect of the active enantiomer dexfenfluramine (DXF) on AA nephrotoxicity in a rat model for CHN. Groups of 12 salt-depleted male Wistar rats received daily subcutaneous injections of 7 mg/kg body weight DXF (DXF group), 7 mg/kg body weight AA (AA group), a combination of the same doses of AA and DXF (AA+DXF group), or vehicle (control group) for up to 35 days.

High prevalence of fenfluramine-related aortic regurgitation in women with end-stage renal disease secondary to Chinese herb nephropathy.

Background: Non-controlled studies have noted a high prevalence of valvular regurgitation in patients with Chinese herb nephropathy; most of these patients had taken appetite suppressants. We aimed to determine the prevalence of valvular regurgitation and the role of appetite suppressants in patients with Chinese herb nephropathy.

Methods: This case-controlled echocardiographic study included 40 patients with end-stage renal failure due to Chinese herb nephropathy and 37 age-matched controls with end-stage renal disease due to nephropathy of other origin.

Progression rate of Chinese herb nephropathy: impact of Aristolochia fangchi ingested dose.

Background: Renal failure after ingestion of Chinese herbs between 1990 and 1992 was related to the replacement of Stephania tetrandra by Aristolochia fangchi (ST-AF), containing nephrotoxic and carcinogenic aristolochic acids. However, the relationship between ST-AF and renal failure is still a matter of debate. We therefore tested the impact of the ST-AF ingested dose on the progression of renal function deterioration.

Aristolochic acids induce chronic renal failure with interstitial fibrosis in salt-depleted rats.

Chinese-herb nephropathy (CHN) is a rapidly progressive renal fibrosis associated with the intake of a Chinese herb (Aristolochia fangchi) containing nephrotoxic and carcinogenic aristolochic acids (AA). This study attempted to reproduce the main features of human CHN (renal failure, tubular atrophy, and interstitial fibrosis) in a rat model similar to that of cyclosporin-induced nephropathy. Salt-depleted male Wistar rats received daily subcutaneous injections of either 1 mg/kg body wt AA (low-dose AA group), 10 mg/kg body wt AA (high-dose AA group), or vehicle (control group) for 35 d.