scholarly journals Aristolochic Acids: Newly Identified Exposure Pathways of this Class of Environmental and Food-Borne Contaminants and its Potential Link to Chronic Kidney Diseases

Toxics ◽  
2019 ◽  
Vol 7 (1) ◽  
pp. 14 ◽  
Author(s):  
Chi-Kong Chan ◽  
Yushuo Liu ◽  
Nikola Pavlović ◽  
Wan Chan
Keyword(s):  
Kidney Diseases ◽  
Balkan Peninsula ◽  
Danube River ◽  
Herbal Remedies ◽  
Balkan Endemic Nephropathy ◽  
Chronic Kidney Diseases ◽  
Aristolochic Acids ◽  
Causative Agents ◽  
Endemic Nephropathy ◽  
Potential Link

Aristolochic acids (AAs) are nitrophenanthrene carboxylic acids naturally produced by Aristolochia plants. These plants were widely used to prepare herbal remedies until AAs were observed to be highly nephrotoxic and carcinogenic to humans. Although the use of AA-containing Aristolochia plants in herbal medicine is prohibited in countries worldwide, emerging evidence nevertheless has indicated that AAs are the causative agents of Balkan endemic nephropathy (BEN), an environmentally derived disease threatening numerous residents of rural farming villages along the Danube River in countries of the Balkan Peninsula. This perspective updates recent findings on the identification of AAs in food as a result of the root uptake of free AAs released from the decayed seeds of Aristolochia clematitis L., in combination with their presence and fate in the environment. The potential link between AAs and the high prevalence of chronic kidney diseases in China is also discussed.

Organic Compounds Derived from Pliocene Lignite and the Etiology of Balkan Endemic Nephropathy

2003 ◽  
Author(s):  
Calin A. Tatu ◽  
Victor Dumitrascu
Keyword(s):  
Kidney Diseases ◽  
Renal Dialysis ◽  
Disease Diagnosis ◽  
Rapid Onset ◽  
Danube River ◽  
Balkan Endemic Nephropathy ◽  
Normocytic Anemia ◽  
Clinical Onset ◽  
Endemic Nephropathy ◽  
Stage Renal Disease

Acknowledged for the first time as a medical entity in the late 1950s, Balkan endemic nephropathy (BEN) is a chronic and irreversible kidney disease of unknown cause. BEN is geographically confined to several rural regions of central and southeastern Serbia, southwestern Romania, northwestern Bulgaria, southeastern Croatia, and parts of Bosnia and Kosovo, confined to the alluvial valleys of tributaries of the lower Danube River (Ceovic et al. 1992, Hall 1992, Tatu et al. 1998). It is estimated that several thousand people in the affected countries are currently suffering from the disease, and that thousands more will be diagnosed with BEN in the next few years. Although no single feature is sufficient for disease diagnosis, BEN has several characteristics that allow it to be distinguished from other chronic kidney diseases: These characteristics are: . . . ·The age of clinical onset is usually between 30 and 50 years, with a slightly higher frequency in women (female:male sex ratio is ~1.5:1), probably due to some social and genetic factors. . . . . . . ·There is a long subclinical “incubation” period and a rapid onset of end-stage renal disease; the only therapeutic solutions left are chronic renal dialysis or kidney transplantation. . . . . . . ·There is a family history of the disease, with an aggregation of the disease in certain households. . . . . . . ·BEN patients exhibit normal blood pressure in ~80% of the cases (a feature unusual for most other kidney diseases) and normochromic and normocytic anemia is common in BEN. . . . . . . ·BEN patients have lived for at least 10-20 years in one or more of the endemic villages. A slight decrease in the incidence of the disease has been noticed in the last two years in Serbia and Romania (Cukuranovic et al. 2000); however, this seems to follow the usual oscillating pattern of the disease, with lows and highs of incidence, and another epidemic outbreak is likely to occur in these areas in the future. . . .

Ocular fundus abnormalities in patients with Balkan endemic nephropathy and other chronic kidney diseases

2015 ◽  
Vol 47 (10) ◽  
pp. 1693-1701 ◽  
Author(s):  
Jasmina Djordjevic Jocic ◽  
Rade Cukuranovic ◽  
Predrag Jovanovic ◽  
Vidosava Djordjevic ◽  
Marija Mihajlovic ◽  
...  
Keyword(s):  
Kidney Diseases ◽  
Balkan Endemic Nephropathy ◽  
Chronic Kidney Diseases ◽  
Ocular Fundus ◽  
Endemic Nephropathy

scholarly journals Genetic loci that affect aristolochic acid-induced nephrotoxicity in the mouse

2011 ◽  
Vol 300 (6) ◽  
pp. F1360-F1367 ◽  
Author(s):  
Thomas A. Rosenquist
Keyword(s):  
Proximal Tubule ◽  
Genetic Predisposition ◽  
Aristolochic Acid ◽  
Herbal Remedies ◽  
Balkan Endemic Nephropathy ◽  
Traditional Medicines ◽  
Aristolochic Acids ◽  
F2 Population ◽  
Endemic Nephropathy ◽  
Upper Urothelial Cancer

Aristolochic acids (AA) are plant-derived nephrotoxins and carcinogens found in traditional medicines and herbal remedies. AA causes aristolochic acid nephropathy (AAN) and is a suspected environmental agent in Balkan endemic nephropathy (BEN) and its associated upper urothelial cancer. Approximately 5–10% of individuals exposed to AA develop renal insufficiency and/or cancer; thus a genetic predisposition to AA sensitivity has been proposed. The mouse is an established animal model of AAN, and inbred murine strains vary in AA sensitivity, confirming the genetic predisposition. We mapped quantitative trait loci (QTL) correlated with proximal tubule dysfunction after exposure to AA in an F2 population of mice, derived from breeding an AA-resistant strain ( C57BL/6J) and an AA-sensitive strain ( DBA/2J). A single main QTL was identified on chromosome 4 ( Aanq1); three other interacting QTLs, ( Aanq2–4) also were detected. The Aanq1 region was also detected in untreated mice, raising the possibility that preexisting differences in proximal tubule function may affect the severity of AA-elicited toxicity. This study lays the groundwork for identifying the genetic pathways contributing to AA sensitivity in the mouse and will further our understanding of human susceptibility to AA found widely in traditional medicines.

scholarly journals Higher dose of erythropoietin for anemia correction in Balkan endemic nephropathy patients

2012 ◽  
Vol 140 (7-8) ◽  
pp. 456-461
Author(s):  
Ljiljana Lukic ◽  
Djordje Mitrovic ◽  
Sanda Kovacevic ◽  
Momir Stanisic ◽  
Snezana Pelemis ◽  
...  
Keyword(s):  
Kidney Diseases ◽  
Ferritin Level ◽  
Hemoglobin Level ◽  
Obstructive Nephropathy ◽  
Balkan Endemic Nephropathy ◽  
Recombinant Erythropoietin ◽  
Severe Anemia ◽  
Human Recombinant Erythropoietin ◽  
Endemic Nephropathy ◽  
Regular Hemodialysis

Introduction. Balkan endemic nephropathy (BEN) patients maintained with hemodialysis have more severe anemia than patients with other kidney diseases. Objective. The aim of the study was to compare the improvement of anemia in BEN patients and those with other kidney diseases during treatment with human recombinant erythropoietin (rHuEpo). Methods. The study involved 240 patients on regular hemodialysis for more than one year. Out of them 146 had BEN and 94 other kidney diseases (21 glomerulonephritis, 20 hypertension, 18 diabetes, 10 policystic kidney disease, 5 obstructive nephropathy, 18 other diseases). Treatment with rHuEpo was carried out according to European guidelines for the management of anemia. Results. Patients with BEN were older and were less frequently treated with ACEi than patients with other kidney diseases. At the onset of the study mean hemoglobin level (109.6?22.3 vs. 112.7?11.3 g/l) was significantly lower, but serum ferritin level and rHuEpo dose (65.4?22.3 vs. 57.5?22.5 U/kg/week) were significantly higher in BEN patients than in others. In prospective four months study these differences in hemoglobin levels and rHuEpo doses maintained. The rate of anemia improvement was examined in 15 BEN patients and 10 patients with other kidney diseases at the beginning of rHuEpo treatment. No difference in the rate of anemia improvement was found between the two groups but higher rHuEpo doses were used in BEN patients. Conclusion. Patients with BEN on regular hemodialysis had more severe anemia and required higher rHuEpo doses for maintaining target hemoglobin level.

scholarly journals MicroRNA Profiling in Patients with Upper Tract Urothelial Carcinoma Associated with Balkan Endemic Nephropathy

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Katerina Popovska-Jankovic ◽  
Predrag Noveski ◽  
Ljubinka Jankovic-Velickovic ◽  
Slavica Stojnev ◽  
Rade Cukuranovic ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Strong Association ◽  
Upper Tract Urothelial Carcinoma ◽  
Danube River ◽  
Balkan Endemic Nephropathy ◽  
Upper Tract ◽  
Microrna Profiling ◽  
Endemic Nephropathy ◽  
Urothelial Bladder ◽  
Balkan Region

Balkan endemic nephropathy (BEN) is a disease that affects people that live in the alluvial plains along the tributaries of the Danube River in the Balkan region. BEN is a chronic tubulointerstitial disease with a slow progression to terminal renal failure and has strong association with upper tract urothelial carcinoma (UTUC). There are several hypotheses about the etiology of BEN, but only the toxic effect of aristolochic acid has been confirmed as a risk factor in the occurrence of the disease. Aberrantly expressed miRNAs have been shown to be associated with many types of cancers. A number of studies have investigated the expression of microRNAs in urothelial carcinoma, mainly on urothelial bladder cancer, and only a few have included patients with UTUC. Here we present the first study of microRNA profiling in UTUC tissues from patients with BEN (BEN-UTUC) and patients with UTUC from nonendemic Balkan regions (non-BEN-UTUC) in comparison to normal kidney tissues. We found 10 miRNAs that were differentially expressed in patients with BEN-UTUC and 15 miRNAs in patients with non-BEN-UTUC. miRNA signature determined in BEN-UTUC patients differs from the non-BEN-UTUC patients; only miR-205-5p was mutual in both groups.

scholarly journals Etiology of Balkan Endemic Nephropathy: An Update on Aristolochic Acids Exposure Mechanisms

2018 ◽  
Vol 31 (11) ◽  
pp. 1109-1110 ◽  
Author(s):  
Chi-Kong Chan ◽  
Yushuo Liu ◽  
Nikola M. Pavlović ◽  
Wan Chan
Keyword(s):  
Balkan Endemic Nephropathy ◽  
Aristolochic Acids ◽  
Endemic Nephropathy

Comparison of Kidney Size between Patients with Balkan Endemic Nephropathy and Other Kidney Diseases

2008 ◽  
Vol 31 (5) ◽  
pp. 307-312 ◽  
Author(s):  
Visnja Ležaić ◽  
Ivko Marić ◽  
Dijana Jovanović ◽  
Milan Radović ◽  
Zoran Kovačević ◽  
...  
Keyword(s):  
Kidney Diseases ◽  
Balkan Endemic Nephropathy ◽  
Kidney Size ◽  
Endemic Nephropathy

scholarly journals Co-Exposure to Aristolochic Acids I and II Increases DNA Adduct Formation Responsible for Aristolochic Acid I-Mediated Carcinogenicity in Rats

2021 ◽  
Vol 22 (19) ◽  
pp. 10479
Author(s):  
František Bárta ◽  
Alena Dedíková ◽  
Michaela Bebová ◽  
Šárka Dušková ◽  
Jaroslav Mráz ◽  
...  
Keyword(s):  
Plant Extract ◽  
Aristolochic Acid ◽  
Adduct Formation ◽  
Dna Adduct ◽  
Renal Diseases ◽  
Balkan Endemic Nephropathy ◽  
Chemical Research ◽  
Aristolochic Acids ◽  
Endemic Nephropathy

The plant extract aristolochic acid (AA), containing aristolochic acids I (AAI) and II (AAII) as major components, causes aristolochic acid nephropathy (AAN) and Balkan endemic nephropathy (BEN), unique renal diseases associated with upper urothelial cancer. Recently (Chemical Research in Toxicology 33(11), 2804–2818, 2020), we showed that the in vivo metabolism of AAI and AAII in Wistar rats is influenced by their co-exposure (i.e., AAI/AAII mixture). Using the same rat model, we investigated how exposure to the AAI/AAII mixture can influence AAI and AAII DNA adduct formation (i.e., AA-mediated genotoxicity). Using 32P-postlabelling, we found that AA-DNA adduct formation was increased in the livers and kidneys of rats treated with AAI/AAII mixture compared to rats treated with AAI or AAII alone. Measuring the activity of enzymes involved in AA metabolism, we showed that enhanced AA-DNA adduct formation might be caused partially by both decreased AAI detoxification as a result of hepatic CYP2C11 inhibition during treatment with AAI/AAII mixture and by hepatic or renal NQO1 induction, the key enzyme predominantly activating AA to DNA adducts. Moreover, our results indicate that AAII might act as an inhibitor of AAI detoxification in vivo. Consequently, higher amounts of AAI might remain in liver and kidney tissues, which can be reductively activated, resulting in enhanced AAI DNA adduct formation. Collectively, these results indicate that AAII present in the plant extract AA enhances the genotoxic properties of AAI (i.e., AAI DNA adduct formation). As patients suffering from AAN and BEN are always exposed to the plant extract (i.e., AAI/AAII mixture), our findings are crucial to better understanding host factors critical for AAN- and BEN-associated urothelial malignancy.

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