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Aristolochic acids, compounds derived from Aristolochiaceae plant species, are associated with significant renal nephrotoxicity and carcinogenicity. Aristolochic acid I (AAI), the most predominant and potent of these compounds, is a primary etiological agent in acute and chronic kidney diseases such as Aristolochic Acid Nephropathy (AAN) and Balkan Endemic Nephropathy (BEN). Due to the kidneys' critical role in xenobiotic excretion, they are the primary organs affected by AAI toxicity. Recent in vitro and in vivo studies have highlighted mitochondrial dysfunction as a crucial factor in the pathogenesis of these kidney diseases. This review provides an update on the recent advances in understanding the causes of acquired mitochondrial dysfunction within the context of AAN and BEN. Key findings include the identification of mitochondrial DNA depletion, loss of mitochondrial membrane potential, and decreased ATP production as significant contributors to kidney damage. Additionally, oxidative stress markers and inflammatory mediators have been implicated in disease progression. Potential therapeutic approaches, such as the use of antioxidants like vitamin C and catalpol, have shown promise in mitigating AAI-induced cytotoxicity. Furthermore, future predictive approaches like pharmacogenomics could pave the way for novel mitochondria-targeted treatments. A comprehensive characterization of mitochondrial function, its underlying molecular mechanisms, and specific biomarkers could offer valuable insights and potential therapeutic options, significantly impacting the current management of AAN and BEN. [ABSTRACT FROM AUTHOR]

Rationale: Over the past six decades, residents of farming villages in multiple countries of the Balkan peninsula have been suffering from a unique type of chronic renal disease, Balkan endemic nephropathy (BEN). It was speculated that environmental pollution by aristolochic acids (AAs) produced naturally by Aristolochia clematitis L., a weed that grows in the area, was causing the disease. However, the human exposure pathway to this class of phytotoxin remains obscure. Knowledge of the sink and stability of AAs in the environment would assist in the formulation of policy reducing exposure risk. Methods: Using our newly developed liquid chromatography/tandem mass spectrometry method of high sensitivity and selectivity, we analysed over 130 soil samples collected from cultivation fields in southern Serbia for the presence of AAs. The environmental stability of AAs was also investigated by incubating soil samples spiked with AAs at various temperatures. Results: The analysis detected AA‐I in over two‐fifths of the tested samples at sub‐μg/kg to μg/kg levels, with higher concentrations observed in more acidic farmland soil. Furthermore, analysis of soil samples incubated at various temperatures revealed half‐lives of over 2 months, indicating that AAs are relatively resistant to degradation. Conclusions: Cultivation soil in southern Serbia is being extensively contaminated with AAs released from the decomposition of A. clematitis weeds. Since AAs are resistant to degradation, it is possible that AAs could have been taken up by root absorption and transported to the edible part of food crops. Prolonged exposure to AA‐contaminated food grown from polluted soil could be one of the main aetiological mechanisms of BEN observed in the area. [ABSTRACT FROM AUTHOR]

Highlights • Nephrotoxic aristolochic acids (AA) contaminated food and soil of Balkans. • Chronic exposure to AA via AA-tainted food resulted in renal fibrosis and cancer. • A new LC–MS/MS method was developed for analysis of AAs in food and soil samples. • Zn/H+ treatment dramatically increase analytical sensitivity of AA in LC–MS/MS. • The method detects for the first time AA in supermarket flour samples in Balkan area. Abstract Prolonged dietary exposure to AA-contaminated food crops cultivated in contaminated farmland was shown to be one of the main culprits of Balkan endemic nephropathy. Ultra-sensitive methods for the detection of AA at trace levels are important for surveillance purposes. We report the development of a novel liquid chromatography-tandem mass spectrometry (LC–MS/MS) method for AA-detection. One striking feature of the method is that the Zn/H+-induced nitroreduction convert AA into their respective aristolactams, which dramatically enhances their analytical sensitivity. The method was applied to quantitate AA in food grains and soil samples collected from farming villages of Serbia, and flour samples purchased from supermarkets. To the best of our knowledge, this is the first report of detecting AA in food ingredients available in supermarkets, which is alarming because it reveals AA poses insidious threats not only to residents of rural farming villages, but also to people residing in urban areas. [ABSTRACT FROM AUTHOR]

Balkan Endemic Nephropathy occurs with a high rate of prevalence in Serbia, Bulgaria, Romania, Bosnia and Herzegovina, and Croatia. The first cases described in Bulgaria, Serbia and Romania date to the late 1950s and early 1960s. BEN has been characterized to date as a chronic, slowly progressive familial tubular interstitial renal disease of unknown aetiology. The disease is characterized by its endemic nature, long incubation period, the familial clustering of the disease, and a exceptionally high incidence of upper urothelial tumour associated with BEN. To date several hypotheses have presented some findings that could be relevant to the etiology of BEN, but only one of them, chronic poisoning with Aristolochic acids, has provided convincing evidence related to BEN etiology and its clinical characteristics. [ABSTRACT FROM AUTHOR]

Balkan endemic nephropathy (BEN), originally described in 1956, is a unique familial, chronic renal disease encountered with a high-prevalence rate in Serbia, Bulgaria, Romania, Croatia and Bosnia and Herzegovina. The most prominent features of the disease are its endemic nature, long-incubation period, familial clustering of the disease and an unusually high incidence of associated upper urothelial cancer (UUC). There are no clear-cut data on BEN incidence and prevalence, since the studies carried out in different endemic areas yielded contradictory information. In spite of intermittent variations, the incidence of new cases has remained stable over time. It has been estimated that almost 100 000 people are at risk of BEN, whereas 25 000 have the disease. The clinical signs and symptoms of BEN are non-specific and often remain unrecognized for years. There are no pathognomonic diagnostic features of BEN, but the set of epidemiological, clinical and biochemical data along with the pattern of pathologic injury in the absence of any other renal diseases are highly suggestive of this entity. Although the aetiology has been extensively studied, fostering the publication of various hypotheses, only one of them has provided conclusive evidence related to the aetiology of BEN. Studies conducted over the past decade have provided particularly strong arguments that BEN and UUC are caused by chronic poisoning with aristolochic acids (AAs). In light of these later studies, one can raise the question whether AAs could be responsible for previously and currently widespread unrecognized global renal disease and UUC. [ABSTRACT FROM PUBLISHER]

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. [ABSTRACT FROM AUTHOR]

Described in the 1950s, Balkan Endemic Nephropathy (BEN) has been recognized as a chronic kidney disease (CKD) with clinical peculiarities and multiple etiological factors. Environmental contaminants – aromatic compounds, mycotoxins and phytotoxins like aristolochic acids (AAs) – polluting food and drinking water sources, were incriminated in BEN, due to their nephrotoxic and carcinogenic properties. The implication of AAs in BEN etiology is currently a highly debated topic due to the fact that they are found within the Aristolochiaceae plants family, used around the globe as traditional medicine and they were also incriminated in Aristolochic Acid Nephropathy (AAN). Exposure pathways have been investigated, but it is unclear to what extent AAs are acting alone or in synergy with other cofactors (environmental, genetics) in triggering kidney damage. Experimental studies strengthen the hypothesis that AAI, the most studied compound in the AAs class, is a significant environmental contaminant and a most important causative factor of BEN. The aim of this review is to compile information about the natural exposure pathways to AAI, via traditional medicinal plants, soil, crop plants, water, food, air. Data that either supports or contradicts the AAI theory concerning BEN etiology was consolidated and available solutions to reduce human exposure were discussed. Because AAI is a phytotoxin with physicochemical properties that allow its transportation in environmental matrices from different types of areas (endemic, nonendemic), and induce CKDs (BEN, AAN) and urinary cancers through bioaccumulation, this review aims to shed a new light on this compound as a biogenic emerging pollutant. [Display omitted] • Soil and vegetables accumulate aristolochic acids from Aristolochia clematitis. • Bioaccumulation of aristolochic acids is influenced by plant and soil properties. • Aristolochic acids-containing edible plants represent a health risk. • Preventive measures should include control of traditional herbs and soil remediation. [ABSTRACT FROM AUTHOR]

Aristolochic acids (AAs) are persistent soil pollutants in the agricultural fields of the Balkan Peninsula that are endemic for Aristolochia clematitis L. This class of carcinogenic and nephrotoxic phytotoxins is taken up by crops through root absorption and contaminates staple foods across the peninsula. Human exposure to AAs via dietary intake has recently been recognized as a cause of Balkan endemic nephropathy. For the sake of public health, human exposure to AAs from all sources should be minimized in a timely manner. However, currently, there is no available remediation method to remove AAs from soil. In this study, we developed the first soil remediation method for AAs using Fenton's reagent (FR), a combination of ferrous ion and hydrogen peroxide, and optimized factors, including pH, temperature, time, and dose of FR, to achieve the best degradation performance. The maximum AA degradation efficiency was found to be >97% in soil with 500 μg kg-1 of AAs. We anticipate that this developed method, mediated via Fenton reaction, will be useful to effectively eliminate AAs from the Balkan farmlands. Unlabelled Image • Soil remediation method to degrade AAs with Fenton's reagent is developed. • Conditions of Fenton reaction were optimized for best degradation performance. • Fenton's reagent modified with EDTA enhances AA degradation efficiency at near circumneutral pH. • Remediation method provides maximum AA degradation efficiency >97% in contaminated soil. [ABSTRACT FROM AUTHOR]