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The presence of anemia in people with diabetes mellitus type 2. (T2DM) is a common and significant finding, representing a substantial and often unrecognized burden. This study aimed to investigate the prevalence and characteristics of anaemia in T2DM patients, with an emphasis on the roles that iron deficiency and persistent inflammation may play. The differentiation between these factors is particularly challenging in countries like Libya, where iron deficiency is prevalent. Additionally, the presence of other underlying causes of anaemia further complicates the interpretation. The study identified renal disease, including renal impairment and albuminuria, as significant risk factors for anaemia in T2DM patients. The results indicated that approximately two-thirds of T2DM patients in the study were anaemic, with a predominance of microcytic hypochromic anaemia. Furthermore, when the prevalence of chronic renal disease and albuminuria rose among T2DM individuals, the severity of anaemia also escalated. These findings highlight the importance of early detection and management of anaemia in T2DM, particularly in patients with renal complications. [ABSTRACT FROM AUTHOR]

Context: Nephropathy is a severe complication of type 1 diabetes (T1DM). However, the interaction between the PDHA1-regulated mechanism and CD4+ T cells in the early stage of kidney tubular injury remains unknown. Objective: To evaluate the role of PDHA1 in the regulation of tubular cells and CD4+ T cells and further to study its interaction in tubular cell injury in T1DM. Methods: Plasma and total RNA were collected from T cells of T1DM patients (n = 35) and healthy donors (n = 33) and evaluated for neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1, PDHA1, and biomarkers of CD4+ T cells including T helper 1 cells (Th1) and regulatory T cells (Treg) markers. HK-2 cells cocultured with CD4+ T cells from T1DM patients or healthy donors (HDs) to evaluate the interaction with CD4+ T cells. Results: Increased PDHA1 gene expression levels in CD4+ T cells were positively associated with the plasma level of NGAL in T1DM patients and HDs. Our data demonstrated that the Th1/Treg subsets skewed Th1 in T1DM. Knockdown of PDHA1 in kidney tubular cells decreased ATP/ ROS production, NAD/NADH ratio, mitochondrial respiration, and cell apoptosis. Furthermore, PDHA1 depletion induced impaired autophagic fux. Coculture of tubular cells and T1DM T cells showed impaired CPT1A, upregulated FASN, and induced kidney injury. Conclusion: Our fndings indicate that Th1 cells induced tubular cell injury through dysregulated metabolic reprogramming and autophagy, thereby indicating a new therapeutic approach for kidney tubular injury in T1DM. [ABSTRACT FROM AUTHOR]

To the Editor, Aristolochic acid is one of major causes for upper tract urothelial carcinoma, especially in younger population. While it is mentioned as a cause in guidelines, little is actually known about the toxin by urologists. We are aiming in our letter to provide some direct and clear information to ourselves that would help us to know more about that toxin and how it can adversely affect our patients [...].

Currently used diagnostic criteria in different endemic (Balkan) nephropathy (EN) centers involve different combinations of parameters, various cut-off values and many of them are not in agreement with proposed international guidelines. Leaders of EN centers began to address these problems at scientific meetings, and this paper is the outgrowth of those discussions. The main aim is to provide recommendations for clinical work on current knowledge and expertise. This document is developed for use by general physicians, nephrologists, urologist, public health experts and epidemiologist, and it is hoped that it will be adopted by responsible institutions in countries harboring EN. National medical providers should cover costs of screening and diagnostic procedures and treatment of EN patients with or without upper urothelial cancers.

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. AA initially was involved in the outbreak of cases of rapidly progressive renal fibrosis reported in Belgium after intake of root extracts of Aristolochia fangchi imported from China. A high prevalence of UTUC was found in these patients. The common molecular link between Balkan and Belgian nephropathy cases was the detection of aristolactam-DNA adducts in renal tissue and UTUC. These adducts are not only biomarkers of prior exposure to AA, but they also trigger urothelial malignancy by inducing specific mutations (A:T to T:A transversion) in critical genes of carcinogenesis, including the tumor-suppressor TP53. Such mutational signatures are found in other cases worldwide, particularly in Taiwan, highlighting the general public health issue of AA exposure by traditional phytotherapies. [ABSTRACT FROM AUTHOR]

Aristolochic acid (AA) has, in the last decade, become widely promoted as the cause of the Balkan endemic nephropathy and associated renal or urothelial tumours, although without substantial focal evidence of the quantitative dietary exposure via bread in specific households in hyperendemic villages. Occasional ethnobotanical use of Aristolochia clematitis might be a source of AA, and Pliocene lignite contamination of well-water is also a putative health risk factor. The aim of this study was two-fold: to verify if extracts of A. clematitis and Pliocene, or AA by itself, could induce the development of renal or urothelial tumours, and to test the utility of the ribosomal protein p-S6 to identify preneoplastic transformation. Rats were given extracts of A. clematitis in drinking water or AA I, by gavage. After seven months, renal morphology was studied using conventional haematoxylin and eosin and immunohistochemistry for ribosomal p-S6 protein. Plant extracts (cumulative AA approximately 1.8 g/kg b.w.) were tolerated and caused no gross pathology or renal histopathological change, with only faint diffuse p-S6 protein (except in the papilla) as in controls. Cumulative AA I (150 mg/kg b.w. given over 3 days) was also tolerated for seven months by all recipients, without gross pathology or kidney tumours. However, p-S6 protein over-expression was consistent particularly within the renal papilla. In one case given AA I, intense p-S6 protein staining of a proximal tubule fragment crucially matched the pre-neoplastic histology in an adjacent kidney section. We briefly discuss these findings, which compound uncertainty concerning the cause of the renal or upper urinary tract tumours of the Balkan endemic nephropathy.

In the context of the mysterious Balkan endemic nephropathy of the 1900s, and the discovery in the 1960s of the potent mycotoxin ochratoxin A, experimental research projects sought to explore any inter-relationship. Experimental lifetime administration of the toxin to male rats had revealed renal DNA adducts with the toxin, correlated with renal tumours, confirmation of which required molecular evidence. Consequently, production of 14 C-ochratoxin A of a high specific radioactivity was required, practical biosynthetic detail of which had not previously been published. A fermentation study of Aspergillus ochraceous was carried out during 2002 for a European project, to select for the production of high-quality 14 C-ochratoxin A, necessarily exploring for the maximum diversion of 14 C-sodium acetate into the pentaketide portion of mycotoxin. Experimentation necessarily had to optimise the competitive context of fungal growth dynamics and addition of the biosynthetic precursor in the early days of shaken-flask fermentation before adding the radiolabelled precursor. From optimal fermentation, 50 mg of the 14 C ochratoxin A was supplied within a European project for DNA adduct experimentation, but that proved negative as subsequently published. Experimental description of the radiolabelled ochratoxin A production was later made in a doctoral thesis, but is first publicised here. Further review of the literature reveals an explanation for the published failure to confirm rat DNA/ochratoxin A adduct formation, for which further experimentation is now recommended., Competing Interests: The authors declare no conflicts of interest.

Emerging evidence suggests that aristolochic acids (AA) produced naturally by a common weed Aristolochia clematitis in the cultivation fields is contaminating the food products in Balkan Peninsula and acting as the etiological agent in the development of Balkan endemic nephropathy. In this study, we investigated the combined use of natural anti-oxidative “food additives” and different cooking methods to find a solution for the widespread contamination of AA in food products. The results indicated that the addition of healthy dietary supplements (such as cysteine, glutathione, ascorbic acid, citric acid and magnesium) during cooking, is a highly efficient method in lowering the concentration of AA in the final food products. Because previous observation indicated one of the toxicological mechanisms by which AA exert its toxicity is to induce oxidative stress in internal organs, it is anticipated that these added anti-oxidants will also help to attenuate the nephrotoxicity of AA. [ABSTRACT FROM AUTHOR]

Short or long-term ex situ conservation is becoming increasingly important in conservation of plants in today’s changing environments. One of the important steps in ex situ conservation is the collection and storage of seeds and the consequent establishment of seed germination protocols. Cerastium dinaricum (Caryophyllaceae) is an endemic, high elevation and rare species of European conservation concern. Because of its severely fragmented distribution along the Dinaric Alps, the populations are likely to undergo further shrinkage in the future, which addresses the need of a long-term effective conservation management. From the potential ex situ population management perspective, we focused our study on germination ecology of C. dinaricum. The study revealed that temperature considerably affected the germination of seeds, which germinate better at 20 °C rather than 10 °C. A period of cold-wet stratification also significantly improved the final germination percentage with more pronounced increase at 20 °C, while addition of GA3 increased the final germination percentage by breaking the dormancy of non-stratified seeds. Mechanical scarification did not improve germination; on the contrary, it resulted in the lowest germination success. Seeds grown in complete darkness germinated significantly better compared to control when they were exposed to cold-wet stratification. Contrary to previous studies on some alpine species, which germinate better when exposed to light, dark treatment resulted in the highest germination percentages with 70 and 90% germination success after 4 and 8 weeks of stratification, respectively. [ABSTRACT FROM AUTHOR]

Immunoglobulin A nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide and the most common cause of end‐stage renal disease in young adults. However, there are still no specific therapies capable of targeting key pathways involved in disease pathogenesis. Recently, many large randomized controlled trials have been reported, such as Supportive Versus Immunosuppressive Therapy for the Treatment of Progressive IgA Nephropathy, Targeted‐release Budesonide Versus Placebo in Patients with IgA Nephropathy and Therapeutic Evaluation of Steroids in IgA Nephropathy Global, which are considered to update the 2012 Kidney Disease: Improving Global Outcomes Guideline. More importantly, with a deeper understanding of the roles of mucosal immunity, B‐cell activation and complement activation in IgAN, the studies of targeting pathogenic pathways are ongoing. In this review, by systemically searching the clinical trials in IgAN on ClinicalTrials.gov (https://clinicaltrials.gov/), we update the evidence for corticosteroids/immunosuppressive therapy in IgAN and explore the promising targeting pathogenic pathway therapeutic options. With better understanding of pathogenesis of IgAN, emerging therapies will soon become a reality in future. Summary at a Glance: By systemically searching the clinical trials in immuglobulin A nephropathy, we update the available treatments and explore the promising targeting pathogenic pathway therapeutic options. [ABSTRACT FROM AUTHOR]

This is a review of scientific publications on renal involvement in antiphospholipid syndrome (APS), with focus on clinical and histopathological findings and treatment. A search for English-language articles on renal involvement in APS covering the period 1980-2017 was conducted in Medline/PubMed and Scopus databases using the MeSH terms “antiphospholipid syndrome”, “antiphospholipid antibodies”, “glomerulonephritis” and “thrombotic microangiopathy” (TMA). APS nephropathy is primarily the result of thromboses in renal arteries or veins, intraparenchymatous arteries and glomerular capillaries. On histology, APS nephropathy is characterized by TMA, but chronic vaso-occlusive lesions are also commonly observed (fibrous intimal hyperplasia, focal cortical atrophy, fibrous occlusions of arteries). Anticardiolipin and lupus anticoagulant are the most prevalent antibodies in patients with APS nephropathy. The spectrum of renal manifestations includes renal vein thrombosis, renal artery thrombosis/stenosis, TMA, increased allograft vascular thrombosis and malignant hypertension. Anticoagulation is the standard treatment of thrombotic events. In systemic lupus erythematosus (SLE) patients with antiphospholipid antibodies (aPL), kidney failure due to SLE nephritis (immune-complex disease) should be clearly distinguished from kidney failure due to APS-related TMA. In such cases, renal biopsy is mandatory. SLE nephritis requires immunosuppressive therapy, whereas APS nephropathy is usually treated with anticoagulants. Recently, eculizumab and sirolimus have been proposed as a rescue therapy. Based on our review, APS nephropathy appears to be a distinct clinical condition. TMA is a characteristic histopathological finding in APS and is strongly associated with the presence of aPL. This has important therapeutic implications and allows distinguishing APS nephropathy from lupus nephritis. [ABSTRACT FROM AUTHOR]

Aristolochic acids (AAs) are carcinogenic and nephrotoxic plant alkaloids present in Aristolochia species, used in traditional medicine. Recent biomolecular and environmental studies have incriminated these toxins as an etiological agent in Balkan endemic nephropathy (BEN), a severe kidney disease occurring in the Balkan Peninsula. The questions on how the susceptible populations are exposed to these toxins have not yet been clearly answered. Exposure to AAs through the food chain, and environmental pollution (soil/dust), could provide an explanation for the presence of BEN in the countries where no folkloric use of the plant has been documented (Bulgaria, Croatia). Additional exposure pathways are likely to occur, and we have shown previously that AAs can contaminate crop plants through absorption from soil, under controlled laboratory environment. Here, we attempt to provide additional support to this potential exposure pathway, by revealing the presence of AAI in soil and soil organic matter samples collected from BEN and non-BEN areas. The samples were processed in order to be analyzed by high-pressure liquid chromatography, and ion trap mass spectrometry. Our results showed the presence of AAI in small concentrations, both in BEN and non-BEN soils, especially where Aristolochia plants and seeds were present. [ABSTRACT FROM AUTHOR]

Balkan endemic nephropathy (BEN) is an irreversible, lethal kidney disease that occurs in regions of the Balkans where residents drink untreated well water. A key factor contributing to the development of BEN may be consumption of dissolved organic matter leached from low-rank coal called lignite. This hypothesis-known as lignite-water hypothesis-was first posed for areas of the Balkans. It is possible that a BEN-like condition exists in the United States (US) Gulf Coast region in parts of the Mississippi Embayment and the Texas Coastal Uplands aquifers -Arkansas, Louisiana, and Texas, for instance-that rely heavily on groundwater from aquifers that contain lignite. This study utilizes a geographic information system (GIS) to map the distributions of end-stage renal disease (ESRD) in relation to water from lignite-containing aquifers in the tri-state region. Regional patterns emerged from geospatial analysis, suggesting that counties that relied on lignite-containing aquifers for their main water source had higher rates of ESRD in comparison to other populations in the region that rely on other water sources, including surface water and groundwater from aquifers not associated with lignite seams. Statewide rates of ESRD and diabetes associated ESRD (ESRD-DM) showed strong correlations to the percent of families at or below poverty level and the percentage of African Americans. These confounding factors somewhat mitigate the association seen between ESRD and lignite-containing regions at the state level. However, at the larger tri-state view, there is a significant (p = 0.002) increase in incidence rates where groundwater is connected to lignite-containing aquifers when considering both race and poverty. Additionally, no relationship was observed between the rate of public water supply withdrawal from lignite-bearing aquifers and rates of ESRD or ESRD-DM at the state or tri-state regions, supporting the observation that the risk associated with water from lignite-containing aquifers is limited to water from untreated domestic supply. [ABSTRACT FROM AUTHOR]

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Background/Introduction: Chronic kidney disease (CKD) is a risk factor for contrast induced acute kidney injury (CI-AKI). Contrast angiography in CKD patients is a common procedure. Creatinine is a delayed marker of CI-AKI and delays diagnosis which results in significant morbidity and mortality. Aim: Early diagnosis of CI-AKI requires validated novel biomarkers. Design: A prospective observation study of 301 consecutive CKD patients undergoing coronary angiography was performed. Methods: Samples for plasma neutrophil gelatinase-associated lipocalin (NGAL), serum liver fatty acid-binding protein (LFABP), serum kidney injury marker 1, serum interleukin 18 and serum creatinine were taken at 0, 1, 2, 4, 6 and 48h postcontrast. Urinary NGAL and urinary cystatin C were collected at 0, 6 and 48 h. Incidence of major adverse clinical events (MACE) was recorded at 1 year. CI-AKI was defined as an absolute delta rise in creatinine of ≥26.5 mmol/l or a 50% relative rise from baseline at 48h following contrast. Results: CI-AKI occurred in 28 (9.3%) patients. Plasma NGAL was most predictive of CI-AKI at 6 h. L-FABP performed best at 4h. A combination of Mehran score> 10, 4h L-FABP and 6h NGAL improved specificity to 96.7%. MACE was statistically higher at 1 year in CI-AKI patients (25.0 vs. 6.2% in non--CI-AKI patients). Discussion/Conclusion: Mehran risk score, 4h serum L-FAPB and 6 h plasma NGAL performed best at early CI-AKI prediction. CI-AKI patients were four times more likely to develop MACE and had a trebling of mortality risk at 1 year. [ABSTRACT FROM AUTHOR]

Introduction: Chronic kidney disease (CKD) is a significant public health problem and it is not possible to precisely predict its progression to terminal renal failure. According to current guidelines, CKD stages are classified based on the estimated glomerularfiltration rate (eGFR) and albuminuria. Aims of this study were to determine the reliability of predictive equation in estimation of CKD prevalence in Croatian areas with endemic nephropathy (EN), compare the results with non-endemic areas, and to determine if the prevalence of CKD stages 3-5 was increased in subjects with EN. Materials and methods: A total of 1573 inhabitants of the Croatian Posavina rural area from 6 endemic and 3 non-endemic villages were enrolled. Participants were classified according to the modified criteria of the World Health Organization for EN. Estimated GFR was calculated using Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI). Results: The results showed a very high CKD prevalence in the Croatian rural area (19%). CKD prevalence was significantly higher in EN then in non EN villages with the lowest eGFR value in diseased subgroup. Conclusions: eGFR correlated significantly with the diagnosis of EN. Kidney function assessment using CKD-EPI predictive equation proved to be a good marker in differentiating the study subgroups, remained as one of the diagnostic criteria for EN. [ABSTRACT FROM AUTHOR]

A characteristic tumor suppressor protein 53 (p53) mutational profile of genotoxic action of aristolochic acid was identified in the upper urothelial carcinoma (UUTT) associated with Balkan nephropathy (BEN). In the present study, we examined the prognostic value of tissue-based molecular markers in overall-survival (OS) risk after surgical treatment of UUTT, adjusted for gender, age and urological characteristics in 32 patients with BEN. Immunohistochemical examination of p53, the proliferation cell nuclear antigen (PCNA), the human epidermal growth factor receptor 2 (c-ErbB2; also known as HER-2/neu) proto-oncogene and the in situ terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay for apoptosis detection were used to examine serial tumor sections. The median OS-time was 60 months for UUTT operation; the mortality rate (18.7%) was related to (new) disease (re)occurrence or invasion in 12-216 months. High-grade (p=0.029), TUNEL>0.36%+ cells (p=0.010), and c-ErbB2+ cells (p=0.014) can define the risk of tumor invasion. Patients with Balkan nephropathy that develop UUTT at a stage greater than pT1 (with apoptosis TUNEL+ cells >0.36% and p53+ cells greater than 10%) were at high risk of poor-OS after the tumor surgery (h(x)=6.35; p=0.045). The obtained data present evidence for p53, cErbB2 and apoptosis deregulation, as a result of environmental toxin action. This is the first report of molecular biomarker linkage with OS for BEN-associated UUTT.

The epithelium lining is defined as the mucosal surfaces of the renal collecting tubules, calyces and pelvis, as well as the ureter, bladder and urethra. The term 'urothelium' is used to refer to these surfaces. Upper tract urothelial carcinoma is a rare subset of urothelial cancers with a poor prognosis. Urinary bladder cancer is the most common malignancy involving the urinary system. Upper tract urothelial carcinoma is more common in men than in women, with a male-to-female ratio of 2:1. The incidence of urinary bladder cancer is also higher in men. Cigarette smoking and occupational exposure are the main upper tract urothelial carcinoma and urinary bladder cancer risk factors, while other factors are more specific to the carcinogenesis of upper tract urothelial carcinoma (i.e. Balkan endemic nephropathy, Chinese herb nephropathy). In Egypt until recent years, urinary bladder cancer was the most frequently diagnosed cancer due to Schistosoma haematobium. Substantial knowledge exists regarding the causes of upper tract urothelial carcinoma and urinary bladder cancer, and epidemiological studies have identified various chemical carcinogens that are believed to be responsible for most cases of urothelial carcinoma. In the era of precision medicine, genetic effects might play a direct role in the initiation and progression of urothelial carcinoma. [ABSTRACT FROM AUTHOR]

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1H NMR spectroscopy of urine has been applied to exploring metabolomic differences between people diagnosed with Balkan endemic nephropathy (BEN), and treated by haemodialysis, and those without overt renal disease in Romania and Bulgaria. Convenience sampling was made from patients receiving haemodialysis in hospital and healthy controls in their village. Principal component analysis clustered healthy controls from both countries together. Bulgarian BEN patients clustered separately from controls, though in the same space. However, Romanian BEN patients not only also clustered away from controls but also clustered separately from the BEN patients in Bulgaria. Notably, the urinary metabolomic data of two people sampled as Romanian controls clustered within the Romanian BEN group. One of these had been suspected of incipient symptoms of BEN at the time of selection as a ‘healthy’ control. This implies, at first sight, that metabolomic analysis can be predictive of impending morbidity before conventional criteria can diagnose BEN. Separate clustering of BEN patients from Romania and Bulgaria could indicate difference in aetiology of this particular silent renal atrophy in different geographic foci across the Balkans.

Aristolochic acids (AAs) are naturally occurring genotoxic carcinogens linked to Balkan endemic nephropathy and aristolochic acid nephropathy. Aristolochic acid I and II (AA-I and AA-II) are the most abundant AAs, and AA-I has been reported to be more genotoxic and nephrotoxic than AA-II. This study aimed to explore metabolic differences underlying the differential toxicity. We developed a novel microdialysis sampling coupled with solid-phase extraction liquid chromatography-tandem mass spectrometry (MD-SPE-LC-MS/MS) to simultaneously study the toxicokinetics (TK) of AA-I and AA-II and their corresponding aristolactams (AL-I and AL-II) in the blood of Sprague Dawley rats co-treated with AA-1 and AA-II. Near real-time monitoring of these analytes in the blood of treated rats revealed that AA-I was absorbed, distributed, and eliminated more rapidly than AA-II. Moreover, the metabolism efficiency of AA-I to AL-I was higher compared to AA-II to AL-II. Only 0.58% of AA-I and 0.084% of AA-II was reduced to AL-I and AL-II, respectively. The findings are consistent with previous studies and support the contention that differences in the in vivo metabolism of AA-I and AA-II may be critical factors for their differential toxicities., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The spreading of mycotoxic nephropathy in animals/humans was studied. The possible etiological causes provoking this nephropathy were carefully reviewed and analyzed. The natural content of the most frequent nephrotoxic mycotoxins in target feedstuffs/foods were investigated, in addition to their significance for development of renal damages in endemic areas. An estimation of the level of exposure of humans to the nephrotoxic mycotoxin, ochratoxin A (OTA), is made. The possible synergism or additive effects between some target mycotoxins in the development of nephropathy is also covered. The significance of joint mycotoxin interaction and masked mycotoxins, in addition to some newly isolated fungal toxic agents in the complicated etiology of mycotoxic nephropathy ranged in Balkan countries is discussed. The importance of some target fungal species which can induce kidney damages was evaluated. The morphological/ultrastructural, functional and toxicological similarities between human and animal nephropathy are studied. The possible hazard of low content of combinations of some target mycotoxins in food or feedstuff ingested by pigs, chickens or humans under natural conditions is evaluated and a risk assessment was made. Some different but more effective manners of prophylaxis and/or prevention against OTA contamination of feedstuffs/foods are suggested. A survey was made in regard to the best possible ways of veterinary hygiene control of OTA-exposed animals at slaughter time for preventing the entrance of OTA in commercial feedstuffs/food channels with a view to reduce the possible health hazard for humans. The economic efficacy and applicability of such preventive measures is additionally discussed and some practical suggestions are made. [ABSTRACT FROM AUTHOR]

Background/aim: We analyzed the clinical and pathological features and prognosis of 106 children with persistent asymptomatic microscopic hematuria (PAMH) with or without mild proteinuria. Materials and methods: This was a retrospective study of 106 children who were referred to our clinics from 2000 to 2013 for evaluation of PAMH. Results: Among the 106 patients, 69 (65%) were female and 37 (35%) were male. The patients were divided into two groups: 101 patients with isolated microscopic hematuria (IMH) and 5 patients with asymptomatic microscopic hematuria and mild proteinuria (AMHP). Renal biopsy was performed in all 5 children with AHMP: 2 patients had hereditary nephropathy and 2 patients had focal segmental glomerulosclerosis (FSGS). One biopsy specimen revealed nonspecific findings. Renal biopsy was performed in 9 children with IMH: 4 patients had hereditary nephropathy and 5 patients had nonspecific findings. None of the patients received any specific treatment prior to renal biopsy. During the follow-up period, none of the patients developed impaired renal function. Among all the children, only one patient with AMHP developed hypertension and 2 patients with IMH developed proteinuria. Conclusion: Long-term follow-up must be done carefully for isolated microscopic hematuria and renal biopsy should be performed in selected cases. [ABSTRACT FROM AUTHOR]

Balkan endemic nephropathy (BEN) is a unique, chronic renal disease frequently associated with upper urothelial cancer (UUC). It only affects residents of specific farming villages located along tributaries of the Danube River in Bosnia-Herzegovina, Croatia, Macedonia, Serbia, Bulgaria, and Romania where it is estimated that ~100,000 individuals are at risk of BEN, while ~25,000 have the disease. This review summarises current findings on the aetiology of BEN. Over the last 50 years, several hypotheses on the cause of BEN have been formulated, including mycotoxins, heavy metals, viruses, and trace-element insufficiencies. However, recent molecular epidemiological studies provide a strong case that chronic dietary exposure to aristolochic acid (AA) a principal component of Aristolochia clematitis which grows as a weed in the wheat fields of the endemic regions is the cause of BEN and associated UUC. One of the still enigmatic features of BEN that need to be resolved is why the prevalence of BEN is only 3-7 %. This suggests that individual genetic susceptibilities to AA exist in humans. In fact dietary ingestion of AA along with individual genetic susceptibility provides a scenario that plausibly can explain all the peculiarities of BEN such as geographical distribution and high risk of urothelial cancer. For the countries harbouring BEN implementing public health measures to avoid AA exposure is of the utmost importance because this seems to be the best way to eradicate this once mysterious disease to which the residents of BEN villages have been completely and utterly at mercy for so long. [ABSTRACT FROM AUTHOR]

Rationale/background: Approximately 14% of Americans are living with chronic kidney disease (CKD). The prevalence of end-stage renal disease (ESRD), the result of progressing CKD continues to rise by 21,000 per year. There are no updated, evidence-based antibiotic prophylaxis guidelines for patients with renal disease undergoing dental treatment. The most recent was a scientific statement from the American Heart Association (AHA) in 2003. Presented in three parts, the goal of the first part of this study is to determine the current protocol being used to treat renal patients at U.S. dental schools.Methods and Materials: A 21 multiple-choice question survey was e-mailed to 58 clinic deans of accredited dental schools in the United States regarding renal treatment protocol details including antibiotic prophylaxis.Results: Fifty-two percent of programs report having no established renal patient treatment protocol. For programs with a protocol, when using prophylactic antibiotics, 54% followed AHA protocol, whereas 62% used a modified protocol.Conclusion: There is a lack of consistent, established protocols among undergraduate dental programs. It is suggested that evidence-based guidelines for the safe treatment of patients be developed. [ABSTRACT FROM AUTHOR]

Since ochratoxin A (OTA) was discovered, it has been ubiquitous as a natural contaminant of moldy food and feed. The multiple toxic effects of OTA are a real threat for human beings and animal health. For example, OTA can cause porcine nephropathy but can also damage poultries. Humans exposed to OTA can develop (notably by inhalation in the development of acute renal failure within 24 h) a range of chronic disorders such as upper urothelial carcinoma. OTA plays the main role in the pathogenesis of some renal diseases including Balkan endemic nephropathy, kidney tumors occurring in certain endemic regions of the Balkan Peninsula, and chronic interstitial nephropathy occurring in Northern African countries and likely in other parts of the world. OTA leads to DNA adduct formation, which is known for its genotoxicity and carcinogenicity. The present article discusses how renal carcinogenicity and nephrotoxicity cause both oxidative stress and direct genotoxicity. Careful analyses of the data show that OTA carcinogenic effects are due to combined direct and indirect mechanisms (e.g., genotoxicity, oxidative stress, epigenetic factors). Altogether this provides strong evidence that OTA carcinogenicity can also occur in humans. [ABSTRACT FROM AUTHOR]

TASK-2, a member of the Two-Pore Domain (K2P) subfamily of K+ channels, is encoded by the KCNK5 gene. The channel is expressed primarily in renal epithelial tissues and a potentially deleterious missense variant in KCNK5 has recently been shown to be prevalent amongst patients predisposed to the development of Balkan Endemic Nephropathy (BEN), a chronic tubulointerstitial renal disease of unknown etiology. In this study we show that this variant (T108P) results in a complete loss of channel function and is associated with a major reduction in TASK-2 channel subunits at the cell surface. Furthermore, these mutant subunits have a suppressive or ‘dominant-negative’ effect on channel function when coexpressed with wild-type subunits. This missense variant is located at the extracellular surface of the M2 transmembrane helix and by using a combination of structural modelling and further functional analysis we also show that this highly-conserved threonine residue is critical for the correct function of other K2P channels. These results therefore provide further structural and functional insights into the possible pathophysiological effects of this missense variant in TASK-2. [ABSTRACT FROM AUTHOR]

Background and Purpose: Aristolochic acid (AristA) is found in plants used in traditional medicines to treat pain. We investigated the action of AristA on TREK and TRESK, potassium (K2P) channels, which are potential therapeutic targets in pain. Balkan endemic nephropathy (BEN) is a renal disease associated with AristA consumption. A mutation of TASK-2 (K2P 5.1) channels (T108P) is seen in some patients susceptible to BEN, so we investigated how both this mutation and AristA affected TASK-2 channels.Experimental Approach: Currents through wild-type and mutated human K2P channels expressed in tsA201 cells were measured using whole-cell patch-clamp recordings in the presence and absence of AristA.Key Results: TREK-1- and TREK-2-mediated currents were enhanced by AristA (100 μM), whereas TRESK was inhibited. Inhibition of TRESK did not depend on the phosphorylation of key intracellular serines but was completely blocked by mutation of bulky residues in the inner pore (F145A_F352A). The TASK-2_T108P mutation markedly reduced both current density and ion selectivity. A related mutation (T108C) had similar but less marked effects. External alkalization and application of flufenamic acid enhanced TASK-2 and TASK-2_T108C current but did not affect TASK-2_T108P current. AristA (300 μM) produced a modest enhancement of TASK-2 current.Conclusions and Implications: Enhancement of TREK-1 and TREK-2 and inhibition of TRESK by AristA may contribute to therapeutically useful effects of this compound in pain. Whilst AristA is unlikely to interact directly with TASK-2 channels in BEN, loss of functional TASK-2 channels may indirectly increase susceptibility to AristA toxicity. [ABSTRACT FROM AUTHOR]

Nephropathia epidemica (NE), caused by the hantavirus infection, is endemic in Tatarstan Russia. The majority of patients are adults, with infection rarely diagnosed in children. This limited number of pediatric NE cases means there is an inadequate understanding of disease pathogenesis in this age category. Here, we have analyzed clinical and laboratory data in adults and children with NE to establish whether and how the disease severity differs between the two age groups. Serum cytokines were analyzed in samples collected from 11 children and 129 adult NE patients during an outbreak in 2019. A kidney toxicity panel was also used to analyze urine samples from these patients. Additionally, serum and urine samples were analyzed from 11 control children and 26 control adults. Analysis of clinical and laboratory data revealed that NE was milder in children than in adults. A variation in serum cytokine activation could explain the differences in clinical presentation. Cytokines associated with activation of Th1 lymphocytes were prominent in adults, while they were obscured in sera from pediatric NE patients. In addition, a prolonged activation of kidney injury markers was found in adults with NE, whilst only a short-lasting activation of these markers was observed in children with NE. These findings support previous observations of age differences in NE severity, which should be considered when diagnosing the disease in children.

The Balkan endemic nephropathy (BEN) is a chronic nephropathy described in some regions from the Balkan Peninsula and in Romania. Ochratoxin A is considered to be one of the factors involved in BEN triggering. Ochratoxins are secondary metabolites produced by fungus and it was shown that OTA is principally nephrotoxic but also genotoxic or immunotoxic. The aim of the present paper was to investigate the nephrotoxic effect of a low dose of OTA (50ppb) administrated to weanling pig. Twelve weanling piglets were fed a corn-soybean meal basal diet for 33 days and randomly assigned to either a control or OTA group. The following biochemical markers were assessed in plasma of weanling piglets: urea, creatinine, phosphorus, calcium, protein and albumin. The expression of genes involved in inflammation: genes for cytokines (IL-1 beta, TNF alpha, IL-8, IL-4) or for other markers (p38, Nf-KB, iNOS, Cox2) were assessed in kidney by real time PCR. The expression of cytokines: IFN gamma, IL-4, IL-6, TNF alpha, IL-1, IL-10 were assessed by ELISA. Administration of 50µg/kg OTA to the weanling piglets has no effect on urea, creatinine, phosphorus or calcium concentration, but induced a significant decrease (P<0.05) of total protein and albumin. OTA doesn't affect the expression of the investigated cytokines or the other inflammatory molecules. In conclusion, 50mg/kg OTA, as the recommended guidance values by EU for OTA in pigs, administered to weanling piglets for 33 days induced some alterations of the serum biochemical parameters, with little or no effect on inflammation. [ABSTRACT FROM AUTHOR]

About 70% of patients with idiopathic membranous nephropathy (iMN) have autoantibodies to the phospholipase A2 receptor PLA2R1. We screened sera from iMN patients for their cross-reactivity to human (h), rabbit (rb) and mouse (m) PLA2R1 by western blot (WB) and antigen-specific ELISAs. All iMN patients recognized hPLA2R1 and rbPLA2R1 by WB, and a rbPLA2R1 ELISA was as sensitive as the standardized hPLA2R1 ELISA to monitor anti-PLA2R1 in patients with active disease or in drug-induced remission. In contrast, only 51% of patients were reactive to mPLA2R1 by WB, and a maximum of 78% were weakly to highly positive in the mPLA2R1 ELISA, suggesting that iMN patients exhibit different subsets of anti-PLA2R1 autoantibodies against epitopes that are shared or not among PLA2R1 orthologs. In a cohort of 41 patients with a mean follow-up of 42 months from anti-PLA2R1 assay, the detection of anti-mPLA2R1 autoantibodies was an independent predictor of clinical outcome in multivariate analysis (p = 0.009), and a ROC curve analysis identified a threshold of 605 RU/mL above which 100% of patients (12 patients) had a poor renal outcome (p < 0.001). A similar threshold could not be defined in hPLA2R1 and rbPLA2R1 ELISAs. We conclude that rbPLA2R1 is an alternative antigen to hPLA2R1 to measure anti-PLA2R1 in active disease while mPLA2R1 is a unique antigen that can detect a subset of anti-PLA2R1 autoantibodies present at high levels (>605 RU/mL) only in iMN patients at risk of poor prognosis, and is thus useful to predict iMN outcome. [ABSTRACT FROM AUTHOR]

Background. Aristolochia clematitis (AC), a herbaceous plant that belongs to the family of Aristolochiaceae, is today considered as being responsible for Balkan endemic nephropathy (BEN). Very scarce information is available in the medical literature about the presence of AC outside Balkan area. This article reports on the finding of AC in Northwest Italy and the results of a questionnaire delivered to locals on their knowledge about AC. Methods. AC was found in an uncultivated piece of land of a hilly area of Northwest Italy. It was identified by matching it with images available in the literature and Internet. The questionnaire, which was delivered with a set of 12 photographs and a bunch of true AC, contained 15 questions aimed at collecting information on the knowledge of the respondents about the existence, name, distribution and possible uses of AC. Results. A total of 23 locals, mostly farmers, were interviewed. Among them, 22 (95.6%) had already seen AC, mostly in uncultivated areas; 4 (18%) had a name for it; 21 (95.4%) considered it as a weed and denied any personal use of it; 18 (81.8%) stated that breeding animals disliked AC and no one was aware that AC might damage kidneys. Conclusions. This study demonstrates that AC can be found outside the Balkan region and that people know it but today do not make any use of it. Other studies carried out by nephrologists in other geographic areas could expand our knowledge about AC outside the basin of BEN. [ABSTRACT FROM AUTHOR]

Aristolochic acid I (AAI) is a plant alkaloid causing aristolochic acid nephropathy, Balkan endemic nephropathy and their associated urothelial malignancies. AAI is detoxified by cytochrome P450 (CYP)-mediated O-demethylation to 8-hydroxyaristolochic acid I (aristolochic acid Ia, AAIa). We previously investigated the efficiencies of human and rat CYPs in the presence of two other components of the mixed-functions-oxidase system, NADPH:CYP oxidoreductase and cytochrome b5, to oxidize AAI. Human and rat CYP1A are the major enzymes oxidizing AAI. Other CYPs such as CYP2C, 3A4, 2D6, 2E1, and 1B1, also form AAIa, but with much lower efficiency than CYP1A. Based on velocities of AAIa formation by examined CYPs and their expression levels in human and rat livers, here we determined the contributions of individual CYPs to AAI oxidation in these organs. Human CYP1A2 followed by CYP2C9, 3A4 and 1A1 were the major enzymes contributing to AAI oxidation in human liver, while CYP2C and 1A were most important in rat liver. We employed flexible in silico docking methods to explain the differences in AAI oxidation in the liver by human CYP1A1, 1A2, 2C9, and 3A4, the enzymes that all O-demethylate AAI, but with different effectiveness. We found that the binding orientations of the methoxy group of AAI in binding centers of the CYP enzymes and the energies of AAI binding to the CYP active sites dictate the efficiency of AAI oxidation. Our results indicate that utilization of experimental and theoretical methods is an appropriate study design to examine the CYP-catalyzed reaction mechanisms of AAI oxidation and contributions of human hepatic CYPs to this metabolism. [ABSTRACT FROM AUTHOR]

BEN is a primary, chronic tubulointerstitial nephritis characterized with chronic anemia, absence of edema, xantoderma, normal blood pressure and normal findings on the fundus oculi. The disease is distributed in restricted areas in Bulgaria, Romania, Croatia, Bosnia, Former Yugoslavia. Despite numerous studies on genetic and environmental factors and their possible involvement in BEN, its etiopathogenesis still remains elusive. Our recent study aim to elucidate the possible epigenetic component in BEN development. Whole genome DNA array methylation analysis was applied to compare the methylation profiles of male and female BEN patients from endemic regions in Bulgaria and Serbia and healthy controls. All three most prominent candidate genes with aberrations in the epigenetic profile discovered with this study are involved in the inflammatory/immune processes and oncogenesis. These data are in concordance with the reported pathological alterations in BEN. This research supports the role of epigenetic changes in BEN pathology. Exome sequencing of 22.000 genes with Illumina Nextera Exome Enrichment Kit revealed three mutant genes (CELA1, HSPG2, and KCNK5) in BEN patients which encode proteins involved in basement membrane/extracellular matrix and vascular tone, tightly connected to process of angiogenesis. We suggest that an abnormal process of angiogenesis plays a key role in the molecular pathogenesis of BEN. [ABSTRACT FROM AUTHOR]

Background: Kidney size may differ between healthy members of Balkan endemic nephropathy (BEN) and non-BEN families. The present study was designed to elucidate this, in comparison with values for BEN patients. Methods: A total of 71 BEN patients (34 males, 64.4 ± 12.0 years), 74 healthy BEN family members (39 males, 49.1 ± 12.2 years), and 59 non-BEN family members (19 males, 49.2 ± 12.3 years) were involved. We measured the longest craniocaudal length and minimal parenchymal thickness on each kidney of all examined subjects using ultrasound. Results: No significant difference was found between the kidney length of healthy subjects from BEN (11.0 ± 0.8 cm) and non-BEN families (10.9 ± 0.8 cm), but kidneys were significantly longer than in BEN patients (9.9 ± 1.3 cm). Minimal parenchymal thickness was similar in all three groups. When subjects from each group were divided according to estimated glomerular filtration rate (eGFR), kidney length of the healthy groups was significantly longer than in BEN patients both in stage 1 (p =0.039) and stage 2 (p =0.044) of chronic kidney disease. The parental history of BEN was not associated with kidney dimensions, eGFR, or urinary excretion of albumin and alpha1-microglobulin. Conclusion: Kidneys of BEN patients were significantly shorter than in healthy members of both BEN and non-BEN families, but no difference was found in kidney length and parenchymal thickness between healthy members of BEN and non-BEN families. No significant association was found between parental history of BEN and kidney size and function either in BEN patients or in healthy members from BEN families. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to examine the ocular fundus pathology in patients with Balkan endemic nephropathy (BN) and chronic kidney diseases (CKD). Methods: The study included 51 patients with BN from the South Morava River region in Serbia, and 102 subjects with different stages of chronic renal diseases, matched according to age and gender, obtained from a database used in a recently published study. All patients had visited Outpatient Department of the Clinic of Nephrology, Clinical Center Nis. All patients underwent routine ophthalmic examinations. Results: There were significantly more ( P < 0.001) patients with age-related macular degeneration (AMD) in the group with BN (31.37 %) than in those with CKD (5.88 %). Multivariate logistic regression analysis confirmed that the significant factors related to AMD in the group with BN were albuminuria ( P < 0.05) and proteinuria ( P < 0.05); in CKD patients, the level of HDL ( P < 0.05), while negative correlation with the level of triglyceride was registered ( P < 0.05). There was no association between estimated glomerular filtration rate and AMD. The significant factors related to retinopathy in the group with BN are age ( P < 0.05) and serum creatinine values ( P < 0.05), in patients with CKD increasing age ( P < 0.001) and DM ( P < 0.05). Conclusion: Ocular fundus pathology in patients with BN is similar to the pathology of other CKD, but with significantly more AMD (about four times), probably related to the genetic/epigenetic factors. [ABSTRACT FROM AUTHOR]

Background: Balkan endemic nephropathy (BEN) is a chronic tubulointerstitial kidney disease occurring in people living in along the tributaries of the Danube River. The aim of the study was to determine serum level and urinary excretion of placental growth factor (PlGF) and placental protein 13 (PP13) in patients with BEN.Methods: Thirty patients with BEN from the South Morava River region of Serbia and 18 controls were studied. Age of patients was 74 yr (53–87) and 73 yr (66–83) in controls.Results: In patients with BEN, serum creatinine was significantly higher than in controls (129.7 vs. 83.2 µmol/L, respectively), but GFR was lower in patients than in controls (40.7 vs. 54.6 mL/min). Serum PlGF was significantly higher in BEN patients than in controls (9.90 vs. 6.80 pg/mL), urinary excretion being significantly lower in patients (0.20 vs. 0.90 pg/mmol creat.). Serum PP13 was significantly lower in BEN patients (208.2 vs. 291.0 pg/mL). Urinary excretion of PP13 was also significantly lower in BEN patients than in controls (32.5 vs. 182.5 pg/mmol creat). In multivariate regression analysis BEN, sex and age were significant determinants of the observed changes in PlGF and PP13.Conclusion: Important changes of PlGF and PP13 in patients with BEN were demonstrated, where kidney disease, female sex, and the age have been significant determinants. [ABSTRACT FROM PUBLISHER]

Ochratoxin A (OTA) is a fungal metabolite dangerous for human and animal health due to its nephrotoxic, immunotoxic, mutagenic, teratogenic and carcinogenic effects, classified by the International Agency for Research on Cancer in group 2B, possible human carcinogen. This toxin has been stated as a wine contaminant since 1996. The aim of this study was to develop a conceptual model for the dynamic simulation of the A. carbonarius life cycle in grapes along the growing season, including OTA production in berries. Functions describing the role of weather parameters in each step of the infection cycle were developed and organized in a prototype model called OTA-grapes. Modelling the influence of temperature on OTA production, it emerged that fungal strains can be shared in two different clusters, based on the dynamic of OTA production and according to the optimal temperature. Therefore, two functions were developed, and based on statistical data analysis, it was assumed that the two types of strains contribute equally to the population. Model validation was not possible because of poor OTA contamination data, but relevant differences in OTA-I, the output index of the model, were noticed between low and high risk areas. To our knowledge, this is the first attempt to assess/model A. carbonarius in order to predict the risk of OTA contamination in grapes. [ABSTRACT FROM AUTHOR]