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Background: Posterior reversible encephalopathy syndrome (PRES) is characterized by cerebral blood flow dysregulation and the blood-brain barrier (BBB) disruption. While renal insufficiency has been considered a factor in BBB fragility, the relationship between renal insufficiency and the PRES lesions volume remains unclear., Methods: This observational study was performed retrospectively. PRES patients were categorized into two groups with renal insufficiency, defined as an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73m 2 on the day of symptom occurrence. Lesion volume was measured using fluid-attenuated inversion recovery (FLAIR) imaging, and the brain was divided into nine regions. The volume of the parietal-occipital-temporal lobe was considered typical, while the other six regions were labeled as atypical., Results: The study included 200 patients, of whom 94 (47%) had renal insufficiency. Patients with renal insufficiency had a larger lesion volume (144.7 ± 125.2 cc) compared to those without renal insufficiency (110.5 ± 93.2 cc; p = 0.032); particularly in the atypical lesions volume (49.2 ± 65.0 vs. 29.2 ± 44.3 cc; p = 0.013). However, there was no difference in the reversibility of the lesions (35.2 ± 67.5 vs. 18.8 ± 33.4 cc; p = 0.129). Multiple regression analysis revealed that decreases in eGFR (β = -0.34, 95% CI -0.62-0.05, p = 0.020) were positively associated with total lesion volume., Conclusion: Our findings suggest that PRES patients with renal insufficiency experience more severe lesion volumes, likely due to the atypical brain regions involvement. The lesions involving atypical regions may have a similar pathophysiology to typical lesions, as the PRES lesions reversibility was found to be similar between individuals with and without renal insufficiency., (© 2024. Fondazione Società Italiana di Neurologia.)

Background: Myocardial ischemia-reperfusion (MI/R) occurs due to temporary or permanent interruptions in the coronary and circulatory system, indirectly affecting kidney function through reduced cardiac output for metabolic needs. In this study, the aim was to explore the indirect effects of using human amniotic membrane mesenchymal stem cells (hAMSCs) with the PGS-co-PCL/PGC/PPy/Gelatin scaffold in male rats with renal failure induced by miocardial ischemia-reperfusion., Methods: MI/R injury was induced in 48 male Wistar rats through left anterior descending artery ligation, divided into four groups (n=12); control group, cell group, scaffold group, and celss+scaffold group. Evaluations were conducted at two and thirty days post MI/R injury, encompassing echocardiography, biochemical, inflammatory markers analysis, and histological assessment., Results: Echocardiographic findings exhibited notable enhancement in ejection fraction, fractional shortening, and stroke volume of treated groups compared to controls after 30 days (P< 0.05). Serum creatinine (P< 0.001) and urea (P< 0.05) levels significantly decreased in the scaffold+cells group) compared to the control group. The treated cells+ scaffold group displayed improved kidney structure, evidenced by larger glomeruli and reduced Bowman's space compared to the control group (P< 0.01). Immunohistochemical analysis indicated reduced TNF-α protein in the scaffold+ cells group (P< 0.05) in contrast to the control group (P< 0.05). Inflammatory factors IL-6, TNF-α, and AKT gene expression in renal tissues were improved in scaffold+ cells-treated animals., Conclusion: Our research proposes the combination of hAMSCs and the PGS-co-PCL/PGC/PPy/Gelatin scaffold in MI/R injured rats appears to enhance renal function and reduce kidney inflammation by improving cardiac output., Competing Interests: Declaration of Competing Interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2024. Published by Elsevier Ltd.)

Objectives: To establish a rat model that accurately replicates the clinical characteristics of male infertility (MI) with Liver Depression and Kidney Deficiency (LD & KD) and investigate the pathogenesis., Methods: After subjecting the rats to chronic restraint stress (CRS) and adenine treatment, a series of tests were conducted, including ethological assessments, evaluations of reproductive characteristics, measurements of biochemical parameters, histopathological examinations, and analyses of urinary metabolites. Additionally, bioinformatics predictions were performed for comprehensive analysis., Results: Compared to the control, the model exhibited significant manifestations of MI with LD & KD, including reduced responsiveness, diminished frequency of capturing estrous female rats, and absence of mounting behavior. Additionally, the kidney coefficient increased markedly, while the coefficients of the testis and epididymis decreased significantly. Sperm counts and viabilities decreased notably, accompanied by an increase in sperm abnormalities. Dysregulation of reproductive hormone levels in the serum was observed, accompanied by an upregulation of proinflammatory cytokines expressions in the liver and kidney, as well as exacerbated oxidative stress in the penile corpus cavernosum and testis. The seminiferous tubules in the testis exhibited a loose arrangement, loss of germ cells, and infiltration of inflammatory cells. Furthermore, utilizing urinary metabolomics and bioinformatics analysis, 5 key biomarkers and 2 crucial targets most closely linked to MI were revealed., Conclusion: The study successfully established a clinically relevant animal model of MI with LD & KD. It elucidates the pathogenesis of the condition, identifies key biomarkers and targets, and provides a robust scientific foundation for the prediction, diagnosis, and treatment of MI with LD & KD., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Shen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

This report describes the case of a 76-year-old man with ulcerative colitis who developed interstitial nephritis after starting 5-Aminosalicylic acid (5-ASA) therapy. The patient experienced an initial improvement in symptoms, but developed fatigue, anorexia, and severe renal dysfunction 2.5 months later. Renal biopsy confirmed drug-induced interstitial nephritis, and conservative treatment with fluid replacement and the discontinuation of 5-ASA improved the patient's condition. Clinicians should monitor patients receiving 5-ASA therapy for potential adverse effects, particularly renal injury, and promptly investigate symptoms of renal dysfunction. Early recognition and discontinuation of the offending agent may prevent further damage and improve patient outcomes.

The use of conventional gadolinium(Gd)-based contrast agents in magnetic resonance imaging (MRI) poses a significant risk of Nephrogenic Systemic Fibrosis (NSF) syndrome in patients with impaired renal function (grades 4 and 5). To address this issue, a new study has introduced a novel metabolic Gadolinium oxide nanoparticle (Gd2O3 NPs) coated with β-cyclodextrin (βCD). The study aims to investigate NSF syndrome by quantifying tissue Gd deposition biodistribution in renal impairment rats using MR molecular imaging. This is the first study of its kind to use this approach. A group of 20 rats were divided into four groups, each containing five rats that underwent 5/6 nephrectomy. The rats received 12 intravenous injections of a novel homemade synthesized gadolinium oxide polycyclodextrin (Gd2O3@PCD) at a dose of 0.1 mmol/kg, conventional contrast agents (CAs) drugs of Omniscan (Gd-DTPA-BMA) and Dotarem (Gd-DOTA), at a dose of 2.5 mmol/kg, and 250 μl saline for two injections per week during six weeks. T1-weighted MR imaging was performed before the injections and once a week for six weeks to quantify Gd deposition in four different organs (skin, liver, heart, and lung) in rats using inductively coupled plasma mass spectrometry (ICP-MS). The relationship between Signal-to-Noise Ratio (SNR) and biodistribution of Gd deposition due to NSF-induced syndrome was also calculated. The results of the study showed that the Gd concentrations in tissues were significantly higher in the Gd2O3@PCD group compared to the other groups, without any significant histopathological changes (P < 0.05). In the Gd2O3@PCD group, Gd was mainly deposited in the skin, followed by the liver, lung, and heart, without any symptoms of thickening or hardening of the skin. The Gd concentrations in the skin, liver, lung, and heart were significantly lower in the Dotarem group than in the Omniscan group (P < 0.05). In the histopathological examinations, the Omniscan group showed increased cellularity in the dermis. A significant hyperintensity was observed in the Gd2O3@PCD-treated rats compared to the Dotarem and Omniscan groups in the liver, heart, and lung. Compared to conventional Gd-based CAs, the novel metabolically Gd2O3@PCD with increased SNR, biosafety, and a considerably lower probability of developing NSF, has potential applicability for diagnosing patients with renal diseases in clinical MR Molecular Imaging (MRMI)., (Copyright © 2024. Published by Elsevier Inc.)

Cyclosporine A (CsA) is employed for organ transplantation and autoimmune disorders. Nephrotoxicity is a serious side effect that hampers the therapeutic use of CsA. Hesperidin and sitagliptin were investigated for their antioxidant, anti-inflammatory, and tissue-protective properties. We aimed to investigate and compare the possible nephroprotective effects of hesperidin and sitagliptin. Male Wistar rats were utilized for induction of CsA nephrotoxicity (20 mg/kg/day, intraperitoneally for 7 days). Animals were treated with sitagliptin (10 mg/kg/day, orally for 14 days) or hesperidin (200 mg/kg/day, orally for 14 days). Blood urea, serum creatinine, albumin, cystatin-C (CYS-C), myeloperoxidase (MPO), and glucose were measured. The renal malondialdehyde (MDA), glutathione (GSH), catalase, and SOD were estimated. Renal TNF-α protein expression was evaluated. Histopathological examination and immunostaining study of Bax, Nrf-2, and NF-κB were performed. Sitagliptin or hesperidin attenuated CsA-mediated elevations of blood urea, serum creatinine, CYS-C, glucose, renal MDA, and MPO, and preserved the serum albumin, renal catalase, SOD, and GSH. They reduced the expressions of TNF-α, Bax, NF-κB, and pathological kidney damage. Nrf2 expression in the kidney was raised. Hesperidin or sitagliptin could protect the kidney against CsA through the mitigation of oxidative stress, apoptosis, and inflammation. Sitagliptin proved to be more beneficial than hesperidin., (© 2024. The Author(s).)

The prevalence of chronic kidney disease (CKD) is in progress that causes kidney failure, leading to global problems. This manuscript investigated the nephroprotective effects of chicory (CLE) and/or artichoke (ALE) leaves extracts on carbon tetrachloride (CCl 4 ) and gamma-irradiation (Rad)-induced chronic nephrotoxicity in rats. Rats were divided into 10 groups (10 animals/group): group 1: control, groups 2-7 rats were treated with CLE, ALE, CLE/ALE, CCl 4 , Rad, and CCl 4 /Rad, respectively. Groups 8 to 10, rats were intoxicated with CCl 4 /Rad, and treated with CLE, ALE, and CLE/ALE extracts, respectively, for 4 weeks. The data demonstrated that CCl 4 administration or Rad exposure induced high levels of urea and creatinine, with low levels of total protein and albumin in the serum. However, high levels of malondialdehyde (MDA), nitric oxide (NO), hydrogen peroxide (H 2 O 2 ), some pro-inflammatory markers such as interleukins (IL-1β, IL-2, IL-6), TNF-α, NF-κB, the fibrotic marker; TGF-β1, calcium, and copper, low contents of reduced glutathione (GSH), iron, and zinc, and suppression of the antioxidant enzymes' activity, superoxide dismutase (SOD), and catalase (CAT) were observed. In addition, the Wnt and β-catenin protein expression ratios were up-regulated in the kidney tissues of the CCl 4 , and Rad intoxicated animals. However, the combined treatment CCl 4 /Rad augmented these measurements. On the other hand, CLE, ALE, and CLE/ALE treatments demonstrated nephroprotection in the kidney tissues of CCl 4 /Rad intoxicated animals, in the order of CLE/ALE>ALE>CLE by ameliorating the investigated parameters. Kidney tissues' histopathological examinations confirmed these results. In conclusion, CLE and/or ALE demonstrated nephroprotection against CCl 4 /Rad co-toxicity mediated by down-regulation of renal Wnt/β-catenin protein expressions., (© 2023 Wiley Periodicals LLC.)

Introduction: We aimed to investigate the relationship between nuclear factor erythroid 2-related factor 2 (Nrf2) protein expression levels, lupus nephritis (LN) disease activity, and the degree of renal injury (based on the estimated glomerular filtration rate [eGFR]) in patients with LN., Methods: We selected 40 healthy control participants and 102 patients with LN who were treated in the Second Hospital of Jilin University, China, for inclusion in this study. Patients with LN were classified into LN with high-eGFR and LN with low-eGFR groups. Nrf2 protein levels were measured in the serum and renal tissues of the participants in both groups to assess the correlation between Nrf2 protein levels and different LN disease states., Results: There was a significantly positive correlation between serum Nrf2 protein levels, the degree of renal injury, and systemic lupus erythematosus disease activity index (SLEDAI) scores in patients with LN. Nrf2 protein levels were higher in the LN with high-eGFR group than in the healthy control and LN with low-eGFR groups. In follow-up patients in the LN high eGFR group, Nrf2 protein levels decreased significantly after remission of disease activity., Conclusion: Nrf2 protein expression has a dual role in patients with LN. Nrf2 protein levels not only correlate with disease activity in patients with LN, but also with the degree of kidney injury. Before implementing targeted therapy for Nrf2, evaluating both Nrf2 protein expression and the disease state in patients with LN is necessary to better identify and place each patient in an appropriate patient group., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Guo, Wei, Zhu, Luo and Luo.)

Background: To classify the different clinical phenotypes and compare the distinct prognoses of microscopic polyangiitis (MPA)., Methods: A retrospective analysis of 436 patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) from 2015 to 2022 was conducted in our center, of which 90 patients were diagnosed with MPA and underwent renal biopsy., Results: Among the 90 MPA patients, 63% were female, and the median age at onset was 63 years (25th-75th percentile: 58-68). The median follow-up time was 26 months (25th-75th percentile: 10-53). We identified four subtypes: renal impairment type (cluster 1, 39%), pure type (cluster 2, 22%), systemic inflammation type (cluster 3, 26%), and rapid progress type (cluster 4, 13%). Cluster 1, characterized by renal dysfunction at onset (80%), demonstrated poor prognoses with only 26% achieved complete remission (CR), 11% dying, and 19% developing renal failure. In contrast, patients in cluster 2, exclusively female, most had only kidney involvement showed the best prognoses with 55% achieving CR and none experiencing death or renal failure within 10 years. Cluster 3 mostly consisted of males; high fever and C-reactive protein levels were the primary characteristics. These cases exhibited moderate prognoses with 53% achieving CR, 9% dying, and 4% developing renal failure. Finally, patients in cluster 4, which was characterized by rapidly progressive glomerulonephritis, had the worst prognoses, with none achieving CR, 8% dying, and 75% developing renal failure despite aggressive treatment., Conclusions: MPA is classified into four subtypes with distinct clinical manifestations and prognoses., (© 2023. The Author(s).)

Background: The risk of compounds/drugs, including aristolochic acid-induced nephrotoxicity remains high and is a significant public health concern. Therefore, it is particularly important to select reasonable animal models for rapid screening and evaluation of different samples with complex chemical systems. The zebrafish (Danio rerio) has been used to study chemical-induced renal toxicity. However, most of the published literature was performed on individual components or drugs, and the key evidence confirming the applicability of zebrafish larvae for the evaluation of aristolochic acid-related nephrotoxicity in complex chemical systems, such as in traditional Chinese medicine (TCM), was insufficient., Methods: High-performance liquid chromatography (HPLC) was used to determine the content of aristolochic acid (AA) in herbs and Chinese patent medicines. The zebrafish larvae at 4 days post-fertilization (dpf) were used to evaluate the nephrotoxicity of various samples, respectively, based on the phenotype of the kidney and histological, and biochemical. Transcriptome technology was used to investigate the related signaling pathways and potential mechanisms after treatment with AA, which was verified by RT-PCR technology., Results: The results showed that the total amounts of AAI, AAII, and ALI ranged from 0.0004 to 0.1858 g·g-1( %) from different samples, including Aristolochia debilis, Fibraurea recisa, Asarum, Wantongjingu tablets, Jiuweiqianghuo granules, and Xiaoqinglong granules in descending order. Moreover, compared with the negative/blank control, substantial changes in phenotype, histomorphology and biochemical parameters of renal function were observed in the groups challenged with the sublethal concentration of drugs. The transcriptomics results showed the upregulation of most genes in PERK/ATF4/CHOP, ATM/Chk2/p53, Caspase/Bax/Bcl-2a, TGF/Smad/ERK, PI3K/Akt, induced by aristolochic acid analogues, which were essentially consistent with those of the q-RT-PCR experiments, highlighting the similar toxicity response to the previously published article with the other traditional evaluation model., Conclusion: The stability, accuracy and feasibility of the zebrafish larval model in screening and evaluating the nephrotoxicity of TCM were validated for the first time on the AAs-related drugs in a unified manner, confirming and promoting the applicability of zebrafish in assessing nephrotoxicity of samples with complex chemical character., Competing Interests: Declaration of Competing Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Objective: This study aimed to investigate the effect of oral administration of naringenin in combination with an aqueous mixture of coconut water (CW) and Arabic gum (AG) on renal function, lipid profile, antioxidant activity, and morphology in gentamicin-induced kidney injury in rats., Materials and Methods: Forty adult male Wistar rats were equally divided into four groups. 1-Negative control group, 2-positive control group (Gentamicin), 3-Naringenin+AG+CW, 4-Gentamicin+Naringenin+AG+CW: groups 2 and 4 were treated with gentamicin. After six weeks, the rats were anesthetized with diethyl ether, and blood was collected by cardiac puncture and dissected to collect the kidneys. Biochemical studies were performed to determine the levels of urea, creatinine, lipids, total antioxidant capacity, and lipid peroxide, antioxidant enzyme activity in the kidney, total phenolic content (TPC), radical-scavenging activity, calcium, magnesium, and potassium in AG, CW, and their mixture. Also, kidney histopathology was performed., Results: Renal injury manifests as elevated serum urea and creatinine levels. A significant increase in total cholesterol, triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and malondialdehyde (MDA) was also noted. The activities of antioxidant capacity (TAC) and reduced glutathione (GSH) significantly decreased in the serum. There was a reduction in the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) activities in kidney homogenates. Gentamicin administration induces morphological changes in the kidneys. Oral administration of naringenin+AG+CW significantly overturned all of the above-mentioned abnormalities., Conclusions: These results show that the naringenin+AG+CW combination exhibited an additive effect against renal dysfunction and structural damage through antioxidant and anti-inflammatory mechanisms, as well as replenishing and balancing intracellular and extracellular electrolytes. Therefore, oral administration of these three ingredients could potentially provide better protection and serve as a unique therapeutic tool against nephrotoxicity caused by gentamicin.

Objectives: It is unclear whether renal insufficiency (RI) itself is a risk factor for adverse outcomes after gastric endoscopic submucosal dissection (ESD). We aimed to evaluate the safety and efficacy of gastric ESD in patients with and without RI using propensity score-matching analysis., Methods: In all, 4775 patients with 4775 early gastric cancer lesions undergoing ESD were analyzed. 1:1 propensity score-matching was performed between patients with and without RI using 12 variables. After matching, logistic regression and survival analyses were performed for short- and long-term outcomes of ESD, respectively., Results: The matching yielded 188 pairs of patients with and without RI. In both univariable and multivariable analyses, the presence of RI was not significantly associated with postprocedural bleeding (unadjusted odds ratio 1.81, 95% confidence interval 0.74-4.42; adjusted odds ratio 1.86, 95% confidence interval 0.74-4.65, respectively). When RI patients were subclassified into patients with estimated glomerular filtration rate (eGFR) 30-59 mL/min/1.73 m 2 and eGFR <30 mL/min/1.73 m 2 , no significant differences in bleeding rates were found compared to their matched controls in both groups. Perforation, en bloc resection, en bloc and R0 resection, and curative resection rates of RI patients were 2.1%, 98.4%, 91.0%, and 78.2%, respectively, which were comparable to those of non-RI patients. During a median follow-up of 119 months, there was no difference in gastric cancer-specific survival between patients with and without RI (P = 0.143)., Conclusion: The outcomes of ESD were comparable in patients with and without RI. Decreased renal function itself may not be a reason to keep patients with RI from receiving gastric ESD., (© 2023 Japan Gastroenterological Endoscopy Society.)

CINAC-patients present renal proximal tubular cell lysosomal lesions which are also observed in patients experiencing calcineurin inhibitor (CNI) nephrotoxicity, suggesting that CINAC is a toxin-induced nephropathy. An alternative hypothesis advocates chronic dehydration as a major etiological factor for CINAC. Here, we evaluated histological and molecular changes in dehydrated versus toxin exposed rats. Wistar rats were divided in 3 groups. Group 1 (n = 6) had free access to drinking water (control group). Group 2 (n = 8) was water deprived for 10 h per 24 h, 5 days/week and placed in an incubator (37 °C) for 30 min/h during water deprivation. Group 3 (n = 8) underwent daily oral gavage with cyclosporine (40 mg/kg body weight). After 28 days, renal function, histopathology and proteomic signatures were analysed. Cyclosporine-treated rats developed focal regions of atrophic proximal tubules with associated tubulo-interstitial fibrosis. PASM staining revealed enlarged argyrophilic granules in affected proximal tubules, identified as lysosomes by immunofluorescent staining. Electron microscopy confirmed the enlarged and dysmorphic phenotype of the lysosomes. Overall, these kidney lesions resemble those that have been previously documented in farmers with CINAC. Dehydration resulted in none of the above histopathological features. Proteomic analysis revealed that dehydration and cyclosporine both induce injury pathways, yet of a clear distinct nature with a signature of toxicity only for the cyclosporine group. In conclusion, both cyclosporine and dehydration are injurious to the kidney. However, dehydration alone does not result in kidney histopathology as observed in CINAC patients, whereas cyclosporine administration does. The histopathological analogy between CINAC and calcineurin inhibitor nephrotoxicity in rats and humans supports the involvement of an as-yet-unidentified environmental toxin in CINAC etiology., (© 2023. Springer Nature Limited.)

Karyomegalic interstitial nephritis (KIN) is a rare cause of chronic interstitial nephritis characterized by enlarged renal tubular epithelial nuclei. The first case of KIN reported in a kidney graft was in 2019. Here, we report the first case of KIN in 2 brothers receiving kidneys from 2 different unrelated living donors. A male kidney transplant recipient with focal segmental glomerulosclerosis as the original kidney disease presented with graft impairment and proteinuria, and graft biopsy revealed KIN. This patient had a brother who was also a kidney transplant recipient and had one episode of graft impairment and was diagnosed with KIN as well., (© 2023. The Author(s).)

Use of immunosuppressant calcineurin inhibitors (CNIs) is limited by irreversible kidney damage, hallmarked by renal fibrosis. CNIs directly damage many renal cell types. Given the diverse renal cell populations, additional targeted cell types and signaling mechanisms warrant further investigation. We hypothesized that fibroblasts contribute to CNI-induced renal fibrosis and propagate profibrotic effects via the transforming growth factor-β (TGF-β)/Smad signaling axis. To test this, kidney damage-resistant mice (C57BL/6) received tacrolimus (10 mg/kg) or vehicle for 21 days. Renal damage markers and signaling mediators were assessed. To investigate their role in renal damage, mouse renal fibroblasts were exposed to tacrolimus (1 nM) or vehicle for 24 h. Morphological and functional changes in addition to downstream signaling events were assessed. Tacrolimus-treated kidneys displayed evidence of renal fibrosis. Moreover, α-smooth muscle actin expression was significantly increased, suggesting the presence of fibroblast activation. TGF-β receptor activation and downstream Smad2/3 signaling were also upregulated. Consistent with in vivo findings, tacrolimus-treated renal fibroblasts displayed a phenotypic switch known as fibroblast-to-myofibroblast transition (FMT), as α-smooth muscle actin, actin stress fibers, cell motility, and collagen type IV expression were significantly increased. These findings were accompanied by concomitant induction of TGF-β signaling. Pharmacological inhibition of the downstream TGF-β effector Smad3 attenuated tacrolimus-induced phenotypic changes. Collectively, these findings suggest that 1 ) tacrolimus inhibits the calcineurin/nuclear factor of activated T cells axis while inducing TGF-β1 ligand secretion and receptor activation in renal fibroblasts; 2 ) aberrant TGF-β receptor activation stimulates Smad-mediated production of myofibroblast markers, notable features of FMT; and 3 ) FMT contributes to extracellular matrix expansion in tacrolimus-induced renal fibrosis. These results incorporate renal fibroblasts into the growing list of CNI-targeted cell types and identify renal FMT as a process mediated via a TGF-β-dependent mechanism. NEW & NOTEWORTHY Renal fibrosis, a detrimental feature of irreversible kidney damage, remains a sinister consequence of long-term calcineurin inhibitor (CNI) immunosuppressive therapy. Our study not only incorporates renal fibroblasts into the growing list of cell types negatively impacted by CNIs but also identifies renal fibroblast-to-myofibroblast transition as a process mediated via a TGF-β-dependent mechanism. This insight will direct future studies investigating the feasibility of inhibiting TGF-β signaling to maintain CNI-mediated immunosuppression while ultimately preserving kidney health.

Aluminum (AL) is an important nephrotoxic agent with a high daily exposure rate and property of accumulation in tissues. This study aimed to investigate the potential protective efficacy of N-acetylcysteine (NAC) against AL exposure-induced nephrotoxicity in rats. Twenty-eight rats were randomly divided into 4 groups as control, N-acetylcysteine group (NC), AL, and AL + NC, with an equal number of rats in each group (n = 7). No application was made to the control group. A total of 150 mg/kg/day NAC was administered to the NC group and 30 mg/kg/day AL was administered to the AL group intraperitoneally (i.p.). The AL + NC group received 30 mg/kg/day AL and 150 mg/kg/day NAC i.p. Biochemical parameters in blood serum and histopathological changes in kidney tissue, oxidative stress parameters, spexin (SPX), and apoptotic protein levels were examined after 15 days. Histopathological changes, biochemical parameters, oxidative stress parameters, and apoptotic protein levels were significantly irregular in the AL group compared to the control group. Moreover, SPX levels increased in the AL group. However, NAC treatment regulated AL exposure-related changes in the AL + NC group. NAC treatment may have a prophylactic effect against nephrotoxicity due to AL exposure. SPX may play a role in AL-induced nephrotoxicity., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Rationale & Objective: Challenges in achieving valid risk prediction and stratification impede treatment decisions and clinical research design for patients with glomerular diseases. This study evaluated whether chronic histologic changes, when complementing other clinical data, improved the prediction of disease outcomes across a diverse group of glomerular diseases., Study Design: Multicenter retrospective cohort study., Setting & Participants: 4,982 patients with biopsy-proven glomerular disease who underwent native biopsy at 8 tertiary care hospitals across China in 2004-2020., New Predictors & Established Predictors: Chronicity scores depicted as 4 categories of histological chronic change, as well as baseline clinical and demographic variables., Outcome: Progression of glomerular disease defined as a composite of kidney failure or a ≥40% decrease in estimated glomerular filtration rate from the measurement at the time of biopsy., Analytical Approach: Multivariable Cox proportional hazard models. The performance of predictive models was evaluated by C statistic, time-dependent area under the receiver operating characteristic curve (AUROC), net reclassification index, integrated discrimination index, and calibration plots., Results: The derivation and validation cohorts included 3,488 and 1,494 patients, respectively. During a median of 31 months of follow-up, a total of 444 (8.9%) patients had disease progression in the 2 cohorts. For prediction of the 2-year risk of disease progression, the AUROC of the model combining chronicity score and the Kidney Failure Risk Equation (KFRE) in the validation cohort was 0.76 (95% CI, 0.65-0.87); in comparison with the KFRE model (AUROC, 0.68 [95% CI, 0.56-0.79]), the combined model was significantly better (P = 0.04). The combined model also had a better fit, with a lower Akaike information criterion and a significant improvement in reclassification as assessed by the integrated discrimination improvements and net reclassification improvements. Similar improvements in predictive performance were observed in subgroup and sensitivity analyses., Limitations: Selection bias, relatively short follow-up, lack of external validation., Conclusions: Adding histologic chronicity scores to the KFRE model improved the prediction of kidney disease progression at the time of kidney biopsy in patients with glomerular diseases., Plain-Language Summary: Risk prediction and stratification remain big challenges for treatment decisions and clinical research design for patients with glomerular diseases. The extent of chronic changes is an important component of kidney biopsy evaluations in glomerular disease. In this large multicenter cohort including 4,982 Chinese adults undergoing native kidney biopsy, we evaluated whether histologic chronicity scores, when added to clinical data, could improve the prediction of disease prognosis for a diverse set of glomerular diseases. We observed that adding histologic chronicity scores to the kidney failure risk equation improved the prediction of kidney disease progression at the time of kidney biopsy in patients with glomerular diseases., (Copyright © 2022 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Monoclonal immunoglobulin light chain (LC) crystalline inclusions within podocytes are rare, poorly characterized entities. To provide more insight, we now present the first clinicopathologic series of LC crystalline podocytopathy (LCCP) encompassing 25 patients (68% male, median age 56 years). Most (80%) patients presented with proteinuria and chronic kidney disease, with nephrotic syndrome in 28%. Crystalline keratopathy and Fanconi syndrome were present in 22% and 10%, respectively. The hematologic condition was monoclonal gammopathy of renal significance (MGRS) in 55% and multiple myeloma in 45%. The serum monoclonal immunoglobulin was IgG κappa in 86%. Histologically, 60% exhibited focal segmental glomerulosclerosis (FSGS), often collapsing. Ultrastructurally, podocyte LC crystals were numerous with variable effacement of foot processes. Crystals were also present in proximal tubular cells as light chain proximal tubulopathy (LCPT) in 80% and in interstitial histiocytes in 36%. Significantly, frozen-section immunofluorescence failed to reveal the LC composition of crystals in 88%, requiring paraffin-immunofluorescence or immunohistochemistry, with identification of kappa LC in 87%. The LC variable region gene segment, determined by mass spectrometry of glomeruli or bone marrow plasma cell sequencing, was IGKV1-33 in four and IGKV3-20 in one. Among 21 patients who received anti-plasma cell-directed chemotherapy, 50% achieved a kidney response, which depended on a deep hematologic response. After a median follow-up of 36 months, 26% progressed to kidney failure and 17% died. The mean kidney failure-free survival was 57.6 months and was worse in those with FSGS. In sum, LCCP is rare, mostly associates with IgG κappa MGRS, and frequently has concurrent LCPT, although Fanconi syndrome is uncommon. Paraffin-immunofluorescence and electron microscopy are essential to prevent misdiagnosis as primary FSGS since kidney survival depends on early diagnosis and subsequent clone-directed therapy., (Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a systemic inflammation of small or medium blood vessels that includes microscopic polyangiitis. A diagnosis of ANCA-associated vasculitis can be aided by histological identification of vasculitis, and identification of renal impairment can help predict outcomes. However, kidney biopsy is not generally indicated in the absence of renal findings. We report two cases of ANCA-associated vasculitis diagnosed by kidney biopsy despite the absence of remarkable urinary abnormality and renal impairment. These patients had fever of unknown origin and were positive for myeloperoxidase (MPO)-ANCA but showed few findings that would suggest small-vessel vasculitis in the kidney. Nevertheless, kidney biopsies revealed small-vessel arteritis, necrotizing glomerulonephritis, and interstitial nephritis. Immunofluorescent antibody tests performed using samples of glomeruli were all negative, suggesting microscopic polyangiitis. Therefore, kidney biopsy may be useful in confirming the diagnosis, even if patients have completely normal urinary findings in the absence of other organ lesions., (© 2022. The Author(s) under exclusive licence to The Japan Society of Nephrology.)

Methotrexate (MTX), a cytotoxic chemotherapeutic and immunosuppressant agent, is widely used in the treatment of autoimmune diseases and different types of cancers. However, its use has been limited by its life-threatening side effects, including nephrotoxicity and hepatotoxicity. The purpose of this study was to investigate the protective effect of sitagliptin on methotrexate (MTX)-induced nephrotoxicity in rats. Twenty-four rats were divided into four groups: control group, which received the vehicle for 6 days; MTX group, which received a single dose of MTX, followed by five daily doses of vehicle dosing; MTX + sitagliptin group, which received a single dose of MTX 1 h after the first sitagliptin treatment and six daily doses of sitagliptin; and sitagliptin group, which received sitagliptin for 6 days. Both MTX and sitagliptin were given as intraperitoneal injections at a dose of 20 mg/kg body weight. All rats were euthanized on the seventh day of the study. Kidney tissues were harvested and blood samples were collected. Serum levels of blood urea nitrogen (BUN) and creatinine were evaluated. Furthermore, catalase, glutathione peroxidase, superoxide dismutase activities, and malondialdehyde (MDA) levels were determined in kidney tissue. In addition, histopathological analysis was conducted. Histopathological evaluation showed that MTX-induced marked kidney injury. Biochemical analysis revealed a significant increase of BUN and creatinine in the serum of the MTX group. Furthermore, oxidative stress and depressed antioxidant system of the kidney tissues were evident in the MTX group. Sitagliptin did not affect these endpoints when administered alone, but it significantly attenuated the observed MTX-induced effects. These results suggest that sitagliptin exhibits potent anti-oxidant properties against the nephrotoxicity induced by MTX in rats.

Uric acid has promoted renal fibrosis and inflammation in experimental studies, but some studies have shown nephroprotective effects due to alleviated oxidative stress. We studied the influence of experimental hyperuricaemia in surgically 5/6 nephrectomized rats. Three weeks after subtotal nephrectomy or sham operation, the rats were allocated to control diet or 2.0% oxonic acid (uricase inhibitor) diet for 9 weeks. Then blood, urine and tissue samples were taken, and renal morphology and oxidative stress were examined. Inflammation and fibrosis were evaluated using immunohistochemistry and real-time PCR (RT-PCR). Remnant kidney rats ingesting normal or oxonic acid diet presented with ~60% reduction of creatinine clearance and suppressed plasma renin activity. Oxonic acid diet increased plasma uric acid levels by >80 μmol/L. In remnant kidney rats, moderate hyperuricaemia decreased glomerulosclerosis, tubulointerstitial damage and kidney mast cell count, without influencing the fibrosis marker collagen I messenger RNA (mRNA) content. In both sham-operated and 5/6 nephrectomized rats, the mast cell product 11-epi-prostaglandin-F 2α excretion to the urine and kidney tissue cyclooxygenase-2 (COX-2) levels were decreased. To conclude, hyperuricaemic remnant kidney rats displayed improved kidney morphology and reduced markers of oxidative stress and inflammation. Thus, moderately elevated plasma uric acid had beneficial effects on the kidney in this low-renin model of experimental renal insufficiency., (© 2022 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Tripterygium glycoside tablet (TGT) has been used clinically to alleviate diabetic nephropathy (DN) for decades. However, the mechanism of its anti-DN has not been fully clarified. The aim of this study was to elucidate molecular mechanism of TGT in repairing renal function injury. The results of biochemical parameters and renal histopathology implied that TGT intervention could attenuate creatinine, albumin excretion rate and histological injury of kidney in DN mouse model. Moreover, UHPLC-QTOF-MS/MS-based untargeted metabolomic analysis indicated that 11 metabolites in kidney of mice with DN were restored after TGT treatment, and the most prominent metabolic alteration was triglyceride (TG) metabolism. Mechanistically, TGT effectively improved the function of impaired kidney by promoting TG catabolism via modulation of adipose triglyceride lipase in DN mice. Our findings identified the link between circulating metabolites and DN, suggesting that it might be a possibility to intervene in DN by targeting metabolism., 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 © 2022 Elsevier B.V. All rights reserved.)

Kidney dysplasia is one of the most frequent causes of chronic kidney failure in children. While dysplasia is a histological diagnosis, the term 'kidney dysplasia' is frequently used in daily clinical life without histopathological confirmation. Clinical parameters of kidney dysplasia have not been clearly defined, leading to imprecise communication amongst healthcare professionals and patients. This lack of consensus hampers precise disease understanding and the development of specific therapies. Based on a structured literature search, we here suggest a common basis for clinical, imaging, genetic, pathological and basic science aspects of non-obstructive kidney dysplasia associated with functional kidney impairment. We propose to accept hallmark sonographic findings as surrogate parameters defining a clinical diagnosis of dysplastic kidneys. We suggest differentiated clinical follow-up plans for children with kidney dysplasia and summarize established monogenic causes for non-obstructive kidney dysplasia. Finally, we point out and discuss research gaps in the field., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Objectives: Based on available data, the histological predictors of long-term outcome of lupus nephritis (LN) are not clearly defined. Aims of this retrospective study were: (i) to evaluate the change of chronicity index from the first to second kidney biopsy and to find the predictors of chronicity index increase and (ii) to detect the clinical/histological features at first and at second kidney biopsy associated with long-term kidney function impairment., Methods: Among 203 biopsy proven LN subjects, 61 repeated kidney biopsy 49 months after the first biopsy. The reasons for repeated biopsy were: nephritic flares in 25 (41%), proteinuric flares in 21 (36%) of patients and protocol biopsy in 14 (23%) of cases., Results: During 23-year follow-up, 25 patients presented a decrease in glomerular filtration rate (eGFR) ≥30%. At repeat biopsy, chronicity index increased in 44 participants (72%) and did not increase in 17 (28%). Nephritic syndrome and serum creatinine >1.6 mg/dL at presentation correlated with chronicity index increase (p=0.031, 0.027, respectively), cyclophosphamide therapy tended to protect against chronicity index increase (p=0.059). Kidney flares occurred in 53.6% of patients with vs 23.5% of those without chronicity index increase (p=0.035). Chronicity index increases of 3.5 points in patients with kidney flares vs 2 in those without flares (p=0.001). At second, but not at first kidney biopsy, two different models predicted eGFR decrease at multivariate analysis. The first included activity index >3 (OR: 3.230; p=0.013) and chronicity index >4 (OR: 2.905; p=0.010), and the second model included moderate/severe cellular/fibrocellular crescents (OR: 4.207; p=0.010) and interstitial fibrosis (OR: 2.525; p=0.025)., Conclusion: At second biopsy, chronicity index increased in 3/4 of participants. Its increase was predicted by kidney dysfunction at presentation and occurrence of LN flares. Kidney function impairment was predicted by both activity and chronicity index and by some of their components at repeated biopsy, but not at first biopsy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Amikacin (AK) has the largest spectrum of aminoglycosides. However, its use is constrained because of nephrotoxicity and ototoxicity. Ellagic acid (EA) is a polyphenol present in plants. It has antioxidant, anticarcinogenic, and antimutagenic characteristics. Cilostazol (CTZ) is a phosphodiesterase Ш inhibitor, it is a potent vasodilator and antiplatelet drug. CTZ has an inhibitory effect on reactive oxygen species and superoxide generation in addition to hydroxyl radicals scavenging action. This study determines whether EA and cilostazol have a protective effect against AK-induced nephrotoxicity. Forty-nine rats were divided into seven equal groups: control normal; AK 400 mg/kg; EA 10 mg/kg; CTZ 10 mg/kg; AK 400 mg/kg plus EA 10 mg/kg; AK 400 mg/kg plus CTZ 10 mg/kg; AK 400 mg/kg plus EA 10 mg/kg and CTZ 10 mg/kg. For seven days, drugs were administered using gavage one hour before intramuscular injection of AK. Twenty-four hours after the last AK dosage, blood samples were collected to determine blood urea nitrogen and creatinine levels. Kidneys were removed for histopathological examination and measurement of: malondialdehyde (MDA), catalase (CAT), decreased glutathione (GSH), superoxide dismutase (SOD), interleukin 6 (IL6), tumor necrosis factor-alpha (TNFα), nuclear factor kappa B (NFκB), and Bcl-2 associated x protein (BAX). AK caused kidney damage, inflammatory mediator elevation, and oxidative stress and apoptotic markers. Rats receiving EA or CTZ indicated significant improvement in kidney function, decrease in oxidative stress and inflammation through NF-kB down-regulation and BAX expression. The combination of EA and CTZ showed a synergistic effect. In conclusion, EA and CTZ might play a beneficial role in preventing nephrotoxicity induced by AK partially by inhibition of tissue inflammation and apoptosis., Competing Interests: The authors have declared that no competing interests exist.

It's crucial to comprehend the impact of oxidative stress and pro-inflammatory cytokines in the gentamicin-induced kidney injury mechanism. Celecoxib was administered orally either before or after intraperitoneal therapy with gentamicin in mice. The serum levels of creatinine (SCr), blood urea nitrogen (BUN), IL-6, and TNF-α were measured by ELISA test, as well as the levels of the kidney tissue malondialdehyde (MDA), and glutathione (GSH) were also estimated spectrophotometrically. The renal expression of nuclear factor-κB (NF-κB), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and cyclooxygenase 2 (COX-2) mRNAs were evaluated by qPCR. Histopathological evaluation and Immunohistochemical examination of kidney NF-κB, IL-6, and COX-2 were also, performed. Celecoxib successfully prevented gentamicin-induced kidney damage as indicated by reducing blood BUN, SCr, and tissue MDA levels and increasing renal tissue GSH levels as well as lowering the blood IL-6 and TNF-α in comparison to mice received gentamicin. Furthermore, celecoxib has inhibited COX-2, NF-κB, IL-6, and TNF-α expression in the renal tissue. It is noteworthy that celecoxib therapy after gentamicin administration brought about substantially the same results as celecoxib treatment before gentamicin injection in mice. Our results showed the role of celecoxib as a therapeutic tool for gentamicin-induced nephrotoxicity as well as raised its beneficial prophylactic role in this medical challenge by attenuating oxidative stress and inflammation., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Background: Acute and chronic kidney diseases are important comorbidities in People Living With HIV (PLWH). Biopsy is often pursued in this cohort with ongoing renal impairment without a clear aetiology, in order to establish the diagnosis and to guide management. Despite the importance of renal disease in PLWH, there is a paucity of biopsy data-especially in the Australian setting. Consequently, who and when to biopsy is mainly based on clinical experience. The aims of this study were to describe biopsy-proven renal disease in PLWH at our institution and to assess for correlation between any demographic or laboratory characteristics with histological diagnosis., Methods: A retrospective review of all PLWH who underwent renal biopsy between January 2010 and December 2020 at Royal Prince Alfred Hospital, Sydney, Australia was performed. All PLWH over 18 years, who were not transplant recipients were included. Demographic, laboratory and biopsy data was extracted from the electronic medical records. Basic descriptive statistics were performed, and correlation was assessed using chi square and Kendall's coefficient of rank test., Results: 19 renal biopsies were included in the study. The majority of PLWH were Australian born (53%), male (84%) and had a mean age of 48 years (SD 13). Comorbid hypertension and diabetes were present in 74% and 21% of people respectively. The mean serum creatinine was 132 µmol/L (SD 55) and the mean estimated glomerular filtration rate (eGFR) was 61 ml/min/1.73m 2 (SD 24). The most common histological diagnosis was tubulointerstial nephritis in 5 people (24%). Hypertensive glomerulosclerosis and IgA nephropathy were present in 4 (19%) and 3 (14%) people respectively. There were no cases of HIV-associated nephropathy. There was no significant correlation between any cohort characteristics and diagnoses., Conclusions: This study represents the first description of biopsy-proven kidney disease in the HIV-infected population of Australia. Our results support the use of renal biopsy in PLWH with ongoing renal impairment for accurate diagnosis and to guide further management. Although a small sample size, our study is larger than other published international biopsy studies., (© 2022. The Author(s).)

Aims: Aprepitant, a neurokinin-1 (NK1) receptor antagonist, is a clinically approved anti-emetic drug. Recently, inhibition of the NK1 receptor has been reported as a potential nephroprotective strategy. We aimed to assess the pharmacological mechanisms of aprepitant against diclofenac (DIC)-induced renal toxicity., Main Methods: An in vivo study was conducted using twenty-four male Wistar rats, divided into 4 groups. Aprepitant was administered for 5 days (5 mg/kg/day) with or without DIC which was given on the 4th and 5th days (50 mg/kg, i.p.). At the end of the study, renal function biomarkers, renal oxidative parameters, prostaglandin E (PGE-2), and NADPH oxidase (NOX-4) were measured. Histopathological changes as well as expression of renal inflammatory and apoptotic markers (tumor necrosis factor alpha (TNF-α) and caspase-3) were investigated., Key Findings: DIC caused significant renal damage, as evidenced by deterioration of renal functions, oxidative stress, inflammatory and apoptotic markers, and confirmed by histopathological findings. Pretreatment with aprepitant successfully ameliorated and improved all biochemical and molecular parameters induced by DIC. Moreover, aprepitant restored the decrease in renal PGE-2 concentration and inhibited DIC-activated Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling in renal tissues., Significance: The protective effect of aprepitant is possibly attributed to its anti-oxidant and anti-inflammatory roles via the NOX-4/JAK/STAT pathway., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Cisplatin (CP) is a conventional chemotherapeutic agent with serious adverse effects. Its toxicity was linked to the stimulation of oxidative stress and inflammation. As a result, this study explored the protective effect of baicalein and alpha-tocopherol in nephrotoxicity induced by cisplatin. Until receiving an intraperitoneal injection of CP (3 mg/kg BW), rats were given baicalein orally 100 mg/kg for seven days or/and a single intraperitoneal injection of α-tocopherol 250 mg/kg. Renal function was tested to explore whether baicalein and α-tocopherol have any beneficial effects; blood urea nitrogen (BUN), serum creatinine, malondialdehyde (MDA) content, antioxidant activity biomarkers and histopathology of renal tissue, oxidative stress biomarkers, inflammatory response markers, and histopathological features of kidney architecture were measured. Cisplatin treatment resulted in extreme renal failure, as measured by high serum creatinine and BUN levels and severe renal changes. Cisplatin therapy resulted in increased lipid peroxidation and decreased glutathione and superoxide dismutase levels, reflecting oxidative stress. Upon treatment with α-tocopherol, baicalein, and combined therapy, there was augmentation in the antioxidant status as well as a reduction in IL-6, NF-κB, TNF, TLR2, and TLR4 and a significant increase in Keap-1 and NRF-2. The combined treatment was the most effective and the nearest to the normal status. These findings suggest that baicalein and α-tocopherol may be useful in preventing cisplatin-induced nephrotoxicity.

Chronic kidney disease involves disturbances in iron metabolism including anemia caused by insufficient erythropoietin (EPO) production. However, underlying mechanisms responsible for the dysregulation of cellular iron metabolism are incompletely defined. Using the unilateral ureteral obstruction (UUO) model in Irp1 +/+ and Irp1 -/- mice, we asked if iron regulatory proteins (IRPs), the central regulators of cellular iron metabolism and suppressors of EPO production, contribute to the etiology of anemia in kidney failure. We identified a significant reduction in IRP protein level and RNA binding activity that associates with a loss of the iron uptake protein transferrin receptor 1 (TfR1), increased expression of the iron storage protein subunits H- and L-ferritin, and a low but overall variable level of stainable iron in the obstructed kidney. This reduction in IRP RNA binding activity and ferritin RNA levels suggests the concomitant rise in ferritin expression and iron content in kidney failure is IRP dependent. In contrast, the reduction in the Epo mRNA level in the obstructed kidney was not rescued by genetic ablation of IRP1, suggesting disruption of normal hypoxia-inducible factor (HIF)-2α regulation. Furthermore, reduced expression of some HIF-α target genes in UUO occurred in the face of increased expression of HIF-α proteins and prolyl hydroxylases 2 and 1, the latter of which is not known to be HIF-α mediated. Our results suggest that the IRP system drives changes in cellular iron metabolism that are associated with kidney failure in UUO but that the impact of IRPs on EPO production is overridden by disrupted hypoxia signaling. NEW & NOTEWORTHY This study demonstrates that iron metabolism and hypoxia signaling are dysregulated in unilateral obstructive nephropathy. Expression of iron regulatory proteins (IRPs), central regulators of cellular iron metabolism, and the iron uptake (transferrin receptor 1) and storage (ferritins) proteins they target is strongly altered. This suggests a role of IRPs in previously observed changes in iron metabolism in progressive renal disease. Hypoxia signaling is disrupted and appeared to dominate the action of IRP1 in controlling erythropoietin expression.

The efficacy of n-3 polyunsaturated fatty acids (PUFAs) in improving outcomes in a renal ischemia-reperfusion injury (IRI) model has previously been reported. However, the underlying mechanisms remain poorly understood and few reports demonstrate how dietary n-3 PUFAs influence the composition of membrane phospholipids in the kidney. Additionally, it has not been elucidated whether perilla oil (PO), which is mainly composed of the n-3 alpha-linolenic acid, mitigates renal IRI. In this study, we investigated the effect of dietary n-3 PUFAs (PO), compared with an n-6 PUFA-rich soybean oil (SO) diet, on IRI-induced renal insufficiency in a rat model. Levels of membrane phospholipids containing n-3 PUFAs were higher in the kidney of PO-rich diet-fed rats than the SO-rich diet-fed rats. Levels of blood urea nitrogen and serum creatinine were significantly higher in the ischemia-reperfusion group than the sham group under both dietary conditions. However, no significant differences were observed in blood urea nitrogen, serum creatinine, or histological damage between PO-rich diet-fed rats and SO-rich diet-fed rats. In the kidney of PO-rich diet-fed rats, levels of arachidonic acid and arachidonic acid-derived pro-inflammatory lipid mediators were lower than SO-rich diet-fed rats. Eicosapentaenoic acid and eicosapentaenoic acid-derived lipid mediators were significantly higher in the kidney of PO-rich than SO-rich diet-fed rats. These results suggest that dietary n-3 PUFAs alter the fatty acid composition of membrane phospholipids and lipid mediators in the kidney; however, this does not attenuate renal insufficiency or histological damage in a renal IRI model., Competing Interests: Declaration of competing interest The authors declare no conflicts of interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

ATP6AP2 expression is increased in the nephron during high-fat diet (HFD) and its knockout (ATP6AP2 KO) reduces body weight (WT) in mice. We evaluated the contribution of ATP6AP2 to urinary glucose (UG) and albumin (Ualb) handling during HFD. We hypothesized that nephron ATP6AP2 KO increases UG and Ualb and minimizes HFD-induced obesity. Eight-week-old male C57BL/6J mice with inducible nephron-specific ATP6AP2 KO and noninduced controls were fed either normal diet (ND, 12% kcal fat) or HFD (45% kcal fat) for 6 months. ATP6AP2 KO mice on ND had 20% (P < 0.01) lower WT compared with controls. HFD-fed mice had 41% (P < 0.05) greater WT than ND-fed control mice. In contrast, ATP6AP2 KO abrogated the increase in WT induced by HFD by 40% (P < 0.05). Mice on HFD had less caloric intake compared with ND controls (P < 0.01). There were no significant differences in metabolic rate between all groups. UG and Ualb was significantly increased in ATP6AP2 KO mice on both ND and HFD. ATP6AP2 KO showed greater levels of proximal tubule apoptosis and histologic evidence of proximal tubule injury. In conclusion, our results demonstrate that nephron-specific ATP6AP2 KO is associated with glucosuria and albuminuria, most likely secondary to renal proximal tubule injury and/or dysfunction. Urinary loss of nutrients may have contributed to the reduced WT of knockout mice on ND and lack of WT gain in response to HFD. Future investigation should elucidate the mechanisms by which loss of renal ATP6AP2 causes proximal tubule injury and dysfunction., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Salt-sensitive (SS) hypertension is accompanied with severe cardiorenal complications. In this condition, elevated blood pressure (BP) resulting from salt retention is associated with counterintuitively lower levels of atrial natriuretic peptide (ANP). In plasma, ANP is degraded by the neprilysin; therefore, pharmacological inhibition of this metalloprotease (i.e., with sacubitril) can be employed to increase ANP level. We have shown earlier that sacubitril in combination with valsartan (75 μg/day each) had beneficial effects on renal function in Dahl SS rats. The goal of this study was to evaluate the effects of a higher dose of sacubitril on renal damage in this model. To induce hypertension, male Dahl SS rats were fed a 4% NaCl diet (HS) for 21 days, and were administered sacubitril (125 μg/day) or vehicle via s.c. osmotic pumps. At the end of the HS challenge, both groups exhibited similar outcomes for GFR, heart weight, plasma electrolytes, BUN, and creatinine. Sacubitril exacerbated kidney hypertrophy, but did not affect levels of renal fibrosis. We also observed aggravated glomerular lesions and increased formation of protein casts in the sacubitril-treated animals compared to controls. Thus, in Dahl SS rats, administration of sacubitril without renin-angiotensin-system blockage had adverse effects on renal disease progression, particularly in regards to glomerular damage and protein cast formation. We can speculate that while ANP levels are increased because of neprilysin inhibition, there are off-target effects of sacubitril, which are detrimental to renal function in the SS hypertensive state.

Background: Cefepime-induced neurotoxicity (CIN) is an increasingly reported adverse event; however, the toxicity threshold remains unclear. This study was conducted to provide a comprehensive examination of the most appropriate threshold for CIN, and evaluate the ability of current dosing regimens to attain therapeutic targets., Methods: Data of the incidence of CIN and cefepime plasma concentrations were collected retrospectively from patients administered cefepime. Population pharmacokinetic modelling was used to determine daily cefepime trough concentration (C min ), maximum serum concentration and area under the concentration-time curve. The ability of each pharmacokinetic parameter to predict CIN was evaluated using receiver operating characteristic (ROC) curves, from which optimal toxicity thresholds were determined. Pharmacokinetic simulation was used to evaluate the ability of cefepime dosing guidelines to meet established efficacy targets, whilst maintaining exposure below the determined CIN threshold., Results: In total, 102 cefepime courses were evaluated, with CIN reported in 10. ROC analyses showed that all cefepime pharmacokinetic parameters were strongly predictive of CIN. C min of 49 mg/L was identified as the optimal toxicity target, based on its predictive ability (0.88, 95% confidence interval 0.758-0.999, P<0.001) and ease of clinical use. Assessment of cefepime dosing regimens predicted that only 29% of simulated patients achieve therapeutic targets, with patients with impaired renal function more likely to exhibit subtherapeutic concentrations (89%), and patients with normal renal function likely to have potentially toxic exposure (64%)., Conclusions: The findings from this study provide evidence that cefepime exposure is highly predictive of CIN, with C min of 49 mg/L being the most appropriate toxicity threshold. Further research is required to optimize cefepime dosing in the context of this therapeutic target., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

A woman aged 63 years presented at the gynecological oncology outpatient clinic with the following medical history: smoking history (smoking index of 10); systemic arterial hypertension diagnosed 6 years ago; menarche at 16 years; menopause at 52 years; 4 pregnancies, 4 deliveries; beginning of active sexual life at 18 years; 3 sexual partners; and no early cancer detection method in her life. Her performance status per ECOG criteria was 1. The patient presented with transvaginal bleeding with 5 months of evolution. Upon physical exploration, a 5 x 5 cm tumor in the cervix was detected, with the following characteristics: exophytic, friable, bleeding, with invasion to the lower third of the vagina, affection to the cul-de-sac and parametria, and bilaterally fixed to the pelvic wall. A biopsy of the cervix showed moderately differentiated invasive squamous cell carcinoma.

Background: The long-term outcome of COVID-19-associated collapsing glomerulopathy is unknown., Methods: We retrospectively identified 76 native kidney biopsies from patients with history of COVID-19 between March 2020 and April 2021. Presenting and outcome data were obtained for all 23 patients with collapsing glomerulopathy and for seven patients with noncollapsing podocytopathies. We performed APOL1 genotyping by Sanger sequencing, immunostaining for spike and nucleocapsid proteins, and in situ hybridization for SARS-CoV-2., Results: The 23 patients with COVID-19-associated collapsing glomerulopathy were median age 57 years (range, 35-72), included 16 men, and were predominantly (91%) Black. Severity of COVID-19 was mild or moderate in most (77%) patients. All but one patient presented with AKI, 17 had nephrotic-range proteinuria, and six had nephrotic syndrome. Fourteen (61%) patients required dialysis at presentation. Among 17 patients genotyped, 16 (94%) were high-risk APOL1 . Among 22 (96%) patients with median follow-up at 155 days (range, 30-412), 11 (50%) received treatment for COVID-19, and eight (36%) received glucocorticoid therapy for podocytopathy. At follow-up, 19 (86%) patients were alive, and 15 (68%) were dialysis free, including seven of 14 who initially required dialysis. The dialysis-free patients included 64% (seven of 11) of those treated for COVID-19 and 75% (six of eight) of those treated with glucocorticoids for podocytopathy. Overall, 36% achieved partial remission of proteinuria, 32% had no remission, and 32% reached combined end points of ESKD or death. Viral infection of the kidney was not detected., Conclusions: Half of 14 patients with COVID-19-associated collapsing glomerulopathy requiring dialysis achieved dialysis independence, but the long-term prognosis of residual proteinuric CKD remains guarded, indicating a need for more effective therapy., (Copyright © 2021 by the American Society of Nephrology.)

Cisplatin (CDDP) is a highly potent anticancer drug that is widely used in the treatment of several cancers. CDDP-induced nephrotoxicity (CIN) is one of the most significant adverse effects, and oxidative stress is thought to be one of the mechanisms underlying CIN. Although there are some studies available on the variability in transporter expression in the kidney after a single CDDP dose, none have reported the change in renal transporter expression after multiple CDDP dose administrations. P-glycoprotein (P-gp), a transporter, is reported to be induced by oxidative stress. Ascorbic acid is a vitamin with antioxidant potential and therefore, may regulate the expression of P-gp transporter and affect CIN. In the present study, our aim was to assess the variability in expression of several renal transporters after multiple CDDP dose administrations and the antioxidant effect of ascorbic acid against transporter expression and CIN. Multiple doses of CDDP affected markers of kidney injury and antioxidants in the kidneys. Also, the expression of P-gp, breast cancer resistance protein, and multidrug resistance-associated protein 4 was upregulated by CDDP. Using a normal kidney cell line, we demonstrated that ascorbic acid attenuated CDDP-induced cytotoxicity due to its high superoxide scavenging ability. CDDP and ascorbic acid were injected into rats once a week for three weeks, and it was observed that co-administration of ascorbic acid attenuated CIN and regulated antioxidant marker. In addition, ascorbic acid reduced P-gp expression, which was upregulated by CDDP. In conclusion, ascorbic acid may attenuate CIN and reverse P-gp-mediated changes in drug pharmacokinetics., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: This study was designed to probe into the changes and clinical significance of GRP78 and miR-495-3p in renal failure (RF) patients during high-flux dialysis (HFD) combined with hemoperfusion (HP)., Methods: Sixty-five RF patients and 74 health check-ups who were admitted in our hospital from March 2015 to February 2017 were prospectively selected, and the related characteristics were retrospectively collected for analysis. GRP78 and miR-495-3p were detected in RF patients at admission (before treatment), 12 weeks after treatment (during treatment), 24 weeks after treatment (after treatment), and the control group at admission, and the relationship between the two and the occurrence, efficacy, and recurrence of RF was analyzed., Results: Before treatment, the GRP78 mRNA level in RF patients was higher than that in health check-ups, while the miR-495-3p level was lower ( P < 0.05). GRP78 mRNA in RF patients was lower than that before treatment and was the lowest after treatment. On the contrary, miR-495-3p was higher than that before treatment and was the highest after treatment ( P < 0.05). The two had a significant effect on predicting RF before treatment, efficacy of patients, and their recurrence after treatment (all P < 0.001)., Conclusion: GRP78 decreased during the treatment of high-flux hemodialysis (HF-HD) combined with systemic HP in RF patients, while miR-495-3p increased. Both of them have a good reference value for RF occurrence, treatment results, and recurrence., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Wei Fan et al.)

Objective and Methods: The aim of this study was to retrospectively analyze the renal prognosis of elderly coronary artery disease (CAD) patients complicated with renal insufficiency., Results: A total of 307 patients were included. The mean follow-up period was 25±11months. The average age was 79±7 years. In the worsening renal function group, there were higher occurrence rate of heart failure and severe coronary artery stenosis, lower rate of percutaneous coronary intervention, lower medication rate of renin-angiotensin blocker, lower plasma albumin, magnesium and hemoglobulin level. There was no significant difference in the rate of worsening renal function or gastrointestinal bleeding between patients who took anti-platelet agents/statins and those without. Patients with reduced left ventricular ejective fraction had higher rate of worsening renal function, yet lower medication rate of renin-angiotensin blockers, lower plasma albumin and hemoglobulin level. Anemia, malnutrition and worsening cardiac function were risk factors of renal function deterioration and mortality., Conclusions: In the elderly coronary artery disease patients who had renal insufficiency, antiplatelet agents and statin have non-adverse effects on renal function; lower medication rate of renin-angiotensin blocker were found in patients with either worsening renal function or heart failure. Anemia, malnutrition and worsening cardiac function are risk factors of renal function deterioration and mortality.

Thrombocytopenia, anasarca, fever, reticulin fibrosis, renal insufficiency, and organomegaly (TAFRO) syndrome is a heterogeneous entity manifesting with a constellation of symptoms described above that can occur in the context of idiopathic multicentric Castleman disease (iMCD) as well as infectious diseases, malignancies, and rheumatologic disorders. So, iMCD-TAFRO is an aggressive subtype of iMCD with TAFRO syndrome and often hyper-vascularized lymph nodes. Since we proposed diagnostic criteria of iMCD-TAFRO in 2016, we have accumulated new insights on the disorder and additional cases have been reported worldwide. In this systematic review and cohort analysis, we established and validated a definition for iMCD-TAFRO. First, we searched PubMed and Japan Medical Abstracts Society databases using the keyword "TAFRO" to extract cases. Patients with possible systemic autoimmune diseases and hematologic malignancies were excluded. Our search identified 54 cases from 50 articles. We classified cases into three categories: (1) iMCD-TAFRO (TAFRO syndrome with lymph node histopathology consistent with iMCD), (2) possible iMCD-TAFRO (TAFRO syndrome with no lymph node biopsy performed and no other co-morbidities), and (3) TAFRO without iMCD or other co-morbidities (TAFRO syndrome with lymph node histopathology not consistent with iMCD or other comorbidities). Based on the findings, we propose an international definition requiring four clinical criteria (thrombocytopenia, anasarca, fever/hyperinflammatory status, organomegaly), renal dysfunction or characteristic bone marrow findings, and lymph node features consistent with iMCD. The definition was validated with an external cohort (the ACCELERATE Natural History Registry). The present international definition will facilitate a more precise and comprehensive approach to the diagnosis of iMCD-TAFRO., (© 2021 Wiley Periodicals LLC.)

Objective: To aid the clinician in correctly interpreting serum tryptase levels., Data Sources: Primary peer-reviewed literature., Study Selections: Clinical and basic science peer-reviewed studies characterizing the genetic and physiological bases for tryptase generation, secretion, and elevation, including those describing serum tryptase levels in population-based cohort studies., Results: Clinically measured basal serum tryptase (BST) consists of ostensibly inactive alpha- and beta-tryptase precursors. The autosomal dominant genetic trait hereditary alpha-tryptasemia is the most often cause for elevated BST levels, with other acquired causes, such as renal failure and clonal myeloid diseases being far less common. Acute increases in serum tryptase levels resulting from release of mature tryptase from secretory granules is specific to mast cell degranulation but is not detected in all cases of systemic anaphylaxis., Conclusion: Understanding the differences and distinguishing between acute increases in serum tryptase and chronic elevations in BST owing to inherited or acquired conditions is critical in the correct interpretation of this useful clinical biomarker., (Published by Elsevier Inc.)

No longitudinal data link intraglomerular hemodynamic dysfunction with end-stage kidney disease (ESKD) in people with type 2 diabetes (T2D). Afferent (R A ) and efferent (R E ) arteriolar resistance and intraglomerular pressure (P GLO ) are not directly measurable in humans but are estimable from glomerular filtration rate (GFR), renal plasma flow (RPF), blood pressure, hematocrit, and plasma oncotic pressure. We examined the association of the R A -to-R E ratio and P GLO with ESKD incidence in 237 Pima Indian individuals with T2D who underwent serial measures of GFR (iothalamate) and RPF ( p -aminohippurate). Their association with kidney structural lesions was also examined in a subset of 111 participants. Of the 237 participants (mean age 42 years, diabetes duration 11 years, and GFR 153 mL/min and median urine albumin-to-creatinine ratio 36 mg/g), 69 progressed to ESKD during a median follow-up of 17.5 years. In latent class analysis, distinct trajectories characterized by increasing R A -to-R E ratio (HR 4.60, 95% CI 2.55-8.31) or elevated P GLO followed by a rapid decline (HR 2.96, 95% CI 1.45-6.02) strongly predicted incident ESKD. P GLO ( R 2 = 21%, P < 0.0001) and R A -to-R E ratio ( R 2 = 15%, P < 0.0001) also correlated with mesangial fractional volume, a structural predictor of DKD progression. In conclusion, intraglomerular hemodynamic parameters associated strongly with incident ESKD and correlated with structural lesions of DKD., (© 2021 by the American Diabetes Association.)

Background: The incidence of and risk factors for late-onset kidney failure among survivors over the very long term remains understudied., Materials and Methods: A total of 25,530 childhood cancer survivors (median follow-up 22.3 years, interquartile range 17.4-28.8) diagnosed between 1970 and 1999, and 5045 siblings from the Childhood Cancer Survivor Study were assessed for self-reported late-onset kidney failure, defined as dialysis, renal transplantation, or death attributable to kidney disease. Piecewise exponential models evaluated associations between risk factors and the rate of late-onset kidney failure., Results: A total of 206 survivors and 10 siblings developed late-onset kidney failure, a 35-year cumulative incidence of 1.7% (95% confidence interval [CI] = 1.4-1.9) and 0.2% (95% confidence interval [CI] = 0.1-0.4), respectively, corresponding to an adjusted rate ratio (RR) of 4.9 (95% CI = 2.6-9.2). High kidney dose from radiotherapy (≥15Gy; RR = 4.0, 95% CI = 2.1-7.4), exposure to high-dose anthracycline (≥250 mg/m 2 ; RR = 1.6, 95% CI = 1.0-2.6) or any ifosfamide chemotherapy (RR = 2.6, 95% CI = 1.2-5.7), and nephrectomy (RR = 1.9, 95% CI = 1.0-3.4) were independently associated with elevated risk for late-onset kidney failure among survivors. Survivors who developed hypertension, particularly in the context of prior nephrectomy (RR = 14.4, 95% CI = 7.1-29.4 hypertension with prior nephrectomy; RR = 5.9, 95% CI = 3.3-10.5 hypertension without prior nephrectomy), or diabetes (RR = 2.2, 95%CI = 1.2-4.2) were also at elevated risk for late-onset kidney failure., Conclusions: Survivors of childhood cancer are at increased risk for late-onset kidney failure. Kidney dose from radiotherapy ≥15 Gy, high-dose anthracycline, any ifosfamide, and nephrectomy were associated with increased risk of late-onset kidney failure among survivors. Successful diagnosis and management of modifiable risk factors such as diabetes and hypertension may mitigate the risk for late-onset kidney failure. The association of late-onset kidney failure with anthracycline chemotherapy represents a novel finding that warrants further study., Competing Interests: Conflict of interest statement Authors have no competing financial or non-financial interests in relation to the present work., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Hypocalcemia, associated with Calcium neurotoxicity, has been reported to induce nerve dysfunction, which is a significant problem of renal failure. This study identifies a molecular mechanism of the O-linked N-acetylglucosamine transferase (OGT)-mediated enhancer of zeste homolog 2 (EZH2)/krüppel-like factor 2 (KLF2)/chemokine (C-X-C motif) ligand 1 (CXCL1) axis underlying the hypercalcemia-induced nerve injury in renal failure. Bioinformatics analyses were used to screen out the key factors in hypercalcemia-induced nerve injury in renal failure. Chronic kidney disease (CKD) was induced by an adenine diet in mice, followed by injection of adenovirus vector carrying short hairpin RNA targeting OGT, followed by behavioral tests and collection of the cerebral cortex for primary neurons. Calcium level in neurons was measured by Fluo-4-am and Perkin Elmer+ Operetta. Neuronal apoptosis and viability were detected by flow cytometry and the MTS method. The binding of EZH2 to KLF2 promoter was verified by chromatin immunoprecipitation assay. The concentration of Ca 2+ in brain tissues of CKD model mice was increased, and nerve functions were obviously damaged. High expression of OGT occurred in kidney tissue of CKD model mice. Silencing OGT reduced the hypercalcemia-induced toxicity of neurons by inhibiting the expression of EZH2, which elevated the expression of CXCL1 in primary neurons by diminishing KLF2. Silencing OGT attenuated hypercalcemia-induced neurotoxicity by regulating the EZH2/KLF2/CXCL1 axis. In vivo experiments further confirmed that silencing OGT could reduce hypercalcemia-induced nerve injury in CKD mice. Taken together, silencing OGT downregulates EZH2, which increases the expression of KLF2 and then decreases the expression of CXCL1, thus alleviating hypercalcemia-induced nerve injury in renal failure., (© 2021. The Author(s).)

Formoterol is a long-acting β 2 agonist (LABA). Agonism of the β 2 -adrenergic receptor by formoterol is known to stimulate mitochondrial biogenesis (MB) in renal proximal tubules and recover kidney function. However, formoterol has a number of cardiovascular side effects that limits its usage. The goal of this study was to design and develop an intravenous biodegradable and biocompatible polymeric nanoparticle delivery system that targets formoterol to the kidney. Poly(ethylene glycol) methyl ether-block-poly(lactide-co-glycolide) nanoparticles containing encapsulated formoterol were synthesized by a modified single-emulsion solvent evaporation technique resulting in nanoparticles with a median hydrodynamic diameter of 442 + 17 nm. Using primary cell cultures of rabbit renal proximal tubular cells (RPTCs), free formoterol, encapsulated formoterol polymeric nanoparticles, and drug-free polymeric nanoparticles were biocompatible and not cytotoxic over a wide concentration range. In healthy male mice, polymeric nanoparticles were shown to localize in tubules of the renal cortex and improved the renal localization of encapsulated formoterol compared to the free formoterol. At a lower total formoterol dose, the nanoparticle localization resulted in increased expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), the master regulator of MB, and increased electron transport chain proteins, markers of MB. This was confirmed by direct visual quantification of mitochondria and occurred with both free formoterol and the encapsulated formoterol polymeric nanoparticles. At the same time, localization of nanoparticles to the kidneys resulted in reduced induction of MB markers in the heart. These new nanoparticles effectively target formoterol to the kidney and successfully produce MB in the kidney.

Adriamycin (ADR)-induced nephropathy is frequently utilized in rodent models of podocytopathy. However, the application of this model in mice is limited to a few strains, such as BALB/c mice. The most commonly used mouse strain, C57BL/6 (B6), is resistant to ADR-induced nephropathy, as are all mouse strains with a B6 genetic background. Reportedly, the R2140C variant of the Prkdc gene is the cause of susceptibility to ADR-induced nephropathy in mice. To verify this hypothesis, we produced Prkdc mutant B6 mice, termed B6-Prkdc R2140C , that possess the R2140C mutation. After administration of ADR, B6-Prkdc R2140C mice exhibited massive proteinuria and glomerular and renal tubular injuries. In addition, there was no significant difference in the severity between B6-Prkdc R2140C and BALB/c. These findings demonstrated that B6-Prkdc R2140C show ADR-induced nephropathy susceptibility at a similar level to BALB/c, and that the PRKDC R2140C variant causes susceptibility to ADR-induced nephropathy. In future studies, ADR-induced nephropathy may become applicable to various kinds of genetically modified mice with a B6 background by mating with B6-Prkdc R2140C ., Competing Interests: Declaration of competing interest The authors have no conflicts of interest directly relevant to the content of this article., (Copyright © 2021 Elsevier Inc. All rights reserved.)

We aimed to compare the demographic, clinical and laboratory characteristics between IgG4-related kidney disease (IgG4-RKD+) and extrarenal IgG4-related disease (IgG4-RKD-) in a large Chinese cohort, as well as describing the radiological and pathological features of IgG4-RKD+. We retrospectively analyzed the medical records of 470 IgG4-related disease (IgG4-RD) patients at Peking University People's Hospital from January 2004 to January 2020. The demographic, clinical, laboratory, radiological and pathological characteristics between IgG4-RKD+ and IgG4-RKD- were compared. Twenty IgG4-RD patients who had definite etiology of renal impairment including diabetes, hypertension and etc. were excluded. Among the remained 450 IgG4-RD patients, 53 were diagnosed with IgG4-RKD+ . IgG4-RKD+ patients had older age at onset and at diagnosis. Male to female ratio of IgG4-RKD+ patients is significantly higher. In the IgG4-RKD+ group, the most commonly involved organs were salivary gland, lymph nodes and pancreas. It was found that renal function was impaired in approximately 40% of IgG4-RKD+ patients. The most common imaging finding is multiple, often bilateral, hypodense lesions. Male sex, more than three organs involved, and low serum C3 level were risk factors for IgG4-RKD+ in IgG4-RD patients. These findings indicate potential differences in pathogenesis of these two phenotypes.

Glutamate N -methyl-d-aspartate receptor (NMDAR) hyperfunction is known to contribute to acute renal failure due to ischemia-reperfusion and endotoxemia. d-Serine is a coagonist for NMDAR activation, but whether NMDARs play a role in d-serine-mediated nephrotoxicity remains unclear. Here, we demonstrate that NMDAR blockade ameliorated d-serine-induced renal injury. In NMDAR-expressing LLC-PK 1 cells, which were used as a proximal tubule model, d-serine but not l-serine induced cytotoxicity in a dose-dependent manner, which was abrogated by the selective NMDAR blockers MK-801 and AP-5. Time-dependent oxidative stress, evidenced by gradually increased superoxide and H 2 O 2 production, was associated with d-serine-mediated cytotoxicity; these reactive oxygen species could be alleviated not only after NMDAR inhibition but also by NADPH oxidase (NOX) inhibition. Activation of protein kinase C (PKC)-δ and PKC-ζ is a downstream signal for NMDAR-mediated NOX activation because PKC inhibition diminishes the NOX activity that is induced by d-serine. Renal injury was further confirmed in male Wistar rats that intraperitoneally received d-serine but not l-serine. Peak changes in glucosuria, proteinuria, and urinary excretion of lactate dehydrogenase and malondialdehyde were found after 24 h of treatment. Persistent tubular damage was observed after 7 days of treatment. Cotreatment with the NMDAR blocker MK-801 for 24 h abolished d-serine-induced functional insufficiency and tubular damage. MK-801 attenuated renal superoxide formation by lowering NOX activity and protein upregulation of NOX4 but not NOX2. These results reveal that NMDAR hyperfunction underlies d-serine-induced renal injury via the effects of NOX4 on triggering oxidative stress. NEW & NOTEWORTHY Ionotropic N -methyl-d-aspartate receptors (NMDARs) are not only present in the nervous system but also expressed in the kidney. Overstimulation of renal NMDARs leads to oxidative stress via the signal pathway of calcium/protein kinase C/NADPH oxidase in d-serine-mediated tubular cell damage. Intervention of NMDAR blockade may prevent acute renal injury caused by d-serine.

Rationale & Objective: A previous study that evaluated associations of kidney biopsy findings with disease progression in patients with C3 glomerulopathy (C3G) proposed a prognostic histologic index (C3G-HI) that has not yet been validated. Our objective was to validate the performance of the C3G-HI in a new patient population., Study Design: Multicenter, retrospective cohort study., Setting & Participants: 111 patients fulfilling diagnostic criteria of C3G between January 1995 and December 2019, from 33 nephrology departments belonging to the Spanish Group for the Study of Glomerular Diseases (GLOSEN)., Predictors: Demographic, clinical parameters, C3G-HI total activity score, and the C3G-HI total chronicity score., Outcome: Time to kidney failure., Analytical Approach: Intraclass correlation coefficients and κ statistic were used to summarize inter-rater reproducibility for assessment of histopathology in kidney biopsies. The nonlinear relationships of risk of kidney failure with the total activity score and total chronicity score were modeled using Cox proportional hazards analysis that incorporated cubic splines., Results: The study group included 93 patients with C3 glomerulonephritis and 18 with dense-deposit disease. Participants had an overall meanage of 35±22 (SD) years. Forty-eight patients (43%) developed kidney failure after a mean follow-up of 65±27 months. The overall inter-rater reproducibility was very good for the total activity score (intraclass correlation coefficient [ICC]=0.63) and excellent for total chronicity score (ICC=0.89). Baseline estimated glomerular filtration rate (eGFR), 24-hour proteinuria, and treatment with immunosuppression were the main determinants of kidney failure in a model with only clinical variables. Only tubular atrophy and interstitial fibrosis were identified as predictors in a model with histological variables. When the total activity score and total chronicity score were added to the model, only the latter was identified as an independent predictor of kidney failure., Limitations: Only a subset of the kidney biopsies was centrally reviewed. Residual confounding., Conclusions: We validated the performance of C3G-HI as a predictor of kidney failure in patients with C3G. The total chronicity score was the principal histologic correlate of kidney failure., (Copyright © 2020 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

PAX2 is a transcription factor essential for kidney development and the main causative gene for renal coloboma syndrome (RCS). The mechanisms of PAX2 action during kidney development have been evaluated in mice but not in humans. This is a critical gap in knowledge since important differences have been reported in kidney development in the two species. In the present study, we hypothesized that key human PAX2-dependent kidney development genes are differentially expressed in nephron progenitor cells from induced pluripotent stem cells (iPSCs) in patients with RCS relative to healthy individuals. Cap analysis of gene expression revealed 189 candidate promoters and 71 candidate enhancers that were differentially activated by PAX2 in this system in three patients with RCS with PAX2 mutations. By comparing this list with the list of candidate Pax2-regulated mouse kidney development genes obtained from the Functional Annotation of the Mouse/Mammalian (FANTOM) database, we prioritized 17 genes. Furthermore, we ranked three genes-PBX1, POSTN, and ITGA9-as the top candidates based on closely aligned expression kinetics with PAX2 in the iPSC culture system and susceptibility to suppression by a Pax2 inhibitor in cultured mouse embryonic kidney explants. Identification of these genes may provide important information to clarify the pathogenesis of RCS, human kidney development, and kidney regeneration.