Search

Kidney disease is frequent in HIV-patients. We present a case of a 44-year-old woman, with known uncontrolled HIV infection and chronic kidney disease due to HIV-associated nephropathy. After starting dolutegravir, the patient developed eosinophilia and worsening kidney function. A kidney biopsy confirmed the diagnosis of acute interstitial nephritis. Given the time relation with dolutegravir introduction, it was deemed the culprit medication. Dolutegravir was stopped, and corticosteroids were initiated, with moderate improvement in renal function. To our knowledge, this is the first reported case of acute interstitial nephritis to dolutegravir, which should raise awareness of previously undocumented renal effects of antiretroviral therapy.

A major consequence of diabetes (type 2) is diabetic nephropathy and its leading cause of chronic kidney disease. This study was amid to determination of insulin like growth factor −1 in diabetic nephropathy patients and its relation with other biochemistry. This study was carried out at the National Diabetes Center/ Mustansiriyah University during the period from 1/11/2020 to 30/3/2021. A highly significant increase of serum fasting blood sugar, total cholesterol, triglyceride, low density lipoprotein, and insulin like growth factor −1 in Nephropathy with Diabetes Mellitus when compared with Nephropathy without Diabetes Mellitus and highly significant decrease of glomerular filtration rate in Nephropathy with Diabetes Mellitus when compared with Nephropathy without Diabetes Mellitus. as Higher serum levels of fasting blood sugar, hypertension, and disturbances in lipid profile and kidney function are found in nephropathy with diabetes mellitus patients. Lower serum insulin like growth factor −1 levels were found to be positively linked with diabetic nephropathy. We propose that serum insulin like growth factor −1 levels be included in routine nephropathy studies in diabetic individuals.

Background There is no a unified opinion in the treatment of IgA nephropathy. This prospective cohort study was to explore the effectiveness and safety of tacrolimus for treatment of IgA (Immunoglobulin A) nephropathy patients. Methods In this study, we assigned 50 patients with biopsy-proven IgA nephropathy in a 1:1.5 ratio to receive oral tacrolimus or full-dose glucocorticoid for 6 months. All the patients had 24-h urine protein excretion ≥ 2.0 g/24 h and estimated glomerular filtration rate ≥ 50 mL/min/1.73 m2. Primary endpoint was rate of complete remission. Results After 6 months of treatment, seven participants achieved complete remission in the tacrolimus group and twelve participants in the glucocorticoid group, the complete remission rate was 35% and 40%, respectively. There were not significantly differences between two groups (P = 0.7). However, the serum creatinine level from baseline was an increase of 13 ± 13.5 μmol/L in the tacrolimus group and a decrease of 8.2 ± 20 μmol/L in the glucocorticoid group. When patients stopped taking tacrolimus for 3 months, creatinine level can almost fall to normal level. Thus, patients with renal insufficiency have a high incidence in the tacrolimus group. Conclusions Tacrolimus was noninferior to full-dose glucocorticoid in inducing proteinuria remission at 6 months. This suggested that those IgA nephropathy patients who are unwilling to full-dose glucocorticoid could consider tacrolimus, but need to pay attention to the impact on renal function.

Rationale & Objective Benefits of sodium-glucose co-transporter 2 inhibitors on kidney outcomes have been demonstrated in clinical trials. Among patients with type 2 diabetes and established cardiovascular (CV) disease enrolled in EMPA-REG Outcome Study (NCT01131676), empagliflozin added to standard of care (SoC) reduced the risk of incident or worsening nephropathy compared to SoC alone. This analysis evaluated the cost-effectiveness of empagliflozin versus SoC alone in the subpopulation with diabetic kidney disease (DKD) from the perspective of United States (US) commercial insurers and Medicare. Study Design Discrete event simulation model. Setting & Population Patients with DKD in a US healthcare system. Interventions Empagliflozin 10 or 25 mg with SoC versus SoC alone. SoC included glucose-lowering therapies and medications to treat CV risk factors. Outcomes Incremental cost-effectiveness ratios (ICERs, 2020 US dollars per quality-adjusted life-year [QALY] gained). Costs and QALYs were discounted 3.0%/year. Model, Perspective, & Timeframe: Cost-effectiveness analysis, commercial insurers and Medicare perspective, lifetime horizon. Results The ICER of empagliflozin with SoC versus SoC alone was $25,974/QALY. Empagliflozin added 0.67 QALYs and $17,322/patient over a lifetime horizon. Results were driven by fewer clinical events (including CV death, heart failure [HF] hospitalization, albuminuria progression, and a composite kidney outcome) experienced by patients receiving empagliflozin with SoC versus SoC alone. Results were sensitive to rates of CV death, non-fatal MI, and HF hospitalization, as well as to drug costs, and time horizon. Probabilistic sensitivity analyses indicated 91% of simulations falling below $50,000/QALY. Limitations The EMPA-REG Outcome Study was not powered to assess treatment benefits in a subgroup and excluded patients with estimated glomerular filtration rate Conclusion Based on EMPA-REG Outcome Study, this cost-effectiveness analysis suggests that for commercial insurers and Medicare, adding empagliflozin to SoC may be a cost-effective treatment option for patients with DKD.

Aim To determine the association and the prognostic value of soluble ST2 (sST2) levels in the development of diabetic retinopathy (DR), diabetic macular oedema (DMO) or diabetic nephropathy (DN), in a cohort of patients with type 1 diabetes (T1D). Methods A total of 269 individuals with T1D (154 males and 115 females) were recruited. The overall mean age was 43.2 ± 14.9 years, and the diabetes duration was 17.1 ± 12.1 years. Levels of sST2 in serum were evaluated, and the presence as well as the degree of DR, DMO and DN was recorded. Additionally, other clinical and analytical parameters including demographic variables were recovered from patients’ electronic health record. Ten years later, the presence and stage of DR, DMO and DN were again recorded under the same criteria. The association between previously mentioned parameters with DR and DN was analysed by univariate and multivariate logistic regression. The variables in the final multivariate models were adjusted from complete models via backward elimination and maintained only when significant. Results An increase of 10 ng/ml in the levels of sST2 was associated with a 1.50 (1.02–2.19) and 1.48 (1.05–2.08) prevalence odds ratio (OR) in DMO and DR, respectively. There was no association between sST2 levels and DN. Meanwhile, sST2 levels did not display a prognostic effect in any of the microangiopathic diabetic complications studied. Conclusions Levels of sST2 are associated with the presence of DR and DMO, they do not seem to be predictive for the development or deterioration of DR, DMO or DN.

The complement system is a first line of defence against infectious, tumoral or autoimmune processes, and it is constitutively regulated to avoid excessive or unspecific activation. Factor H (FH), a most relevant complement regulator, controls complement activation in plasma and on the cellular surfaces of autologous tissues. FH shares evolutionary origin and structural features with a group of plasma proteins known as FH-Related Proteins (FHRs), which could act as FH functional antagonists. Studies in patient cohorts of atypical Haemolytic-Uraemic Syndrome (aHUS), C3 Glomerulopathy (C3G), and IgA nephropathy (IgAN), have identified rare genetic variants that give rise to severe FH and FHRs dysfunctions, and are major genetic predisposing factors. These patients also have a higher frequency of a few polymorphisms whose relevance as disease risk factors is incompletely understood. In the last years, the availability of specific reagents has allowed a more precise quantitation of FH and FHRs in plasma samples from patients and controls. These studies have revealed that some aHUS, C3G or IgAN risk polymorphisms determine mild changes in FH or FHRs levels that could somehow perturb complement regulation and favour disease pathogenesis.

Objectives IgA nephropathy (IgAN) is the most common primary chronic glomerulonephritis and a major cause of end-stage kidney disease worldwide. Novel biomarkers, including the aberrantly glycosylated IgA1 and glycan-specific antibodies, could be useful in the diagnosis of IgAN. The aim of this study was to assess the cost analysis of IgAN screening using novel biomarkers in addition to the conventional screening compared with conventional screening alone. Methods To estimate the medical expense of each strategy related to renal disease for 40 years, we developed an analytical decision model. The decision tree started at “40 years of age with first-time hematuria.” It simulated 2 clinical strategies: IgAN screening using the novel biomarkers (group N) and conventional screening (group C). The analysis results were presented as medical expenses from a societal perspective. Discounting was not conducted. Results The expected medical expense per person for 40 years was ¥31.2 million (~$291 000) in group N and ¥33.4 million (~$312 000) in group C; hence, expense in group N was lower by ¥2.2 million (~$21 000). In group N, the expected value of IgAN increased by 5.67% points (N 48.44%, C 42.77%) and that of dialysis introduction decreased by 0.85% points (N 19.06%, C 19.91%). In the sensitivity analysis, expenses could be reduced in almost all cases except when renal biopsy using conventional screening was performed at the rate of 73% or higher. Conclusion Screening for IgAN using novel biomarkers would reduce renal disease–related expenses.

Kidney transplantation (KT) from deceased donors with hepatitis C virus (HCV) into HCV-negative recipients has become more common. However, the risk of complications such as BK polyomavirus (BKPyV) remains unknown. We assembled a retrospective cohort at four centers. We matched recipients of HCV-viremic kidneys to highly similar recipients of HCV-aviremic kidneys on established risk factors for BKPyV. To limit bias, matches were within the same center. The primary outcome was BKPyV viremia ≥1000 copies/ml or biopsy-proven BKPyV nephropathy; a secondary outcome was BKPyV viremia ≥10 000 copies/ml or nephropathy. Outcomes were analyzed using weighted and stratified Cox regression. The median days to peak BKPyV viremia level was 119 (IQR 87-182). HCV-viremic KT was not associated with increased risk of the primary BKPyV outcome (HR 1.26, p = .22), but was significantly associated with the secondary outcome of BKPyV ≥10 000 copies/ml (HR 1.69, p = .03). One-year eGFR was similar between the matched groups. Only one HCV-viremic kidney recipient had primary graft loss. In summary, HCV-viremic KT was not significantly associated with the primary outcome of BKPyV viremia, but the data suggested that donor HCV might elevate the risk of more severe BKPyV viremia ≥10 000 copies/ml. Nonetheless, one-year graft function for HCV-viremic recipients was reassuring.

Childhood IgA nephropathy (IgAN) includes a wide spectrum of clinical presentations, from isolated hematuria to acute nephritis with rapid loss of kidney function. In adults, IgAN is an autoimmune disease and its pathogenesis involves galactose deficient (Gd) IgA1, IgG anti-Gd-IgA1 autoantibodies and the soluble IgA Fc receptor (CD89). However, implication of such factors, notably soluble CD89, in childhood IgAN pathogenesis remains unclear. Here, we studied these biomarkers in a cohort of 67 patients with childhood IgAN and 42 pediatric controls. While Gd-IgA1 was only moderately increased in patient plasma, levels of circulating IgA complexes (soluble CD89-IgA and IgG-IgA) and free soluble CD89 were markedly increased in childhood IgAN. Soluble CD89-IgA1 complexes and free soluble CD89 correlated with proteinuria, as well as histological markers of disease activity: mesangial, endocapillary hypercellularity and cellular crescents. Soluble CD89 was found in patient's urine but not in urine from pediatric controls. Mesangial deposits of soluble CD89 were detected in biopsies from patients with childhood IgAN. Serum chromatographic fractions containing covalently linked soluble CD89-IgA1 complexes or free soluble CD89 from patients induced mesangial cell proliferation in vitro in a soluble CD89-dependent manner. Recombinant soluble CD89 induced mesangial cell proliferation in vitro which was inhibited by free soluble recombinant CD71 (also a mesangial IgA receptor) or mTOR blockers. Interestingly, injection of recombinant soluble CD89 induced marked glomerular proliferation and proteinuria in mice expressing human IgA1. Thus, free and IgA1-complexed soluble CD89 are key players in mesangial proliferation. Hence, our findings suggest that soluble CD89 plays an essential role in childhood IgAN pathogenesis making it a potential biomarker and therapeutic target.

Antiphospholipid syndrome (APS) is an acquired autoimmune thrombophilia characterized by venous or arterial thrombosis, and/or pregnancy loss or complications in the presence of persistently positive antiphospholipid antibodies. Organ involvement, referred to as non-criteria manifestations, includes livedo reticularis, thrombocytopenia and nephropathy. Non-thrombotic inflammatory mechanisms are increasingly identified in the pathogenesis of APS, alongside a recognition that obstetric APS might be a specific subset of APS. Treatment remains focused on life-long anticoagulation and prevention of further thrombosis or obstetric complications. Identification of novel mechanisms is, however, leading the development of diagnostic tests and more targeted therapies to improve disease management.

La enfermedad por coronavirus de 2019 (COVID-19) es una emergencia sanitaria pública global con numerosas facetas clínicas que incluyen renopatía aguda y enfermedad cerebrovascular aguda. Es necesario un conocimiento adicional de su mecanismo patogénico. Los trastornos de coagulación están claramente incluidos en dichos mecanismos. La gammapatía monoclonal se caracteriza por la sobreproducción de inmunoglobulina monoclonal causada por proliferación clonal. Utilizando un estudio postmortem de biopsias básicas percutáneas ecoguiadas, el objetivo de este informe es presentar nuestras observaciones sobre la patología del síndrome respiratorio agudo severo por infección de coronavirus 2 (SARS-CoV2) con gammapatía monoclonal. La presentación clínica fue insuficiencia renal aguda. Los hallazgos patológicos revelaron nefropatía por depósito de cadenas ligeras kappa. La inmunohistoquímica de SARS-CoV-2 fue positiva en ciertas células tubulares renales. La presencia de megacariocitos alveolares (alta densidad) fue un hallazgo notable, que explica probablemente el resultado final del paciente (enfermedad cerebrovascular aguda). El estudio inmunohistoquímico frente a SARS-CoV-2 no verifica el efecto patogénico del virus y, por tanto, su contribución a la nefropatía aguda.

Introduction The usefulness of the Oxford classification (MEST-C score) for deciding the management approach for IgA nephropathy (IgAN) remains unclear. Methods Effects of steroid therapy on the long-term prognosis for all 858 patients with IgAN and patients classified according to each MEST-C score were evaluated using Kaplan-Meier and Cox regression analyses. Steroid responder score (SRS) and steroid nonresponder score (SNRS) were determined using individual pathology scores when steroids were found to be independently associated, or not, with clinical benefits. In addition, the effects of steroid therapy according to the total SRS/SNRS were analyzed. Results Steroid therapy improved the 20-year renal survival rates of patients with IgAN after matching (steroids[+] vs. steroids[−]; estimated glomerular filtration rate [eGFR] [ml/min per 1.73 m2]: 79.4 vs. 77.0, not significant; proteinuria [g/d]: 0.80 vs. 0.62, not significant; renal survival rate: 75.5% vs. 61.7%; P = 0.025) and of patients with M1, E1, S1, C1+2, and T0 scores. Therefore, we considered the total of the M1, E1, S1, and C1+2 scores (point 0: low, 1–2: medium, and 3–4: high) as the SRS and the total of the T1+2 scores (0: low and 1: high) as the SNRS. Multivariate Cox regression analyses revealed that steroid therapy improved the renal prognosis of patients with IgAN with high SRS and any SNRS, unlike patients with IgAN with medium SRS and any SNRS. Conclusion Patients with M1, E1, S1, and C1+2 scores responded to steroid therapy; however, those with T1+2 scores did not. Although a high SRS was a useful indicator for steroid therapy, SNRS indicated resistance to steroid therapy., Graphical abstract

Background MRNA COVID-19 vaccine is more effective than traditional vaccines due to superior immune activation. However, the impact of mRNA COVID-19 vaccine on triggering de novo/relapsing glomerulonephritis (GN) is limited. We report a case series of patients who developed new or relapsing GN post vaccination. Method We evaluated baseline characteristics, vaccine type and clinical outcomes of 13 patients from our institution who had a new diagnosis or relapse of their GN post mRNA COVID-19 vaccination. Results Of 13 patients, 8 patients were newly diagnosed GNs and 5 patients had relapse. Median age was 62 years (range 19-83 years). Autoimmune disease (38%) was the most prevalent underlying disease followed by cancer (23%). Majority of patients were white male. IgA nephropathy (IgAN) was the most common GN in our series (5 patients, 38%) followed by membranous nephropathy (MN) (3 patients, 23%). One patient with IgAN had evidence of IgA deposits prior to vaccination suggesting that the immune activation following vaccination triggered a flare of the disease. Our case series also included the first case report of tip-variant focal segmental glomerulosclerosis, NELL-1 associated MN, and atypical anti-GBM nephritis. Seventy seven percent developed acute kidney injury with the majority being KDIGO stage 1 (67%). Outcome are favorable with 80% responding to therapy. Conclusions New cases and relapse of GN can present shortly after mRNA COVID-19 vaccination. New cases of IgAN may result from unmasking of undiagnosed IgAN due to robust immune activation rather than development of new deposits.

Primary and disseminated lymphoma of the female reproductive tract are rare types of lymphoma. However, in the setting of solid organ transplant, recipients have an approximately doubled risk of acquiring and dying from malignancy. Multiple treatment modalities are available for post-transplant lymphoproliferative diseases (PTLD), including chemotherapy, radiotherapy, surgery, and immunosuppression radiotherapy. We report a case of a 61-year-old female with multifocal nodal diffuse large B-cell lymphoma and a history of a renal transplant secondary to IgA nephropathy who developed metastatic diffuse large B-cell lymphoma to the uterus. While the baseline incidence of PTLD is elevated when compared with lymphoma in the general population, metastatic uterine lymphoma is rare. Awareness of reproductive organ involvement by lymphomas and increased malignancy risk in organ transplant patients are important considerations for diagnostic evaluation, including radiologic assessment.

Red-colored urine occurring in the intraoperative and early postoperative periods after cardiac surgery is often a cause for concern. This observation may be a result of hematuria from pathology within the urinary tract, anticoagulant-related nephropathy, drug-induced acute interstitial nephropathy, excretion of heme pigment-containing proteins, such as myoglobin and hemoglobin, and hemolysis occurring during extracorporeal circulation. Within the kidneys, heme-containing compounds result in pigment nephropathy, which is a significant contributory factor to cardiac surgery-associated acute kidney injury. Concerted efforts to reduce red blood cell damage during cardiopulmonary bypass, together with early recognition of the at-risk patient and the institution of prompt therapeutic intervention, may improve outcomes. This review addresses the diagnosis, causes, and management of red-discolored urine occurring during and after cardiac surgery.

Chikungunya nephropathy is an uncommon etiology of acute kidney injury, associated with the mosquito-borne chikungunya arbovirus (CHIKV). The very limited number of pathologic reports to date have only involved postmortem analyses. We here report 5 cases of acute kidney injury for which kidney biopsies were performed in patients with confirmed acute CHIKV infection, during the recent outbreak of chikungunya disease in the French West Indies. The patients ranged from 42 to 76 years of age. All of the patients developed kidney injury, 3 of whom required short-term dialysis and underwent a kidney biopsy. Analysis of kidney biopsies revealed 2 main histopathologic patterns: acute interstitial nephritis with predominant lymphoid inflammation and acute tubular injury. Epithelioid granulomas were observed in 2 cases. There were no glomerular lesions, except in biopsies from 2 patients, including 1 with a previous known primary focal segmental glomerulosclerosis. CHIKV antigen immunofluorescence microscopy revealed staining in tubular cells. In all of the cases, the short-term outcome was favorable, with recovery of kidney function.

Resumen: Desde el año 2000, la región de Mesoamérica ha presentado una elevada incidencia de casos de enfermedad renal crónica de origen desconocido. Bajo el nombre de nefropatía endémica mesoamericana (NeM) han concurrido numerosas hipótesis incluyendo la deshidratación, el estrés por calor, la exposición a contaminantes ambientales e incluso determinadas infecciones, sin que actualmente exista unanimidad en la etiología de dicha patología. La NeM afecta principalmente a varones jóvenes dedicados a actividades agrícolas con antecedente de exposición a temperaturas especialmente elevadas. Clínicamente cursa con síntomas inespecíficos como febrícula y disuria y, analíticamente, con deterioro de la función renal y alteraciones hidroelectrolíticas. El diagnóstico exige de la realización de una biopsia renal que muestra invariablemente datos de nefritis tubulointersticial, principalmente crónica. A pesar de que la NeM condiciona una elevada morbimortalidad en las regiones endémicas, no existe un tratamiento específico, por lo que la prevención, basada en disminuir la exposición a elevadas temperaturas y asegurar el correcto estado de hidratación son de gran importancia. En la presente revisión, y basándonos en un caso clínico, actualizamos la evidencia disponible sobre un problema de salud pública con relevantes consecuencias renales. Abstract: From 2000, Mesoamerican region has reached an important rate of chronic kidney disease of unknown etiology. Under the name of Meroamerican Nephropathy (MeN) several hypotheses (including dehydration, heat stress, environmental or toxic exposure or even infections) have tried to explain the etiology this new disease. MeN affects young men, agricultural workers exposed to high temperatures. MeN courses with unspecific symptoms as low-grade fever and dysuria and progressive kidney disease with impaired renal function and hydroelectrolyte disturbances. The diagnosis requires kidney biopsy showing tubule-interstitial nephritis (usually at chronic stage). Although MeN conditions a high morbi-mortality in endemic regions, there is a lack of specific treatment and only preventive measures have demonstrated some effect of prognosis (avoid heat stress, constant hydration). In this review we aim to summarize the available information of MeN, illustrating the information in a case report.

Background Glomerular deposition of C4d is a widely used biomarker for activation of the lectin pathway in the complement system and is reported to be associated with kidney progression in immunoglobulin A nephropathy (IgAN). The aim of this study was to evaluate whether glomerular C4d deposition, as a new biomarker, improves the prediction of kidney prognosis in IgAN. Study Design Systematic review and meta-analysis. Setting & Population Patients with biopsy-proven primary IgAN without age limitations. Selection Criteria for Studies: Cross-sectional or cohort studies reporting the prevalence of glomerular C4d deposition or evaluating its association with IgAN progression. Predictor Glomerular C4d deposition. Outcome Composite progression event of a >30% decline in estimated glomerular filtration rate or end-stage kidney disease. Results 12 studies with 1,251 patients were included. The prevalence of glomerular C4d deposition was 34% (95% CI, 27%-41%), with large heterogeneity (I2 = 86%; P

Kidney international 100(4), 753-779 (2021). doi:10.1016/j.kint.2021.05.015, Published by Elsevier, New York, NY

Introduction Evaluating histopathology via machine learning has gained research and clinical interest, and the performance of supervised learning tasks has been described in various areas of medicine. Unsupervised learning of histological images has the advantage of reproducibility for labeling; however, the relationship between unsupervised evaluation and clinical information remains unclear in nephrology. Methods We propose an unsupervised approach combining convolutional neural networks (CNNs) and a visualization algorithm to cluster the histological images and calculate the score for patients. We applied the approach to the entire images or patched images of the glomerulus of kidney biopsy samples stained with hematoxylin and eosin obtained from 68 patients with immunoglobulin A nephropathy. We assessed the relationship between the obtained scores and clinical variables of urinary occult blood, urinary protein, serum creatinine (SCr), systolic blood pressure, and age. Results The glomeruli of the patients were classified into 12 distinct classes and 10 patches. The output of the fine-tuned CNN, which we defined as the histological scores, had significant relationships with assessed clinical variables. In addition, the clustering and visualization results suggested that the defined clusters captured important findings when evaluating renal histopathology. For the score of the patch-based cluster containing crescentic glomeruli, SCr (coefficient = 0.09, P = 0.019) had a significant relationship. Conclusion The proposed approach could successfully extract features that were related to the clinical variables from the kidney biopsy images along with the visualization for interpretability. The approach could aid in the quantified evaluation of renal histopathology., Graphical abstract

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerular disease worldwide. The diagnostic histologic hallmark is dominant or codominant IgA staining on kidney biopsy; however, patients may present with various clinical syndromes ranging from asymptomatic abnormalities noted on urinalysis to rapidly progressive glomerulonephritis. Given substantial heterogeneity in the clinical course of disease, online risk calculators are available that may assist in prognostication and inform discussions with patients. Comprehensive supportive treatment is central in the initial therapy of IgAN; the additive benefit of currently available immunosuppressive agents remains an area of controversy. Although proteinuria is attenuated by the use of corticosteroids, the long-term benefits have been questioned, and the use of corticosteroids is associated with severe adverse effects, notably infection. Recent advances in our understanding of mucosal immunity and the role of the complement system in IgAN pathogenesis are leading to development of novel therapeutic options, which are being evaluated in ongoing clinical trials. In this installment of the AJKD Core Curriculum in Nephrology, IgAN pathogenesis, clinical manifestations, histology, prediction tools, and treatment are reviewed, and case examples are presented to illustrate the approach to the management of patients with IgAN.

Background and aim The liver is the primary organ affected by cholestasis, and complications such as renal injury, renal failure, and the need for renal transplantation are associated with cholestatic liver disease. There is substantial evidence indicating that reactive oxygen species (ROS) and mitochondrial impairment are fundamental mechanisms underlying cholestasis-induced hepatic and renal injury. Edaravone (EDV) is a potent radical scavenger and antioxidant that may prevent oxidative stress and improve impaired mitochondrial function in various diseases. This study was performed to evaluate the effects and mechanisms of action of EDV on hepatic and renal injury in an animal model of cholestasis. Methods Rats subjected to bile duct ligation (BDL) were treated with EDV 1 or 10 mg/kg/day intraperitoneally for 14 consecutive days. Biomarkers of oxidative stress and mitochondrial impairment in the liver and kidney were assessed in EDV-treated and untreated rats with cholestasis. Results Significant increases in tissue ROS level, lipid peroxidation, protein carbonylation, and oxidized glutathione level were detected in rats subjected to BDL. Additionally, significant decreases in tissue glutathione level and antioxidant capacity were observed in the hepatic and renal tissues of rats with cholestasis. Markers of mitochondrial impairment, including mitochondrial depolarization, lipid peroxidation, mitochondrial permeabilization, depleted adenosine triphosphate content, and decreased dehydrogenase activity, were also detected in rats subjected to BDL. Furthermore, portal inflammation, necrosis, and tissue fibrosis were detected in the liver and significant tubular atrophy and interstitial inflammation, as well as fibrotic lesions, were detected in the kidneys of rats with cholestasis. EDV treatment significantly mitigated cholestasis-associated hepatic and renal injury. Conclusions The antioxidative properties of EDV and its positive effects on the indices of mitochondrial function may be critical factors contributing to protection against cholestasis-associated hepatic and renal injury.

Item does not contain fulltext Personalizing immunosuppression is a major objective in transplantation. Transplant recipients are heterogeneous regarding their immunological memory and primary alloimmune susceptibility. This biomarker-guided trial investigated whether in low immunological-risk kidney transplants without pretransplant DSA and donor-specific T cells assessed by a standardized IFN-γ ELISPOT, low immunosuppression (LI) with tacrolimus monotherapy would be non-inferior regarding 6-month BPAR than tacrolimus-based standard of care (SOC). Due to low recruitment rates, the trial was terminated when 167 patients were enrolled. ELISPOT negatives (E-) were randomized to LI (n = 48) or SOC (n = 53), E+ received the same SOC. Six- and 12-month BPAR rates were higher among LI than SOC/E- (4/35 [13%] vs. 1/43 [2%], p = .15 and 12/48 [25%] vs. 6/53 [11.3%], p = .073, respectively). E+ patients showed similarly high BPAR rates than LI at 6 and 12 months (12/55 [22%] and 13/66 [20%], respectively). These differences were stronger in per-protocol analyses. Post-hoc analysis revealed that poor class-II eplet matching, especially DQ, discriminated E- patients, notably E-/LI, developing BPAR (4/28 [14%] low risk vs. 8/20 [40%] high risk, p = .043). Eplet mismatch also predicted anti-class-I (p = .05) and anti-DQ (p < .001) de novo DSA. Adverse events were similar, but E-/LI developed fewer viral infections, particularly polyoma-virus-associated nephropathy (p = .021). Preformed T cell alloreactivity and HLA eplet mismatch assessment may refine current baseline immune-risk stratification and guide immunosuppression decision-making in kidney transplantation.

Introduction Immunoglobulin (Ig)A nephropathy (IgAN) is the most frequently diagnosed primary glomerulonephritis worldwide. Despite the common diagnostic feature of mesangial IgA-containing immune complex deposition, the clinical course of the disease is extremely variable, with 30% of patients developing end-stage kidney disease within 20 years of diagnosis. Therefore, identifying which patients are likely to progress is paramount. Results In this pilot study, we found that urinary exosomal miR-204 expression was significantly reduced in IgAN compared with healthy subjects. However, there was no difference in miR-204 expression between IgAN and non-IgAN chronic kidney disease controls. Analysis of miR-204 expression in kidney biopsy cores by next-generation sequencing followed by quantitative polymerase chain reaction validation in independent cohorts demonstrated that expression of miR-204 was significantly lower in IgAN compared with thin-membrane nephropathy but not compared with membranous nephropathy. Patients with IgAN at high risk of future progression had significantly lower expression of miR-204 than those at low risk of progression. Cortical localization indicated that miR-204 was preferentially expressed in the interstitium compared with glomeruli in IgAN nonprogressors and that this distribution was lost in IgAN progressors. Receiver operating characteristic curve analysis between the 2 IgAN cohorts revealed an area under the curve of 0.82. In addition, miR-204 expression correlated with known clinicopathological prognostic risk factors. Importantly, incorporating miR-204 into the International IgAN risk prediction tool improved the diagnostic power of the algorithm to predict risk of progression. Conclusion Additional large-scale studies are now needed to validate the additive value of miR-204 in improving risk prediction in IgAN and more broadly in chronic kidney disease., Graphical abstract

Focal segmental glomerulosclerosis (FSGS) is a commonly occurring cause of steroid-resistant nephrotic syndrome and frequently progresses to renal failure. Podocyte epithelial-mesenchymal transition (EMT) is thought to induce podocyte detachment in glomerular diseases, and severe degeneration and shedding of glomerular podocytes plays a major role in the progression of FSGS. We showed that fibroblast specific protein 1 (FSP1), an EMT marker, is strongly expressed in podocytes of FSGS patients, but the significance of podocyte expression of FSP1 to the pathophysiology of FSGS remained unclear. Here, we investigated FSP1 expression in podocytes from mice with adriamycin (ADR)-induced nephropathy, a murine model of FSGS. The number of FSP1-positive (FSP1+) podocytes was increased in ADR-treated mice and positively correlated with the degree of proteinuria and glomerulosclerosis in ADR-treated mice. ADR-induced FSGS and the attendant proteinuria were significantly ameliorated in FSP1 knockout mice as compared to wild type mice. These findings indicate that podocyte expression of FSP1 plays a crucial role in the pathogenesis of FSGS, which makes FSP1 a potential target for treatment of FSGS.

Extracellular vesicles can mediate cell-to-cell communication, or relieve the parent cell of harmful substances, in order to maintain cellular integrity. The content of extracellular vesicles includes miRNAs, mRNAs, growth factors, complement factors, cytokines, chemokines and receptors. These may contribute to inflammatory and infectious diseases by the exposure or transfer of potent effectors that induce vascular inflammation by leukocyte recruitment and thrombosis. Furthermore, vesicles release cytokines and induce their release from cells. Extracellular vesicles possess immune modulatory and anti-microbial properties, and induce receptor signaling in the recipient cell, not least by the transfer of pro-inflammatory receptors. Additionally, the vesicles may carry virulence factors systemically. Extracellular vesicles in blood and urine can contribute to the development of kidney diseases or exhibit protective effects. In this review we will describe the role of EVs in inflammation, thrombosis, immune modulation, angiogenesis, oxidative stress, renal tubular regeneration and infection. Furthermore, we will delineate their contribution to renal ischemia/reperfusion, vasculitis, glomerulonephritis, lupus nephritis, thrombotic microangiopathies, IgA nephropathy, acute kidney injury, urinary tract infections and renal transplantation. Due to their content of miRNAs and growth factors, or when loaded with nephroprotective modulators, extracellular vesicles have the potential to be used as therapeutics for renal regeneration.

Despite recent advances in the management of chronic kidney disease (CKD), morbidity and mortality rates in these patients remain high. Although pressure-mediated injury is a well-recognized mechanism of disease progression in CKD, emerging data indicate that an intermediate phenotype involving chronic inflammation, oxidative stress, hypoxia, senescence, and mitochondrial dysfunction plays a key role in the etiology, progression, and pathophysiology of CKD. A variety of factors promote chronic inflammation in CKD, including oxidative stress and the adoption of a proinflammatory phenotype by resident kidney cells. Regulation of proinflammatory and anti-inflammatory factors through NF-κB- and nuclear factor, erythroid 2 like 2 (Nrf2)-mediated gene transcription, respectively, plays a critical role in the glomerular and tubular cell response to kidney injury. Chronic inflammation contributes to the decline in glomerular filtration rate (GFR) in CKD. Whereas the role of chronic inflammation in diabetic kidney disease (DKD) has been well-elucidated, there is now substantial evidence indicating unresolved inflammatory processes lead to fibrosis and eventual end-stage kidney disease (ESKD) in several other diseases, such as Alport syndrome, autosomal-dominant polycystic kidney disease (ADPKD), IgA nephropathy (IgAN), and focal segmental glomerulosclerosis (FSGS). In this review, we aim to clarify the mechanisms of chronic inflammation in the pathophysiology and disease progression across the spectrum of kidney diseases, with a focus on Nrf2.

The etiology of diabetic nephropathy in type 2 diabetes is multifactorial. Sustained hyperglycemia is a major contributor, but additional contributions come from the hypertension, obesity, and hyperlipidemia that are also commonly present in patients with type 2 diabetes and nephropathy. The leptin deficient BTBR ob/ob mouse is a model of type 2 diabetic nephropathy in which hyperglycemia, obesity, and hyperlipidemia, but not hypertension, are present. We have shown that reversal of the constellation of these metabolic abnormalities with leptin replacement can reverse the morphologic and functional manifestations of diabetic nephropathy. Here we tested the hypothesis that reversal specifically of the hypertriglyceridemia, using an antisense oligonucleotide directed against ApoC-III, an apolipoprotein that regulates the interactions of VLDL (very low density lipoproteins) with the LDL receptor, is sufficient to ameliorate the nephropathy of Type 2 diabetes. Antisense treatment resulted in reduction of circulating ApoC-III protein levels and resulted in substantial lowering of triglycerides to near-normal levels in diabetic mice versus controls. Antisense treatment did not ameliorate proteinuria or pathologic manifestations of diabetic nephropathy, including podocyte loss. These studies indicate that pathologic manifestations of diabetic nephropathy are unlikely to be reduced by lipid-lowering therapeutics alone, but does not preclude a role for such interventions to be used in conjunction with other therapeutics commonly employed in the treatment of diabetes and its complications.

Renal cystic disease encompasses a large variety of illnesses with various phenotypic expressions that can manifest in utero, in infancy, and in childhood. These diseases may be unilateral or bilateral and present with single or multiple cysts. Various cystic diseases may also progress to chronic kidney disease (CKD), including kidney failure, and hepatic disease, thus potentially being life threatening. The prevalence and serious complications of CKD in the pediatric population make it vital that health care providers detect these conditions early and provide effective management. This installment of AJKD's Core Curriculum in Nephrology discusses various genetic and sporadic kidney cystic diseases, including multicystic dysplastic kidney, nephronophthisis, cystic dysplasia, hepatocyte nuclear factor 1-β (HNF1-β) nephropathy, Bardet-Biedl syndrome, Meckel-Gruber syndrome, Zellweger syndrome, calyceal diverticulum, autosomal recessive polycystic kidney disease (ARPKD), and autosomal dominant polycystic kidney disease (ADPKD). This article discusses the epidemiology, genetics and pathophysiology, diagnosis, presentation, and management for each of these renal cystic diseases, with particular attention to prenatal care and pregnancy counseling.

Introduction Foot process effacement and mitochondrial fission associate with kidney disease pathogenesis. Electron microscopy is the gold-standard method for their visualization, but the observable area of electron microscopy is smaller than light microscopy. It is important to develop alternative ways to quantitatively evaluate these microstructural changes because the lesion site of renal diseases can be focal. Methods We analyzed elastica-Masson trichrome (EMT) and periodic acid-Schiff (PAS) stained kidney sections using structured illumination microscopy (SIM). Results EMT staining revealed three-dimensional (3D) structures of foot process, whereas ponceau xylidine acid fuchsin azophloxine solution induced fluorescence. Conversion of foot process images into their constituent frequencies by Fourier transform showed that the concentric square of (1/4)2-(1/16)2 in the power spectra (PS) included information for normal periodic structures of foot processes. Foot process integrity, assessed by PS, negatively correlated with proteinuria. EMT-stained sections revealed fragmented mitochondria in mice with mitochondrial injuries and patients with tubulointerstitial nephritis; Fourier transform quantified associated mitochondrial injury. Quantified mitochondrial damage in patients with immunoglobulin A (IgA) nephropathy predicted a decline in estimated glomerular filtration rate (eGFR) after kidney biopsy but did not correlate with eGFR at biopsy. PAS-stained sections, excited by a 640 nm laser, combined with the coefficient of variation values, quantified subtle changes in the basement membranes of patients with membranous nephropathy stage I. Conclusions Kidney microstructures are quantified from sections prepared in clinical practice using SIM.

Background and aims The term contrast-induced nephropathy is used to describe acute deterioration of renal function after the intravenous administration of iodinated contrast material. We aimed to estimate the incidence of contrast-induced nephropathy and to analyze the evolution of different biomarkers of renal function in patients who underwent computed tomography with intravenous contrast administration after premedication with oral hydration and N-acetylcysteine. Material and methods This prospective observational study included 112 patients with chronic renal failure (glomerular filtration rate (GFR) 30ml-60ml/min/1.73m2) scheduled for computed tomography with intravenous iodinated contrast material. We recorded demographic variables, dose of contrast material, diabetes mellitus, hypertension, and serum hemoglobin. We measured serum creatinine and GFR after premedication and after the CT examination. We summarized variables as means, standard deviations, and percentages. We used the Wilcoxon and Mann-Whitney tests to compare pre- and post-CT values and Pearson's r to analyze correlations. Results Incidence acute kidney injury: 0.9%; 95%CI: 0.36-1.4. Mean difference between pre- and post-CT creatinine: 0.04; 95%CI: 0.002-0.09, p Conclusions The incidence of contrast-induced nephropathy in patients with chronic renal failure and GFR 30ml-60ml/min/1.73m2 is low. The biomarkers of renal function analyzed improve in patients who receive premedication and the minimum dose of contrast material.

We present a rare case of crystalglobulinemia causing cutaneous vasculopathy and acute nephropathy in a 66-year-old female kidney transplant recipient. The patient presented with acute kidney injury (AKI), volume overload, anuria, retiform purpura, and blue-black necrosis of her toes. She received a living kidney transplant 7 months earlier with baseline creatinine of 0.6 mg/dl. Transplant kidney biopsy showed massive pseudo-thrombi filling glomerular capillary lumina. Electron microscopy of thrombi revealed an ultrastructural crystalline pattern of linear and curvilinear bundles with ladder-like periodicity typical of crystalglobulin-induced nephropathy. Similar crystalline pseudo-thrombi were detected ultrastructurally in a skin biopsy specimen, indicating systemic involvement. She required several sessions of hemodialysis. Plasmapheresis was initiated to decrease the number of circulating crystalglobulins. In order to treat the underlying paraproteinemia, the patient was started on bortezomib and dexamethasone. After treatment with five cycles of bortezomib, the patient's free kappa to lambda ratio improved to 2.35 from 5.52. Acute kidney injury (AKI) and the cutaneous vasculopathy gradually improved with treatment. This is an extremely rare occurrence of crystalglobulin in a living kidney transplant recipient.

Background and aims Glycoproteins play a key role in inflammatory and cardiometabolic processes. Their implication in atherosclerosis in type 1 diabetes (T1D) is unknown. We assessed the relationships between classic inflammatory markers, glycoproteins measured by nuclear magnetic resonance (1H-NMR), and preclinical atherosclerosis in these patients. Methods and results We selected patients with T1D, without cardiovascular disease (CVD), with: age ≥40 years, nephropathy (micro/macroalbuminuria), or ≥10 years of evolution with another risk factor. The presence of plaque (intima-media thickness >1.5 mm) was determined by ultrasonography. Concentrations of high-sensitive C-reactive protein (hsCRP), circulating leukocytes (classical inflammation markers) and 1H-NMR-glycoproteins (GlycA, GlycB, GlycF, and the height/width [H/W] ratios of GlycA and GlycB) were determined. We included 189 patients (58% male, age 47.0 [40.7–55.2] years). Thirty-five percent presented plaques (22%, ≥2 plaques). There was no association between hsCRP or leukocytes and atherosclerosis. However, in age- and sex-adjusted models, GlycA, GlycF, and the H/W ratios of GlycA and GlycB gradually increased with the number of plaques (0, 1, ≥2 plaques) only in patients without statins (p Conclusion In T1D individuals without lipid-lowering treatment, 1H-NMR-glycoproteins were independently associated with the presence and amount of carotid atherosclerosis, unlike other classical inflammatory markers. Further studies are needed to ascertain their utility as CVD biomarkers.

APOL1 kidney risk variants (RVs) were identified in 2010 as major drivers of glomerular, tubulointerstitial and renal microvascular disease in individuals with sub-Saharan African ancestry. In December 2020, the “APOL1 at Ten” conference summarized the first decade of progress and discussed controversies and uncertainties that remain to be addressed. Topics included trypanosome infection and its role in the evolution of APOL1 kidney RVs, clinical phenotypes in APOL1-associated nephropathy, relationships between APOL1 RVs and background haplotypes on cell injury and molecular mechanisms initiating disease, the role of clinical APOL1 genotyping, and development of novel therapies for kidney disease. Future goals were defined, including improved characterization of various APOL1 RV phenotypes in patients and experimental pre-clinical models; further dissection of APOL1-mediated pathways to cellular injury and dysfunction in kidney (and other) cells; clarification of gene-gene and gene-environment interactions; and evaluation of the role for existing and novel therapies.

Purpose Renal Resistive Index (RRI) is a newly introduced sonographic index in predicting contrast-induced nephropathy (CIN) development. It has been suggested that RRI > 0.69 should be considered as a risk factor for CIN development. The present study aimed to calculate the predictive value of RRI using a cutoff point of 0.69. Methods A total of 90 patients who were a candidate for coronary vessels angiography were enrolled in this study. Color Doppler ultrasonography was performed and RRI was measured. Patients were followed up for 48 hours after contrast media exposure for the CIN development. The diagnosis of CIN was based on a 25% relative rise or 0.5 mg/dL absolute rise in creatinine level. The predictive values of RRI were measured using 0.69 as a cutoff point. Results Out of 90 patients, CIN developed in 3 patients and 17 patients had preprocedural RRI > 0.69. Of 3 patients with CIN, 1 had RRI > 0.69. Using 0.69 as the cutoff point, the measured sensitivity and specificity of RRI were 33.3% and 83.9%, respectively. Conclusions RRI > 0.69 is not a sensitive index in predicting the CIN development and cannot be used as an independent factor.

Subclinical nephropathy is underestimated in systemic sclerosis (SSc). Study aim is to evaluate the role of renal resistance indices (RRI) and estimated glomerular filtration rate (eGFR) assessed by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) as predictive markers of mortality during 10 years of follow-up in SSc patients.181 SSc patients (60 years, 152 females) were enrolled. At baseline, the GFR was estimated in 181 SSc patients and RRI was measured in 122 SSc patients. During a follow-up of 10 years we recorded the main complications of disease, date and causes of death.eGFR shows a linear negative correlation with RRI. RRI showed a correlation with systolic pulmonary artery pressure (sPAP). Overall survival is lower in SSc patients with eGFR60 ml/min and RRI ≥0.70 than in SSc patients with eGFR≥60 ml/min (p0.0001) and with RRI0.70 (p0.01) both for mortality due to SSc and all causes. In multivariate analysis, eGFR60 ml/min [HR 6.429, 95%CI (1.006-41.08), p0.05] and forced vital capacity (FVC) [HR 0.954, 95%CI (0.911-1), p0.05] are predictive markers of mortality due to SSc, while eGFR [HR 3.617, 95%CI (1.370-9.554), p0.01], RRI [HR 0.210, 95% CI (0.068-0.649), p0.01], age [HR 1.062, 95%CI (1.023-1.103), p0.01], FVC [HR 0.967, 95%CI (0.946-0.989), p0.01] and disease activity index (DAI) [HR 1.663, 95%CI (1.262-2.191), p0.0001] are predictive markers of mortality due to all causes.We demonstrate that eGFR is a predictive marker of mortality due to SSc and to all causes, conversely RRI is predictive marker of mortality due to all causes.

Purpose This study assessed the long-term (10-year) tolerability and efficacy of a low-dose corticosteroid combined with mycophenolate mofetil (CS + MMF) in the treatment of immunoglobulin A nephropathy (IgAN) with stage 3/4 chronic kidney disease and proteinuria in clinical practice in China. Methods Data from patients with biopsy-proven IgAN, stage 3/4 chronic kidney disease (estimated glomerular filtration rate 15–59 mL/min/1.73 m2), and proteinuria (urinary protein excretion ≥1.0 g/d) and who were treated with uncontrolled supportive care (USC), CS, or CS + MMF between January 2008 and December 2017 were included. The primary end point was the prevalence of the composite outcome of any of the following conditions: a reduction in estimated glomerular filtration rate of ≥50%, end-stage renal disease, and death. Findings Of the 120 enrolled patients, 44, 25, and 51 were treated with USC, CS, and CS + MMF, respectively. The median follow-up time was 40.1 months (IQR, 29.1–67.8 months). The prevalences of the composite outcome were 63.6%, 56.0%, and 19.6%, respectively (P Implications CS + MMF may have more promising efficacy than USC or CS in renal-function preservation in patients with IgAN and chronic kidney disease in the Chinese population. However, attention should be paid to the increased risk for death due to severe pneumonia.

Introduction Disease-causing mutations in the protocadherin FAT1 have been recently described both in patients with a glomerulotubular nephropathy and in patients with a syndromic nephropathy. Methods We identified 4 patients with FAT1-associated disease, performed clinical and genetic characterization, and compared our findings to the previously published patients. Patient-derived primary urinary epithelial cells were analyzed by quantitative polymerase chain reaction (qPCR) and immunoblotting to identify possible alterations in Hippo signaling. Results Here we expand the spectrum of FAT1-associated disease with the identification of novel FAT1 mutations in 4 patients from 3 families (homozygous truncating variants in 3, compound heterozygous missense variants in 1 patient). All patients show an ophthalmologic phenotype together with heterogeneous renal phenotypes ranging from normal renal function to early-onset end-stage kidney failure. Molecular analysis of primary urine-derived urinary renal epithelial cells revealed alterations in the Hippo signaling cascade with a decreased phosphorylation of both the core kinase MST and the downstream effector YAP. Consistently, we found a transcriptional upregulation of bona fide YAP target genes. Conclusion A comprehensive review of the here identified patients and those previously published indicates a highly diverse phenotype in patients with missense mutations but a more uniform and better recognizable phenotype in the patients with truncating mutations. Altered Hippo signaling and de-repressed YAP activity might be novel contributing factors to the pathomechanism in FAT1-associated renal disease., Graphical abstract

Introduction Childhood IgA nephropathy (cIgAN) is a primary glomerulonephritis clinically characterized by microscopic hematuria and proteinuria, the presence of which may potentially overlap with Alport syndrome. Interestingly, earlier studies suggested that familial IgAN could be linked to the chromosome 2q36 region, also the coding region for collagen type 4 alpha 3/4 (COL4A3/A4). Methods To investigate a possible relationship or phenocopy between Alport syndrome and cIgAN, COL4A3, COL4A4, and COL4A5 exons were sequenced in 36 cIgAN patients. Clinical data and treatment were collected retrospectively. COL4A3/A4/A5 variants were classified according to American College of Medical Genetics and the Association for Molecular Pathology (ACMG/AMP) guidelines. Results Four of 36 cIgAN patients were affected by ACMG class 4/5 COL4A3 heterozygous variants (COL4A3-cIgAN). We found no COL4A4 or COL4A5 variant. Despite having rare and deleterious COL4A3 variants, 3 of 4 COL4A3-cIgAN children developed clinical and biologic features of active IgAN rather than Alport syndrome. Response to intensive immunosuppressive treatment was favorable, leading to a reduction of endocapillary and extracapillary proliferation lesions. High levels of immune immunoglobulin G and A (IgG/IgA) complexes, reduction of proteinuria, and gradual stabilization of estimated glomerular filtration rate (eGFR) argued against Alport syndrome. Nevertheless, COL4A3-cIgAN patients seemed predisposed to a more serious IgAN presentation compared with the non‒COL4A3-cIgAN group, with more glomerulosclerosis and a lower eGFR over time. One of the 4 patients underwent kidney transplant with subsequent IgAN recurrence. Conclusions Predisposition factors for developing serious cIgAN flare-up should be considered for cIgAN with COL4A3 pathologic heterozygous variants. COL4A3 variants, usually responsible for Alport syndrome in adults, should not automatically exclude an immunosuppressive regimen in cIgAN. Moreover, evidence of an ACMG class 4/5 COL4A3 variant in early-stage cIgAN could be a helpful tool for stratifying severity of cIgAN beyond the Oxford classification., Graphical abstract

Introduction Mutations affecting genes involved in oxidative and signaling pathways may be associated with kidney disease in sickle cell anemia. We determined the allele and genotype frequencies of some polymorphisms in the promoter regions of the Heme Oxygenase-1 (HMOX1) [rs2071746 (A > T) and (GT)n repeats, short (S) and long (L) alleles] and Bone Morphogenetic Protein Receptor type-1B (BMPR1B) [rs17022863 (A > G), rs4331783 (A > G) and rs1470409 (A > G)] genes in 75 adult patients with sickle cell anemia and 160 healthy controls and investigated whether these polymorphisms may influence the estimated glomerular filtration rate for the patients. Methods The single nucleotide polymorphisms were genotyped using the TaqMan assays, the HMOX1(GT)n repeats were determined by polymerase chain reaction fragment size analysis and the estimated glomerular filtration rate was calculated by the Modification of Diet in Renal Disease formula. Results Regarding the HMOX1rs2071746, the estimated glomerular filtration rate median was significantly higher in TT patients (p = 0.019), including when TT was compared with AT + AA (p = 0.009); for the (GT)n repeats, the estimated glomerular filtration rate medians of SS, SL and LL significantly differed (p = 0.009), being the LL estimated glomerular filtration rate median significantly higher, when compared with the LS + SS (p = 0.005). These results suggest that both the homozygotes, TT for rs2071746 and LL for (GT)n repeats, lead to a higher risk of developing renal complications. Concerning the BMPR1B, the frequencies of GG for rs17022863 and AA for rs4331783 were significantly higher in patients than in controls (p = 0.002 and p = 0.008, respectively), however no association with estimated glomerular filtration rate was found. Conclusion These results contribute to a better understanding of the genetic factors related to the development of nephropathy in sickle cell anemia patients.

Introduction The identification of specific molecular signatures and the development of new targeted drugs have changed the paradigm of onco-nephrology, now allowing a multiscale approach of kidney involvement related to hematological malignancies relying on combined hematological and molecular assessments. In this study, we aimed to refine the spectrum of kidney disorders associated with chronic myelomonocytic leukemia (CMML) or BCR-ABL-negative myeloproliferative neoplasms (MPN), two very rare conditions scarcely described. Methods Case series. Patients with myeloid neoplasms who were referred to Toulouse University Hospital Nephrology Unit and were diagnosed with acute kidney injury (AKI), chronic kidney disease (CKD) or urine abnormalities were retrospectively included. Results Eighteen patients (males n=13; CMML n=8; essential thrombocytosis n=7; polycythemia vera n=1 and myelofibrosis n=2) developed kidney disease 7.7±2 years after the diagnosis of the malignancy. Twelve patients had acute kidney injury at presentation. Eight patients had glomerular presentation (high range proteinuria 33%, microscopic hematuria 56%). Kidney biopsy (n=14) showed various patterns including pauci-immune glomerulosclerosis (n=5), extra-medullar hematopoiesis (n=6) or tubular atrophy and interstitial fibrosis with polymorphic inflammation (n=8). Immunostaining of CD61 confirmed the infiltration of megakaryocytes within glomeruli or interstitium in 5/8 patients. Other pictures of glomerulopathy were identified in 3 patients (IgA nephropathy n=2, AA amyloidosis n=1). Massive kidney infiltration by CMML was identified in one patient. After a mean follow-up of 24±6 months, malignancy was considered as stable in 11 patients (61%), but 22% of patients had progressed to end-stage renal failure. The remaining had persistently reduced kidney function. No correlation between the malignancy and the renal presentation and outcomes could be identified. Conclusions Kidney complications of CMML/MPN are heterogeneous and kidney biopsy may help to identify new molecular targets to prevent the development of kidney fibrosis.

Background Fc receptor-like (FCRL) molecules were considered to play a role in the pathogenesis of certain autoimmune diseases. Nonetheless, the clinical significance of FCRLs in IgA nephropathy (IgAN) remains unclear. Objective This study is aimed at investigating the expression levels of FCRLs molecules in IgAN patients and determining its relevance to disease activity. Methods The mRNA expression levels of FCRLs were determined in peripheral blood mononuclear cells (PBMCs) of 42 IgAN patients and 48 healthy controls by quantitative real-time PCR (qRT-PCR). FCRLs proteins expression in B cells of 25 IgAN patients, 14 patients with non-IgAN glomerulonephritis, and 29 healthy controls were detected by Flow cytometry. The Spearman correlation test was used to assess the correlation of FCRLs expression with clinical parameters of IgAN patients. Results Our results indicated significant down-regulation of FCRL2 and FCRL3 mRNA levels in IgAN patients compared to healthy subjects. Surface protein expression of FCRLs molecules confirmed the qRT-PCR results. But FCRL2 and FCRL3 protein levels did not correlate with clinicopathologic phenotypes of IgAN patients. However, we found a significant positively correlation of FCRL2 and FCRL3 mRNA expression with the core 1 β1,3-galactosyltransferase (C1GALT1) and its molecular chaperone (Cosmc) mRNA levels in IgAN patients. Conclusions FCRL2 and FCRL3 expression levels in IgAN patients are significantly decreased and correlated with CIGALT1 and Cosmc mRNA expression.

Chronic kidney disease (CKD), defined as dysfunction of the glomerular filtration apparatus, is an independent risk factor for the development of coronary artery disease (CAD). Patients with CKD are at a substantially higher risk of cardiovascular mortality compared with the age- and sex-adjusted general population with normal kidney function. The risk of CAD and mortality in patients with CKD is correlated with the degree of renal dysfunction including presence of microalbuminuria. A greater cardiovascular risk, albeit lower than for patients receiving dialysis, persists even after kidney transplantation. Congestive heart failure, commonly caused by CAD, also accounts for a significant portion of the cardiovascular-related events observed in CKD. The optimal strategy for the evaluation of CAD in patients with CKD, particularly before renal transplantation, remains a topic of contention spanning over several decades. Although the evaluation of coexisting cardiac disease in patients with CKD is desirable, severe renal dysfunction limits the use of radiographic and magnetic resonance contrast agents due to concerns regarding contrast-induced nephropathy and nephrogenic systemic sclerosis, respectively. In addition, many patients with CKD have extensive and premature (often medial) calcification disproportionate to the severity of obstructive CAD, thereby limiting the diagnostic value of computed tomography angiography. As such, echocardiography, non-contrast-enhanced magnetic resonance, nuclear myocardial perfusion, and metabolic imaging offer a variety of approaches to assess obstructive CAD and cardiomyopathy of advanced CKD without the need for nephrotoxic contrast agents.

The endocannabinoid system has multiple effects. Through interacting with cannabinoid receptor type 1 and type 2, this system can greatly affect disease progression. Previously, we showed that activated cannabinoid receptor type 2 (CB2) mediated kidney fibrosis. However, the underlying mechanisms remain underdetermined. Here, we report that CB2 was upregulated predominantly in kidney tubular epithelial cells in unilateral urinary obstruction and ischemia-reperfusion injury models in mice, and in patients with a variety of kidney diseases. CB2 expression was closely correlated with the progression of kidney fibrosis and accompanied by the activation of β-catenin. Furthermore, CB2 induced the formation of a β-arrestin 1/Src/β-catenin complex, which further triggered the nuclear translocation of β-catenin and caused fibrotic injury. Incubation with XL-001, an inverse agonist to CB2, or knockdown of β-arrestin 1 inhibited CB2-triggered activation of β-catenin and fibrotic injury. Notably, CB2 potentiated Wnt1-induced β-arrestin 1/β-catenin activation and augmented the pathogenesis of kidney fibrosis in mice with unilateral ischemia-reperfusion injury or folic acid-induced nephropathy. Knockdown of β-arrestin 1 inhibited the CB2 agonist AM1241-induced β-catenin activation and kidney fibrosis. By promoter sequence analysis, putative transcription factor binding sites for T-cell factor/lymphoid enhancer factor were found in the promoter regions of the CB2 gene regardless of the species. Overexpression of β-catenin induced the binding of T-cell factor/lymphoid enhancer factor-1 to these sites, promoted the expression of CB2, β-arrestin 1, and the proto-oncogene Src, and triggered their accumulation. Thus, the CB2/β-catenin pathway appears to create a reciprocal activation feedback loop that plays a central role in the pathogenesis of kidney fibrosis.

Fluorofenidone (AKF-PD) is a novel pyridone agent that reduces the deposition of extracellular matrix (ECM) in various models of renal fibrosis. However, there are no reports on the effect of AKF-PD in preventing fibrosis in the folic acid nephropathy model. Besides, the mechanisms of action of AKF-PD in preventing renal fibrosis are not fully understood. In the study, we observed that AKF-PD reduced folate-induced kidney injury, ameliorated the deterioration of renal function, and suppressed the deposition of ECM by decreasing the expression of collagen I, collagen III, transforming growth factor-β (TGF-β), fibronectin (FN), and alpha smooth muscle actin (α-SMA) in the folic acid nephropathy model. Additionally, AKF-PD suppressed the activation of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome to reduce the production of caspase-1 and IL-1β, and alleviated mitochondrial oxidative damage by promoting mitochondrial energy metabolism and reducing the expression of NADPH oxidase 4 (NOX4). The results of in vitro experiments demonstrated that AKF-PD suppressed NLRP3 inflammasome activation in activated peritoneal-derived macrophages (PDMs) and renal tubular epithelial cells (RTECs). AKF-PD increased the intracellular ATP content and decreased the expression of NOX4, while preventing the excessive production of mitochondrial reactive oxygen species (mtROS) in activated PDMs. In conclusion, this study demonstrated that AKF-PD inhibited renal fibrosis by suppressing the mtROS-NLRP3 pathway in the folic acid nephropathy model. These findings provide new evidence in support of the clinical use of AKF-PD in the treatment of diseases related to renal fibrosis.

International audience; We have previously shown that ultrasonography can detect hyperechogenic crystal deposits in the kidney medulla of patients with gout. In this cross-sectional study we investigated the frequency and clinical correlates of hyperechogenic kidney medulla in 502 consecutive primary consultants for gout (ACR/EULAR criteria) at the Vien Gut medical center in Ho Chi Minh City, Vietnam. None of these patients received urate-lowering drugs. Kidney medulla echogenicity on B-mode ultrasonography was compared to that of the kidney cortex. Overall, 36% patients showed a hyperechoic pattern of Malpighi pyramids. On univariate analysis, the pattern was significantly associated with age, estimated gout duration, steroid-dependency, clinical tophi, urate arthropathy, double contour thickness at the scanned joints, coronary heart disease, arterial hypertension, hyperuricemia, proteinuria, leukocyturia, and decreased estimated glomerular filtration rate. On multivariable analysis, the hyperechoic pattern was associated with estimated disease duration, clinical tophi, urate arthropathy, double contour thickness and decreased estimated glomerular filtration rate. No hyperechoic pattern was observed in 515 consecutive consultants without gout. Thus, hyperechoic kidney medulla was frequently demonstrated in Vietnamese patients with tophaceous gout and associated with features of tubulointerstitial nephritis. This finding revives the hypothesis of microcrystalline nephropathy of gout, predominantly seen in untreated gouty patients, which could be an important target for urate-lowering therapy.

Diagnostic criteria for chronic active T cell-mediated rejection (CA-TCMR) were revised in the Banff 2017 consensus, but it is unknown whether the new criteria predict graft prognosis of kidney transplantation. We enrolled 406 kidney allograft recipients who underwent a 1-year protocol biopsy (PB) and investigated the diagnostic significance of Banff 2017. Interobserver reproducibility of the 3 diagnosticians showed a substantial agreement rate of 0.68 in Fleiss's kappa coefficient. Thirty-three patients (8%) were classified as CA-TCMR according to Banff 2017, and 6 were previously diagnosed as normal, 12 as acute TCMR, 10 with borderline changes, and 5 as CA-TCMR according to Banff 2015 criteria. Determinant factors of CA-TCMR were cyclosporine use (vs tacrolimus), previous acute rejection, and BK polyomavirus-associated nephropathy. In survival analysis, the new diagnosis of CA-TCMR predicted a composite graft endpoint defined as doubling serum creatinine or death-censored graft loss (log-rank test, P < .001). In multivariate analysis, CA-TCMR was associated with the second highest risk of the composite endpoint (hazard ratio: 5.42; 95% confidence interval, 2.02-14.61; P < .001 vs normal) behind antibody-mediated rejection. In conclusion, diagnosis of CA-TCMR in Banff 2017 may facilitate detecting an unfavorable prognosis of kidney allograft recipients who undergo a 1-year PB.

Background and objectives: Glomerulonephritis (GN) is one of the main causes of chronic terminal kidney disease; however, few studies assess its prognosis in dialysis. We analyze the survival and characteristics of patients on peritoneal dialysis (PD) with primary GN (PGN), and compare their results with other kidney patients. Methods: This prospective observational study took place from 1995 to 2014. We included all incident patients who were initiated on the technique in the Levante registry. Data were transferred to an anonymized database in Access. Statistical analysis was performed using SPSS software (version 19.0). Results: The study included 2243 patients, with GN representing the main cause of primary kidney disease (21,5%). IgA nephropathy was the most frequent histologically confirmed form of PGN. Compared with the rest of the sample, patients with PGN were more often men (65% vs 58%, p = .004), and they were on average younger (48 years vs 55 years, p