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Patients with autosomal dominant polycystic kidney disease (ADPKD), a genetic disease due to mutations of the PKD1 or PKD2 gene, show signs of complement activation in the urine and cystic fluid, but their pathogenic role in cystogenesis is unclear. We tested the causal relationship between complement activation and cyst growth using a Pkd1KO renal tubular cell line and newly generated conditional Pkd1-/- C3-/- mice. Pkd1-deficient tubular cells have increased expression of complement-related genes (C3, C5, CfB, C3ar, and C5ar1), while the gene and protein expression of complement regulators DAF, CD59, and Crry is decreased. Pkd1-/- C3-/- mice are unable to fully activate the complement cascade and are characterized by a significantly slower kidney cystogenesis, preserved renal function, and reduced intrarenal inflammation compared with Pkd1-/- C3+/+ controls. Transgenic expression of the cytoplasmic C-terminal tail of Pkd1 in Pkd1KO cells lowered C5ar1 expression, restored Daf levels, and reduced cell proliferation. Consistently, both DAF overexpression and pharmacological inhibition of C5aR1 (but not C3aR) reduced Pkd1KO cell proliferation. In conclusion, the loss of Pkd1 promotes unleashed activation of locally produced complement by downregulating DAF expression in renal tubular cells. Increased C5a formation and C5aR1 activation in tubular cells promotes cyst growth, offering a new therapeutic target.

Background: Administration of recombinant erythropoietin (EPO), a kidney-produced hormone with erythropoietic functions, has been shown to have multiple immunoregulatory effects in mice and humans, but whether physiological levels of EPO regulate immune function in vivo has not been previously evaluated., Methods: We generated mice in which we could downregulate EPO production using a doxycycline (DOX)-inducible, EPO-specific silencing RNA (shEPOrtTA POS ), and we crossed them with B6.MRL-Fas lpr /J mice that develop spontaneous lupus. We treated these B6.MRL/lpr shEPOrtTA POS with DOX and serially measured anti-dsDNA antibodies, analyzed immune subsets by flow cytometry, and evaluated clinical signs of disease activity over 6 months of age in B6.MRL/lpr shEPOrtTA POS and in congenic shEPOrtTA NEG controls., Results: In B6.MRL/lpr mice, Epo downregulation augmented anti-dsDNA autoantibody levels and increased disease severity and percentages of germinal center B cells compared with controls. It also increased intracellular levels of IL-6 and MCP-1 in macrophages., Discussion: Our data in a murine model of lupus document that endogenous EPO reduces T- and B-cell activation and autoantibody production, supporting the conclusion that EPO physiologically acts as a counterregulatory mechanism to control immune homeostasis., 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 © 2023 Bin, Cantarelli, Horwitz, Gentile, Podestà, La Manna, Heeger and Cravedi.)

Background/objectives: Estimation of muscle mass is an integral part of nutritional assessment in End-Stage Kidney Disease (ESKD) patients on chronic hemodialysis (HD). In this respect, muscle ultrasound (US) is a valid and reliable tool but has not been previously related to outcomes in this population. Aims of this study were to assess the relationship between quadriceps muscle thickness as assessed by US and outcomes in ESKD patients on HD; we also compared US with anthropometry and malnutrition inflammation score (MIS)., Subjects/methods: In this prospective study, 181 prevalent patients on HD were included. Thickness of the quadriceps rectus femoris and vastus intermedius (VIT) were assessed separately using ultrasonography, and were indexed for height squared. Mid-arm muscle circumference (MAMC) and area (MAMA) were assessed by anthropometry. MIS was evaluated. In the absence of predetermined cut-offs, values below the median of the distribution of VIT index were considered low. Instead, cut-off for anthropometric values such as MAMC and MAMA were set at ≥90% of agreement with the 50th percentile of the sex- and age-specific normal distribution. Cox-regression analysis was used to assess the association of US, MIS, and anthropometric parameters with mortality., Results: Patients were followed for a median of 35 months. During this period 36% of patients died. Multivariable Cox-regression analysis (adjusted for demographic, biochemical and clinical variables), demonstrated that higher VIT distal index values were independently associated with lower mortality risk (HR: 0.76 (0.59-0.99); P = 0.040), whilst higher MIS values were independently associated with higher (HR 1.22 (1.10-1.35); P < 0.001) mortality risk. When assessing muscle parameters as categorical variables, both low VIT distal index (HR: 1.71 (1.01-2.89); 0.045) and MAMC (HR: 1.74 (1.02-2.96); 0.042) were independently associated with increased risk of death., Conclusion: Indexed distal VIT was independently associated with mortality both as continuous and as a categorical variable. Muscle US is a simple practical tool that adds prognostic information to the bedside nutritional assessment in ESKD patients on maintenance HD., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: In patients admitted to the Intensive Care Unit (ICU), Kidney Replacement Therapy (KRT) is an important risk factor for hypophosphataemia. However, studies addressing the development of hypophosphatemia during prolonged intermittent KRT modalities are lacking. Thus, we evaluated the incidence of hypophosphatemia during Sustained Low-Efficiency Dialysis (SLED) in ICU patients; we also examined the determinants of post-SLED serum phosphate level (s-P) and the relation between s-P and phosphate supplementation and ICU mortality., Methods: We conducted a retrospective analysis on a cohort of critically ill patients with severe renal failure and KRT need, who underwent at least three consecutive SLED sessions at 24-72 h time intervals with daily monitoring of s-P concentration. SLED with Regional Citrate Anticoagulation (RCA) was performed with either conventional dialysis machines or continuous-KRT monitors and standard dialysis solutions. When deemed necessary by the attending physician, intravenous phosphate supplementation was provided by sodium glycerophosphate pentahydrate. We used mixed-effect models to examine the determinants of s-P and Cox proportional hazards regression models with time-varying covariates to examine the adjusted relation between s-P, intravenous phosphate supplementation and ICU mortality., Results: We included 65 patients [mean age 68 years (SD 10.0); mean Acute Physiology and Chronic Health Evaluation II score 25 (range 9-40)] who underwent 195 SLED sessions. The mean s-P before the start of the first SLED session (baseline s-P) was 5.6 ± 2.1 mg/dL (range 1.5-12.3). Serum phosphate levels at the end of each SLED decreased with increasing age, SLED duration and number of SLED sessions (P < .05 for all). The frequency of hypophosphatemia increased after the first through the third SLED session (P = .012). Intravenous phosphate supplementation was scheduled after 12/45 (26.7%) SLED sessions complicated by hypophosphataemia. The overall ICU mortality was 23.1% (15/65). In Cox regression models, after adjusting for potential confounders and for current s-P, intravenous phosphate supplementation was associated with a decrease in ICU mortality [adjusted hazard ratio: 0.24 (95% confidence interval: 0.06 to 0.89; P = 0.033)]., Conclusions: Hypophosphatemia is a frequent complication in critically ill patients undergoing SLED with standard dialysis solutions, that worsens with increasing SLED treatment intensity. In patients undergoing daily SLED, phosphate supplementation is strongly associated with reduced ICU mortality., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Despite progressive improvements in the management of patients with coronavirus disease 2019 (COVID-19), individuals with end-stage kidney disease (ESKD) are still at high risk of infection-related complications. Although the risk of infection in these patients is comparable to that of the general population, their lower rate of response to vaccination is a matter of concern. When prevention strategies fail, infection is often severe. Comorbidities affecting patients on maintenance dialysis and kidney transplant recipients clearly account for the increased risk of severe COVID-19, while the role of uremia and chronic immunosuppression is less clear. Immune monitoring studies have identified differences in the innate and adaptive immune response against the virus that could contribute to the increased disease severity. In particular, individuals on dialysis show signs of T cell exhaustion that may impair antiviral response. Similar to kidney transplant recipients, antibody production in these patients occurs, but with delayed kinetics compared with the general population, leaving them more exposed to viral expansion during the early phases of infection. Overall, unique features of the immune response during COVID-19 in individuals with ESKD may occur with severe comorbidities affecting these individuals in explaining their poor outcomes., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Type I interferons (IFNs) are pleiotropic cytokines with potent antiviral properties that also promote protective T cell and humoral immunity. Paradoxically, type I IFNs, including the widely expressed IFNβ, also have immunosuppressive properties, including promoting persistent viral infections and treating T-cell-driven, remitting-relapsing multiple sclerosis. Although associative evidence suggests that IFNβ mediates these immunosuppressive effects by impacting regulatory T (Treg) cells, mechanistic links remain elusive. Here, we found that IFNβ enhanced graft survival in a Treg-cell-dependent murine transplant model. Genetic conditional deletion models revealed that the extended allograft survival was Treg cell-mediated and required IFNβ signaling on T cells. Using an in silico computational model and analysis of human immune cells, we found that IFNβ directly promoted Treg cell induction via STAT1- and P300-dependent Foxp3 acetylation. These findings identify a mechanistic connection between the immunosuppressive effects of IFNβ and Treg cells, with therapeutic implications for transplantation, autoimmunity, and malignancy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Exhaustion of T cells occurs in response to long-term exposure to self and foreign antigens. It limits T cell capacity to proliferate and produce cytokines, leading to an impaired ability to clear chronic infections or eradicate tumors. T-cell exhaustion is associated with a specific transcriptional, epigenetic, and metabolic program and characteristic cell surface markers' expression. Recent studies have begun to elucidate the role of T-cell exhaustion in transplant. Higher levels of exhausted T cells have been associated with better graft function in kidney transplant recipients. In contrast, reinvigorating exhausted T cells by immune checkpoint blockade therapies, while promoting tumor clearance, increases the risk of acute rejection. Lymphocyte depletion and high alloantigen load have been identified as major drivers of T-cell exhaustion. This could account, at least in part, for the reduced rates of acute rejection in organ transplant recipients induced with thymoglobulin and for the pro-tolerogenic effects of a large organ such as the liver. Among the drugs that are widely used for maintenance immunosuppression, calcineurin inhibitors have a contrasting inhibitory effect on exhaustion of T cells, while the influence of mTOR inhibitors is still unclear. Harnessing or encouraging the natural processes of exhaustion may provide a novel strategy to promote graft survival and transplantation tolerance., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The acute and long-term effects of severe acute respiratory syndrome coronavirus 2 infection in individuals with GN are still unclear. To address this relevant issue, we created the International Registry of COVID-19 infection in GN., Methods: We collected serial information on kidney-related and -unrelated outcomes from 125 GN patients (63 hospitalized and 62 outpatients) and 83 non-GN hospitalized patients with coronavirus disease 2019 (COVID-19) and a median follow-up period of 6.4 (interquartile range 2.3-9.6) months after diagnosis. We used logistic regression for the analyses of clinical outcomes and linear mixed models for the longitudinal analyses of eGFR. All multiple regression models were adjusted for age, sex, ethnicity, and renin-angiotensin-aldosterone system inhibitor use., Results: After adjustment for pre-COVID-19 eGFR and other confounders, mortality and AKI did not differ between GN patients and controls (adjusted odds ratio for AKI=1.28; 95% confidence interval [CI], 0.46 to 3.60; P =0.64). The main predictor of AKI was pre-COVID-19 eGFR (adjusted odds ratio per 1 SD unit decrease in eGFR=3.04; 95% CI, 1.76 to 5.28; P <0.001). GN patients developing AKI were less likely to recover pre-COVID-19 eGFR compared with controls (adjusted 6-month post-COVID-19 eGFR=0.41; 95% CI, 0.25 to 0.56; times pre-COVID-19 eGFR). Shorter duration of GN diagnosis, higher pre-COVID-19 proteinuria, and diagnosis of focal segmental glomerulosclerosis or minimal change disease were associated with a lower post-COVID-19 eGFR., Conclusions: Pre-COVID-19 eGFR is the main risk factor for AKI regardless of GN diagnosis. However, GN patients are at higher risk of impaired eGFR recovery after COVID-19-associated AKI. These patients (especially those with high baseline proteinuria or a diagnosis of focal segmental glomerulosclerosis or minimal change disease) should be closely monitored not only during the acute phases of COVID-19 but also after its resolution., Competing Interests: O. Bestard reports patents and inventions with Oxford Immunotec and is associate editor of Transplant International and Frontiers in Immunology. A. Bruchfeld reports consultancy agreements with AstraZeneca, Chemocentryx, Fresenius, and Merck; a research grant from AstraZeneca; honoraria from Bayer, Chemocentryx, Fresenius, Merck, and Vifor; and is a member of the ERA-EDTA scientific advisory board 2018–2024, chair of the ERA-EDTA Immunonephrology Working Group, and vice-chair of the Swedish Renal Fund. G. Comai reports honoraria from Alexion, Astellas, and Novartis. P. Cravedi reports honoraria as an advisor for Chinook Therapeutics and is associate editor for the Journal of Nephrology and the American Journal of Transplantation. G. Fernandez Juarez reports research funding from Instituto Salud Calos III and honoraria from Alexion and GSK. E. Fiaccadori is on the editorial board of the Journal of Nephrology and Blood Purification and is a member of the Italian Society of Nephrology and the European Society of Parenteral and Enteral Nutrition. O. Flossmann reports consultancy agreements with Vifor Pharma has other interests/relationships with the British Medical Association, European Vasculitis Society, Renal Association (UK), Royal College of Physicians London, and UK Ireland Vasculitis Society. C. García-Carro reports consultancy agreements with Astellas, AstraZeneca, Boehringer Ingelheim Lilly, Esteve, Novartis and Baxter, Novo Nordisk, and Otsuka; honoraria from Astellas, AstraZeneca, Boehringer Ingelheim Lilly, Esteve, Novartis and Baxter, Novo Nordisk, and Otsuka; and is a scientific advisor for or member of AstraZeneca, Boehringer Ingelheim Lilly, Mundipharma, and Novo Nordisk. M. Griffith reports honoraria from Retrophin’s advisory board. A. J. Hamilton is on the editorial board of the Journal of Kidney Care and is a member of the SONG-Kids Life Participation Expert Working Group. T. Leach reports honoraria from Janssen for conference attendance in 2012 and is a scientific advisor to the National Institute for Health and Care Excellence. L. Lightstone reports consultancy agreements with Achillion, Alexion, AstraZeneca, Aurinia, BMS, GSK, Kezar, Novartis, Pfizer, and Roche; honoraria from Alexion, AstraZeneca, BMS, GSK, and Pfizer; is a scientific advisor or member of EU Exec Lupus Nephritis Trials Network; is on the advisory board of Nature Reviews Nephrology; participates in a speakers’ bureau for Alexion and GSK; is a trustee of Kidney Research UK 2018–2022; is an executive member of the International Society of Nephrology 2021–2023; is deputy chair of Western Regional Board of the International Society of Nephrology; and is a clinical expert representing the Renal Association response to NICE on STA for belimumab in lupus 2020–2021. U. Maggiore reports consultancy agreements with Biotest, Chiesi, GSK, Hansa, Novartis, Sandoz, and Takeda. J. Manrique is a scientific advisor for or member of AstraZeneca, Boehringer, and Viphor Pharma. E. Morales reports consultancy agreements with Alexion, Celgene, Viphor Fresenius, and Vifor Pharma. J.A. Niño-Cruz reports research funding from Pfizer Scientific Institute and participates in a speakers’ bureau for Takeda and Roche. A. Ortiz reports consultancy agreements with Retrophin and Sanofi Genzyme; research funding from AstraZeneca, Mundipharma, and Sanofi Genzyme; honoraria from Advicciene, Alexion, Amgen, Amicus, Astellas, AstraZeneca, Bayer, Chiesi, Fresenius Medical Care, Idorsia, Kyowa Kirin, Menarini, Otsuka, Sanofi Genzyme, and Vifor Fresenius Medical Care Renal Pharma; is a member of the Spanish Society of Nephrology; is editor-in-chief of the Clinical Kidney Journal; is on the editorial boards of the Journal of Nephrology, Journal of the American Society of Nephrology, and Peritoneal Dialysis International; is a member of SOMANE and ERA Councils; is on the board of directors for IIS-Fundacion Jimenez Diaz UAM; is on the scientific advisory board of the Dutch Kidney Foundation; honoraria listed above are for speaker engagements: Advicciene, Alexion, Astellas, AstraZeneca, Amicus, Amgen, Bayer, Chiesi, Fresenius Medical Care, Idorsia, Kyowa Kirin, Menarini, Otsuka, Sanofi Genzyme, and Vifor Fresenius Medical Care Renal Pharma. S. Sinha reports consultancy agreements with Sanifit; research funding from Amgen, AstraZeneca, and Ethicon; and honoraria from AstraZeneca, Bayer, Napp Pharmaceuticals, Novartis, and Sanofi Genzyme. M.F. Slon-Roblero reports consultancy agreements with Baxter, Fresenius, and Nipro; and honoraria from Baxter, Fresenius, and Nipro. M.J. Soler reports consultancy agreements with AstraZeneca, Bayer, Boehringer, Esteve, Jansen, Mundipharma, Novo Nordisk, Travere, and ICU; research funding from Abbvie and Boehringer; honoraria from AstraZeneca, Boehringer, Esteve, FMC, Jansen, ICU Medical, Mundipharma, Novo Nordisk, Otsuka, and Travere; patents and inventions: U691ES00; is a scientific advisor for or member of BMC Nephrology and Clinical Kidney Journal; is a former member of ERA-EDTA Council; participates in a speakers’ bureau for AstraZeneca, Bayer, Boehringer, Esteve, FMC, Jansen, Mundipharma, Novo Nordisk, and Vifor; is a member of the Sociedad Española de Nefrología and Sociedad Catalana de Nefrologia; and is elected editor-in-chief of the Clinical Kidney Journal. All remaining authors have nothing to disclose., (Copyright © 2022 by the American Society of Nephrology.)

Focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) are common forms of idiopathic nephrotic syndrome. The causes of these diseases are incompletely understood, but the response of patients to immunosuppressive therapies suggests that their pathogenesis is at least in part immune mediated. Preclinical and clinical research indicates that activation of the classical pathway of complement contributes to glomerular injury in FSGS. Glomerular IgM deposits are also prominent in some patients, raising the possibility that IgM is a trigger of classical pathway activation. In the present study, we examined the pattern of complement activation in the glomeruli and plasma of patients with nephrotic syndrome. We also tested whether patients with FSGS and MCD have elevated levels of natural IgM reactive with epitopes on glomerular endothelial cells and cardiolipin. We found evidence of classical pathway activation in patients with idiopathic nephrotic syndrome compared with healthy control subjects. We also detected higher levels of self-reactive IgM to both targets. Based on these results, IgM and classical pathway activation may contribute to disease pathogenesis in some patients with FSGS and MCD. NEW & NOTEWORTHY IgM is detected in biopsies from some patients with nephrotic syndrome, although this has been attributed to passive trapping of the protein. We found, however, that IgM colocalizes with complement activation fragments in some glomeruli. We also found that affected patients had higher levels of IgM reactive to glomerular endothelial cell epitopes. Thus, IgM activates the complement system in the glomeruli of some patients with nephrotic syndrome and may contribute to injury.

Background: Although high-affinity IgG auto- and alloantibodies are important drivers of kidney inflammation that can result in ESKD, therapeutic approaches that effectively reduce such pathogenic antibodies remain elusive. Erythropoietin (EPO) has immunomodulatory functions, but its effects on antibody production are unknown., Methods: We assessed the effect and underlying mechanisms of EPO/EPO receptor (EPOR) signaling on primary and secondary, T cell-dependent and T-independent antibody formation using in vitro culture systems, murine models of organ transplantation and lupus nephritis, and mice conditionally deficient for the EPOR expressed on T cells or B cells., Results: In wild-type mice, recombinant EPO inhibited primary, T cell-dependent humoral immunity to model antigens and strong, polyclonal stimuli, but did not alter T-independent humoral immune responses. EPO also significantly impaired secondary humoral immunity in a potent allogeneic organ transplant model system. The effects required T cell, but not B cell, expression of the EPOR and resulted in diminished frequencies of germinal center (GC) B cells and T follicular helper cells (T FH ). In vitro and in vivo experiments showed that EPO directly prevented T FH differentiation and function via a STAT5-dependent mechanism that reduces CD4 + T cell expression of Bcl6 . In lupus models, EPO reduced T FH , GC B cells, and autoantibody production, and abrogated autoimmune glomerulonephritis, demonstrating clinical relevance. In vitro studies verified that EPO prevents differentiation of human T FH cells., Conclusions: Our findings newly demonstrate that EPO inhibits T FH -dependent antibody formation, an observation with potential implications for treating antibody-mediated diseases, including those of the kidney., (Copyright © 2021 by the American Society of Nephrology.)

B cell depleting therapies permit immunosuppressive drug withdrawal and maintain remission in patients with frequently relapsing nephrotic syndrome (FRNS) or steroid-dependent nephrotic syndrome (SDNS), but lack of biomarkers for treatment failure. Post-depletion immune cell reconstitution may identify relapsing patients, but previous characterizations suffered from methodological limitations of flow cytometry. Time-of-flight mass cytometry (CyTOF) is a comprehensive analytic modality that simultaneously quantifies over 40 cellular markers. Herein, we report CyTOF-enabled immune cell comparisons over a 12-month period from 30 children with SDNS receiving B cell depleting therapy who either relapsed (n = 17) or remained stable (n = 13). Anti-CD20 treatment depleted all B cells subsets and CD20 depleting agent choice (rituximab vs ofatumumab) did not affect B cell subset recovery. Despite equal total numbers of B cells, 5 subsets of B cells were significantly higher in relapsing individuals; all identified subsets of B cells were class-switched. T cell subsets (including T follicular helper cells and regulatory T cells) and other major immune compartments were largely unaffected by B cell depletion, and similar between relapsing and stable children. In conclusion, CyTOF analysis of immune cells from anti-CD20 antibody treated patients identifies class-switched B cells as the main subset whose expansion associates with disease relapse. Our findings set the basis for future studies exploring how identified subsets can be used to monitor treatment response and improve our understanding of the pathogenesis of the disease., 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 © 2021 Fribourg, Cioni, Ghiggeri, Cantarelli, Leventhal, Budge, Bin, Riella, Colucci, Vivarelli, Angeletti, Perin and Cravedi.)

Acute kidney injury (AKI) is a common finding in kidney donors and recipients. AKI in kidney donor, which increases the risk of delayed graft function (DGF), may not by itself jeopardize the short- and long-term outcome of transplantation. However, some forms of AKI may induce graft rejection, fibrosis, and eventually graft dysfunction. Therefore, various strategies have been proposed to identify conditions at highest risk of AKI-induced DGF, that can be treated by targeting the donor, the recipient, or even the graft itself with the use of perfusion machines. AKI that occurs early post-transplant after a period of initial recovery of graft function may reflect serious and often occult systemic complications that may require prompt intervention to prevent graft loss. AKI that develops long after transplantation is often related to nephrotoxic drug reactions. In symptomatic patients, AKI is usually associated with various systemic medical complications and could represent a risk of mortality. Electronic systems have been developed to alert transplant physicians that AKI has occurred in a transplant recipient during long-term outpatient follow-up. Herein, we will review most recent understandings of pathophysiology, diagnosis, therapeutic approach, and short- and long-term consequences of AKI occurring in both the donor and in the kidney transplant recipient.