Protective Role of the Podocyte IL-15 / STAT5 Pathway in Focal Segmental Glomerulosclerosis.

Introduction: During glomerular diseases, podocyte-specific pathways can modulate the intensity of histological disease and prognosis. The therapeutic targeting of these pathways could thus improve the management and prognosis of kidney diseases. The Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway, classically described in immune cells, has been recently described in detail in intrinsic kidney cells. Methods: We describe STAT5 expression in human kidney biopsies from patients with focal segmental glomerulosclerosis (FSGS) and studied mice with a podocyte-specific Stat5 deletion in experimental glomerular diseases. Results: Here, we show, for the first time, that STAT5 is activated in human podocytes in FSGS. In addition, podocyte-specific Stat5 inactivation aggravates the structural and functional alterations in a mouse model of FSGS. This could be due, at least in part, to an inhibition of autophagic flux. Finally, interleukin 15 (IL-15), a classical activator of STAT5 in immune cells, increases STAT5 phosphorylation in human podocytes, and its administration alleviates glomerular injury in vivo by maintaining autophagic flux in podocytes. Conclusion: Activating podocyte STAT5 with commercially available IL-15 represents a potential new therapeutic avenue for FSGS.

Corrigendum: Ex vivo normothermic preservation of a kidney graft from uncontrolled donation after circulatory death over 73 hours.

[This corrects the article DOI: 10.3389/fbioe.2023.1330043.].

Simulation-based learning in nephrology.

Simulation is a technique to replace and amplify real experiences with guided ones that evoke or replicate substantial aspects of the real world in a fully interactive fashion. In nephrology (a particularly complex specialty), simulation can be used by patients, nurses, residents, and attending physicians alike. It allows one to learn techniques outside the stressful environment of care such as central venous catheter placement, arteriovenous fistula management, learning about peritoneal dialysis, or performing a kidney biopsy. Serious games and virtual reality are emerging methods that show promise. Simulation could also be important in relational aspects of working in a team or with the patient. The development of simulation as a teaching tool in nephrology allows for maintaining high-quality training for residents, tailored to their future practice, and minimizing risks for patients. Additionally, this education helps nephrologists maintain mastery of technical procedures, making the specialty attractive to younger generations. Unfortunately, the inclusion of simulation training programmes faces occasional logistical or funding limitations that universities must overcome with the assistance and innovation of teaching nephrologists. The impact of simulation-based teaching on clinical outcomes needs to be investigated in clinical studies.

Kidney organoid models reveal cilium-autophagy metabolic axis as a therapeutic target for PKD both in vitro and in vivo.

Human pluripotent stem cell-derived kidney organoids offer unprecedented opportunities for studying polycystic kidney disease (PKD), which still has no effective cure. Here, we developed both in vitro and in vivo organoid models of PKD that manifested tubular injury and aberrant upregulation of renin-angiotensin aldosterone system. Single-cell analysis revealed that a myriad of metabolic changes occurred during cystogenesis, including defective autophagy. Experimental activation of autophagy via ATG5 overexpression or primary cilia ablation significantly inhibited cystogenesis in PKD kidney organoids. Employing the organoid xenograft model of PKD, which spontaneously developed tubular cysts, we demonstrate that minoxidil, a potent autophagy activator and an FDA-approved drug, effectively attenuated cyst formation in vivo. This in vivo organoid model of PKD will enhance our capability to discover novel disease mechanisms and validate candidate drugs for clinical translation.

Kidney Transplantation in Patients With AA Amyloidosis: Outcomes in a French Multicenter Cohort.

RATIONALE & OBJECTIVE: Outcomes of kidney transplantation for patients with renal AA amyloidosis are uncertain, with reports of poor survival and high rates of disease recurrence. However, the data are inconclusive and mostly based on studies from the early 2000s and earlier. STUDY DESIGN: Retrospective multicenter cohort study. SETTING & PARTICIPANTS: We searched the French national transplant database to identify all patients with renal AA amyloidosis who underwent kidney transplantation between 2008 and 2018. EXPOSURES: Age, cause of amyloidosis, use of biotherapies, and C-reactive protein levels. OUTCOMES: Outcomes were all-cause mortality and allograft loss. We also reported amyloidosis allograft recurrence, occurrence of acute rejection episodes, as well as infectious, cardiovascular, and neoplastic disease events. ANALYTICAL APPROACH: Kaplan-Meier estimator for mortality and cumulative incidence function method for allograft loss. Factors associated with patient and allograft survival were investigated using a Cox proportional hazards model and a cause-specific hazards model, respectively. RESULTS: 86 patients who received kidney transplants for AA amyloidosis at 26 French centers were included. The median age was 49.4 years (IQR, 39.7-61.1). The main cause of amyloidosis was familial Mediterranean fever (37 cases; 43%). 16 (18.6%) patients received biotherapy after transplantation. Patient survival rates were 94.0% (95% CI, 89.1-99.2) at 1 year and 85.5% (77.8-94.0) at 5 years after transplantation. Cumulative incidences of allograft loss were 10.5% (4.0-17.0) at 1 year and 13.0% (5.8-20.1) at 5 years after transplantation. Histologically proven AA amyloidosis recurrence occurred in 5 transplants (5.8%). An infection requiring hospitalization developed in 55.8% of cases, and there was a 27.9% incidence of acute allograft rejection. Multivariable analysis showed that C-reactive protein concentration at the time of transplantation was associated with patient survival (HR, 1.01; 95% CI, 1.00-1.02; P=0.01) and allograft survival (HR, 1.68; 95% CI, 1.10-2.57; P=0.02). LIMITATIONS: The study lacked a control group, and the effect of biotherapies on transplantation outcomes could not be explored. CONCLUSIONS: This relatively contemporary cohort of patients who received a kidney transplant for AA amyloidosis experienced favorable rates of survival and lower recurrence rates than previously reported. These data support the practice of treating these patients with kidney transplantation for end-stage kidney disease. PLAIN-LANGUAGE SUMMARY: AA amyloidosis is a severe and rare disease. Kidney involvement is frequent and leads to end-stage kidney disease. Because of the involvement of other organs, these patients are often frail, which has raised concerns about their suitability for kidney transplantation. We reviewed all patients with AA amyloidosis nephropathy who underwent kidney transplantation in France in the recent era (2008-2018) and found that the outcomes after kidney transplantation were favorable, with 85.5% of patients still alive 5 years after transplantation, a survival rate that is comparable to the outcomes of patients receiving a transplant for other forms of kidney diseases. Recurrence of amyloidosis in the transplanted kidney was infrequent (5.8%). These data support the practice of kidney transplantation for patients with AA amyloidosis who experience kidney failure.

Immunoadsorption-Based HLA Desensitization in Patients Awaiting Deceased Donor Kidney Transplantation: An Interventional, Non-Randomised, Single Cohort Study.

Whether immunoadsorption (IADS) as part of desensitization protocols could facilitate deceased donor kidney transplantation (KT) in highly sensitized (HS) patients remains to be proven. We retrospectively analyzed our IADS based desensitization protocol for deceased donor KTs between 2013 and 2018. Fifteen HS patients (age 52 years [40-56]) were included. Waiting time before IADS was 6 years [5-10] and the interval between IADS initiation and KT was 5 months [1-12] for the 14 transplanted patients. Nine patients had prior KT. Calculated panel reactive antibody decreased significantly during the protocol (99.3% [92.5-99.9] vs. 79.4% [56.7-81.9]; p = 0.004). Death-censored graft survival was 85.7% at 1 and 2 years post-transplantation. One-year median plasma creatinine level was 135 µmol/L [111-202]. Six developed active antibody mediated rejection (ABMR) at 1 year, with a median delay of 13 days [11-26]. Eight patients developed severe infections, including two fatal outcomes. Finally, compared to 93% of patients who received desensitization receiving a KT, only 43% of a control with similar characteristics underwent transplantation. However, no difference was found in overall probability of being alive with a functioning graft at the end of follow-up. The results indicate that our IADS-based desensitization strategy was not effective due to a high rate of ABMR and severe infectious complications which pose a challenge to its universalization.

Hepatitis B Virus Reactivation in Kidney Transplant Recipients Treated With Belatacept.

Introduction: Hepatitis B virus (HBV) reactivation in kidney transplant recipients has been reported in 3% to 9% of anti-HBc antibody (HBcAb)-positive HBs antigen (HBsAg)-negative patients. It has not been studied in patients receiving belatacept, a selective costimulation blocker. Methods: We performed a retrospective study of all transplant recipients receiving belatacept in 2 kidney transplantation centers in France. Among HBcAb-positive patients, we analyzed HBV reactivation rate, outcomes, and risk factors. Results: A total of 135 patients treated with belatacept were included: 32 were HBcAb-positive and 2 were HBsAg-positive. Seven patients reactivated HBV (21.9% of HBcAb-positive patients), including 5 HBsAg-negative patients (16.7% of HBcAb-positive HBsAg-negative patients). Reactivation occurred 54.8 (± 70.9) months after transplantation. One patient presented with severe hepatitis and 1 patient developed cirrhosis. There was no significant difference in survival between patients that reactivated HBV and patients that did not: 5-year patient survival of 100% (28.6; 100) and 83.4% (67.6; 100), respectively (P = 0.363); and 5-year graft survival of 100% (28.6; 100) and 79.8% (61.7; 100), respectively (P = 0.335). No factor, including HBsAb positivity and antiviral prophylaxis, was statistically associated with the risk of HBV reactivation. Conclusion: HBV reactivation rate was high in patients treated with belatacept when compared with previous transplantation studies. HBV reactivation did not impact survival. Further studies are needed to confirm these results. A systematic antiviral prophylaxis for these patients should be considered and evaluated.

Additional Benefits of Rituximab and Plasma Exchange on Top of Standard Induction Therapy in Kidney Transplant Recipients With a Negative CDC Crossmatch but High Preformed Donor Specific Antibody Titer.

Optimal induction strategy in highly sensitized kidney transplant recipients (KTRs) is still a matter of debate. The place of therapies, such as plasma exchange and rituximab, with potential side effects and high cost, is not clearly established. We compared two induction strategies with (intensive) or without (standard) rituximab and plasma exchange in KTRs with high levels of preformed DSA transplanted between 2012 and 2019. Sixty KTRs with a mean age of 52.2 ± 12.2 years were included, 36 receiving standard and 24 intensive induction. Mean fluorescence intensity of immunodominant DSA in the cohort was 8,903 ± 5,469 pre-transplantation and similar in both groups. DSA level decrease was similar at 3 and 12 months after transplantation in the two groups. An intensive induction strategy was not associated with better graft or patient survival, nor more infectious complications. The proportion of patients with rejection during the first year was similar (33% in each group), but rejection occurred later in the intensive group (211 ± 188 days, vs. 79 ± 158 days in the standard group, p < 0.01). Our study suggests that an intensive induction therapy including rituximab and plasma exchanges in highly sensitized kidney recipients is not associated with better graft survival but may delay biopsy-proven rejection.

Exome-First Strategy in Adult Patients With CKD: A Cohort Study.

Introduction: Exome sequencing (ES) has widened the field of nephrogenomics in adult nephrology. In addition to reporting the diagnostic yield of ES in an adult cohort study, we investigated the clinical implications of molecular diagnosis and developed a clinical score to predict the probability of obtaining positive result. Methods: From September 2018 we have used ES to prospectively perform a first-tier liberal exploration of adult nephropathies of unknown origin and/or when a genetic kidney disease was clinically suggested. We also analyzed copy number variant using the same assay. Results: Molecular diagnosis was made in 127 of 538 patients sequenced (diagnostic yield: 24%), comprising 47 distinct monogenic disorders. Eight of these monogenic disorders (17% [8/47]) accounted for 52% of genetic diagnoses. In 98% (n = 125/127) of the patients, the genetic information was reported to have major clinical implications. We developed a 4-value clinical score to predict the probability of obtaining a molecular diagnosis (area under the receiver operating characteristics curve [AUC] 0.726 [95% confidence interval: 0.670-0.782]) (available at http://allogenomics.com/score). Conclusion: This study reinforces the role of ES as a first-tier exploration for adult chronic kidney disease patients in whom phenotypes are often poor and atypical. Although external validation is required, our clinical score could be a useful tool for the implementation of nephrogenomics in adults.

Corrigendum to Persistent Aseptic Pyelonephritis After Acute Bacterial Pyelonephritis: Possible Role of Corticosteroids Kidney International Reports, Volume 7, Issue 8, August 2022, Pages 1897-1900.

[This corrects the article DOI: 10.1016/j.ekir.2022.05.025.].

Ex vivo normothermic preservation of a kidney graft from uncontrolled donation after circulatory death over 73 hours.

The transplant community is focused on prolonging the ex vivo preservation time of kidney grafts to allow for long-distance kidney graft transportation, assess the viability of marginal grafts, and optimize a platform for the translation of innovative therapeutics to clinical practice, especially those focused on cell and vector delivery to organ conditioning and reprogramming. We describe the first case of feasible preservation of a kidney from a donor after uncontrolled circulatory death over a 73-h period using normothermic perfusion and analyze hemodynamic, biochemical, histological, and transcriptomic parameters for inflammation and kidney injury. The mean pressure and flow values were 71.24 ± 9.62 mmHg and 99.65 ± 18.54 mL/min, respectively. The temperature range was 36.7°C-37.2°C. The renal resistance index was 0.75 ± 0.15 mmHg/mL/min. The mean pH was 7.29 ± 0.15. The lactate concentration peak increased until 213 mg/dL at 6 h, reaching normal values after 34 h of perfusion (8.92 mg/dL). The total urine output at the end of perfusion was 1.185 mL. Histological analysis revealed no significant increase in acute tubular necrosis (ATN) severity as perfusion progressed. The expression of KIM-1, VEGF, and TGFß decreased after 6-18 h of perfusion until 60 h in which the expression of these genes increased again together with the expression of ß-catenin, Ki67, and TIMP1. We show that normothermic perfusion can maintain a kidney graft viable ex vivo for 3 days, thus allowing a rapid translation of pre-clinical therapeutics to clinical practice.

Sodium Bicarbonate Prescription and Extracellular Volume Increase: Real-world Data Results from the AlcalUN Study.

Oral alkalization with sodium bicarbonate (NaHCO3 ) or citrate is prescribed for conditions ranging from metabolic acidosis to nephrolithiasis. Although most nephrologists/urologists use this method routinely, extracellular volume (ECV) increase is the main feared adverse event reported for NaHCO3 . Thus far, no trial has specifically studied this issue in a real-world setting. AlcalUN (NCT03035812) is a multicentric, prospective, open-label cohort study with nationwide (France) enrollment in 18 (public and private) nephrology/urology units. Participants were adult outpatients requiring chronic (>1 month) oral alkalization by either NaHCO3 -containing or no-NaHCO3 -containing agents. The ECV increase (primary outcome) was judged based on body weight increase (ΔBW), blood pressure increase (ΔBP), and/or new-onset edema at the first follow-up visit (V1). From February 2017 to February 2020, 156 patients were enrolled. After a median 106 days of treatment, 91 (72%) patients reached the primary outcome. They had lower systolic (135 (125, 141) vs. 141 (130, 150), P = 0.02) and diastolic (77 (67, 85) vs. 85 (73, 90), P = 0.03) BP values, a higher plasma chloride (106.0 (105.0, 109.0) vs. 105.0 (102.0, 107.0), P = 0.02) at baseline, and a less frequent history of nephrolithiasis (32 vs. 56%, P = 0.02). Patients experienced mainly slight ΔBP (< 10 mmHg). The primary outcome was not associated (P = 0.79) with the study treatment (129 received NaHCO3 and 27 received citrate). We subsequently developed three different models of propensity score matching; each confirmed our results. Chronic oral alkalization with NaHCO3 is no longer associated with an ECV increase compared to citrate in real-life settings.

[Angiogenesis inhibitors: mechanism of action and nephrotoxicity]. / Anti-angiogéniques : mécanisme d'action et néphrotoxicité.

Tumoral angiogenesis is a key mechanism involved in the growth and spread of cancer cells. The development of angiogenesis inhibitors, particularly those targeting the Vascular Endothelial Growth Factor (VEGF) pathway, has improved the prognosis and survival of many cancer patients since they were approved in 2005 in France. Vascular Endothelial Growth Factor inhibitors have different mechanisms of action, targeting either the ligand (e.g. bevacizumab, anti-Vascular Endothelial Growth Factor monoclonal antibody; aflibercept, recombinant anti-Vascular Endothelial Growth Factor fusion protein), or its receptors such as tyrosine kinase inhibitors (e.g. sunitinib or sorafenib). These treatments can be combined with conventional chemotherapy, or other anti-cancer therapies, and are associated with variable tolerance depending on the patient's clinical condition and comorbidities. Additionally, angiogenesis inhibition may be associated with cardiovascular and/or kidney toxicity and therefore special monitoring is needed during the treatment duration. Development of hypertension and proteinuria are the commonest renal side effects; these are generally manageable and reversible when treatment is stopped. However, more severe toxicities have been reported such as acute kidney injury, glomerular and/or vascular insults such as thrombotic microangiopathy, and more rarely tubulointerstitial damage. The prescribing physician should be aware of these potentially serious. This article describes the mechanisms of action of antiangiogenic agents and their potential toxicities, with particular respect to the kidneys.

In vivo partial reprogramming alters age-associated molecular changes during physiological aging in mice.

Partial reprogramming by expression of reprogramming factors (Oct4, Sox2, Klf4 and c-Myc) for short periods of time restores a youthful epigenetic signature to aging cells and extends the life span of a premature aging mouse model. However, the effects of longer-term partial reprogramming in physiologically aging wild-type mice are unknown. Here, we performed various long-term partial reprogramming regimens, including different onset timings, during physiological aging. Long-term partial reprogramming lead to rejuvenating effects in different tissues, such as the kidney and skin, and at the organismal level; duration of the treatment determined the extent of the beneficial effects. The rejuvenating effects were associated with a reversion of the epigenetic clock and metabolic and transcriptomic changes, including reduced expression of genes involved in the inflammation, senescence and stress response pathways. Overall, our observations indicate that partial reprogramming protocols can be designed to be safe and effective in preventing age-related physiological changes. We further conclude that longer-term partial reprogramming regimens are more effective in delaying aging phenotypes than short-term reprogramming.