Microvascular Inflammation of Kidney Allografts and Clinical Outcomes.

BACKGROUND: The heterogeneous clinical presentation of graft microvascular inflammation poses a major challenge to successful kidney transplantation. The effect of microvascular inflammation on allograft outcomes is unclear. METHODS: We conducted a cohort study that included kidney-transplant recipients from more than 30 transplantation centers in Europe and North America who had undergone allograft biopsy between 2004 and 2023. We integrated clinical and pathological data to classify biopsy specimens according to the 2022 Banff Classification of Renal Allograft Pathology, which includes two new diagnostic categories: probable antibody-mediated rejection and microvascular inflammation without evidence of an antibody-mediated response. We then assessed the association between the newly recognized microvascular inflammation phenotypes and allograft survival and disease progression. RESULTS: A total of 16,293 kidney-transplant biopsy specimens from 6798 patients were assessed. We identified the newly recognized microvascular inflammation phenotypes in 788 specimens, of which 641 were previously categorized as specimens with no evidence of rejection. As compared with patients without rejection, the hazard ratio for graft loss was 2.1 (95% confidence interval [CI], 1.5 to 3.1) among patients with microvascular inflammation without evidence of an antibody-mediated response and 2.7 (95% CI, 2.2 to 3.3) among patients with antibody-mediated rejection. Patients with a diagnosis of probable antibody-mediated rejection had a higher risk of graft failure beyond year 5 after biopsy than those without rejection (hazard ratio, 1.7; 95% CI, 0.8 to 3.5). Patients with a diagnosis of either newly recognized microvascular inflammation phenotype had a higher risk of progression of transplant glomerulopathy during follow-up than patients without microvascular inflammation. CONCLUSIONS: Microvascular inflammation in kidney allografts includes distinct phenotypes, with various disease progression and allograft outcomes. Our findings support the clinical use of additional rejection phenotypes to standardize diagnostics for kidney allografts. (Funded by OrganX. ClinicalTrials.gov number, NCT06496269.).

Single-cell transcriptomics identifies aberrant glomerular angiogenic signalling in the early stages of WT1 kidney disease.

WT1 encodes a podocyte transcription factor whose variants can cause an untreatable glomerular disease in early childhood. Although WT1 regulates many podocyte genes, it is poorly understood which of them are initiators in disease and how they subsequently influence other cell-types in the glomerulus. We hypothesised that this could be resolved using single-cell RNA sequencing (scRNA-seq) and ligand-receptor analysis to profile glomerular cell-cell communication during the early stages of disease in mice harbouring an orthologous human mutation in WT1 (Wt1R394W/+). Podocytes were the most dysregulated cell-type in the early stages of Wt1R394W/+ disease, with disrupted angiogenic signalling between podocytes and the endothelium, including the significant downregulation of transcripts for the vascular factors Vegfa and Nrp1. These signalling changes preceded glomerular endothelial cell loss in advancing disease, a feature also observed in biopsy samples from human WT1 glomerulopathies. Addition of conditioned medium from murine Wt1R394W/+ primary podocytes to wild-type glomerular endothelial cells resulted in impaired endothelial looping and reduced vascular complexity. Despite the loss of key angiogenic molecules in Wt1R394W/+ podocytes, the pro-vascular molecule adrenomedullin was upregulated in Wt1R394W/+ podocytes and plasma and its further administration was able to rescue the impaired looping observed when glomerular endothelium was exposed to Wt1R394W/+ podocyte medium. In comparative analyses, adrenomedullin upregulation was part of a common injury signature across multiple murine and human glomerular disease datasets, whilst other gene changes were unique to WT1 disease. Collectively, our study describes a novel role for altered angiogenic signalling in the initiation of WT1 glomerulopathy. We also identify adrenomedullin as a proangiogenic factor, which despite being upregulated in early injury, offers an insufficient protective response due to the wider milieu of dampened vascular signalling that results in endothelial cell loss in later disease. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Levamisole in childhood idiopathic nephrotic syndrome: new promises, and advocacy for global access.

In the current issue of Kidney International, Sinha et al. present data from an open-label, noninferior, randomized controlled trial comparing 12-months of alternate-day prednisolone, given daily during infection, versus levamisole, in children with frequently relapsing or steroid-dependent nephrotic syndrome. This study suggests that both of these strategies are efficacious and safe. Results of this study should redefine the role of levamisole in future guidelines, and a call for global availability of levamisole should be advocated.

An international, multi-center study evaluated rituximab therapy in childhood steroid-resistant nephrotic syndrome.

The efficacy and safety of rituximab in childhood steroid-resistant nephrotic syndrome (SRNS) remains unclear. Therefore, we conducted a retrospective cohort study at 28 pediatric nephrology centers from 19 countries in Asia, Europe, North America and Oceania to evaluate this. Children with SRNS treated with rituximab were analyzed according to the duration of calcineurin inhibitors (CNIs) treatment before rituximab [6 months or more (CNI-resistant) and under 6 months]. Primary outcome was complete/partial remission (CR/PR) as defined by IPNA/KDIGO guidelines. Secondary outcomes included kidney failure and adverse events. Two-hundred-forty-six children (mean age, 6.9 years; 136 boys; 57% focal segmental glomerulosclerosis, FSGS) were followed a median of 32.4 months after rituximab. All patients were in non-remission before rituximab. (146 and 100 children received CNIs for 6 month or more or under 6 months before rituximab, respectively). In patients with CNI-resistant SRNS, the remission rates (CR/PR) at 3-, 6-, 12- and 24-months were 26% (95% confidence interval 19.3-34.1), 35.6% (28.0-44.0), 35.1% (27.2-43.8) and 39.1% (29.2-49.9), respectively. Twenty-five patients were in PR at 12-months, of which 22 had over 50% reduction in proteinuria from baseline. The remission rates among children treated with CNIs under 6 months before rituximab were 42% (32.3-52.3), 52% (41.8-62.0), 54% (44.3-64.5) and 60% (47.6-71.3) at 3-, 6-, 12-, and 24-months. Upon Kaplan-Meier analysis, non-remission and PR at 12-months after rituximab, compared to CR, were associated with significantly worse kidney survival. Adverse events occurred in 30.5% and most were mild. Thus, rituximab enhances remission in a subset of children with SRNS, is generally safe and CR following rituximab is associated with favorable kidney outcome.

Childhood nephrotic syndrome.

Idiopathic nephrotic syndrome is the most common glomerular disease in children. Corticosteroids are the cornerstone of its treatment, and steroid response is the main prognostic factor. Most children respond to a cycle of oral steroids, and are defined as having steroid-sensitive nephrotic syndrome. Among the children who do not respond, defined as having steroid-resistant nephrotic syndrome, most respond to second-line immunosuppression, mainly with calcineurin inhibitors, and children in whom a response is not observed are described as multidrug resistant. The pathophysiology of nephrotic syndrome remains elusive. In cases of immune-mediated origin, dysregulation of immune cells and production of circulating factors that damage the glomerular filtration barrier have been described. Conversely, up to a third of cases of steroid-resistant nephrotic syndrome have a monogenic origin. Multidrug resistant nephrotic syndrome often leads to kidney failure and can cause relapse after kidney transplant. Although steroid-sensitive nephrotic syndrome does not affect renal function, most children with steroid-sensitive nephrotic syndrome have a relapsing course that requires repeated steroid cycles with significant side-effects. To minimise morbidity, some patients require steroid-sparing immunosuppressive agents, including levamisole, mycophenolate mofetil, calcineurin inhibitors, anti-CD20 monoclonal antibodies, and cyclophosphamide. Close monitoring and preventive measures are warranted at onset and during relapse to prevent acute complications (eg, hypovolaemia, acute kidney injury, infections, and thrombosis), whereas long-term management requires minimising treatment-related side-effects. A subset of patients have active disease into adulthood.

X-linked transient antenatal Bartter syndrome related to MAGED2 gene: enriching the phenotypic description and pathophysiologic investigation.

PURPOSE: Transient Bartter syndrome related to pathogenic variants of MAGED2 is the most recently described antenatal Bartter syndrome. Despite its transient nature, it is the most severe form of Bartter syndrome in the perinatal period. Our aim was to describe 14 new cases and to try to explain the incomplete penetrance in women. METHODS: We report on 14 new cases, including 3 females, and review the 40 cases described to date. We tested the hypothesis that MAGED2 is transcriptionally regulated by differential methylation of its CpG-rich promotor by pyrosequencing of DNA samples extracted from fetal and adult leukocytes and kidney samples. RESULTS: Analysis of the data from 54 symptomatic patients showed spontaneous resolution of symptoms in 27% of cases, persistent complications in 41% of cases and fatality in 32% of cases. Clinical anomalies were reported in 76% of patients, mostly renal anomalies (52%), cardiovascular anomalies (29%) and dysmorphic features (13%). A developmental delay was reported in 24% of patients. Variants were found in all regions of the gene. Methylation analysis of the MAGED2 CpG-rich promotor showed a correlation with gender, independent of age, tissue or presence of symptoms, excluding a role for this mechanism in the incomplete penetrance in women. CONCLUSION: This work enriches the phenotypic and genetic description of this recently described disease, and deepens our understanding of the pathophysiological role and regulation of MAGED2. Finally, by describing the wide range of outcomes in patients, this work opens the discussion on genetic counseling offered to families.

To biopsy or not to biopsy a teenager with typical idiopathic nephrotic syndrome? Start steroids first.

It is well known that minimal change disease (MCD) and focal segmental glomerulosclerosis are the most common histopathology findings in children with idiopathic nephrotic syndrome. Moreover, several studies demonstrated that MCD is associated with high steroid-responsiveness and a low incidence of kidney failure, suggesting that routine kidney biopsy is not warranted. Over time, the indications for performing a kidney biopsy have become increasingly stringent, aiming to limit unnecessary invasive procedures in the paediatric population. The most recent guidelines state that a kidney biopsy is not usually necessary at disease onset. Still, it should be performed in case of atypical features suggestive of systemic diseases or glomerulonephritis and in case of steroid-resistance, to assess the different differential diagnoses, regardless of patient age. Moreover, it has been shown that the best prognostic marker in childhood nephrotic syndrome is response to treatment and that kidney histology is not accurate in predicting prognosis. Furthermore, a kidney biopsy is not necessary to predict the relapsing course. Notably, kidney biopsy is an invasive procedure and may lead to significant complications. Finally, novel non-invasive biomarkers have been validated or are in the process of being approved to guide differential diagnoses and thus limit the need for kidney biopsies in patients with typical nephrotic syndrome. In the following sections, we aim to explain why initiating steroid treatment as the initial approach in teenagers with typical nephrotic syndrome is a reasonable strategy. Additionally, we explore how kidney biopsy indications may be alleviated in this population.

The rationale for nephron-sparing surgery in unilateral non-syndromic Wilms tumour.

The central question of nephron-sparing surgery in unilateral non-syndromic Wilms tumour sits at a crossroads between surgery, oncology, and nephrology. There has been a significant paradigm shift in paediatric oncology towards reducing toxicity and addressing long-term treatment-related sequalae amongst childhood cancer survivors. After paediatric nephrectomy and 30-50 years of follow-up, 40% of patients will have chronic kidney disease, including 22% with hypertension and 23% with albuminuria. It is difficult to predict which patients will progress to develop hypertension, reduced glomerular filtration rate, albuminuria, and a higher cardiovascular risk. For these reasons, nephron-sparing surgery when it is technically feasible must be considered. To decrease the incidence of positive surgical margins (viable tumour present at a resection margin), incomplete lymph node sampling, and complications, these procedures should be performed at specialist and experienced reference centres. Based on the impacts of individual treatment pathways, survivors of childhood WT need to be followed through adulthood for early detection of chronic kidney disease, hypertension, and prevention of cardiovascular events.

Steroid pulse therapy in idiopathic nephrotic syndrome in the era of modern immunosuppressive treatment-still up to date?

BACKGROUND: Intravenous steroid pulses (SP) are successfully used for the treatment of patients with idiopathic nephrotic syndrome (INS) resistant to oral prednisone. METHODS: We performed a retrospective analysis of all patients in the three pediatric nephrology centers of the Paris region from 2002 to 2022 who were resistant to a 30-day course of oral prednisone and who received SP for their first INS flare and analyzed their disease course over 4 years. RESULTS: Forty-seven patients (17 girls), median age 3.4 years, were analyzed. Of them, 68% reached remission within 7 days of SP. No significant short-term side effects were noted. Half of the patients started immunosuppressive treatment immediately after their first remission and 62% of them relapsed at least once, whereas all the patients who did not receive immunosuppressive treatment since their first remission relapsed. Among the SP-sensitive patients, 75% needed calcineurin inhibitor (CNI) or B-cell depletion during their disease course to achieve stable remission. Forty-two percent of the whole cohort received B-cell-depleting agents. Among the 15 SP-resistant patients, all received CNI. Twelve/fifteen patients reached remission. After 4 years, 68% among the SP-sensitive patients and 87% of SP-resistant patients still had an active disease. CONCLUSIONS: SP are helpful to obtain rapid remission in pediatric INS patients resistant to oral steroids. However, as most SP-sensitive patients need immunosuppressive drugs, mainly CNI and B-cell-depleting agents it could be interesting to discuss the possibility to start CNI directly after the 30-day course of prednisone instead of SP.

IgA nephropathy in children with minimal proteinuria: to biopsy or not to biopsy?

BACKGROUND: Tubulointerstitial lesions and glomerular inflammation severity have been shown to correlate with proteinuria in children with IgA nephropathy (cIgAN). However, there is a lack of data regarding severity of histopathologic findings in cIgAN in patients with minimal to absent proteinuria since kidney biopsy indications are not well defined in these cases. METHODS: Twenty-eight cIgAN patients with kidney biopsy from 4 different centers in Paris (France) and Montreal (Canada) with a urine protein/creatinine ratio (UPCr) ≤ 0.03 g/mmol and a normal estimated glomerular filtration rate (eGFR > 90 ml/min/1.73 m2) on the day of kidney biopsy prior to treatment were included. RESULTS: Median age was 11.82 (9.32-13.45) years, and median follow-up was 4 years (2.87-6.53). At time of biopsy, median eGFR was 116 (102.3-139.7) ml/min/1.73 m2, and median UPCr was 0.02 (0.011-0.03) g/mmol. Microscopic or macroscopic hematuria was present in 35.7% and 64.3% of cases, respectively. Kidney biopsy microscopy analysis showed mesangial (M1), endocapillary (E1), or extracapillary (C1) hypercellularity in 53.5%, 32.1%, and 7.1% of patients, respectively. Chronic histological lesions were also present: glomerulosclerosis (S1) in 42.8% and tubular atrophy/interstitial fibrosis in 7.1%. Podocytopathic features were detected in 21.4%. An ACE inhibitor or immunosuppressive therapy (IS) was prescribed in 42.8% and 21.4% of these patients respectively. One-third (35.7%) received no treatment. At last follow-up, median eGFR was 111.9 (90.47-136.1) ml/min/1.73 m2, and median UPCr was 0.028 (0.01-0.03) g/mmol. CONCLUSION: cIgAN with minimal proteinuria at time of biopsy might be linked with acute and chronic glomerular lesions.

IgG-immunoadsorptions and eculizumab combination in STEC-hemolytic and uremic syndrome pediatric patients with neurological involvement.

BACKGROUND: Neurological complications pose a significant threat in pediatric hemolytic and uremic syndrome (HUS) resulting from infections with Shiga toxin-producing Escherichia coli (STEC), with no established treatment. The involvement of complement activation in the pathogenesis of STEC-HUS is acknowledged, and eculizumab (ECZ), a terminal complement blocker, has been documented in several pediatric series with inconsistent results. Antibody-mediated mechanisms have also been suggested, with IgG-immunoadsorption (IgIA) showing promise in adults with neurological complications. We aimed to assess the benefit of combining IgIA with ECZ in pediatric patients with neurological STEC-HUS compared to patients treated with ECZ alone or supportive care. METHODS: Multicenter retrospective study conducted on pediatric patients (< 18 years) with neurological STEC-HUS treated with IgIA + ECZ or ECZ alone from 2010 to 2020 in France. A historical cohort treated with supportive care served as controls. Primary outcome included survival and neurological evaluation at 1-year follow-up (dichotomized as normal vs. abnormal). RESULTS: A total of 42 children were included: 18 treated with IgIA + ECZ, 24 with ECZ alone, and 27 with supportive care. Although there was no significant difference in survival between groups, three deaths occurred in the control group in the acute phase, while none was reported in both the IgIA + ECZ and ECZ alone groups, despite presenting with more severe neurological symptoms for IgIA + ECZ patients. No significant association was found between treatment group and 1-year neurological evaluation after adjustment for age, sex, and initial neurological presentation. CONCLUSIONS: Systematic association of IgIA + ECZ is not supported for all neurological STEC-HUS pediatric patients; potential rescue therapy for severe cases warrants consideration.

IPNA consensus definitions for clinical trial outcomes in steroid-resistant nephrotic syndrome.

Assessment of the true impact of therapeutic interventions is a challenge in the absence of universal, standardized definitions for clinical trial endpoints in children with kidney diseases. Steroid-resistant nephrotic syndrome (SRNS) is a difficult kidney disease to treat, with unremitting disease progressing to kidney failure. Currently, available therapies result in suboptimal cure rates. Clinical trials with innovative, targeted treatments will likely be conducted for this disease in the foreseeable future. An international consortium of the IPNA Best Practices and Standards Committee and the Pediatric Nephrology Expert Group of the conect4children (c4c) network developed through consensus, standardized, internationally acceptable definitions for trial outcomes for SRNS. The endpoint definitions were formulated for use with urine protein to creatinine ratios and estimated glomerular filtration rates. Definitions of complete remission, partial remission, non-remission of disease, reduction in proteinuria, kidney disease progression, kidney failure, and composite kidney outcome were refined using an iterative process until a consensus was achieved.

IPNA clinical practice recommendations for the diagnosis and management of children with IgA nephropathy and IgA vasculitis nephritis.

IgA nephropathy and IgA vasculitis with nephritis, albeit rare, represent two relatively frequent glomerular conditions in childhood. Compared to adults, pediatric IgA nephropathy has a more acute presentation, most frequently with synpharyngitic macrohematuria and histologically with more intense inflammation and less intense chronic damage. Management of these conditions is controversial and supported by little high-quality evidence. The paucity of evidence is due to the disease heterogeneity, its inter-ethnic variability, and the difficulty of extrapolating data from adult studies due to the peculiarities of the condition in children. IgA vasculitis with nephritis is a kidney manifestation of a systemic disorder, typical of the pediatric age, in which both the diagnosis of kidney involvement and its management are poorly defined, and an interdisciplinary approach is crucial. Both conditions can have a profound and long-lasting impact on kidney function and the global health of affected children. The International Pediatric Nephrology Association has therefore convened a diverse international group of experts from different disciplines to provide guidance on the recommended management of these conditions in children and to establish common definitions and define priorities for future high-quality, evidence-based collaborative studies for the benefit of children.

Development of clinical and laboratory biomarkers in an international cohort of 428 children with lupus nephritis.

BACKGROUND: Lupus nephritis (LN) is a very severe manifestation of lupus. There is no consensus on which treatment goals should be achieved to protect kidney function in children with LN. METHODS: We retrospectively analyzed trends of commonly used laboratory biomarkers of 428 patients (≤ 18 years old) with biopsy-proven LN class ≥ III. We compared data of patients who developed stable kidney remission from 6 to 24 months with those who did not. RESULTS: Twenty-five percent of patients maintained kidney stable remission while 75% did not. More patients with stable kidney remission showed normal hemoglobin and erythrocyte sedimentation rate from 6 to 24 months compared to the group without stable kidney remission. eGFR ≥ 90 ml/min/1.73m2 at onset predicted the development of stable kidney remission (93.8%) compared to 64.7% in those without stable remission (P < 0.00001). At diagnosis, 5.9% and 20.2% of the patients showed no proteinuria in the group with and without stable kidney remission, respectively (P = 0.0001). dsDNA antibodies decreased from onset of treatment mainly during the first 3 months in all groups, but more than 50% of all patients in both groups never normalized after 6 months. Complement C3 and C4 increased mainly in the first 3 months in all patients without any significant difference. CONCLUSIONS: Normal eGFR and the absence of proteinuria at onset were predictors of stable kidney remission. Significantly more children showed normal levels of Hb and erythrocyte sedimentation rate (ESR) from 6 to 24 months in the group with stable kidney remission.

Biallelic NPR1 loss of function variants are responsible for neonatal systemic hypertension.

BACKGROUND: Early-onset isolated systemic hypertension is a rare condition of unknown genetic origin. Renovascular, renal parenchymal diseases or aortic coarctation are the most common causes of secondary systemic hypertension in younger children and neonates. We investigated the genetic bases of early-onset isolated systemic hypertension. METHODS: Whole-exome sequencing (WES) was followed by variant filtering and Sanger sequencing for validation and familial segregation of selected variants in a large consanguineous family. mRNA expression was performed to evaluate the impact of the predicted pathogenic variant on gene expression. WES or Sanger sequencing was performed in additional unrelated affected individuals. RESULTS: In one consanguineous family with four children presenting with isolated neonatal-onset systemic hypertension, we identified homozygous stop-gain variant in the NPR1 gene (NM_000906.4:c.1159C>T (p.Arg387Ter)) in the affected individuals. This variant leads to a dramatic reduction of NPR1 RNA levels. NPR1 gene analysis of additional families allowed the identification of another family with two affected children carrying homozygous frameshift variant in NPR1 (NM_000906.4:c.175del (p.Val59TrpfsTer8)). CONCLUSION: We show for the first time that biallelic loss of function of NPR1 is responsible for isolated neonatal-onset systemic hypertension in humans, which represents a new autosomal recessive genetic cause of infantile systemic hypertension or cardiogenic shock. This is consistent with studies reporting early-onset systemic hypertension and sudden death in Npr1-deficient mice. NPR1 gene analysis should be therefore investigated in infants with early-onset systemic hypertension with or without cardiogenic shock of unknown origin.

Vesico-ureteral reflux diagnosis after initial kidney abscess: Results from a Paediatric Tertiary Hospital.

AIMS: Guidelines regarding voiding cystourethrogram (VCUG) indications following a paediatric kidney abscess are lacking. This study evaluates vesicoureteral reflux (VUR) prevalence and outcome after a first kidney abscess. METHODS: This retrospective study included all children presenting to a tertiary paediatric reference centre with de-novo kidney abscesses from 2011 to 2022, diagnosed through imaging (ultrasonography or computed tomography). VCUG's clinical utility was assessed by exploring outcomes related to interventions. RESULTS: Among the 17 patients (median age 9 months, IQR; 6 months-6 years), VCUG identified VUR in 7 (41%; 95% CI: 18-65%), including two with grade IV-V. Median abscess size was 19 mm (IQR; 14-27). 7/8 (88%) children with DMSA scan presented scars, including 4 with hypofunctioning (20%-44%), and one with a non-functioning kidney. Scarring on the DMSA scan was similar regardless of identified VUR. Six children had subsequent pyelonephritis. Three of the remaining 11 had grade I-III and two IV-V VUR. Surgery was required in four children overall: three for recurrent pyelonephritis and one for high-grade VUR and scars. CONCLUSION: Among initial kidney abscess cases, 41% had VUR, similar to children experiencing their first uncomplicated pyelonephritis. VCUG results guided antibiotic prophylaxis but not surgical decisions. We suggest considering VCUG following recurrent pyelonephritis/kidney abscess and/or kidney scarring.

The genetic landscape and clinical spectrum of nephronophthisis and related ciliopathies.

Nephronophthisis (NPH) is an autosomal-recessive ciliopathy representing one of the most frequent causes of kidney failure in childhood characterized by a broad clinical and genetic heterogeneity. Applied to one of the worldwide largest cohorts of patients with NPH, genetic analysis encompassing targeted and whole exome sequencing identified disease-causing variants in 600 patients from 496 families with a detection rate of 71%. Of 788 pathogenic variants, 40 known ciliopathy genes were identified. However, the majority of patients (53%) bore biallelic pathogenic variants in NPHP1. NPH-causing gene alterations affected all ciliary modules defined by structural and/or functional subdomains. Seventy six percent of these patients had progressed to kidney failure, of which 18% had an infantile form (under five years) and harbored variants affecting the Inversin compartment or intraflagellar transport complex A. Forty eight percent of patients showed a juvenile (5-15 years) and 34% a late-onset disease (over 15 years), the latter mostly carrying variants belonging to the Transition Zone module. Furthermore, while more than 85% of patients with an infantile form presented with extra-kidney manifestations, it only concerned half of juvenile and late onset cases. Eye involvement represented a predominant feature, followed by cerebellar hypoplasia and other brain abnormalities, liver and skeletal defects. The phenotypic variability was in a large part associated with mutation types, genes and corresponding ciliary modules with hypomorphic variants in ciliary genes playing a role in early steps of ciliogenesis associated with juvenile-to-late onset NPH forms. Thus, our data confirm a considerable proportion of late-onset NPH suggesting an underdiagnosis in adult chronic kidney disease.

Human kidney-derived hematopoietic stem cells can support long-term multilineage hematopoiesis.

Long-term multilineage hematopoietic donor chimerism occurs sporadically in patients who receive a transplanted solid organ enriched in lymphoid tissues such as the intestine or liver. There is currently no evidence for the presence of kidney-resident hematopoietic stem cells in any mammal species. Graft-versus-host-reactive donor T cells promote engraftment of graft-derived hematopoietic stem cells by making space in the bone marrow. Here, we report full (over 99%) multilineage, donor-derived hematopoietic chimerism in a pediatric kidney transplant recipient with syndromic combined immune deficiency that leads to transplant tolerance. Interestingly, we found that the human kidney-derived hematopoietic stem cells took up long-term residence in the recipient's bone marrow and gradually replaced their host counterparts, leading to blood type conversion and full donor chimerism of both lymphoid and myeloid lineages. Thus, our findings highlight the existence of human kidney-derived hematopoietic stem cells with a self-renewal ability able to support multilineage hematopoiesis.

A multicenter retrospective study of calcineurin inhibitors in nephrotic syndrome secondary to podocyte gene variants.

While 44-83% of children with steroid-resistant nephrotic syndrome (SRNS) without a proven genetic cause respond to treatment with a calcineurin inhibitor (CNI), current guidelines recommend against the use of immunosuppression in monogenic SRNS. This is despite existing evidence suggesting that remission with CNI treatment is possible and can improve prognosis in some cases of monogenic SRNS. Herein, our retrospective study assessed response frequency, predictors of response and kidney function outcomes among children with monogenic SRNS treated with a CNI for at least three months. Data from 203 cases (age 0-18 years) were collected from 37 pediatric nephrology centers. Variant pathogenicity was reviewed by a geneticist, and 122 patients with a pathogenic and 19 with a possible pathogenic genotype were included in the analysis. After six months of treatment and at last visit, 27.6% and 22.5% of all patients respectively, demonstrated partial or full response. Achievement of at least partial response at six months of treatment conferred a significant reduction in kidney failure risk at last follow-up compared to no response (hazard ratio [95% confidence interval] 0.25, [0.10-0.62]). Moreover, risk of kidney failure was significantly lower when only those with a follow-up longer than two years were considered (hazard ratio 0.35, [0.14-0.91]). Higher serum albumin level at CNI initiation was the only factor related to increased likelihood of significant remission at six months (odds ratio [95% confidence interval] 1.16, [1.08-1.24]). Thus, our findings justify a treatment trial with a CNI also in children with monogenic SRNS.

Validation of a prediction system for risk of kidney allograft failure in pediatric kidney transplant recipients: An international observational study.

Predicting long-term kidney allograft failure is an unmet need for clinical care and clinical trial optimization in children. We aimed to validate a kidney allograft failure risk prediction system in a large international cohort of pediatric kidney transplant recipients. Patients from 20 centers in Europe and the United States, transplanted between 2004 and 2017, were included. Allograft assessment included estimated glomerular filtration rate, urine protein-to-creatinine ratio, circulating antihuman leukocyte antigen donor-specific antibody, and kidney allograft histology. Individual predictions of allograft failure were calculated using the integrative box (iBox) system. Prediction performances were assessed using discrimination and calibration. The allograft evaluations were performed in 706 kidney transplant recipients at a median time of 9.1 (interquartile range, 3.3-19.2) months posttransplant; mean estimated glomerular filtration rate was 68.7 ± 28.1 mL/min/1.73 m2, and median urine protein-to-creatinine ratio was 0.1 (0.0-0.4) g/g, and 134 (19.0%) patients had antihuman leukocyte antigen donor-specific antibodies. The iBox exhibited accurate calibration and discrimination for predicting the outcomes up to 10 years after evaluation, with a C-index of 0.81 (95% confidence interval, 0.75-0.87). This study confirms the generalizability of the iBox to predict long-term kidney allograft failure in children, with performances similar to those reported in adults. These results support the use of the iBox to improve patient monitoring and facilitate clinical trials in children.