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Introduction: Genetic disorders are among the most prevalent causes leading to progressive glomerular disease and, ultimately, end-stage renal disease (ESRD) in children and adolescents. Identification of underlying genetic causes is indispensable for targeted treatment strategies and counseling of affected patients and their families. Methods: Here, we report on a boy who presented at 4 years of age with proteinuria and biopsy-proven focal segmental glomerulosclerosis (FSGS) that was temporarily responsive to treatment with ciclosporin A. Molecular genetic testing identified a novel mutation in alpha-actinin-4 (p.M240T). We describe a feasible and efficient experimental approach to test its pathogenicity by combining in silico, in vitro, and in vivo analyses. Results: The de novo p.M240T mutation led to decreased alpha-actinin-4 stability as well as protein mislocalization and actin cytoskeleton rearrangements. Transgenic expression of wild-type human alpha-actinin-4 in Drosophila melanogaster nephrocytes was able to ameliorate phenotypes associated with the knockdown of endogenous actinin. In contrast, p.M240T, as well as other established disease variants p.W59R and p.K255E, failed to rescue these phenotypes, underlining the pathogenicity of the novel alpha-actinin-4 variant. Conclusion: Our data highlight that the newly identified alpha-actinin-4 mutation indeed encodes for a disease-causing variant of the protein and promote the Drosophila model as a simple and convenient tool to study monogenic kidney disease in vivo.

Nephrotic syndrome in patients with cancer may be related to the primary malignancy or chemotherapeutic therapy. Solid organ cancers may cause membranous glomerulonephritis manifesting with nephrotic syndrome; other less common histologic presentations include focal and segmental glomerulosclerosis and minimal change disease. In addition, chemotherapy agents can cause renal toxicity by affecting the small blood vessels, glomeruli, tubules, and interstitium. Tyrosine kinase inhibitors such as sunitinib may cause endothelial and podocyte damage leading to renal limited thrombotic microangiopathy, manifested by proteinuria and hypertension. We report a case of an elderly man with gastrointestinal stromal tumor (GIST) on treatment with sunitinib who had as a complication of a thrombotic microangiopathy manifested with nephrotic syndrome and difficult-to-control hypertension, which was controlled by stopping this drug but with a fatal outcome due to its malignant neoplasm.

Several novel antigens have recently been characterized in membranous nephropathy (MN), but those involved in the rare cases of MN associated with inflammatory neuropathies (IN) remain elusive. Although several antibody specificities were identified in the serum, there is no evidence so far for their deposition in glomeruli. We report the case of a 73 y/o woman who was referred because of subacute onset of proximal asymmetric lower limb weakness together with ataxic gait. She was diagnosed with IN. Blood tests showed an eGFR of 73 ml/min/1.73m2, hypoalbuminemia (2.89 g/dl) and proteinuria (3.6 g/24h). Autoantibodies (ANA, ENA, DNA, LAC, anti-cardiolipin, ANCA) were undetectable. Serum Ig and complement levels were normal. A kidney biopsy with electron microscopy examination showed a classical picture of MN. Anti-PLA2R antibody was negative in the serum and PLA2R and THSD7A antigens were not detected in kidney tissue. Anti-contactin1 (CNTN1) antibody was found by ELISA at 1:100 serum dilution and shown to be mostly of IgG4 subclass by Western blot. CNTN1 antigen was co-localized with IgG4 within immune deposits by confocal microscopy. This observation suggests a pathophysiological link between IN and MN. CNTN1 should be considered as a potential candidate antigen involved in MN and tested in PLA2R negative forms associated with IN.

Treatment with glucocorticoids in children with nephrotic syndrome can be the cause of developmental disorders of the masticatory organ and bone or teeth abnormalities. The aim was to assess the frequency and type of dental abnormalities and the correlation of their occurrence with a dosage of glucocorticoids and treatment time in children with idiopathic nephrotic syndrome.The study group consisted of 31 patients aged 5 to 17 diagnosed with idiopathic steroid-sensitive nephrotic syndrome and 33 overall healthy children. The studies included clinical evaluation of dentition, radiologic diagnostics, and statistical analysis.In the study group, 77.4% of patients were diagnosed with abnormalities in dental development. Tooth number disorders, presence of persistent deciduous teeth and impacted teeth, abnormal crown or root shape, developmental defects of enamel, pulp stones, and bone structure disorders were identified. Statistical analysis showed significant differences in the average treatment time of glucocorticoids in patients without and with tooth developmental abnormalities.Long-term use of glucocorticoids in children with nephrotic syndrome promotes the occurrence of developmental abnormalities of the teeth, calcification of the pulp, and disorders of bone tissue metabolism. For this reason, patients with steroid-sensitive nephrotic syndrome should be under the constant care of a dentist.

Calcimimetic agents allosterically increase the calcium ion sensitivity of the calcium-sensing receptor (CaSR), which is expressed in the tubular system and to a lesser extent in podocytes. Activation of this receptor can reduce glomerular proteinuria and structural damage in proteinuric animal models. However, the precise role of the podocyte CaSR remains unclear. Here, a CaSR knockdown in cultured murine podocytes and a podocyte-specific CaSR knockout in BALB/c mice were generated to study its role in proteinuria and kidney function. Podocyte CaSR knockdown abolished the calcimimetic R-568 mediated calcium ion-influx, disrupted the actin cytoskeleton, and reduced cellular attachment and migration velocity. Adriamycin-induced proteinuria enhanced glomerular CaSR expression in wild type mice. Albuminuria, podocyte foot process effacement, podocyte loss and glomerular sclerosis were significantly more pronounced in adriamycin-treated podocyte-specific CaSR knockout mice compared to wild type littermates. Co-treatment of wild type mice with adriamycin and the calcimimetic cinacalcet reduced proteinuria in wild type, but not in podocyte-specific CaSR knockout mice. Additionally, four children with nephrotic syndrome, whose parents objected to glucocorticoid therapy, were treated with cinacalcet for one to 33 days. Proteinuria declined transiently by up to 96%, serum albumin increased, and edema resolved. Thus, activation of podocyte CaSR regulates key podocyte functions in vitro and reduced toxin-induced proteinuria and glomerular damage in mice. Hence, our findings suggest a potential novel role of CaSR signaling in control of glomerular disease.

Tubular basement membrane (TBM) deposits are very uncommon in non-lupus membranous nephropathy. We report 5 patients with membranous nephropathy and extensive TBM deposits following allogeneic hematopoietic cell transplant. Patients presented with nephrotic syndrome (3 also had acute kidney injury) late post-transplant in association with chronic graft-versus-host disease (cGVHD). Kidney biopsies revealed global subepithelial and extensive TBM immune complex deposits, accompanied by acute tubular injury (n = 4) and tubulointerstitial inflammation (n = 4). Proteomic analysis of glomeruli in 4 cases identified PLA2R in 1, with no significant protein spectra for PLA2R, THSD7A, EX1/2, NELL-1, PCDH7, NCAM1, or SEMA3B detected in the remaining 3. On follow-up (for a mean 42 months), 4 patients had complete and 1 partial remission following prednisone and/or rituximab therapy. We propose that membranous nephropathy with extensive TBM deposits is a distinctive clinicopathologic lesion associated with allogeneic hematopoietic cell transplant. Pathogenesis likely involves cGVHD-driven antibodies against glomerular and TBM components, the identity of which remains to be elucidated.

A diagnosis of nephrotic syndrome (NS) in children with edema relies on urinary albumin excretion and usually plasma protein (Pprot) and albumin (Palb) concentrations.In order to fit laboratory tests to optimal healthcare in low-resource countries, we established correlations between Pprot and Palb in children with NS (217 measurements in 60 patients) and in children with exudative enteropathy and chronic hepatopathy/liver insufficiency (186 measurements in 21 patients); all patients had repeated measurements at various stages of their disease.There was a good correlation between Pprot and Palb in children with idiopathic NS and genetic NS (ICC=0.8, p 0.0001, 95% CI: 0.8-0.9 and ICC=0.8, p 0.0001, 95% CI: 0.7-0.8, respectively), whereas the correlation was average (exudative enteropathy) or absent (chronic hepatopathy) in those without renal protein loss.Since Palb measurement is around two times more expensive than Pprot measurement, these results suggest giving priority to total Pprot measurement in the diagnosis and follow-up of children with the NS, mainly in low-resource countries.

A substantial number of patients with focal segmental glomerulosclerosis (FSGS) have a pathogenic genetic mutation in a podocyte protein as the cause of their disease. The mutations can affect a wide range of cell functions including the actin cytoskeleton, cell adhesion and motility, mitochondrial function, and nuclear pore proteins. The likelihood of a genetic cause declines with age, from approximately 30% in children and adolescents to 10% in adulthood, and the specific proteins involved and the pattern of inheritance differ in the 2 age groups. The presence of a genetic cause for FSGS can have important clinical ramifications including the need for a diagnostic kidney biopsy, medical management, and the risk of recurrent disease after kidney transplantation. This review summarizes the spectrum of genetic causes of nephrotic syndrome, primarily FSGS, in adults with a focus on diagnosis, presentation, and management.

Background Sixty percent of children with nephrotic syndrome have frequently relapsing or steroid-dependent course. Serious infections like peritonitis, cellulitis, pneumonia etc. and anasarca with reduced urine output and complications there of including acute kidney injury and thromboembolism contribute significantly to morbidity and mortality in these children. Methods Questionnaire-based module to study infectious complications in children with nephrotic syndrome was circulated through survey monkey portal to paediatric nephrologists in our country. Twenty-two responded. Forty percent said that they saw patients with severe infections once a month. Fish bone analysis conducted on such patients reporting to our centre over next 3 months revealed that only 22% regularly monitored urine protein by dipstick. We proposed that reduction in time to report relapse by regularly monitoring urine protein could reduce complications in these children. Six urine protein dipsticks were handed over to patients who presented >7 days since relapse or with severe infection or anasarca in the last 1 year. These children were followed up for the next 1 year and given six more urine dipsticks every 3 months. Results Twenty-three patients were given urine protein dipsticks. Nine of them had 12 severe complications in the previous 6 months. None had any serious infections/anasarca on follow-up. Sixteen new patients had 14 serious complications in this time. Conclusions Early detection of relapse by home monitoring of urine protein by dipsticks was effective in significantly reducing the number of patients with severe infections and anasarca with reduced urine output.

Nephrotic syndrome is characterized by severe proteinuria, hypoalbuminaemia, edema and hyperlipidaemia. Genetic studies of nephrotic syndrome have led to the identification of proteins playing a crucial role in slit diaphragm signaling, regulation of actin cytoskeleton dynamics and cell-matrix interactions. The laminin α5 chain is essential for embryonic development and, in association with laminin β2 and laminin γ1, is a major component of the glomerular basement membrane, a critical component of the glomerular filtration barrier. Mutations in LAMA5 were recently identified in children with nephrotic syndrome. Here, we have identified a novel missense mutation (E884G) in the uncharacterized L4a domain of LAMA5 where homozygous mice develop nephrotic syndrome with severe proteinuria with histological and ultrastructural changes in the glomerulus mimicking the progression seen in most patients. The levels of LAMA5 are reduced in vivo and the assembly of the laminin 521 heterotrimer significantly reduced in vitro. Proteomic analysis of the glomerular extracellular fraction revealed changes in the matrix composition. Importantly, the genetic background of the mice had a significant effect on aspects of disease progression from proteinuria to changes in podocyte morphology. Thus, our novel model will provide insights into pathologic mechanisms of nephrotic syndrome and pathways that influence the response to a dysfunctional glomerular basement membrane that may be important in a range of kidney diseases.

Corticosteroids have had a central role in the treatment of nephrotic syndrome. The management of these patients who become dependent to steroids is complex, involving different immunosuppressive drugs patterns. The monoclonal antibody anti CD20, Rituximab, is likely to have beneficial effects in cases of steroid-dependent nephrotic syndrome patients with no easy resolution, even when we cannot make a statement about the specific role in the impact. We bring our personal experience in pediatric patients treated with this medication during the last years, to provide a thorough overview and useful information about the role of Rituximab in this pathology.Retrospective study in patients with steroid-dependent idiopathic nephrotic syndrome controlled in the division of Pediatric Nephrology of a Spanish tertiary hospital in those patients who had received at least one treatment cycle of Rituximab, at any moment along the evolution of the disease.The study involved 8 patients. All of them previously received immunosuppressive therapy. The Rituximab were administered as an intravenous infusion, in a dose of 375 mg/mThe favorable results reported after rituximab treatment in our patients seems to confirm the effectiveness of this drug in the steroid-dependent nephrotic syndrome, making that therapeutic option into consideration and legitimating the use of the drug in complex cases involving pediatric patients. Even so, it seems recommendable to design pertinent studies to clarify, among others, the optimum regimen of the treatment (dose, interval and cycles), clinical repercussion and potential adverse effects in long terms.

Background Nephrotic syndrome (NS) is the most frequent glomerular disease among children. Renal biopsy is the most precise procedure for diagnosing and following childhood NS; however, it is an invasive procedure with potential complications. As a result, early non-invasive diagnostic and prognostic indicators and new treatment targets are urgently needed for this disease. Purpose To assess the miR-142-5p expression in peripheral blood as an indicator of the autoimmune processes in children with NS and the role of differential microRNAs (miR) expression and expression panels in diagnosing and predicting the response to steroid treatment in children with NS. Methods Eighty (80) children with NS and 100 subjects matched for age and gender used as controls constitute the study sample in this case-control study. MiR-142-5p, miR-191, miR-181-5p, miR-30a-5p and miR-50a-5p expression are measured in all enrolled children by real-time PCR. We assessed the sensitivity and accuracy of different MicroRNAs panels. Results miR-142-5p, miR-191, miR-181-5p, miR-30a-5p and miR-150a-5p expressions were significantly increased in the children with NS than controls. There was a significant difference in the five mRNAs differential expressions between steroid-resistant and steroid-sensitive children with NS. Of the selected five microRNAs, miR-142a-5p was the best to allow very good discrimination of the children with NS and predict steroid resistance (AUC = 0.965 and 1.00, respectively), suggesting the possible autoimmunity processes' role in the pathogenesis of NS and the resistance to steroids. The (miR-142a-5p with miR-181a-5p and miR-30a-5p) was the best expression panel to diagnose new NS cases and predict steroid resistance. Conclusions microRNAs expressions, either differential or as a panel, are important for early diagnosing childhood NS and may provide a non-invasive clue for the response to steroid treatment in these patients. The (miR-142a-5p, miR-181-5p, and miR-30a-5p) panel was the best one to cover both the diagnosis of the new cases and prediction of response to steroid treatment. Autoimmunity has an important role in NS pathogenesis and resistance to steroid treatment.

Among youth with incident nephrotic syndrome, those with steroid-resistant nephrotic syndrome (SRNS) often have an ominous clinical course. Identifying them at or shortly after diagnosis would potentially prevent substantial morbidity and even mortality. For those with a specific monogenic form, targeted therapy might be possible, as is the case presently for CoQ10 insufficiency cases. Further, dissecting specific causes and pathways that lead to SRNS may lead to other targeted, potentially highly effective treatments.

International audience; Primary focal and segmental glomerulosclerosis (FSGS) frequently recurs after transplantation and is associated with a poor prognosis. We describe here the successful kidney graft reuse in an adult recipient, 8 months after early primary FSGS recurrence resistant to all available therapeutics. Patient 1, a 23-year-old man, followed for kidney failure secondary to primary FSGS, was first transplanted in 2018 with a deceased donor graft. Unfortunately, we observed an immediate recurrence of biopsy-proven primary FSGS. After 4 lines of treatment (intravenous cyclosporine + corticosteroids, plasma exchanges, immunoadsorption, and rituximab), the patient was still highly nephrotic and kidney function was slowly deteriorating. After approval from both the patient and the health authority (Biomedicine Agency), the graft was detransplanted 8 months after transplantation and reimplanted in patient 2, a 78-year-old nonimmunized and anephric recipient (bi-nephrectomy 2 years previously for bilateral renal carcinoma). We observed immediate kidney function and progressive resolution of proteinuria (serum creatinine of 1.2 mg/dL and proteinuria of 0.1 g/d 1 year later). Biopsies performed after surgery showed persistent FSGS lesions with a decrease in overall foot-process effacement. To our knowledge, this is the first reported case showing that kidney graft transfer may still be a viable option for refractory primary FSGS several months after transplantation.

Resumen: Introducción: El síndrome nefrótico (SN) primario es una glomerulopatía común en la edad pediátrica. Se evaluaron los genotipos y frecuencias alélicas del polimorfismo rs5370 del gen EDN1 en niños con SN primario. Pacientes y métodos: Estudio de casos y controles realizado en el Hospital Infantil Universitario de El Mansura, Egipto, de diciembre de 2015 a enero de 2018. Se seleccionó a 50 pacientes con SN corticosensible (SNCS) y a 50 con SN corticorresistente (SNCR), así como a 100 controles sanos. Además de una evaluación clínica de los pacientes, se hicieron pruebas de cuantificación de albúmina, colesterol, creatinina y urea séricas y de proteinuria en muestra de orina de 24 h. Se emplearon técnicas de reacción en cadena de la polimerasa para analizar los genotipos (GG, GT y TT) y los alelos (T y G) del polimorfismo rs5370 del gen EDN1 en los grupos en estudio. Resultados: El genotipo GT fue el más frecuente del polimorfismo rs5370 del gen EDN1 en el grupo de control (88%, p = 0,001), mientras que el genotipo GG fue más frecuente en el grupo con SN que en el de control (p = 0,02). No se encontraron diferencias estadísticamente significativas entre los grupos de SN y de control en los alelos del polimorfismo rs5370 (p = 0,69). El genotipo GG fue más prevalente en el grupo de SNSC que en los grupos de SNRC y de control (p = 0,03). Las diferencias en las frecuencias alélicas entre los grupos de SNRC, SNSC y de control no fueron significativas (p = 0,89). El genotipo GT se asoció a una presión arterial normal en niños con SN (p = 0,007) mientras que el genotipo GG se asoció a hipertensión (p

Galloway-Mowat syndrome (GAMOS) is an extremely rare clinically heterogeneous autosomal or X-linked inherited recessive disease characterized by early-onset steroid-resistant nephrotic syndrome (SRNS), microcephaly and neurological impairment. In this study, two siblings mainly presenting with decreased head circumference, hypotonia, gross motor delay, and dysmorphic features were initially detected without pathogenic variants by karyotyping, SNP-array and WES. After a 3 year’s follow-up, the proband manifested additional proteinuria, hematuria and “deeper sulci” with a sign of brain atrophy. By reanalysis on the proband’s previous WES data, two novel compound heterozygous variants of OSGEP (c.133dupA; c.608C > T) were identified. Furthermore, functional studies showed that the variants reduced the expression of OSGEP protein and activated the DNA damage response (DDR) signaling in the lymphoblastoid cell lines (LCLs) obtained from the patient. The analysis of protein localization with confocal microscopy revealed that the EGFP-tagged/HA-tagged mutant OSGEP proteins were abnormal aggregation or retained inside the cytosol, respectively. Our study not only expanded the pathogenic variant spectrum of OSGEP but also carried on regular follow-up for kidney involvement and established a strategy for evaluation on the function of mutant OSGFP by subcellular localization assay.

Chimeric antigen receptor T (CAR-T) cell treatment is a rapidly emerging therapy for relapsed/refractory hematologic malignancies. Although cytokine release syndrome is a common complication, a concomitant development of biopsy-proven collapsing glomerulopathy and acute kidney injury (AKI) has not been described with CAR-T cell therapy. We report a man in his early 20s with relapsed/refractory pre–B-cell acute lymphoblastic leukemia and compensated liver cirrhosis who received 3 courses of CD19-directed CAR-T cells. After the third CAR-T cell therapy, he developed severe cytokine release syndrome accompanied by new onset of nephrotic syndrome and AKI. Cytokine release syndrome was treated with tocilizumab. His kidney biopsy showed collapsing glomerulopathy, glomerulitis, and interstitial nephritis along with complete podocyte foot-process effacement. Due to disease progression, he was subsequently treated with bispecific CD19-directed CD3 T-cell engager antibody, blinatumomab, during which he developed another episode of cytokine release syndrome with exacerbation of nephrotic-range proteinuria and his AKI progressed to stage 3 chronic kidney disease. Excess cytokine-induced podocyte and renal tubulointerstitial injury and/or “on-target off-tumor” direct renal cell toxicity are the probable mechanisms of kidney injury. Further such reports will increase our understanding of the pathophysiologic basis of kidney injury with CAR-T treatment.

Primary focal segmental glomerulosclerosis (FSGS) is a podocytopathy with an irregular response to immunosuppressive therapies. FSGS relapse occurs in 30% to 80% of kidney grafts, and poor survival outcomes include large proteinuria and the nephrotic syndrome's cardinal clinical features. Thrombotic microangiopathy (TMA) is caused by endothelial injury due to complement dysregulation including acute kidney injury, proteinuria, and severe hypertension common renal presentations. Both pathologies have well-described genetic forms, but their relationship remains uncertain. FSGS lesions can be found in kidney biopsy specimens in patients with TMA, and TMA has been reported in patients with collapsing glomerulopathy. However, this combination has not been clearly described in renal transplant recipients. We present the case of a 22-year-old man who received his second kidney allograft and developed an early graft disfunction with nephrotic syndrome and clinical TMA. His background was remarkable for primary, biopsy-confirmed FSGS in childhood, and he started hemodialysis in 2006 and received a living donor kidney graft the same year. He presented with a FSGS relapse with malignant hypertension and seizures in the first posttransplant month and had an irregular response to plasma exchange and rituximab, and dialysis was reinitiated 10 years later. A total of 3 biopsies were performed after his second kidney transplant showing the evolution of a FSGS relapse with histologic and clinical TMA in the absence of identified genetic mutations. Partial responses to treatments with plasma exchange, eculizumab, and rituximab were obtained, but the allograft was lost after 26 months. This case is the first report of concomitant FSGS and TMA in a renal transplant recipient.

Graphical abstract, Introduction Nephrotic syndrome is a common pediatric kidney disease. Investigations on several genetic polymorphisms revealed an inconsistent influence on the resistance of patients to steroids. Objectives This study aimed to identify the association of ABCB1 (1236C > T, 2677G > T, 3435C > T), NR3C1 (rs10482634, rs6877893), and CYP3A5 (CYP3A5*3) gene polymorphism as well as sociodemographic and clinicopathological parameters with the risk of developing prednisolone resistance in pediatric patients with nephrotic syndrome. Methods A case-control analysis was performed on 180 nephrotic syndrome patients. Among them, 30 patients were classified as prednisolone resistant group, and 150 were classified as prednisolone sensitive group. Genotyping was performed by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Results No significant association of 1236C > T polymorphism with the risk of prednisolone resistance (p > 0.05) was found. The GT heterozygous of 2677G > T was found to be significantly associated with the development of prednisolone resistance (OR = 3.9, p = 0.034). In the case of 3435C > T, a statistically significant association was observed in TC heterozygous and TT mutant homozygous genotypes (OR = 0.38, p = 0.047; OR = 3.06, p = 0.038, respectively) with prednisolone resistance. For rs10482634 polymorphism, the AG heterozygous and AG+GG genotypes were significantly linked with prednisolone resistance (OR = 2.40, p = 0.033; OR = 2.36, p = 0.034, respectively). We found no association with the risk of prednisolone resistance with rs6877893 and CYP3A5*3 polymorphism (p > 0.05). CTC and TGT haplotypes of ABCB1 and GA haplotype of NR3C1 were also associated with the increased risk of pediatric prednisolone resistance (OR = 4.47, p = 0.0003; OR = 2.71, p = 0.03; and OR = 4.22, p = 0.022, consecutively). We also observed the correlation of different sociodemographic and clinicopathological factors with prednisolone resistance in pediatric nephrotic syndrome. Conclusion Our findings showed a significant association of ABCB1 and NR3C1 gene polymorphisms with prednisolone resistant pediatric nephrotic syndrome.

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

International audience; Calcimimetics allosterically increase the calcium ion sensitivity of the calcium-sensing receptor (CaSR). Using a CaSR knockdown in podocytes and a podocyte-specific CaSR knockout in mice, Mühlig et al. uncovered a stabilizing role for actin cytoskeleton and cell adhesion. Short-term alleviation of albuminuria and proteinuria was observed in 4 children treated with cinacalcet. Here we discuss the potential mechanisms whereby CaSR displays a favorable effect in podocytes and the context in which calcimimetics may alleviate nephrotic syndrome.

There is increasing recognition of monoclonal gammopathy as a cause of proliferative glomerulonephritis (GN), including cases in which glomerular deposition of monoclonal immunoglobulin is demonstrated. Recently, proliferative GN with monoclonal immunoglobulin deposits (PGNMID) has incorporated a light chain variant of the disease (termed PGNMID-LC). Intriguingly, glomerular co-deposition of C3 is found in addition to monotypic light chain, implying complement activation via the alternative pathway (AP). We present a unique case of proliferative GN in a 42-year-old man who presented with nephrotic syndrome and was found to have κ light chain multiple myeloma. Immune staining of the glomerulus was positive only for κ light chain and C3, with the striking appearance of nonamyloid fibrils on electron microscopy. Following clonally targeted therapy for myeloma, the renal clinical abnormalities resolved completely. We present detailed molecular studies for light chain and complement and consider local mechanisms whereby monoclonal κ light chain fibrils may have triggered AP activation within the glomerulus.

Membranous nephropathy (MN) constitutes a major cause of nephrotic syndrome (NS) in adults. After kidney transplantation (KTx), both recurrent and de novo MN has been reported. In addition to PLA2R and THSD7A, recent identification of neural EGFL-like-1 protein, NELL1, as a potential disease antigen has enriched our understanding of MN pathogenesis. To date, NELL1-positive MN has only been described in native kidneys, but never been diagnosed in renal allografts. We here report on a 56-year-old male kidney transplant recipient suffering from amyotrophic lateral sclerosis (ALS), who developed NS 25 years after KTx. Allograft biopsy revealed NELL1-positive MN. Using specifically established immunoblotting techniques, we detected new-onset NELL1-IgG1, IgG3, and IgG4 antibodies in the patient´s serum correlating with the course of proteinuria. While primary renal disease was undetermined, MN recurrence seemed unlikely given the long-time span since KTx. By clinical investigation of de novo etiologies, we did not detect an underlying malignancy. However, previous self-medication with dimercaptopropane sulfonate (DMPS) and alpha lipoic acid (ALA) represented a potential trigger and cessation associated with partial remission of proteinuria. This report illustrates the first case of posttransplant NS due to NELL1-positive MN. Monitoring NELL1 antibodies in the serum promise to be a non-invasive diagnostic tool guiding disease management.

Rituximab is an important second line therapy in difficult nephrotic syndrome (NS), especially given toxicity of long-term glucocorticoid or calcineurin inhibitor (CNI) use. However, clinical response to rituximab is heterogenous. We hypothesized that this was underpinned by immunological differences amongst patients with NS. We recruited a cohort of 18 subjects with glucocorticoid-dependent or glucocorticoid-resistant childhood-onset minimal change NS who received rituximab either due to CNI nephrotoxicity, or due to persistent glucocorticoid toxicity with inadequate response to cyclophosphamide or CNIs. Immunological subsets, T-cell activation assays and plasma cytokines were measured at baseline and 6-months post-rituximab. Time to relapse was bifurcated: 56% relapsed within one year ("early relapse"), while the other 44% entered remission mainly lasting ≥3 years ("sustained remission"). At baseline, early relapse compared to sustained remission group had lower regulatory T-cells (Tregs) [2.94 (2.25, 3.33)% vs 6.48 (5.08, 7.24)%, P

Objective To increase the likelihood of finding a causative genetic variant in patients with a focal segmental glomerulosclerosis (FSGS) lesion, clinical and histologic characteristics were analyzed. Patients and Methods Individuals 18 years and older with an FSGS lesion on kidney biopsy evaluated at Mayo Clinic from November 1, 1999, through October 31, 2019, were divided into 4 groups based on clinical and histologic characteristics: primary FSGS, secondary FSGS with known cause, secondary FSGS without known cause, and undetermined FSGS. A targeted gene panel and a customized gene panel retrieved from exome sequencing were performed. Results The overall rate of detection of a monogenic cause was 42.9% (21/49). Individuals with undetermined FSGS had the highest rate of positivity (87.5%; 7/8) followed by secondary FSGS without an identifiable cause (61.5%; 8/13) and secondary FSGS with known cause (33.3%; 5/15). Four of 5 (80%) individuals in the latter group who had positive genetic testing results also had a family history of kidney disease. Univariate analysis showed that family history of kidney disease (odds ratio [OR], 13.8; 95% CI, 3.7 to 62.4; P Conclusion In adults with FSGS lesions, proper selection of patients increases the rate of positive genetic testing significantly. The majority of individuals with undetermined FSGS in whom the clinical presentation and histologic parameters are discordant had a genetic diagnosis.

Shortage of organs for liver transplantation (LT) and the availability of highly efficient pan-genotypic direct-acting antivirals (DAAs) against hepatitis C virus (HCV) have allowed the use of livers from HCV-positive antibody/negative nucleic acid test donors (dHCV Ab+/NAT-) into aviremic HCV recipients over the last few years. We report the case of a patient who received an LT from an HCV Ab+/NAT- donor and, after HCV viremic conversion, developed a nephrotic syndrome due to a focal proliferative glomerulonephritis early after LT. Patient's renal function and proteinuria resolved after successful treatment with DAAs. Renal and hepatic function remain normal over 24 months of follow-up. This case restates the success of LT using livers from dHCV Ab+/NAT- in aviremic recipients in the context of DAAs while illustrating the risk for potential complications associated with the HCV transmission and reinforcing the importance of early initiation of anti-HCV therapy.

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.

Primary membranous nephropathy is a leading cause of adult nephrotic syndrome. The field took a major step forward with the identification of phospholipase A2 receptor (PLA2R) as a target antigen in the majority of cases and with the ability to measure circulating autoantibodies to PLA2R. Since then, the existence of additional target antigens such as thrombospondin type-1 domain-containing 7A, exostosin 1 and 2, neural EGFL like 1, and semaphorin 3B has been demonstrated. The ability to detect and monitor levels of circulating autoantibodies has opened a new window onto the humoral aspect of primary membranous nephropathy. Clinicians now rely on clinical parameters such as proteinuria, as well as levels of circulating autoantibodies against PLA2R and the results of immunofluorescence staining for PLA2R within kidney biopsy tissue, to guide the management of this disease. The relationship between immunologic and clinical disease course is consistent, but not necessarily intuitive. In addition, kidney biopsy provides only a single snapshot of disease that needs to be interpreted in light of changing clinical and serological findings. A clear understanding of these dynamic parameters is essential for staging, treatment, and management of this disease. This review aims to shed light on current knowledge regarding the development and time course of changes in the serum levels of autoantibodies against PLA2R, proteinuria, and histological findings that underlie the pathophysiology of primary membranous nephropathy.

Renal injury resulting from obesity is a growing concern caused by the global obesity epidemic. We discuss the glomerular structure, obesity-related glomerular changes, and diagnostic pathologic criteria for obesity-related glomerulopathy. The three main hypothesized mechanisms of podocyte injury are mechanical stress on the podocytes, metabolic derangement, and genetic/molecular factors. Weight loss, renin-angiotensin-aldosterone system inhibitors, and improved insulin resistance may slow the progression. A more comprehensive understanding of obesity-related glomerulopathy will help in developing more effective therapies.

We report on the development of minimal change disease (MCD) with nephrotic syndrome and acute kidney injury (AKI), shortly after first injection of the BNT162b2 COVID-19 vaccine (Pfizer-BioNTech). A 50-year-old previously healthy man was admitted to our hospital following the appearance of peripheral edema. Ten days earlier, he had received the first injection of the vaccine. Four days after injection, he developed lower leg edema, which rapidly progressed to anasarca. On admission, serum creatinine was 2.31 mg/dL and 24-hour urinary protein excretion was 6.9 grams. As kidney function continued to decline over the next days, empirical treatment was initiated with prednisone 80 mg/d. A kidney biopsy was performed and the findings were consistent with MCD. Ten days later, kidney function began to improve, gradually returning to normal. The clinical triad of MCD, nephrotic syndrome, and AKI has been previously described under a variety of circumstances, but not following the Pfizer-BioNTech COVID-19 vaccine. The association between the vaccination and MCD is at this time temporal and by exclusion, and by no means firmly established. We await further reports of similar cases to evaluate the true incidence of this possible vaccine side effect.

Introduction Although evidence suggests that neurological complications, including seizures and epilepsy, are more common among sickle cell disease (SCD) patients, few studies have assessed the risk factors of developing seizures among SCD patients Methods We used a nested case–control study design to compare pediatric and adult SCD patients who experienced seizures with patients who did not experience any seizure regarding clinical and laboratory parameters. We conducted a secondary analysis using the data from the Cooperative Study of Sickle Cell Disease in this study Results There were 153 out of 2804 (5.5%) pediatric patients who had seizures with a median age of 8.5 (Interquartile range [IQR] = 10.1) years at first seizure and 115 out of 1281 (9.0%) adult patients who had seizures with a median age of 28.0 (IQR = 10.6) years at first seizure. Cerebrovascular accident ([CVA], OR = 5.7, 95% CI = 2.9–11.0), meningitis (OR = 3.6, 95% CI = 1.8–7.2), and eye disease (OR = 3.4, 95% CI = 1.5–8.0) were associated with increased risk of developing seizures among pediatric patients. While CVA (OR = 7.5, 95% CI = 3.5–16.0), meningitis (OR = 5.6, 95% CI = 1.5–20.0), nephrotic syndrome (OR = 3.0, 95% CI = 1.2–7.9), spleen sequestration (OR = 2.7, 95% CI = 1.1–6.3), and pneumonia (OR = 2.1, 95% CI = 1.0–4.4) were associated with increased risk of developing seizures among adult patients Conclusion These findings suggest the need for treatment optimization and regular neurological follow up for SCD patients with these identified risk factors to prevent the development of seizures.

Familial Hypercholesterolemia (FH) is an autosomal dominant disease with an estimated prevalence between 1/200-250. It is under-treated and underdiagnosed. Massive data screening can increase the detection of patients with FH.Study population: Residents in the health coverage area (N: 195.000 inhabitants) and with at least one determination of cholesterol linked to low-density lipoproteins (LDL-C) carried out between January 1, 2010 and December 30, 2019. The highest LDL-C values were selected.nephrotic syndrome, hypothyroidism, Hypothyroid treatment or triglycerides400 mg / dL. Seven algorithms suggestive of Familial Hypercholesterolemia Phenotype (HF-P) were analyzed, selecting the most efficient algorithm that could easily be translated into clinical practice.Based on 6.264.877 assistances and 288.475 patients, after applying the inclusion-exclusion criteria, 504.316 tests were included, corresponding to 106.382 adults and 10.50918 years. The selected algorithm presented a prevalence of 0.62%. 840 patients with HF-P were detected, 55.8% being women and 17818 years old, 9.3% had a history of cardiovascular disease (CVD) and 16.4% had died. 65% of the patients in primary prevention had LDL-C values130 mg / dL and 83% in secondary prevention values70mg / dL. A ratio of 7.64 (1-18) patients with HF-P per analytical requesting physician was obtained.Massive data screening and patient profiling are effective tools and easily applicable in clinical practice for the detection of patients with FH.

Introduccion: In nephrotic syndrome, increased podocyturia accompanies pathologic proteinuria. The therapeutic regimen with enalapril, losartan and amiloride could reduce both variables. Objetives: Evaluate the anti-proteinuric effect of 2 non-immunological therapeutic regimens, the quantitative relationship between podocyturia and proteinuria. Material and methods: We included children aged 4–12 years with corticoresistant nephrotic syndrome, using 2 different schemes: group A, enalapril + losartan, and group B, enalapril + losartan + amiloride. Results: In group A, 17 patients completed the study, the initial mean proteinuria was 39 mg/m2/h and mean proteinuria at the end was 24 mg/m2/h, while in group B 14 patients were treated and the initial average proteinuria was 36 mg/m2/h and the end average proteinuria was 13 mg/m2/h. The paired T test showed significant differences in the decrease in proteinuria, for patients in group B without variation in podocyturia. The 2 factors associated with an increase in proteinuria were podocyturia and the time elapsed from the diagnosis of cortico-resistant nephrotic syndrome to the start of treatment anti-proteinuric. Conclusions: The use of amiloride decreased proteinuria, without significantly modifying podocyturia; we did not observe a positive relationship between both variables. Resumen: Introducción: En el síndrome nefrótico, la podocituria aumentada acompaña a la proteinuria patológica. El tratamiento con enalapril, losartán y amiloride podría reducir ambas variables. Objetivos: Evaluamos el efecto antiproteinúrico de 2 esquemas terapéuticos no inmunológicos, la relación cuantitativa entre la podocituria y la proteinuria, y las variables de riesgo asociadas con la proteinuria. Material y métodos: Incluimos niños de 4 a 12 años de edad con síndrome nefrótico corticorresistente, utilizando 2 esquemas terapéuticos distintos: grupo A, enalapril + losartán, y grupo B, enalapril + losartán + amiloride. Resultados: En el grupo A finalizaron el estudio 17 pacientes, la proteinuria promedio inicial fue de 39 mg/m2/h y la proteinuria media al finalizar fue de 24 mg/m2/h, en tanto que en el grupo B tratamos a 14 pacientes, la proteinuria promedio inicial fue de 36 mg/m2/h y la proteinuria promedio final de 13 mg/m2/h, y si bien ningún paciente redujo su proteinuria a valores fisiológicos, tanto la prueba t apareada (11,5, p

The most important contributors to the anemia of patients with chronic kidney disease are insufficient erythropoietin production and erythropoietin hyporesponsiveness, decreased red blood cell half-life, iron deficiency, and inflammation. However, in contrast to the role of kidney failure, that of proteinuria and nephrotic syndrome is less clear. Bissinger et al. now provide evidence in mouse models and patients with chronic kidney disease that heavy proteinuria alters erythrocyte metabolism and increases erythrocyte death.

The understanding and management of membranous nephropathy, a common cause of nephrotic syndrome that is more frequently encountered in adults than in children, has rapidly evolved over the past decade. Identification of target antigens has allowed for more precise molecular diagnoses, and the ability to monitor circulating autoantibodies has added a new vantage point in terms of disease monitoring and decisions about immunosuppression. Although immunosuppression with alkylating agents combined with corticosteroids, or with calcineurin inhibitor-based regimens, has been the historical mainstay of treatment, observational and now randomized controlled trials with the B-cell-depleting agent rituximab have moved this agent to the forefront of therapy for primary membranous nephropathy. In this Core Curriculum, we discuss the typical features of primary and secondary disease; highlight the target antigens such as the phospholipase A2 receptor, thrombospondin type 1 domain-containing 7A, neural epidermal growth factor-like 1, and semaphorin-3B; describe the relationship between the immunologic and clinical courses of disease; and review modern management with supportive care or immunosuppressive treatment based on these composite parameters.

Pembrolizumab is currently a standard first-line treatment option in stage IV non-small cell lung cancer (NSCLC) patients without targetable mutations. Discrepancies between pembrolizumab registration and its application in daily practice exist due to lack of clinical data in specific patient populations. Pharmacokinetic monitoring of pembrolizumab concentrations might provide more insight in the impact of certain conditions on immunotherapy exposure. In this report, we describe a 55-year-old male with metastasized programmed death ligand 1 (PD-L1)-high NSCLC and clinically diagnosed nephrotic syndrome with widespread edema, proteinuria, and severe hypoalbuminemia. The patient was treated with first-line 200 mg pembrolizumab every 3 weeks. Nephrotic syndrome is reported to be a potential source of therapeutic antibody loss during immunotherapy, due to increased protein turnover and excretion. Serum and urine pembrolizumab levels were measured to assess pembrolizumab exposure. Despite severe hypoalbuminemia and proteinuria, treatment was successful. The patient achieved therapeutic exposure and had an impressive clinical response with a vast improvement of edema and hypoalbuminemia, a radiological partial tumor response and ECOG performance status improving from 2 to 0.

The causes of kidney disease in pediatric patients are evenly divided between congenital abnormalities of the kidney and urinary tract and acquired disorders. Nearly 10% to 15% of adults in the United States have chronic kidney disease (CKD); there are no comparable data in children. Regardless of patient age, CKD is a systemic problem that affects every organ system, including the lung. We review the tests used to diagnose and evaluate kidney disease and the main clinical syndromes that are likely to be encountered to aid the pulmonology consultant who is asked to evaluate patients with kidney disease.

Focal segmental glomerulosclerosis (FSGS) is the main pathology underlying steroid-resistant nephrotic syndrome (SRNS) and a leading cause of chronic kidney disease. Monogenic forms of pediatric SRNS are predominantly caused by recessive mutations, while the contribution of de novo variants (DNVs) to this trait is poorly understood. Using exome sequencing (ES) in a proband with FSGS/SRNS, developmental delay, and epilepsy, we discovered a nonsense DNV in TRIM8, which encodes the E3 ubiquitin ligase tripartite motif containing 8. To establish whether TRIM8 variants represent a cause of FSGS, we aggregated exome/genome-sequencing data for 2,501 pediatric FSGS/SRNS-affected individuals and 48,556 control subjects, detecting eight heterozygous TRIM8 truncating variants in affected subjects but none in control subjects (p = 3.28 × 10(−11)). In all six cases with available parental DNA, we demonstrated de novo inheritance (p = 2.21 × 10(−15)). Reverse phenotyping revealed neurodevelopmental disease in all eight families. We next analyzed ES from 9,067 individuals with epilepsy, yielding three additional families with truncating TRIM8 variants. Clinical review revealed FSGS in all. All TRIM8 variants cause protein truncation clustering within the last exon between residues 390 and 487 of the 551 amino acid protein, indicating a correlation between this syndrome and loss of the TRIM8 C-terminal region. Wild-type TRIM8 overexpressed in immortalized human podocytes and neuronal cells localized to nuclear bodies, while constructs harboring patient-specific variants mislocalized diffusely to the nucleoplasm. Co-localization studies demonstrated that Gemini and Cajal bodies frequently abut a TRIM8 nuclear body. Truncating TRIM8 DNVs cause a neuro-renal syndrome via aberrant TRIM8 localization, implicating nuclear bodies in FSGS and developmental brain disease.

Oxidative stress and inflammation are central in the pathophysiology of light-chain amyloid cardiomyopathy (AL-CM). High-density lipoprotein cholesterol (HDLC) is an antioxidant and acts as an anti-inflammatory regulator. In this study, the prognostic value of serum HDL-C was explored in AL-CM.In this prospective single-center study, two hundred consecutive patients with biopsy-confirmed light-chain amyloidosis (AL) and cardiac involvement were enrolled. Patients were classified into low or normal serum HDL-C groups (HDL-C 40 mg/dL and HDL-C ≥ 40 mg/dL, respectively). Univariate and multivariate Cox models were used to identify predictors of survival. Kaplan-Meier analysis was performed to compare survival between patients with low or normal serum HDL-C.Patients with low serum HDL-C were more likely to present with higher levels of cardiac troponin-T (123.4 ng/L vs. 79.1 ng/L, p = 0.026) and higher levels of N-terminal pro-B-type natriuretic peptide (9146 pg/mL vs. 4945 pg/mL, p = 0.011). Patients were followed for a median follow-up period of 19 months, in which 118 (59%) patients died. The median overall survival times for patients with low or normal serum HDL-C were 7 and 16 months, respectively (p = 0.002). Multivariate analysis demonstrated that serum HDL-C (HR 0.984, 95% CI 0.973-0.994, p = 0.003) was independently associated with prognosis, after adjusting for nephrotic syndrome, hepatic involvement, nutritional state, renal function, SBP, DBP, serum uric acid, total cholesterol, Mayo AL 2004 stage, and treatment with chemotherapy.HDL-C is a novel serum biomarker for disease severity and prognosis in light-chain cardiac amyloidosis.

Introduction Treatment of hypercholesterolemia in refractory nephrotic syndrome remains a therapeutic challenge. There is not enough evidence supporting the efficacy of statins, and these drugs can be associated with an increased incidence of adverse effects. Herein we summarize our clinical experience with 12 patients suffering from refractory nephrotic syndrome with associated vascular disease and uncontrolled hypercholesterolemia despite treatment with statins who were treated with proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors. Methods Twelve adult patients with primary nephrotic syndrome refractory to multiple lines of immunosuppressive treatment who suffered from clinical atheromatous vascular disease were treated with PCSK9 inhibitors according to the prescription guidelines for secondary prevention of cardiovascular events. Eight patients with refractory nephrotic syndrome without vascular disease treated with atorvastatin comprised the control group. Results Four weeks after treatment with PCSK9 inhibitors, a statistically significant decrease in total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels was observed without significant changes in serum albumin levels or proteinuria. The mean LDL-C decrease was 36.8% ± 4.9% mmol/L at 4 weeks and remained unchanged throughout the follow-up period. In the control group, there were no significant changes in the levels of total cholesterol or LDL-C during the follow-up period. At the diagnosis of nephrotic syndrome, plasma PCSK9 levels were 334 ± 40 ng/mL and correlated significantly with serum LDL-C levels (r = 0.49, P = 0.023). Six months after starting treatment with PCSK9 inhibitors, plasma PCSK9 levels were significantly reduced to values of 190 ± 36 ng/mL (P = 0.001) with a mean relative reduction of 42.3% ± 12.6%. No local adverse effects were seen at the injection site and no significant changes were seen in the levels of transaminase, creatine phosphokinase, or aldolase. Conclusion PCSK9 inhibitors may be an effective and safe alternative for the treatment of hypercholesterolemia associated with refractory nephrotic syndrome., Graphical abstract

Membranous glomerulopathy (MGN) is characterized by global subepithelial immune deposits that stain most intensely by immunofluorescence for IgG. Here we describe the clinical and pathologic findings in a cohort of patients with MGN in which, by definition, only segmental immune deposits are present. This rare variant, termed segmental MGN (sMGN), is poorly characterized. We retrospectively identified all patients with sMGN diagnosed at Columbia University from January 2010 to October 2018, excluding those with systemic lupus erythematosus. Data on presenting features, pathologic findings, and outcomes were collected. Fifty cases of sMGN were identified, representing 2.5% of MGN. In 21 of 50 biopsies, there was an alternative, predominant disease process. The remaining 29 patients with isolated sMGN had a median creatinine of 0.97 mg/dl, median 24-hour urine protein 3.1 g/day, and 32% had nephrotic syndrome. Staining for NELL-1 (a protein kinase C binding protein) was positive in five of 17 cases. Staining for PLA2R, THSD7A, and exostosin 1 (autoantigens in primary MGN) was negative in all biopsies evaluated. Ultrastructural evaluation revealed predominantly early stage sMGN (stage 1 or 1-2 in 14/29). Follow-up was available for 21 of the 29 patients with isolated sMGN (median 12 months), including seven who received immunosuppression (primarily glucocorticoids). During follow-up, 86% had stable/improved kidney function and 45% achieved complete while 15% achieved partial remission. Among the 15 patients with isolated sMGN without full nephrotic syndrome, only two received immunosuppression; nonetheless, 50% achieved complete while 21% achieved partial remission. Thus, sMGN is a rare PLA2R-negative variant of MGN with 29% NELL-1 positivity and favorable prognosis, even in the absence of immunosuppressive treatment.

Light chain amyloidosis is a disease in which clonal plasma cells produce toxic immunoglobulin light chains that form amyloid fibrils with deposition in organs, most commonly the heart and kidneys, but also the nervous system, gastrointestinal tract, and soft tissues. Treatment directed at the clonal cells eliminates light chain production and further deposition and may enable organ improvement and decrease the risk of organ failure. Supportive care manages the symptoms of organ involvement and the side effects of treatment. Supportive care also addresses the psychological and social issues that may arise in patients with light chain amyloidosis.

Membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults. Rituximab, a type I anti-CD20 antibody, has been shown to be an effective therapy in treatment of patients with MN associated with M-type phospholipase A2 receptor (PLA2R) antibodies. Despite its effectiveness, up to 40% of patients may fail to respond to rituximab, which may be related to higher PLA2R antibody titers. Obinutuzumab, a type II anti-CD20 depleter, has been shown to produce a more profound CD20 depletion and be more efficacious in treating certain hematologic malignancies compared with rituximab. We report 3 patients with PLA2R-associated MN for whom rituximab failed to induce immunologic or clinical remisison, but who were successfully treated with obinutuzumab. Obinutuzumab resulted in complete immunologic remission in all 3 cases and was followed by partial remission in 2 of the cases. Obinutuzumab appears to be a promising treatment strategy for PLA2R-associated MN that fails to respond to rituximab.

Kidney injury is a well-known complication in people with coronavirus disease 2019 (COVID-19). In kidney transplant recipients with COVID-19, presentation with nephrotic syndrome has not been well described. We report on a 49-year-old African American female kidney transplant recipient who presented 25 years after transplantation with clinical features of nephrotic syndrome following a diagnosis of COVID-19. Histological examination showed acute tubular injury with unremarkable glomeruli on light microscopy and diffuse foot process effacement of podocytes on electron microscopy, consistent with minimal change–like podocyte injury. Apolipoprotein L1 (APOL1) genetic testing confirmed two high-risk APOL1 alleles in the kidney donor. We speculate that COVID-19-induced systemic or local cytokine release could serve as a second hit in the presence of APOL1 risk alleles and mediate a podocytopathy manifesting as nephrotic syndrome. The presented case with minimal change like disease, occurring in the context of the donor high-risk APOL1 genotype, extends the spectrum of clinical manifestations in COVID-19-associated nephropathy.

There are few case reports of concomitant chronic inflammatory demyelinating polyneuropathy (CIDP) and focal segmental glomerulosclerosis. A rare autoantibody to a neuronal and podocyte structural component, neurofascin, may be contributory. A Black man in his 40s presented with worsening polyneuropathy requiring mechanical ventilation and initially acute inflammatory demyelinating polyneuropathy was diagnosed. After a poor response to intravenous immunoglobulin, plasmapheresis was initiated. The patient also had concomitant new-onset nephrotic-range proteinuria. A limited kidney biopsy was interpreted as minimal change disease and was treated with prednisone. After some improvement, the patient was extubated; however, he later re-presented with worsening symptoms requiring mechanical ventilation and was re-treated with plasmapheresis. Due to the protracted course and poor response to intravenous immunoglobulin, acute-onset CIDP was diagnosed and a neuromuscular antibody workup returned positive for neurofascin, supporting the diagnosis of seropositive acute-onset CIDP. A repeat kidney biopsy demonstrated focal segmental glomerulosclerosis and acute tubular damage. The patient was treated with steroids and tacrolimus and later transitioned to rituximab. Neurofascin enzyme-linked immunosorbent assay then tested negative with concomitant resolution of both neuropathy and proteinuria. Further studies will help validate these findings and the treatment strategy.

Focal segmental glomerulosclerosis (FSGS) is a common cause of steroid-resistant nephrotic syndrome. Spontaneous remission of FSGS is rare and steroid-resistant FSGS frequently progresses to renal failure. Many inheritable forms of FSGS have been described, caused by mutations in proteins that are important for podocyte function. Here, we show that a basic leucine zipper transcription factor, MafB, protects against FSGS. MAFB expression was found to be decreased in the podocytes of patients with FSGS. Moreover, conditional podocyte-specific MafB-knockout mice developed FSGS with massive proteinuria accompanied by depletion of the slit diaphragm-related proteins (Nphs1 and Magi2), and the podocyte-specific transcription factor Tcf21. These findings indicate that MafB plays a crucial role in the pathogenesis of FSGS. Consistent with this, adriamycin-induced FSGS and attendant proteinuria were ameliorated by MafB overexpression in the podocytes of MafB podocyte-specific transgenic mice. Thus, MafB could be a new therapeutic target for FSGS.

Rationale & Objective Surrogate outcomes for end-stage kidney disease often assume linear changes, which may not reflect true estimated glomerular filtration rate (eGFR) trajectories. This study’s objective was to characterize nonlinear eGFR trajectories in nephrotic syndrome. Study Design Observational cohort study. Setting & Participants Nephrotic Syndrome Study Network (NEPTUNE) is a multicenter study of adult and pediatric patients with proteinuria enrolled at clinically indicated kidney biopsy or initial presentation of disease (pediatric only). Predictors Patient demographic, clinical, and pathology variables at study enrollment and follow-up time. Outcome eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (patients ≥ 18 years old) or modified Chronic Kidney Disease in Children Study–Schwartz (patients < 18 years) formulas. The probability of nonlinearity (PNL) was calculated for individual eGFR trajectories. Analytical Approach Associations between predictors and PNL were assessed using multivariable linear regression. Results 453 patients with ≥3 eGFR measurements and 1 or more year of follow-up were included (median follow-up, 3.6 years). Median PNL was 0.052; 56% and 16% had PNL < 10% and >50%, respectively. In both adults and pediatric patients, higher baseline eGFR was associated with higher PNL, whereas longer follow-up time was associated with lower PNL. Higher urine protein-creatinine ratio and steroid use were also associated with higher PNL in adults. Higher percentages of tubular atrophy and foot-process effacement were associated with lower and higher PNLs, respectively, in adults. Limitations Relatively short follow-up time, inability to assess acute kidney injury events, and variable eGFR measurement frequency across patients. Conclusions Although increasing follow-up time resulted in more linear trajectories, nonlinear eGFR trajectories were common in this cohort. Future studies in nephrotic syndrome should consider novel outcomes that do not rely on linearity assumptions., Graphical abstract

The importance of the glomerular basement membrane (GBM) in glomerular filtration is underscored by the manifestations of Alport and Pierson syndromes, caused by defects in type IV collagen α3α4α5 and the laminin β2 chain, respectively. Lamb2 null mice, which model the most severe form of Pierson syndrome, exhibit proteinuria prior to podocyte foot process effacement and are therefore useful for studying GBM permselectivity. We hypothesize that some LAMB2 missense mutations that cause mild forms of Pierson syndrome induce GBM destabilization with delayed effects on podocytes. While generating a CRISPR/Cas9-mediated analogue of a human LAMB2 missense mutation in mice, we identified a 44-amino acid deletion (LAMB2-Del44) within the laminin N-terminal domain, a domain mediating laminin polymerization. Laminin heterotrimers containing LAMB2-Del44 exhibited a 90% reduction in polymerization in vitro that was partially rescued by type IV collagen and nidogen. Del44 mice showed albuminuria at 1.8-6.0 g/g creatinine (ACR) at one to two months, plateauing at an average 200 g/g ACR at 3.7 months, when GBM thickening and hallmarks of nephrotic syndrome were first observed. Despite the massive albuminuria, some Del44 mice survived for up to 15 months. Blood urea nitrogen was modestly elevated at seven-nine months. Eight to nine-month-old Del44 mice exhibited glomerulosclerosis and interstitial fibrosis. Similar to Lamb2−/− mice, proteinuria preceded foot process effacement. Foot processes were widened but not effaced at one-two months despite the high ACRs. At three months some individual foot processes were still observed amid widespread effacement. Thus, our chronic model of nephrotic syndrome may prove useful to study filtration mechanisms, long-term proteinuria with preserved kidney function, and to test therapeutics.

Podocyte injury is the initiating step in the pathway toward clinically evident forms of nephrotic syndrome known as podocytopathies, represented as either minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS). There are hallmark differences in the histologic appearances of MCD and FSGS, which in turn represent distinct pathogenic models after initial podocyte injury (eg, no change in podocyte number in MCD vs podocyte detachment and death in FSGS). However, MCD and FSGS also share a number of common causes, supporting the theory that these diseases lie along a shared podocytopathy spectrum. In this installment of AJKD's Core Curriculum in Nephrology, we demonstrate how the podocytopathies can be classified according to pathogenesis and treatment response as an alternative to histologic description. Using case examples, we show how these alternative classification schemes can assist not only diagnosis, but also long-term management of podocytopathies.