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Nephropathic apolipoprotein L1 (APOL1) risk alleles (G1/G2) have been associated with focal segmental glomerulosclerosis, HIV-associated nephropathy, Systemic lupus erythematosus (SLE)-associated collapsing glomerulopathy and other glomerulonephritides. These alleles confer protection from Trypanosoma brucei infections which are enriched in sub-Saharan African populations. We present a young woman with obesity, hypertension, subnephrotic range proteinuria who was found to have obesity-related glomerulopathy on kidney biopsy while harbouring two high-risk APOL1 alleles (G1/G2). Given the potential effects on lipid metabolism and their association with obesity, the presence of APOL1 risk alleles may impact cardiovascular health in addition to renal disease in these patients.

An essential step in renal function entails the formation of an ultrafiltrate that is delivered to the renal tubules for subsequent processing. This process, known as glomerular filtration, is controlled by intrinsic regulatory systems and by paracrine, neuronal, and endocrine signals that converge onto glomerular cells. In addition, the characteristics of glomerular fluid flow, such as the glomerular filtration rate and the glomerular filtration fraction, play an important role in determining blood flow to the rest of the kidney. Consequently, disease processes that initially affect glomeruli are the most likely to lead to end-stage kidney failure. The cells that comprise the glomerular filter, especially podocytes and mesangial cells, express many different types of ion channels that regulate intrinsic aspects of cell function and cellular responses to the local environment, such as changes in glomerular capillary pressure. Dysregulation of glomerular ion channels, such as changes in TRPC6, can lead to devastating glomerular diseases, and a number of channels, including TRPC6, TRPC5, and various ionotropic receptors, are promising targets for drug development. This review discusses glomerular structure and glomerular disease processes. It also describes the types of plasma membrane ion channels that have been identified in glomerular cells, the physiological and pathophysiological contexts in which they operate, and the pathways by which they are regulated and dysregulated. The contributions of these channels to glomerular disease processes, such as focal segmental glomerulosclerosis (FSGS) and diabetic nephropathy, as well as the development of drugs that target these channels are also discussed.

The development of focal and segmental glomerulosclerosis (FSGS) as a consequence of glomerular hypertension resulting from arterial hypertension is widely considered a podocyte disease. However, the primary damage is encountered in the mesangium. In acute settings, mesangial cells disconnect from their insertions to the glomerular basement membrane, causing a ballooning of capillaries and severe changes of the folding pattern of the glomerular basement membrane, of the arrangement of the capillaries, and thereby of the architecture of the tuft. The displacement of capillaries led to contact of podocytes and parietal epithelial cells, initiating the formation of tuft adhesions to Bowman's capsule, the committed lesion to progress to FSGS. In addition, the displacement of capillaries also caused an abnormal stretching of podocytes, resulting in podocyte damage. Thus, the podocyte damage that starts the sequence to FSGS is predicted to develop secondary to the mesangial damage. This sequence was found in two hypertensive rat models of FSGS and in human hypertensive nephrosclerosis.

Background Detachment of podocytes represents a turning point in the development of glomerular sclerosis and consequently, of CKD progression. Furthermore, detachment may differentiate minimal change disease (MCD) cases—which have only podocyte effacement—from early focal segmental glomerulosclerosis (FSGS) in which effacement and detachment are observed by electron microscopy. Noteworthy, it is not uncommon for early FSGS to present with clinical presentation and light microscopy (LM) pictures identical to MCD. In our routine practice, we often find cells that lie freely in Bowman’s space by LM. In this study, we try to determine whether these cells are detached podocytes that are worth reporting or just an artifact that can be ignored. Methods To the best of our knowledge, no study has discussed the accuracy of LM in detecting detached podocytes by the routinely used stains. We retrospectively selected 118 cases that were diagnosed as MCD by LM, and searched for detached cells in Bowman’s space in their archived, routinely stained LM slides. After that, we tried to find any correlation between the clinical course, detached cells in LM picture and the EM reports. Results LM can significantly detect detached podocytes with a positive predictive value of 93%, specificity of 85%, and sensitivity of 46%. Significant correlations were found between detached cells and degree of proteinuria and late steroid resistance. Conclusion Detecting detached podocytes by LM is a specific finding that must be reported whenever detected, as it predicts response to steroids and may be able to differentiate MCD from early FSGS by identifying patients who could have podocytopenia.

Background: Idiopathic or Primary Nephrotic Syndrome (INS) is a common glomerular disease in pediatric population, characterized by proteinuria, edema and hypoalbuminemia with var-iable findings in renal histopathology. Objective: This review aims to summarize current data on the etiopathogenesis diagnosis, protocols of treatment and potential therapeutic advances in INS. Methods: This narrative review searched for articles on histopathology, physiopathology, genetic causes, diagnosis and treatment of INS in pediatric patients. The databases evaluated were PubMed and Scopus. Results: INS is caused by an alteration in the permeability of the glomerular filtration barrier with unknown etiology. There are several gaps in the etiopathogenesis, response to treatment and clinical course of INS that justify further investigation. Novel advances include the recent understanding of the role of podocytes in INS and the identification of genes associated with the disease. The role of immune system cells and molecules has also been investigated. The diagnosis relies on clinical find-ings, laboratory exams and renal histology for selected cases. The treatment is primarily based on steroids administration. In case of failure, other medications should be tried. Recent studies have al-so searched for novel biomarkers for diagnosis and alternative therapeutic approaches. Conclusion: The therapeutic response to corticosteroids still remains the main predictive factor for the prognosis of the disease. Genetic and pharmacogenomics tools may allow the identification of cases not responsive to immunosuppressive medications.

Long-term calcineurin inhibitor (CNI) administration causes irreversible nephrotoxicity. Therefore, early CNI-induced nephrotoxicity detection is necessary for patients who will need long-term CNI administration. There is no pathological indicator for early CNI-induced nephrotoxicity. Here, serial protocol kidney biopsy specimens from five kidney-transplant patients with severe CNI-induced nephrotoxicity were examined. We observed that the increase in CD44 expression in glomerular parietal epithelial cells (PECs) preceded the chronic pathological changes of CNI-induced nephrotoxicity such as tubular atrophy/interstitial fibrosis, arterial hyaline thickening, and focal segmental glomerulosclerosis (FSGS). This result suggests that CD44-positive PECs have pivotal roles in FSGS development in human CNI-induced nephrotoxicity as well as rodent models. CD44 could be useful as a pathological marker for early CNI-induced nephrotoxicity detection post kidney transplantation.

Podocyte injury due to either drug, toxin, infection, or metabolic abnormality is a great concern as it increases the risk of developing focal segmental glomerulosclerosis (FSGS) and proteinuric kidney diseases. The direct podocyte injury due to doxorubicin is associated with an increase in proinflammatory cytokines and induction of cathepsin L. The increased activity of cathepsin L in turn may degrade the glomerular slit diaphragm resulting in proteinuric kidney injury. The angiotensin-II type 2 receptor (AT2R) has earlier been reported to be associated with the preservation of slit diaphragm proteins and prevention of proteinuria. Recent in vivo findings by Zhang and colleagues further support the anti-proteinuric role of AT2R in preventing podocyte injury via down-regulating cytokines ccl2, and hence, cathepsin L, thereby, limiting the progression of FSGS.

Podocytes are unique, highly specialized, terminally differentiated cells, which are restricted in a post-mitotic state with limited ability to repair or regenerate. Re-entering the mitotic phase causes podocyte mitotic catastrophe, thereby leading to podocyte death and glomerular injury. Myeloid-derived growth factor (MYDGF) is a novel secreted protein and plays an important role in the regulation of cardiovascular function. However, whether MYDGF is expressed in kidney parenchymal cells and whether it has biological functions in the kidney remain unknown. Here, we found that MYDGF was expressed in kidney parenchymal cells and was significantly reduced in podocytes from mice with models of focal segmental glomerulosclerosis and diabetic kidney disease. Podocyte-specific deletion of Mydgf in mice exacerbated podocyte injury and proteinuria in both disease models. Functionally, MYDGF protected podocytes against mitotic catastrophe by reducing accumulation of podocytes in the S phase, a portion of the cell cycle in which DNA is replicated. Mechanistically, MYDGF regulates the expression of the transcription factor RUNX2 which mediates some MYDGF effects. Importantly, a significant reduction of MYDGF was found in glomeruli from patients with glomerular disease due to focal segmental glomerulosclerosis and diabetic kidney disease and the level of MYDGF was correlated with glomerular filtration rate, serum creatinine and podocyte loss. Thus, our studies indicate that MYDGF may be an attractive therapeutic target for glomerular disease.

Focal segmental glomerulosclerosis (FSGS) is characterized by podocyte damage and severe proteinuria. The exact mechanism of podocyte damage and loss remains unclear. Necroptosis, a lytic form of programmed cell death mediated by RIP3 and MLKL, has emerged as an important cell death pattern in multiple tissues and cell types. Necroptosis in FSGS has not been investigated.Public GEO data regarding podocyte treated with vehicle or adriamycin (ADR) was identified and analyzed. Cultured human podocytes were used to explore the activation of necroptosis upon ADR stimulation. The expression of necroptosis pathway molecules, p-RIP3 and p-MLKL, was examined in the glomeruli and defoliated urinary podocytes of patients with FSGS. The effect of necroptosis inhibition was assessed in ADR-induced glomerulopathy mice using GSK872.Publicly available RNA-sequencing data analysis showed that both necroptosis and NLRP3 inflammasome pathway were up-regulated in ADR-injured podocyte. Immunofluorescent staining showed increased expression of p-RIP3 and p-MLKL, the active forms of RIP3 and MLKL, in podocytes of FSGS patients and ADR-induced glomerulopathy mice but not in the normal control. GSK872, an RIP3 kinase inhibitor, significantly inhibited the expression of p-RIP3, p-MLKL and activation of NLRP3 in cultured podocytes treated with ADR. GSK872 treatment of mice with ADR-induced nephropathy resulted in the reduced expression of p-RIP3, p-MLKL, NLRP3 and caspase-1 p20. GSK872 also significantly inhibited the expression of p-MLKL in the podocytes of ADR-induced nephropathy, resulting in the attenuation of proteinuria and renal histological lesions.Necroptosis pathway might be a valuable target for the treatment of FSGS.

Focal segmental glomerulosclerosis (FSGS) is not a disease, rather a pattern of histological injury occurring from a variety of causes. The exact pathogenesis has yet to be fully elucidated but is likely varied based on the type of injury and the primary target of that injury. However, the approach to treatment is often based on the degree of podocyte foot process effacement and clinical presentation without sufficient attention paid to etiology. In this regard, there are many monogenic causes of FSGS with variable presentation from nephrotic syndrome with histological features of primary podocytopathy to more modest degrees of proteinuria with limited evidence of podocyte foot process injury. It is likely that genetic causes are largely underdiagnosed, as the role and the timing of genetic testing in FSGS is not established and genetic counseling, testing options, and interpretation of genotype in the context of phenotype may be outside the scope of practice for both nephrologists and geneticists. Yet most clinicians believe that a genetic diagnosis can lead to targeted therapy, limit the use of high-dose corticosteroids as a therapeutic trial, and allow the prediction of the natural history and risk for recurrence in the transplanted kidney. In this manuscript, we emphasize that genetic FSGS is not monolithic in its presentation, opine on the importance of genetic testing and provide an algorithmic approach to deployment of genetic testing in a timely fashion when faced with a patient with FSGS.

Knowledge of dasatinib-induced nephrotic syndrome is largely based on case reports. The clinical features of dasatinib-induced nephrotic syndrome are unknown. We collected case reports of 25 patients with nephrotic syndrome and analyzed their clinical characteristics. Overall, the onset of nephrotic syndrome ranged from 10 days to 5 years after dasatinib administration. Nine patients (36.0%) had clinical symptoms, mainly periorbital edema and lower-extremity edema. Serum albumin ranged from 1.2 g/dL to 3.7 g/dL in 10 patients (38.5%). The 24-h urine protein values ranged from 3.54 g/day to 118 g/day. Kidney biopsy of 13 patients (52.0%) mainly showed focal foot process effacement, mesangial hyperplasia, endothelial cell damage and focal segmental glomerulosclerosis. Proteinuria resolved or recovered after dasatinib discontinuation or dose reduction or switching to other tyrosine kinase inhibitors (TKIs).

BACKGROUND: Heterogeneity in disease course and treatment response among patients with MCD/FSGS necessitates a granular evaluation of kidney tissue features. This study aimed to identify histologic and ultrastructural descriptors of structural changes most predictive of clinical outcomes in the Nephrotic Syndrome Study Network (NEPTUNE). METHODS: Forty-eight histologic (37 glomerular, 9 tubulointerstitial, 2 vascular) and 20 ultrastructural descriptors were quantified by applying the NEPTUNE Digital Pathology Scoring System to NEPTUNE kidney biopsies. Outcomes included time from biopsy to disease progression, first complete remission of proteinuria, and treatment response. Relative importance of pathology and clinical predictors was obtained from random forest models, and predictive discrimination was assessed. RESULTS: Among 224 participants (34% Black, 24% Hispanic), model performance was excellent, with predictive discrimination of 0.9 for disease progression, 0.85 for complete remission, and 0.81 for treatment response. The most predictive descriptors of outcomes included both conventional—e.g., global sclerosis or segmental sclerosis and interstitial fibrosis/tubular atrophy—and novel features, including adhesion, interstitial foam cells, deflation, periglomerular fibrosis, mononuclear white blood cells, endothelial cell abnormalities, microvillous transformation, and acute tubular injury. CONCLUSIONS: The most predictive descriptors of clinical outcomes among MCD/FSGS patients reflected structural changes in multiple renal compartments. Reporting these descriptors should be standardized to guide prognostication of proteinuric glomerular diseases.

Ribosomal protein S6 (rpS6) phosphorylation mediates the hypertrophic growth of kidney proximal tubule cells. However, the role of rpS6 phosphorylation in podocyte hypertrophy and podocyte loss during the pathogenesis of focal segmental glomerulosclerosis (FSGS) remains undefined. Here, we examined rpS6 phosphorylation levels in kidney biopsy specimens from patients with FSGS and in podocytes from mouse kidneys with Adriamycin-induced FSGS. Using genetic and pharmacologic approaches in the mouse model of FSGS, we investigated the role of rpS6 phosphorylation in podocyte hypertrophy and loss during development and progression of FSGS. Phosphorylated rpS6 was found to be markedly increased in the podocytes of patients with FSGS and Adriamycin-induced FSGS mice. Genetic deletion of the Tuberous sclerosis 1 gene in kidney glomerular podocytes activated mammalian target of rapamycin complex 1 signaling to rpS6 phosphorylation, resulting in podocyte hypertrophy and pathologic features similar to those of patients with FSGS including podocyte loss, leading to segmental glomerulosclerosis. Since protein phosphatase 1 is known to negatively regulate rpS6 phosphorylation, treatment with an inhibitor increased phospho-rpS6 levels, promoted podocyte hypertrophy and exacerbated formation of FSGS lesions. Importantly, blocking rpS6 phosphorylation (either by generating congenic rpS6 knock-in mice expressing non-phosphorylatable rpS6 or by inhibiting ribosomal protein S6 kinase 1-mediated rpS6 phosphorylation with an inhibitor) significantly blunted podocyte hypertrophy, inhibited podocyte loss, and attenuated formation of FSGS lesions. Thus, our study provides genetic and pharmacologic evidence indicating that specifically targeting rpS6 phosphorylation can attenuate the development of FSGS lesions by inhibiting podocyte hypertrophy and associated podocyte depletion.

The purpose of this study is to build a prediction model for accurate assessment of the risk of end-stage kidney disease (ESKD) in individuals with primary focal segmental glomerulosclerosis (FSGS) by integrating clinical and pathological features at biopsy. The prediction model was created based on a retrospective study of 99 patients with biopsy-proven primary FSGS diagnosed at our hospital between December 2012 and December 2019. We assessed discriminative ability and predictive accuracy of the model by C-index and calibration plot. Internal validation of the prediction model was performed with 1000-bootstrap procedure. Eight patients (8.1%) progressed to ESKD before 31 March 2021. Univariate analysis revealed that disease duration before biopsy, hematuria, hemoglobin, eGFR, and percentages of sclerosis and global sclerosis were associated with renal outcome. In multivariate analysis, three predictors were included in final prediction model: eGFR, hematuria, and percentage of sclerosis. The C-index of the model was 0.811 and 5-year calibration plot showed good agreement between predicted renal survival probability and actual observation. A nomogram and an online risk calculator were built on the basis of the prediction model. In conclusion, we constructed and internally validated the first prediction model for risk of ESKD in primary FSGS, which showed good discriminative ability and calibration performance. The prediction model provides an accurate and simple strategy to predict renal prognosis which may help to identify patients at high risk of ESKD and guide the management for patients with primary FSGS in clinical practice.

High-altitude polycythemia (HAPC) is a clinical syndrome that occurs in native inhabitants or long-term residents living at altitude. The kidney is one of the most affected organs. However, the clinical and kidney histopathological profiles of HAPC-related kidney disease have rarely been reported. Here, we report kidney biopsy-based clinicopathological study on this disease. HAPC was defined as excessive erythrocytosis [females, hemoglobin 190 g/L or more; males, 210 g/L or more] in patients living above an altitude of 2500 m for more than ten years. A total of 416 Tibetan patients underwent kidney biopsy between January 1, 2016, and November 31, 2020. Of these patients 17 met the diagnostic criteria for HAPC-related kidney disease. Clinically, these patients had a median urinary protein level of 2.5 g/24-hour (range 1.81-6.85). Twelve patients had hyperuricemia, nine had hypertension, and three had kidney insufficiency. On histopathology, glomerular hypertrophy, glomerular basement membrane thickening, podocyte foot process effacement, segmental glomerulosclerosis and global glomerulosclerosis were the main features. Extraglomerular arterial/arteriolar lesions were common, presenting as intimal fibrosis, hyalinosis and endothelial cell swelling/subintimal edema. Expansion of the arterial/arteriolar medial wall area characterized by smooth muscle cell proliferation was clearly observed, potentially indicating vascular remodeling. Hypoxia-inducible factor 2α was expressed in the kidney tissues of these patients. Thus, the pathological changes of HAPC-related kidney disease encompassed both glomerular and extraglomerular vascular lesions, suggesting a key role of both chronic hypoxia itself and secondary hemodynamic changes in the pathogenesis of this disease.

Organ transplant recipients exhibit lower rates of immune response to coronavirus disease 2019 (COVID-19) vaccination. Even when they do mount a demonstrable antibody response, it is unclear what degree of protection is conferred against the myriad potential complications of COVID-19 infection. We present here a case of a kidney transplant recipient who was homozygous for APOL1 risk alleles on low-dose immunosuppression who developed an antibody response to COVID-19 vaccination and subsequently acquired COVID-19 infection. Although she experienced relatively minor effects in other organ systems, she developed severe collapsing focal segmental glomerulosclerosis that left her dependent on hemodialysis on hospital discharge. This suggests that COVID-19 vaccination may not provide protection from infection-associated focal segmental glomerulosclerosis in patients with APOL1 risk alleles.

Apolipoprotein L1 (APOL1)-associated focal segmental glomerulosclerosis (FSGS) is the dominant form of FSGS in Black individuals. There are no targeted therapies for this condition, in part because the molecular mechanisms underlying APOL1's pathogenic contribution to FSGS are incompletely understood. Studying the transcriptomic landscape of APOL1 FSGS in patient kidneys is an important way to discover genes and molecular behaviors that are unique or most relevant to the human disease. With the hypothesis that the pathology driven by the high-risk APOL1 genotype is reflected in alteration of gene expression across the glomerular transcriptome, we compared expression and co-expression profiles of 15,703 genes in 16 Black patients with FSGS at high-risk vs 14 Black patients with a low-risk APOL1 genotype. Expression data from APOL1-inducible HEK293 cells and normal human glomeruli were used to pursue genes and molecular pathways uncovered in these studies. We discovered increased expression of APOL1 and nine other significant differentially expressed genes in high-risk patients. This included stanniocalcin, which has a role in mitochondrial and calcium-related processes along with differential correlations between high- and low-risk APOL1 and metabolism pathway genes. There were similar correlations with extracellular matrix- and immune-related genes, but significant loss of co-expression of mitochondrial genes in high-risk FSGS, and an NF-κB-down regulating gene, NKIRAS1, as the most significant hub gene with strong differential correlations with NDUF family (mitochondrial respiratory genes) and immune-related (JAK-STAT) genes. Thus, differences in mitochondrial gene regulation appear to underlie many differences observed between high- and low-risk Black patients with FSGS.

The present study identified novel renal tubular biomarkers that may influence the diagnosis and treatment of focal segmental glomerulosclerosis (FSGS) based on immune infiltration.Three FSGS microarray datasets, GSE108112, GSE133288 and GSE121211, were downloaded from the Gene Expression Omnibus (GEO) database. The R statistical software limma package and the combat function of the sva package were applied for preprocessing and to remove the batch effects. Differentially expressed genes (DEGs) between 120 FSGS and 15 control samples were identified with the limma package. Disease Ontology (DO) pathway enrichment analysis was conducted with statistical R software to search for related diseases. Gene set enrichment analysis (GSEA) was used to interpret the gene expression data and it revealed many common biological pathways. A protein-protein interaction (PPI) network was built using the Search Tool for the Retrieval of Interacting Genes (STRING) database, and hub genes were identified by the Cytoscape (version 3.7.2) plug-in CytoHubba. The plug-in Molecular Complex Detection (MCODE) was used to screen hub modules of the PPI network in Cytoscape, while functional analysis of the hub genes and hub nodes involved in the submodule was performed by ClusterProfiler. The least absolute shrinkage and selection operator (LASSO) regression and support vector machine recursive feature elimination (SVM-RFE) analysis were used to screen characteristic genes and build a logistic regression model. Receiver operating characteristic (ROC) curve analyses were used to investigate the logistic regression model and it was then validated by an external dataset GSE125779, which contained 8 FSGS samples and 8 healthy subjects. Cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) was used to calculate the immune infiltration of FSGS samples.We acquired 179 DEGs, 79 genes with downregulated expression (44.1%) and 100 genes with upregulated expression (55.9%), in the FSGS samples. The DEGs were significantly associated with arteriosclerosis, kidney disease and arteriosclerotic cardiovascular disease. GSEA revealed that these gene sets were significantly enriched in allograft rejection signaling pathways and activation of immune response in biological processes. Fifteen genes were demonstrated to be hub genes by PPI, and three submodules were screened by MCODE linked with FSGS. Analysis by machine learning methodologies identified nuclear receptor subfamily 4 group A member 1 (NR4A1) and dual specificity phosphatase 1 (DUSP1) as sensitive tubular renal biomarkers in the diagnosis of FSGS, and they were selected as hub genes, as well as hub nodes which were enriched in the MAPK signaling pathway. Immune cell infiltration analysis revealed that the genetic biomarkers were both correlated with activated mast cells, which may amplify FSGS biological processes.DUSP1 and NR4A1 were identified as sensitive potential biomarkers in the diagnosis of FSGS. Activated mast cells have a decisive effect on the occurrence and development of FSGS through tubular lesions and tubulointerstitial inflammation, and they are expected to become therapeutic targets in FSGS.

A 39-year-old woman was hospitalized for nephrotic syndrome. Laboratory test results showed increased serum creatinine levels and urinary excretions of beta-2-microglobulin, and N-acetyl-beta-D-glucosaminidase. A renal biopsy revealed collapsing focal segmental glomerulosclerosis (FSGS) and acute interstitial nephritis. Despite treatment with pulse steroid followed by oral high-dose glucocorticoids and cyclosporines, heavy proteinuria persisted. After low-density lipoprotein apheresis (LDL-A) therapy was initiated, her proteinuria gradually decreased, leading to complete remission. A repeat renal biopsy after treatment revealed no collapsing glomeruli. Immediate LDL-A should be performed to treat cases of collapsing FSGS poorly responding to other treatments.

Posterior reversible encephalopathy syndrome (PRES) is a rare neurological entity, typically manifested by reversible oedema in the parieto-occipital lobes. It is usually associated with primary hypertension, autoimmune diseases and immunosuppressants. Renal disease is an uncommon cause of PRES. We report a case of an 11-year-old boy with STimulator of INterferon Genes-associated vasculopathy with onset in infancy complicated by focal segmental glomerulosclerosis leading to hypertension and PRES. The patient presented with headache, acute bilateral visual loss and hypertension. Brain MRI showed atypical features revealed by parieto-occipital haemorrhage. The child improved few days after antihypertensive therapy. Follow-up MRI showed complete resolution of haemorrhage. It is important to keep high index of suspicion for the uncommon association of PRES with underlying kidney disease with or without immunosuppressive agents. This combination is the first to our knowledge to be described in paediatric population. Atypical MRI features such as haemorrhage should be kept in mind. Symptoms are reversible within days to weeks with early diagnosis and treatment.

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.

Collapsing glomerulopathy is a histologically distinct variant of focal and segmental glomerulosclerosis that presents with heavy proteinuria and portends a poor prognosis. Collapsing glomerulopathy can be triggered by viral infections such as HIV or SARS-CoV-2. Transcriptional profiling of collapsing glomerulopathy lesions is difficult since only a few glomeruli may exhibit this histology within a kidney biopsy and the mechanisms driving this heterogeneity are unknown. Therefore, we used recently developed digital spatial profiling (DSP) technology which permits quantification of mRNA at the level of individual glomeruli. Using DSP, we profiled 1,852 transcripts in glomeruli isolated from formalin fixed paraffin embedded sections from HIV or SARS-CoV-2-infected patients with biopsy-confirmed collapsing glomerulopathy and used normal biopsy sections as controls. Even though glomeruli with collapsing features appeared histologically similar across both groups of patients by light microscopy, the increased resolution of DSP uncovered intra- and inter-patient heterogeneity in glomerular transcriptional profiles that were missed in early laser capture microdissection studies of pooled glomeruli. Focused validation using immunohistochemistry and RNA in situ hybridization showed good concordance with DSP results. Thus, DSP represents a powerful method to dissect transcriptional programs of pathologically discernible kidney lesions.

The podocyte is an important component of the glomerular filtration barrier, and maintenance of the integrity of its highly specified structure and function is critical for normal kidney function. Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) are two crucial effectors of the Hippo signaling pathway, and recent studies have shown that podocyte-specific YAP deletion causes podocyte apoptosis and the development of focal segmental glomerulosclerosis followed by progressive renal failure. In the present study, we investigated a potential role of the YAP paralog TAZ in podocytes. TAZ was found to be constitutively active in podocytes, and mice with podocyte-specific deletion of TAZ (Taz(podKO)) developed proteinuria starting at 4 wk of age and had increased podocyte apoptosis. Using primary cultured podocytes or immortalized mouse podocytes from Taz(flox/flox) mice, we found that TAZ is a transcriptional activator for TEAD-dependent expression of synaptopodin, zonula occludens-1, and zonula occludens-2. This is the first study to determine that TAZ plays an important role in the maintenance of the structure and function of podocytes. NEW & NOTEWORTHY Podocytes play an important role in maintaining the integrity of the structure and function of the kidney. We observed that mice with selective deletion of transcriptional coactivator with PDZ-binding motif (TAZ) in podocytes developed proteinuria. TAZ is constitutively active and critical for expression of synaptopodin, zonula occludens-1, and zonula occludens-2 in podocytes. The findings of this study implicate TAZ as an important mediator of podocyte structural integrity and provide further insights into the role of Hippo-Yes-associated protein/TAZ in podocyte biology.

We herein report a 43-year-old woman with Buerger's disease who presented with nephrotic syndrome, renal dysfunction, and mild hypertension. A kidney biopsy revealed focal segmental glomerulosclerosis (FSGS), but there were no findings associated with frequent secondary FSGS or a history of long-term hypertension. A small focal renal infarction was seen on 99mTc-dimercaptosuccinic acid renal scintigraphy, suggesting that FSGS was due to renal microinfarction associated with Buerger's disease. After the commencement of angiotensin-converting enzyme inhibitor therapy, the hypertension immediately improved, along with significant attenuation of proteinuria. Renal ischemia by vasoconstriction of the glomerular efferent arterioles in association with Buerger's disease may result in glomerular hyperfiltration followed by FSGS.

The pathogenesis of primary focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) remains unknown to date. Some circulating permeability factors are being discussed. This work assessed molecule candidates for permeability in serum samples of patients with nephrotic syndrome (NS). MATERIALS AND METHODS 41 patients with chronic glomerulonephritis (CGN) were included in our study. 17 patients had FSGS, 7 patients had MCD, 5 patients had membranoproliferative glomerulonephritis (MPGN), 6 patients had IgA nephropathy, and 6 patients had membranous nephropathy (MN). The laboratory data were compared with the clinical and histological features of nephritis. Serum levels of plasminogen activator urokinase receptor (uPAR) and cardiotrophin-like cytokine factor 1 (CLCF-1)were measured by ELISA. RESULTS The serum levels of uPAR were higher in FSGS patients before treatment than in patients with other morphological forms (MCD, IgA nephropathy, MN, and MPGN). The levels of uPAR in serum did not correlate with daily proteinuria, serum creatinine/eGFR, arterial hypertension, the number of sclerosed glomeruli, or tubulointerstitial fibrosis. No correlations were found between the levels of CLCF-1 in serum and creatinine levels/glomerular filtration rate, the percentage of sclerosed glomeruli, or the severity of tubulointerstitial fibrosis. There were no significant differences between the histological variants of nephritis. However, we found correlations between CLCF-1 levels and proteinuria and lipid levels. CONCLUSION The data indicate an increase in the serum uPAR levels of FSGS before treatment. CLCF-1 levels in serum do not depend on histological forms of CGN, kidney function, or immunosuppressive treatment, but they correlate with proteinuria and serum lipids in patients with NS.

Nephrotic syndrome (NS) encompasses a variety of disease processes leading to heavy proteinuria and edema. Minimal change disease (MCD) remains the most common primary cause of NS, as well as the most responsive to pharmacologic treatment with often minimal to no chronic kidney disease. Other causes of NS include focal segmental glomerulosclerosis, which follows MCD, and secondary causes, including extrarenal or systemic diseases, infections, and drugs. Although initial diagnosis relies on clinical findings as well as urine and blood chemistries, renal biopsy and genetic testing are important diagnostic tools, especially when considering non-MCD NS. Moreover, biomarkers in urine and serum have become important areas for research in this disease. NS progression and prognosis are variable and depend on etiology, with corticosteroids being the mainstay of treatment. Other alternative therapies found to be successful in inducing and maintaining remission include calcineurin inhibitors and rituximab. Disease course can range from recurrent disease relapse with or without acute kidney injury to end-stage renal disease in some cases. Given the complex pathogenesis of NS, which remains incompletely understood, complications are numerous and diverse and include infections, electrolyte abnormalities, acute kidney injury, and thrombosis. Pediatricians must be aware of the presentation, complications, and overall long-term implications of NS and its treatment.

Background Reliable diagnosis of the cause of renal allograft dysfunction is of clinical importance. The aim of this study is to develop a hybrid deep-learning approach for determining acute rejection (AR), chronic allograft nephropathy (CAN) and renal function in kidney-allografted patients by multimodality integration. Methods Clinical and magnetic resonance imaging (MRI) data of 252 kidney-allografted patients who underwent post-transplantation MRI between December 2014 and November 2019 were retrospectively collected. An end-to-end convolutional neural network, namely RtNet, was designed to discriminate between AR, CAN and stable renal allograft recipient (SR), and secondarily, to predict the impaired renal graft function [estimated glomerular filtration rate (eGFR) ≤50 mL/min/1.73 m2]. Specially, clinical variables and MRI radiomics features were integrated into the RtNet, resulting in a hybrid network (RtNet+). The performance of the conventional radiomics model RtRad, RtNet and RtNet+ was compared to test the effect of multimodality interaction. Results Out of 252 patients, AR, CAN and SR was diagnosed in 20/252 (7.9%), 92/252 (36.5%) and 140/252 (55.6%) patients, respectively. Of all MRI sequences, T2-weighted imaging and diffusion-weighted imaging with stretched exponential analysis showed better performance than other sequences. On pairwise comparison of resulting prediction models, RtNet+ produced significantly higher macro-area-under-curve (macro-AUC) (0.733 versus 0.745; P = 0.047) than RtNet in discriminating between AR, CAN and SR. RtNet+ performed similarly to the RtNet (macro-AUC, 0.762 versus 0.756; P > 0.05) in discriminating between eGFR ≤50 mL/min/1.73 m2 and >50 mL/min/1.73 m2. With decision curve analysis, adding RtRad and RtNet to clinical variables resulted in more net benefits in diagnostic performance. Conclusions Our study revealed that the proposed RtNet+ model owned a stable performance in revealing the cause of renal allograft dysfunction, and thus might offer important references for individualized diagnostics and treatment strategy.

Purpose A previous immunofluorescent study suggests that, in collapsing glomerulopathy, most hyperplastic podocytes that stained positively for a progenitor cell marker CD133 are derived from CD133 + parietal epithelial cells. In pathology practice, not all renal biopsies with collapsing glomerulopathy show the typical morphologic features for this entity, which include florid podocyte hyperplasia, collapsing glomerular capillary loops, and cystic tubular dilation. This study was made to determine if CD133 staining using an immunohistochemical method can be used to confirm hyperplastic podocytes and identify extensive acute tubular injury in collapsing glomerulopathy. Methods Twenty-one collapsing glomerulopathy biopsies were stained for CD133 and compared with 15 biopsies with focal segmental glomerulosclerosis, not otherwise specified (FSGS). Results All patients with collapsing glomerulopathy were of African American descent with prominent renal failure and nephrotic range proteinuria. In contrast, the FSGS group consisted of patients from a variety of ethnic backgrounds with nephrotic range proteinuria but relatively low serum creatinine. The striking finding was that all collapsing glomerulopathy cases showed positive CD133 staining in the clusters of hyperplastic podocytes. There was significantly higher CD133-positive staining rate for hyperplastic podocytes (38%) in the glomeruli of the collapsing glomerulopathy group when compared to small clusters of hyperplastic podocytes in the FSGS group (8%). In addition, when compared to the relatively weak CD133 staining in the proximal tubules of the FSGS group, the proximal tubules of the collapsing glomerulopathy group all showed diffuse and strong CD133 staining as a feature of severe acute tubular injury, which corresponded to the high serum creatinine levels in these patients. Conclusion Our data indicate that the combination of the distinctive mosaic CD133 staining in hyperplastic podocytes and the diffuse tubular CD133 staining is helpful in supporting a diagnosis of collapsing glomerulopathy. Supplementary Information The online version contains supplementary material available at 10.1007/s11255-021-03078-0.

Focal segmental glomerulosclerosis (FSGS) is a major renal complication of human mitochondrial disease. However, its pathogenesis has not been fully explained. In this study, we focused on the glomerular injury of mito-miceΔ and investigated the pathogenesis of their renal involvement. We analyzed biochemical data and histology in mito-miceΔ. The proteinuria began to show in some mito-miceΔ with around 80% of mitochondrial DNA deletion, then proteinuria developed dependent with higher mitochondrial DNA deletion, more than 90% deletion. Mito-miceΔ with proteinuria histologically revealed FSGS. Immunohistochemistry demonstrated extensive distal tubular casts due to abundant glomerular proteinuria. Additionally, the loss of podocyte-related protein and podocyte's number were found. Therefore, the podocyte injuries and its depletion had a temporal relationship with the development of proteinuria. This study suggested mitochondrial DNA deletion-dependent podocyte injuries as the pathogenesis of renal involvement in mito-miceΔ. The podocytes are the main target of mitochondrial dysfunction originated from the accumulation of mitochondrial DNA abnormality in the kidney.

Recurrence of the primary disease is one of the most common causes of graft failure in the first decade after kidney transplantation. We present a case of a patient with an unusually rapid recurrence of focal segmental glomerulonephritis in the graft, the recognition of its occurrence was hampered by the primary graft affection and oligoanuria and by insignificant histological changes in the first two biopsy samples in the early post-transplant period, as well as by unawareness of the disease leading to terminal renal failure, as no renal biopsy was performed due to grade 3 obesity. Only worsening of hypoalbuminemia and finding of massive proteinuria despite oligoanuria were crucial for further management. Disease recurrence in the graft was confirmed by electron microscopy. However, complex targeted therapy did not result in restoration of graft function and decrease in proteinuria. This case history was aimed to draw attention to the knowledge of the importance of the primary disease confirmed by renal biopsy and early (so called pre-emptive) treatment in case of diseases with a high potential of recurrence (Fig. 7, Ref. 10). Text in PDF www.elis.sk Keywords: kidney transplantation, recurrence, minimal changes in glomeruli, focal segmental glomerulosclerosis.

BACKGROUND: To gain insight into the pathogenesis of collapsing glomerulopathy, a rare form of FSGS that often arises in the setting of viral infections, we performed a genome-wide association study (GWAS) among inbred mouse strains using a murine model of HIV-1 associated nephropathy (HIVAN). METHODS: We first generated F1 hybrids between HIV-1 transgenic mice on the FVB/NJ background and 20 inbred laboratory strains. Analysis of histology, BUN, and urinary NGAL demonstrated marked phenotypic variation among the transgenic F1 hybrids, providing strong evidence for host genetic factors in the predisposition to nephropathy. A GWAS in 365 transgenic F1 hybrids generated from these 20 inbred strains was performed. RESULTS: We identified a genome-wide significant locus on chromosome 13-C3 and multiple additional suggestive loci. Crossannotation of the Chr. 13 locus, including single-cell transcriptomic analysis of wildtype and HIV-1 transgenic mouse kidneys, nominated Ssbp2 as the most likely candidate gene. Ssbp2 is highly expressed in podocytes, encodes a transcriptional cofactor that interacts with LDB1 and LMX1B, which are both previously implicated in FSGS. Consistent with these data, older Ssbp2 null mice spontaneously develop glomerulosclerosis, tubular casts, interstitial fibrosis, and inflammation, similar to the HIVAN mouse model. CONCLUSIONS: These findings demonstrate the utility of GWAS in mice to uncover host genetic factors for rare kidney traits and suggest Ssbp2 as susceptibility gene for HIVAN, potentially acting via the LDB1-LMX1B transcriptional network.

Introduction: Recurrence of focal segmental glomerulosclerosis (FSGS) after kidney transplantation (KTx) develops in 40% of patients, leading to graft loss in half of cases. Extracorporeal apheretic treatments, combined with immunosuppressive drugs, seem to be the most promising therapies, but at now limited reports are available, mainly in pediatric patients. Objective: We aimed to assess the efficacy of immunoadsorption (IA) to treat recurrent FSGS in pediatric patients. Methods: We report a case series of 4 pediatric patients (aged 4–12 years) followed at our institution for early recurrent FSGS after KTx. FSGS recurrence was treated with early and intensive apheretic treatments IA. Results: After IA initiation, a partial remission (PR) of proteinuria at 24-month follow-up was achieved only in 1 patient. The others showed a mild reduction of nephrotic proteinuria, without PR, but gained a significant improvement in clinical signs of nephrotic syndrome (reduction of edema, increased serum albumin, and total protein levels). After a median follow-up of 38 (22–48) months, renal function was almost stable over time in all patients, except one who returned to hemodialysis after 22 months. No severe IA-related complications occurred. Conclusions: According to our clinical experience, IA revealed as a safe and effective therapy to treat patients with recurrent FSGS after KTx and it could maintain stable renal function in 75% of patients.

Background: Focal and segmental glomerulosclerosis (FSGS) is a clinical-pathologic condition marked by segmental and localized glomerular damages. Despite investigations, the molecular mechanisms behind FSGS development remain to be more clarified. By a comprehensive analysis of an FSGS-related array set, the aim of this study was to unravel the top pathways and molecules involved in the pathogenesis of this disorder. Methods: FSGS-related microarray dataset (GSE129973) from the Gene Expression Omnibus database was quality checked, analyzed, and its differentially expressed genes (DEGs) (log2 fold change > 1) were used for the construction of a protein-protein interaction (PPI) network (STRING). The degree of centrality was considered to select the hub molecules in the network. The weighted gene co-expression network analysis (WGCNA) was utilized to construct co-expression modules. Hub molecules were selected based on module membership and gene significance values in the disease’s most correlated module. After spotting the key molecules considering both strategies, their expression pattern was checked in other FSGS microarray datasets. Gene ontology and Reactome pathway enrichment analyses were performed on the DEGs of the related module. Results: After quality checking, normalization, and analysis of the dataset, 5,296 significant DEGs, including 2,469 upregulated and 2,827 downregulated DEGs were identified. The WGCNA algorithm clustered the DEGs into nine independent co-expression modules. The disease most correlated module (black module) was recognized and considered for further enrichment analysis. The immune system, cell cycle, and vesicle-mediated transports were among the top enriched terms for the identified module’s DEGs. The immune system, cell cycle, and vesicle-mediated transports were among the top enriched terms for the black module’s DEGs. The key molecules (BMP-2 and COL4A1) were identified as common hub molecules extracted from the two methods of PPI and the co-expressed networks. The two identified key molecules were validated in other FSGS datasets, where a similar pattern of expression was observed for both the genes. Conclusions: Two hub molecules (BMP-2 and COL4A) and some pathways (vesicle-mediated transport) were recognized as potential players in the pathogenesis of FSGS.

Purpose: We aimed to evaluate therapeutic response and long-term renal outcomes of childhood idiopathic steroid-resistant nephrotic syndrome (iSRNS). Methods: We retrospectively reviewed treatment regimens, especially calcineurin inhibitor (CNI), pathologic diagnoses, and long-term renal outcomes of iSRNS patients for 30 years. Results: Of 516 patients with idiopathic NS, 52 (10.1%) had iSRNS. Renal biopsies from 48 patients showed minimal change disease (MCD) in 23 (47.9%), focal segmental glomerulosclerosis in 24 (50.0%), and mesangioproliferative glomerulonephritis in 1 (2.1%). The median follow-up period was 66.5 (range, 4–275) months, and 90.4% of them were treated with a CNI. CNI induced remission in 70.2% within 50.4 ± 43.5 days. Of the patients with MCD and focal segmental glomerular sclerosis (FSGS), 86.4% (19/22) and 45.0% (9/20) (p = 0.005) responded to CNI, respectively. Mean time until remission after using CNI was longer with FSGS (90.4 ± 54.0 days) than with MCD (29.6 ± 26.3 days) (p = 0.010). CNI-responsive patients with FSGS or MCD showed preserved renal function, and CNI nonresponsive MCD patients also showed preserved renal function during follow-up. However, end-stage renal disease (ESRD) progressed in 8 out of 11 patients with FSGS nonresponsive to the CNI for an average of 44.9 ± 18.4 months after diagnosis. Conclusion: Different response rates and times for remission were achieved with the CNI according to the pathology of iSRNS. All MCD patients regardless of CNI response and all CNI-responsive patients with FSGS showed excellent renal outcomes, while almost all FSGS patients nonresponsive to CNI eventually progressed to ESRD.

Background Despite renin–angiotensin–aldosterone system blockade and immunosuppressive treatment, focal segmental glomerulosclerosis (FSGS) often progresses to kidney failure. The objective of this prespecified analysis of the dapagliflozin and prevention of adverse outcomes in chronic kidney disease trial (DAPA-CKD) was to assess efficacy and safety of dapagliflozin in a small subgroup of participants with FSGS confirmed by kidney biopsy. Methods In DAPA-CKD, patients with an estimated glomerular filtration rate (eGFR) 25–75 mL/min/1.73 m2 and urinary albumin:creatinine ratio (UACR) 200–5000 mg/g (22.6–565 mg/mol) were randomized to dapagliflozin 10 mg once daily or placebo as an adjunct to standard care and followed for median 2.4 years. The primary composite endpoint was sustained eGFR decline ≥50%, end-stage kidney disease, or kidney or cardiovascular death. The endpoint of interest for this analysis was eGFR slope (acute effects from baseline to Week 2 and chronic effects from Week 2 to end of treatment). Results Of 104 participants with biopsy-confirmed FSGS, 45 were randomized to dapagliflozin and 59 to placebo. Mean (standard deviation) age was 54.0 (14.3) years, mean eGFR 41.9 (11.5) mL/min/1.73 m2 and median (interquartile range) UACR 1248 (749–2211) mg/g. The primary outcome occurred in 4 (8.9%) and 7 (11.9%) participants randomized to dapagliflozin and placebo, respectively [hazard ratio 0.62, 95% confidence interval (95% CI) 0.17, 2.17]. Dapagliflozin led to a larger acute reduction (standard error) in eGFR compared with placebo (−4.5, 95% CI −5.9 to −3.1 versus −0.9, −2.1 to 0.4 mL/min/1.73 m2/2 weeks). Thereafter, mean rates of chronic eGFR decline with dapagliflozin and placebo were −1.9 (−3.0, −0.9) and −4.0 (−4.9, −3.0) mL/min/1.73 m2/year, respectively (difference 2.0, 95% CI 0.6 to 3.5, mL/min/1.73 m2/year). Adverse events leading to study drug discontinuation were similar in both groups; there were fewer serious adverse events with dapagliflozin. Conclusions Among DAPA-CKD participants with FSGS, dapagliflozin reduced the rate of chronic decline of eGFR compared with placebo, although this difference was not statistically significant.

Background Focal segmental glomerulosclerosis (FSGS, OMIM®#603 965) is an overriding cause that leads to end-stage renal disease (ESRD). As a member of TRP superfamily, mutations of TRPC6 gene are closely linked to FSGS. By now, 20 missense mutations have been reported, among them, nine gain-of-function (GOF), and five loss-of-function (LOF) mutations have been recognized according to the effect on TRPC6 channel activity. Systematic investigations of functional mutations will provide valuable evidences for understanding the pathophysiology of TRPC6 involved in FSGS. The aim of this study is to investigate the pathogenicity of a novel TRPC6 mutation p.Q134P in FSGS. Methods High-throughput sequencing was performed to analyse 436 genes which are associated with hereditary kidney diseases in a Chinese pedigree. Then we constructed TRPC6 expression plasmids of wide type and variant. Immunofluorescence, cell-surface biotinylation assays and electrophysiology were used to analyse the localization, cell surface expression, and calcium transport activity of TRPC6. Results A novel variant c.401A>C (p.Q134P) in exon 2 of TRPC6 gene was found. There was no significant difference between the expression levels of p.Q134P mutant and WT TRPC6 protein in the whole cell lysate and cell-surface fraction. Q134P mutant-bearing TRPC6 elicited much higher Ca+ current amplitude than WT. Conclusion We identified a novel GOF mutation p.Q134P of TRPC6 which contributed to late-onset FSGS. Our study expands the mutational spectrum of TRPC6 associated with FSGS and furtherly supports the hypothesis of calcium dose-response dependency that a moderate increased calcium influx elicited a mild FSGS phenotype.

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.

Formin proteins catalyze actin nucleation and microfilament polymerization. Inverted formin 2 (INF2) is an atypical diaphanous-related formin characterized by polymerization and depolymerization of actin. Accumulating evidence showed that INF2 is associated with kidney disease focal segmental glomerulosclerosis and cancers, such as colorectal and thyroid cancer where it functions as a tumor suppressor, glioblastoma, breast, prostate, and gastric cancer, via its oncogenic function. However, studies on the underlying molecular mechanisms of the different roles of INF2 in diverse cancers are limited. This review comprehensively describes the structure, biochemical features, and primary pathogenic mutations of INF2.

Background/aim Compared to healthy controls, mean platelet volume (MPV) is frequently higher in patients with Familial Mediterranean fever (FMF) but lower in AA amyloidosis patients. The reason for the difference in MPV levels in FMF patients with and without AA amyloidosis is unclear. The aim of the study was to determine whether low MPV is unique to AA amyloidosis or MPV is similarly low in all glomerular diseases as a result of proteinuria and/or renal dysfunction. Materials and methods We compared pre-biopsy MPV levels of patients with AA amyloidosis secondary to FMF, to MPV levels of patients with membranous glomerulonephritis, focal segmental glomerulosclerosis (FSGS) and IgA nephropathy that all present with proteinuria and renal dysfunction. Results 703 patients (411 male, 292 female) were included in the study. Mean age was 42.6  14.3 years. There were 124 patients with AA amyloidosis, 224 patients with IgA nephropathy, 188 patients with membranous glomerulonephritis, and 167 patients wit h FSGS. Patients with AA amyloidosis had lower MPV levels compared to patients without AA amyloidosis (7.9  1.2 fL vs. 8.2  0.9 fL respectively, p = 0.008). Patients with AA amyloidosis had significantly lower MPV compared to patients with each of the othe r diagnoses. Independent predictors of MPV were platelet count (β = –0.321, p < 0.001) and CRP (β = – 0.134, p < 0.03). Conclusion This study is the largest study of MPV in patients with biopsy proven AA amyloidosis and confirms previous studies reporting low MPV in AA amyloidosis. This study indicates that low MPV in AA amyloidosis cannot be explained with proteinuria and renal dysfunction.

A 79-year-old Japanese man was admitted to our hospital because of proteinuria and kidney dysfunction. He was diagnosed with chronic myeloid leukemia 13 years before and was treated with imatinib. Deep molecular response was achieved but he developed 1+ proteinuria in the first year, which gradually worsened thereafter. Imatinib was discontinued 12 years later but proteinuria and kidney dysfunction were progressive. Percutaneous kidney biopsy revealed mild mesangial hyper-cellularity and matrix increase, swelling of endothelial cells, and partial double contours of glomerular tufts. Subendothelial edema in the interlobular artery was also noted. Immunofluorescence was not remarkable. Electron microscopy revealed endothelial injury with severe sub-endothelial edema. Since imatinib had already been discontinued, conservative therapy with maximal dose of azilsartan was administered. A second biopsy was performed 1 year later because of further deterioration of kidney function, which revealed markedly increased global glomerulosclerosis and severe interstitial fibrosis and tubular atrophy. Segmental glomerulosclerosis with podocyte hyperplasia was also observed. Electron microscopy revealed glomerulosclerotic changes and partially attenuated endothelial injury. Two and a half years later, proteinuria reduced, progression of kidney dysfunction slowed, and he was independent on dialysis therapy. Molecular response of chronic myeloid leukemia was also maintained. The clinical course suggested that endothelial and podocyte injuries were induced by imatinib, and that the nephrotoxic effects lasted for a few years after discontinuation.

Background The associations of focal segmental glomerulosclerosis (FSGS) histological variants with renal outcomes have rarely been investigated comprehensively by clinically relevant subgroups in this modern age. Methods Data on 304 (173 nephrotic and 131 non-nephrotic) patients with biopsy-confirmed FSGS from 2010 to 2013 were analyzed using the Japanese nationwide renal biopsy registry. The primary outcome was a composite of a 30% decline in estimated glomerular filtration rate or progression to end-stage kidney disease 5 years from the biopsy. We compared outcomes of FSGS variants according to the Columbia classification using survival analyses. Subgroup analyses were performed based on nephrotic syndrome (NS), immunosuppression and proteinuria remission (PR; proteinuria Results The distribution of variants was 48% (n = 145) FSGS not otherwise specified, 19% (n = 57) tip, 15% (n = 47) perihilar, 13% (n = 40) cellular and 5% (n = 15) collapsing. The outcome event occurred in 87 patients (29%). No significant differences in the outcome were found among the variants. Subgroup analyses yielded similar results. However, there was a trend toward improved outcome in patients with PR irrespective of variants [hazard ratio adjusted for histological variant and potential confounders (adjusted HR) 0.19 (95% confidence interval 0.10–0.34)]. NS was marginally associated with better outcome compared with non-NS [adjusted HR 0.50 (95% confidence interval 0.25–1.01)]. Conclusions FSGS variants alone might not have significant impacts on the renal outcome after 5 years, while PR could be predictive of improved renal prognosis for any variant. Specific strategies and interventions to achieve PR for each variant should be implemented for better renal outcomes.

Rituximab (RTX) therapy for primary focal segmental glomerulosclerosis recurrence after kidney transplantation (KT) has been extensively debated. We aimed to assess the benefit of adding RTX to plasmapheresis (PP), corticosteroids, and calcineurin inhibitors (standard of care, SOC). We identified 148 adult patients who received KT in 12/2004-12/2018 at 21 French centers: 109 received SOC (Group 1, G1), and 39 received immediate RTX along with SOC (Group 2, G2). In G1, RTX was introduced after 28 days of SOC in the event of failure (G1a, n = 19) or PP withdrawal (G1b, n = 12). Complete remission (CR) was achieved in 46.6% of patients, and partial remission (PR) was achieved in 33.1%. The 10-year graft survival rates were 64.7% and 17.9% in responders and nonresponders, respectively. Propensity score analysis showed no difference in CR+PR rates between G1 (82.6%) and G2 (71.8%) (p = .08). Following the addition of RTX (G1a), 26.3% of patients had CR, and 31.6% had PR. The incidence of severe infections was similar between patients treated with and without RTX. In multivariable analysis, infection episodes were associated with hypogammaglobulinemia

Background Little population-based data exist about adults with primary nephrotic syndrome. Methods To evaluate kidney, cardiovascular, and mortality outcomes in adults with primary nephrotic syndrome, we identified adults within an integrated health care delivery system (Kaiser Permanente Northern California) with nephrotic-range proteinuria or diagnosed nephrotic syndrome between 1996 and 2012. Nephrologists reviewed medical records for clinical presentation, laboratory findings, and biopsy results to confirm primary nephrotic syndrome and assigned etiology. We identified a 1:100 time-matched cohort of adults without diabetes, diagnosed nephrotic syndrome, or proteinuria as controls to compare rates of ESKD, cardiovascular outcomes, and death through 2014, using multivariable Cox regression. Results We confirmed 907 patients with primary nephrotic syndrome (655 definite and 252 presumed patients with FSGS [40%], membranous nephropathy [40%], and minimal change disease [20%]). Mean age was 49 years; 43% were women. Adults with primary nephrotic syndrome had higher adjusted rates of ESKD (adjusted hazard ratio [aHR], 19.63; 95% confidence interval [95% CI], 12.76 to 30.20), acute coronary syndrome (aHR, 2.58; 95% CI, 1.89 to 3.52), heart failure (aHR, 3.01; 95% CI, 2.16 to 4.19), ischemic stroke (aHR, 1.80; 95% CI, 1.06 to 3.05), venous thromboembolism (aHR, 2.56; 95% CI, 1.35 to 4.85), and death (aHR, 1.34; 95% CI, 1.09 to 1.64) versus controls. Excess ESKD risk was significantly higher for FSGS and membranous nephropathy than for presumed minimal change disease. The three etiologies of primary nephrotic syndrome did not differ significantly in terms of cardiovascular outcomes and death. Conclusions Adults with primary nephrotic syndrome experience higher adjusted rates of ESKD, cardiovascular outcomes, and death, with significant variation by underlying etiology in the risk for developing ESKD.