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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.

Was ist neu? Klinische, serologische, histopathologische Diagnostik der ANCA-assoziierten Vaskulitis Zentraler Bestandteil der Diagnostik der AAV mit renaler Manifestation sind die Bestimmung von PR3- und MPO-ANCA sowie die Nierenbiopsie. Die Behandlung sollte in einem in AAV erfahrenen Zentrum erfolgen und rasch begonnen werden. Remissionsinduktion Die Remissionsinduktion bei ANCA-assoziierter GN erfolgt mit Cyclophosphamid oder Rituximab in Kombination mit Kortikosteroiden. Die Leitlinie gibt Hilfestellung zur Therapieauswahl. Studienbasiert wird eine schnellere Steroidreduktion empfohlen. Remissionserhaltung Zur Remissionserhaltung stehen Rituximab und Azathioprin zur Verfügung. Die Leitlinie gibt Hilfestellung zu Auswahl und Dauer der Therapie, die sich insbesondere nach dem Rezidivrisiko richtet. Anti-GBM-Erkrankung Die Plasmapherese gehört zur Standardtherapie der Anti-GBM-Erkrankung, ist jedoch bei der ANCA-assoziierten GN einer Einzelfallentscheidung bei fulminantem Verlauf vorbehalten. Transplantation Eine Nierentransplantation kann bei ANCA-assoziierter GN nach mindestens 6-monatiger Remission unabhängig vom ANCA-Status erfolgen, bei Patienten mit Anti-GBM-Erkrankung nur nach negativem Antikörpernachweis.

Based on analysis of 819 human biopsies, essential derangement in diabetic nephropathy consists of accumulation of worn-out glomerular basement membrane in the mesangium that may advance to global sclerosis. The most frequent pathway to nephron dropout starts with the penetration of glomerular capillaries into Bowman’s capsule (BC), delivering an exudate into BC that spreads around the entire glomerular circumference and via the glomerulotubular junction onto the tubule, resulting in glomerular sclerosis and chronic tubulointerstitial damage.

Diabetic nephropathy (DN) is manifested by chronic loss of renal function due to damage of glomeruli and renal tubules. Therefore, this study is mainly designed to evaluate the therapeutic role of Azadiracta indica (neem) leaves extract as a novel approach for treatment of DN in rats neonatally induced by streptozotocin (STZ). For this study, 40 offspring were selected after parturition and categorized into four groups (n = 10). Group1: control group, group 2: neem leaves extract supplemented group, group 3: diabetic group that injected with a single dose of STZ and group 4: diabetic group treated with neem extract. The results revealed deleterious histological and ultrstructural changes in the renal tissues of diabetic rats. Such changes included atrophied glomeruli, dilated renal cortical tubules and scattered hemorrhage spots, thickening of glomerular basement membrane, expansion of mesangial matrix and pyknotic podocyte. Additionally, the proximal convoluted tubule and distal tubule showed cytoplasmic vacuolation, vacuolated mitochondria, scattered lipid droplets, lost microvilli and disrupted basal lamina and basal infoldings. Moreover, significant decreased levels of serum antioxidants (SOD&CAT) and significant increased levels of serum MDA, urea and creatinine were noticed in diabetic rats. Neem leaves extract successfully alleviated the histological and ultrastructural as well as biochemical changes induced by diabetes.

BackgroundLow-vacuum scanning electron microscopy (LV-SEM) is applied to diagnostic renal pathology.MethodsTo demonstrate the usefulness of LV-SEM and to clarify the optimal conditions of pathology samples, we investigated the alterations of glomerular basement membrane (GBM) and podocytes in control and experimental active Heymann nephritis (AHN) rats by LV-SEM.ResultsOn week 15 following induction of AHN, spike formation on GBM with diffuse deposition of IgG and C3 developed. Using LV-SEM, diffuse crater-like protrusions were clearly noted three-dimensionally (3D) on surface of GBM in the same specimens of light microscopy (LM) and immunofluorescence (IF) studies only after removal coverslips or further adding periodic acid-silver methenamine (PAM) staining. These 3D ultrastructural findings of GBM surface could be detected in PAM-stained specimens by LV-SEM, although true GBM surface findings could not be obtained in acellular glomeruli, because some subepithelial deposits remained on surface of GBM. Adequate thickness was 1.5–5 μm for 10% formalin-fixed paraffin-embedded (FFPE) and 5–10 μm for the unfixed frozen sections. The foot processes and their effacement of podocytes could be observed by LV-SEM using 10%FFPE specimens with platinum blue (Pt-blue) staining or double staining of PAM and Pt-blue. These findings were obtained more large areas in 2.5% glutaraldehyde-fixed paraffin-embedded (2.5%GFPE) specimens.ConclusionOur findings suggest that LV-SEM is a useful assessment tool for evaluating the alterations of GBM and podocytes in renal pathology using routine LM and IF specimens, as well as 2.5%GFPE specimens.

Diabetic nephropathy is a one of the microvascular complication in patients with type 2 diabetes mellitus due to increased production of free radicals and decreased levels of anti oxidants. The seviority of the disease totally depends on due to damage of foot process of podocytes. Hence, we need to evaluate the altered structural changes of podocytes, glomerular basement membrane in patients with type 2 diabetes mellitus. A total 60 type 2 diabetes mellitus patients were included in the present study and again sub classified into 2 types (Normoalbuminuria 30, Microalbuminuria 30) based on their urinary ACR. Basic laboratory investigations and radio graphical data were collected from the all subjects. A statistical was performed by using SPSS Version 21.0 and P value considers < 0.05 is statistically significant. The significantly elevated levels of plasma FBS, PPBS, Serum Urea, Creatinine, Uric Acid and HbA1c, Urinary albuminuria observed in type 2 diabetes mellitus with microalbuminuria when compared to normoalbuminuria. The radiographical data showed a significantly damaged foot process of podocytes and glomerular basement membrane are observed in patients with microalbuminuria when compared to normoalbuminuria. The increased levels blood sugar and HbA1c, Urinary Albuminuria directly indicates the damage of podocytes and glomerular basement membrane in the kidney. This study suggest continuous monitoring of these parameters may helpful for progression of type 2 diabetes mellitus complications.

Anti-glomerular basement membrane (anti-GBM) disease and anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis are the main causes of pulmonary-renal syndrome (PRS). The concurrence of both ANCA - myeloperoxidase (MPO) and proteinase 3 (PR3) - and anti-GBM antibodies has been described, although positivity for all three antibodies has rarely been reported. The natural history of triple-positive patients as well as the best therapeutic approach remains unknown. We describe a case of an 80-year-old woman that presented to the emergency department with a 3-month history of progressive fatigue, malaise and anorexia, and 5 weeks of cough with blood-streaked sputum and progressive peripheral edema. Through the complementary study, a rare diagnosis of PRS with triple-seropositive for both ANCA (MPO and PR3) and anti-GBM antibodies was made in a patient with untreated chronic hepatitis B virus infection. She was treated with glucocorticoid, cyclophosphamide, plasma exchange and entecavir, with pulmonary recovery. Renal function did not improve. After 2 years, the patient is still in dialysis, but did not have relapse of alveolar hemorrhage and ANCA and anti-GBM antibody titers remain negative. The authors intend to warn to PRS, in particular this rare cause, since delaying diagnosis can lead to significant morbidity and mortality for patients. J Med Cases. 2021;12(10):405-410 doi: https://doi.org/10.14740/jmc3742

Objective To investigate the effect of baicalin on diabetic nephropathy (DN) rats and podocytes and its mechanism. Methods The rat models with DN were established by high-fat and high-sugar diet and intraperitoneal injection of streptozotocin. The fasting blood glucose (FBG) and weight of rats in each group were measured at 0, 1, 2, 3, and 4 weeks. Their biochemical indicators, expression of inflammatory, and antioxidant factors were measured using an automatic biochemical analyzer together with ELISA. Hematoxylin–eosin staining and periodic acid-schiff staining were used to observe the morphological changes in the kidneys of rats in each group. Finally, the expressions of related molecules and PI3K/Akt/mTOR signaling pathway proteins in renal tissues and podocytes were examined by qRT-PCR and Western blot. Results Compared with the DN group, the FBG and weight, serum creatinine, blood urea nitrogen, total cholesterol, triacylglycerol, microalbumin, and albumin/creatinine ratio were all significantly decreased in the Baicalin treatment groups in a concentration-dependent manner. The levels of inflammatory factors in kidney tissue and podocytes were decreased. In addition, the activities of lactate dehydrogenase and malondialdehyde in tissue were decreased, while the superoxide dismutase was increased. The pathological sections showed that glomerular atrophy and glomerular basement membrane thickening caused by hyperglycemia were improved in the Baicalin treatment groups. Meanwhile, baicalin inhibited the downregulation of Nephrin and Podocin expressions and upregulation of Desmin expression caused by DN, and inhibited the expressions of p-PI3K, p-Akt, and p-mTOR proteins. Conclusion Baicalin slows down podocyte injury caused by DN by inhibiting the activity of PI3K/Akt/mTOR signaling pathway.

The extracellular matrix (ECM) is a complex network of collagens, elastin, and interconnecting glycoproteins and proteoglycans that surround cells and provide structural support. The ECM is a dynamic structure, undergoing constant remodeling, and providing services beyond a simple barrier or scaffold (1). Recent studies have demonstrated that the ECM and the broad complement of interacting proteins ( e.g. the matrisome) play significant roles in inflammation and cell-to-cell interactions (2). Low-grade inflammation, a common feature of many kidney diseases, often contributes to aberrant ECM deposition and fibrosis. Significantly, renal fibrosis is a hallmark of renal dysfunction progression and CKD, leading to end-organ failure. Many of the proteins making up the renal ECM are spatially resolved into the glomerular (glomerular basement membrane, the mesangial matrix, and Bowman’s capsule) and tubulointerstitial (tubular basement membranes, tubular capillaries, and interstitial space) compartments. The most abundant proteins in the ECM are collagens, accounting for almost one third of ECM proteins (3). Type IV collagen is the most well described ECM protein in terms of kidney disease. Type IV collagen has six alpha chains that form three different trimer combinations, and the α3.α4.α5 heterotrimer is the most predominant in the glomerular basement membrane (3). Mutations in COL4A3 , COL4A4 , or COL4A5 genes are associated with Alport Syndrome, thin basement membrane disease, and familial FSGS (4,5). Proteomic analysis has identified collagens I, III, VI, VII, XII, XV, and XVIII within the glomerular ECM (6,7). Collagens I, II, III, V, VI, VII, and XV are normally expressed in the tubulointerstitium and increased expression have been associated with fibrosis (3). A recent proteomic analysis of kidneys across different age groups demonstrated consistent increases in collagen VI with aging kidneys (8). Lupus nephritis (LN) is one of the most serious complications of systemic lupus erythematosus (SLE), …

Background Antiglomerular basement membrane (anti-GBM) disease is characterized by GN and often pulmonary hemorrhage, mediated by autoantibodies that typically recognize cryptic epitopes within α345(IV) collagen-a major component of the glomerular and alveolar basement membranes. Laminin-521 is another major GBM component and a proven target of pathogenic antibodies mediating GN in animal models. Whether laminin-521 is a target of autoimmunity in human anti-GBM disease is not yet known. Methods A retrospective study of circulating autoantibodies from 101 patients with anti-GBM/Goodpasture's disease and 85 controls used a solid-phase immunoassay to measure IgG binding to human recombinant laminin-521 with native-like structure and activity. Results Circulating IgG autoantibodies binding to laminin-521 were found in about one third of patients with anti-GBM antibody GN, but were not detected in healthy controls or in patients with other glomerular diseases. Autoreactivity toward laminin-521 was significantly more common in patients with anti-GBM GN and lung hemorrhage, compared with those with kidney-limited disease (51.5% versus 23.5%, P=0.005). Antilaminin-521 autoantibodies were predominantly of IgG1 and IgG4 subclasses and significantly associated with lung hemorrhage (P=0.005), hemoptysis (P=0.008), and smoking (P=0.01), although not with proteinuria or serum creatinine at diagnosis. Conclusions Besides α345(IV) collagen, laminin-521 is another major autoantigen targeted in anti-GBM disease. Autoantibodies to laminin-521 may have the potential to promote lung injury in anti-GBM disease by increasing the total amount of IgG bound to the alveolar basement membranes.

The glomerular basement membrane is a vital component of the filtration barrier of the kidney and is primarily composed of a highly structured matrix of type IV collagen. Specific isoforms of type IV collagen, the α3(IV), α4(IV), and α5(IV) isoforms, assemble into trimers that are required for normal glomerular basement membrane function. Disruption or alteration in these isoforms leads to breakdown of the glomerular basement membrane structure and function and can lead to progressive CKD known as Alport syndrome. However, there is wide variability in phenotype among patients with mutations affecting type IV collagen that depends on a complex interplay of sex, genotype, and X-chromosome inactivation. This article reviews the genetic basis of collagen disorders of the kidney as well as potential treatments for these conditions, including direct alteration of the DNA, RNA therapies, and manipulation of collagen proteins.

Background Pathological findings in Alport syndrome frequently show mesangial proliferation and sometimes incidental IgA deposition, in addition to unique glomerular basement membrane (GBM) changes including thin basement membrane and/or lamellation. However, similar GBM abnormalities are also often observed in IgA nephropathy. Both diseases are also known to show hematuria, proteinuria, and sometimes macrohematuria when associated with viral infection. Therefore, it can be difficult to make a differential diagnosis, even based on clinical and pathological findings. Some recent articles demonstrated that galactose-deficient IgA1 (Gd-IgA1)-specific monoclonal antibody (KM55) could potentially enable incidental IgA deposition to be distinguished from IgA nephropathy. Methods We performed comprehensive gene screening and glomerular Gd-IgA1 and type IV collagen α5 chain immunostaining for five cases with both IgA deposition and GBM changes to confirm that Gd-IgA1 can help to distinguish these two diseases. Results Four of the cases were genetically diagnosed with Alport syndrome (Cases 1–4) and one was IgA nephropathy with massive GBM changes, which had a negative gene test result (Case 5). In Cases 1–4, glomerular Gd-IgA1 deposition was not detected, although there was positivity for IgA in the mesangial area. In Case 5, glomerular Gd-IgA1 deposition was observed. Conclusion Gd-IgA1 expression analysis could clearly differentiate these two disorders. This approach can be applied to identify these two diseases showing identical clinical and pathological findings.

Objective: Double-positive patients (DPPs), combining serum and/or histological findings for glomerular basement membrane (GBM) disease and anti-neutrophil cytoplasmic antibodies (ANCAs), are rare and poorly described. This study aimed to compare characteristics between DPPs and ANCA-associated vasculitis (AAV) patients with severe renal involvement.Method: This retrospective multicentre study compared 33 DPPs and 45 AAV patients with severe renal involvement (serum creatinine > 300 μmol/L), all with biopsy-proven nephropathy.Results: All DPPs (including 18% exhibiting negative serum anti-GBM antibodies) presented severe acute kidney failure with histological GBM involvement. Compared to AAV patients, they had higher serum creatinine (719 vs 501 μmol/L; p = 0.006) and a higher proportion of patients requiring initial renal replacement therapy (82% vs 36%; p < 0.001). Berden classification differed significantly (p = 0.003), with more crescentic glomerulonephritis and fewer sclerotic lesions in DPPs. One-year renal survival was significantly lower in DPPs than in AAV patients (27% vs 64%; p < 0.0002). With comparable proportions of ANCA subtypes (two-thirds with anti-myeloperoxidase autoantibodies), numbers of extrarenal manifestations (mostly pulmonary in two-thirds), remission-inducing immunosuppressants, and median follow-ups (3 years) between groups, relapse rates were similar: 9.1% of DPPs and 10% of AAV patients.Conclusion: Although DPPs have features of both kinds of vasculitis, the anti-GBM component is the dominant phenotype, with more severe renal presentation and prognosis compared to AAV patients with severe renal failure. Simultaneous testing of both antibodies and systematically performed renal biopsy should be recommended in all rapidly progressing glomerulonephritis patients to recognize this difficult-to-treat, rare disease.

Nocardia species are opportunistic bacteria that are frequently contagious by inhalation. Recently, Nocardia abscessus has been described as a different species. We report a 54-year-old male who presented with acute pleuritic chest pain, mimicking pulmonary thromboembolism on the 5th day of discharge from the hospital. The patient was receiving immunosuppressive therapy for newly diagnosed atypical anti-glomerular basement membrane disease. Thorax computed tomography revealed a 17x19 mm soft tissue lesion in the lateral segment of the middle lobe of the right lung. After further examinations, a biopsy decision was made and Nocardia abscessus was isolated in the aerobic culture of the aspiration material.

A 60-year-old Japanese woman with polymyositis (PM) developed hemolytic anemia (hemoglobin of 7.3 g/dL), thrombocytopenia (platelet of 9.1×104/µL), and acute kidney injury (Cre of 4.7 mg/dL) at 14 days after starting steroid therapy. Renal biopsy revealed glomerular endothelial swelling with fibrin thrombi and fragmented erythrocytes in the capillary lumens. Hemolytic uremic syndrome (HUS) with thrombotic microangiopathy (TMA) was diagnosed. Hemodialysis and plasma exchange/plasma transfusion were initiated, but HUS did not subside. After 45 days, the patient died of hemorrhagic respiratory failure. Autopsy showed fibrin thrombi filling the glomerular vascular pole and the small arteries in most glomeruli, resulting in glomerular collapse and glomerular basement membrane (GBM) duplication. Although renal involvement by PM is rare, HUS/TMA should be remembered as one of the serious renal complications of PM.

Various extraglomerular disease processes have been associated with drug-induced secondary minimal change disease (MCD). In a majority of cases, preferably, a hypersensitivity reaction appears to be involved, and in some cases, there is direct toxic effect over glomerular capillaries. There are several reports to demonstrate that rifampicin has been associated with various nephrotoxic adverse effects, but rifampicin-induced secondary minimal change disease (MCD) is very rare. Here, we report the case of a young adult male who presented with nephrotic proteinuria with bland urine sediment after one month of initiation of rifampicin treatment for pulmonary tuberculosis. The patient had no proteinuria before the start of antituberculosis treatment. Renal biopsy showed nonproliferative glomerulopathy and immunofluorescence did not show significant glomerular immune deposits. Electron microscopy showed diffuse effacement of visceral epithelial cell foot processes and did not show any presence of glomerular immune complexes and thickening of glomerular basement membrane, promoting the diagnosis of minimal change nephrotic syndrome. The patient got complete remission after discontinuation of rifampicin.

Hypoxia-inducible factor1 (HIF1) plays a pivotal role in ensuring cells adapt to low-oxygen conditions. Depletion of oxygen, a co-substrate during hydroxylation of prolyl (P402 and P564) residues of HIF1⍺, evades HIF1⍺ ubiquitination and enables its dimerization with HIF1β to mediate global transcriptional response to hypoxia. Though HIF1 is largely considered eliciting a protective role during physiological or pathological hypoxia or ischemia, elevated HIF1 during chronic hypoxia contributes to glomerular diseases’ pathology and proteinuria. The glomerulus is responsible for renal permselectivity and excretion of ultra-filtrated urine. Podocytes are the glomerulus’ major cell types and are instrumental for glomerular filtration, permselectivity, and glomerular basement membrane maintenance. Podocyte injury is expected to impair the efficiency of glomerular filtration and manifestation of glomerulosclerosis and proteinuria. Accumulated evidence suggests that podocytes are susceptible to various insults during chronic hypoxia, including podocyte EMT, slit-diaphragm dysfunction, foot process effacement, and cytoskeletal derangement due to accumulation of HIF1. This review discusses how hypoxia/HIF1 signaling regulates various features and function of podocytes during exposure to chronic hypoxia or inducing HIF1 by various chemical modulators.

Background Immune checkpoint inhibitors and mitogen-activated protein kinase inhibitors have become the standard of care in patients with advanced melanoma bearing V600 mutations. However, little is known about their nephrotoxicity. To date, only two cases of anti-glomerular basement membrane glomerulonephritis after exposure to checkpoint inhibitors have been documented. Herein, we report the first case of a patient with metastatic melanoma who developed linear Immunoglobulin G 3+, Immunoglobulin A 2+, kappa 2+, lambda 1+ anti-glomerular basement membrane glomerulonephritis with negative serology following treatment with checkpoint inhibitors and subsequently mitogen-activated protein kinase inhibitors. Case presentation A 58-year-old Caucasian male was referred to our outpatient nephrology clinic with acute kidney injury and proteinuria. He had received three cycles of ipilimumab and nivolumab for recurrent melanoma positive for the BRAF V600E mutation with metastasis to the lungs. Immunotherapy had been discontinued in the setting of severe adverse effects including dermatitis, colitis, and hepatitis. Because of persistent bilateral lung metastases and left pleural metastases, the patient had been initiated on dabrafenib and trametinib until his presentation to our clinic 6 months later. On presentation, his blood pressure was 172/89 mm/Hg and had 2+ edema bilaterally. His creatinine level was 2.4 mg/dL from a previous normal baseline with a urinary protein-to-creatinine ratio of 2 g/g. His urinalysis showed dysmorphic erythrocytes and red blood cell casts. Serologic testing was negative for antineutrophilic cytoplasmic antibodies, proteinase 3 antigen, myeloperoxidase, and anti-glomerular basement membrane antibody. Complement levels were normal. A renal biopsy showed focal crescentic (2 of 15 glomeruli with cellular crescents), proliferative, and sclerosing glomerulonephritis with diffuse linear staining of glomerular capillary loops dominant for IgG (3+), IgA (2+), kappa (2+), and lambda (1+) minimal changes. He was initiated on oral cyclophosphamide and pulse intravenous methylprednisolone followed by oral prednisone for 6 months, which stabilized his renal function until reinitiation of immunotherapy. Conclusions Acute kidney injury is an increasingly reported adverse effect of both drug classes, mostly affecting the tubulointerstitial compartment and infrequently the glomerulus. Although the biologic effect of these drugs on immune cells is not entirely understood, it is possible that BRAF-induced podocyte injury in combination with direct T-cell-mediated glomerular injury facilitated by checkpoint inhibitors led to the unmasking of cryptic antigens, loss of self-tolerance, and autoimmunity. More importantly, we show that treatment with corticosteroids and cyclophosphamide was able to improve and stabilize our patient’s renal function until the reinitiation of immunotherapy.

Nephrotic syndrome is in adult patients mainly due to membranous nephropathy (MN) characterized by thickening of the glomerular basement membrane (GBM) and immune complex formation between podocytes and the GBM. Autoantibodies directed against the M-type phospholipase A2 receptor (PLA2R) and thrombospondin 1 domain-containing 7 A (THSD7A) can be used as diagnostic biomarkers. THSD7A seems to be of direct pathogenic significance as is suggested by experimental models and plasmapheresis in humans. Recently, further antigens like NELL-1 (neural tissue encoding protein with EGF-like repeats-1), exostosin 1 and 2 have been discovered. Thus, MN should be classified into antibody positive and antibody negative MN. More specific immunosuppressive treatments directed against B-cells and antibody production like rituximab have been introduced in addition to already existing immunosuppressive protocols including steroids, chlorambucil, cyclophosphamide, and calcineurin inhibitors. Antibody removal using immunoadsorption or plasmapheresis leads to short-term reduction in proteinuria and might be indicated only in patients with very severe proteinuria and complications. Studies are needed to identify a more specific immunosuppression directed against the production and effects of autoantibodies in order to protect the kidneys from autoimmune mediated tissue damage and to identify patients who require an immunosuppressive treatment, as the remission rate is high in patients with MN.

Primary Myelofibrosis associated Nephropathy is a recently described entity. Primary Myelofibrosis (PMF) is a Myeloproliferative Neoplasm (MPN) where the marrow space shows fibrosis with megakaryocyte dysplasia. We present a case of a 32 year old patient who was detected to have proteinuria, renal dysfunction and anemia ,on a routine health check up. Primary Myelofibrosis was confirmed by positive Jak 2 expression. Kidney biopsy showed focal segmental glomerulosclerosis along with thickened glomerular basement membrane. The histomorphological features of renal and bonemarrow biopsies are analysed and a detailed review of the literature is done. Keywords: Myeloproliferative neoplasm, Focal segmental glomeruloscerosis, Primary myelofibrosis

Membranous nephropathy (MN) is defined as disease entity characterized by thickening of the glomerular basement membranes due to subepithelial (SE) deposition of immune complexes. It is typically classified into primary MN (70%) when there is no disease association, and secondary MN (30%) when there is an underlying disease association such as lupus, malignancy, infections or drugs. Phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain-containing 7A (THSD7A) are target antigens in 70% and 1–5% of primary MN, respectively. The antigens in the remaining MN were not known. Recently, multiple novel proteins/target antigens have been identified in MN. These include exostosin 1/2, neural epidermal growth-like 1 protein, semaphorin 3B, protocadherin 7 and neural cell adhesion molecule 1. Some of these antigens are present in the setting of primary MN, some in secondary MN and some in both, thus blurring the lines between primary and secondary MN. Preliminary studies show that each of the new antigen-associated MN has distinct clinical, kidney biopsy findings and outcome data. We propose that each new protein/antigen-associated MN is a specific disease that results in the common MN pattern of injury characterized by thickened glomerular basement membrane (GBM) with or without spikes or pinholes on light microscopy, granular immunoglobulin G with or without complement 3 on immunofluorescence microscopy and SE electron-dense deposits on electron microscopy. In other words, MN is truly only a pattern of injury resulting from specific diseases that cause deposition of SE immune deposits along the GBM. It is of paramount importance to ascertain the specific disease entity causing the MN pattern not only for precise diagnosis and management, but also for future studies on these newly described diseases.

Objective: This study explored the therapeutic impact of combined cytotoxic T lymphocyte-associated antigen 4 immunoglobulin (CTLA-4-Ig) treatment and microbubble-mediated exposure in a rat model of diabetic nephropathy (DN). Method: We treated rats using CTLA-4-Ig and/or microbubble exposure. At 8 weeks post-intervention, key parameters were evaluated including blood biochemistry, damage to renal tissue, renal parenchymal elasticity, ultrastructural changes in podocytes, and renal parenchymal expression of CD31, CD34, IL-6, Fn, Collagen I, Talin, Paxillin, α3β1, podocin, nephrin, and B7-1. Result: We found that renal function in the rat model of DN can be significantly improved by CTLA-4-Ig and CTLA-4-Ig + ultrasound microbubble treatment. Treatment efficacy was associated with reductions in renal parenchymal hardness, decreases in podocyte reduction, decreased IL-6, Fn and Collagen I expression, increased Talin, Paxillin and α3β1 expression, elevated podocin and nephrin expression, and decreased B7-1 expression. In contrast, these treatments did not impact CD31 or CD34 expression within the renal parenchyma. Conclusion: These findings clearly emphasize that CTLA-4-Ig can effectively prevent podocyte damage, inhibiting inflammation and fibrosis, and thereby treating and preventing DN. In addition, ultrasound microbubble exposure can improve the ability of CTLA-4-Ig to pass through the glomerular basement membrane in order to access podocytes such that combination CTLA-4-Ig + microbubble exposure treatment is superior to treatment with CTLA-4-Ig only.

Immunotactoid glomerulopathy (ITG) is a rare form of glomerulonephritis for which our understanding is limited to case reports and small case series. Herein we describe the clinical, pathologic, and outcome characteristics of 73 patients with ITG who typically presented with proteinuria, hematuria, and renal insufficiency. Hematologic disorders were present in 66% of patients, including lymphoma in 41% (mainly chronic lymphocytic leukemia/small lymphocytic lymphoma), monoclonal gammopathy in 20%, and multiple myeloma in 6%. Light microscopy revealed endocapillary proliferative (35%), membranoproliferative (29%) and membranous (29%) patterns of glomerular involvement. Electron microscopy revealed characteristic microtubular deposits with a diameter of 14-60 nm, hollow cores, frequent parallel alignment, and a predominant distribution outside of the lamina densa of the glomerular basement membrane. Importantly, immunofluorescence revealed IgG-dominant staining which was light chain and IgG subclass restricted in 67% of cases, indicating monoclonal composition. This finding was used to distinguish monoclonal and polyclonal variants of ITG. As compared to polyclonal, monoclonal ITG had a higher incidence of lymphoma (53% vs. 11%), multiple myeloma (8% vs. 0), and monoclonal gammopathy (22% vs. 16%). Monoclonal ITG was more commonly treated with clone-directed therapy, which was associated with more frequent remission and less frequent end stage kidney disease. Thus, a third of ITG cases are polyclonal but a quarter of these cases are associated with hematologic conditions, underscoring the need for hematologic evaluation in all patients with ITG. Hence, based on these distinctions, ITG should be subclassified into monoclonal and polyclonal variants. Prognosis of ITG is good if the underlying hematologic condition is treated.

Biallelic pathogenic variants in the laminin β2 (LAMB2) gene, which encodes laminin β2, are associated with Pierson syndrome characterized by a congenital nephrotic syndrome that rapidly progresses to end-stage renal disease, distinct ocular maldevelopment with bilateral microcoria, and neurodevelopmental deficits. However, the phenotypic spectrum of LAMB2-associated disorder is broader than expected, and cases with milder phenotypes such as isolated congenital or infantile nephrotic syndrome have also been reported. We report a patient with LAMB2-associated renal disorder showing an extremely mild phenotype. A 5-year-old girl presented with asymptomatic proteinuria and hematuria detected by urinalysis screening. She had been previously healthy without any additional renal symptoms. The serum albumin and creatinine levels were normal. Renal biopsy revealed minor glomerular abnormalities with occasional focal mesangial proliferation. Electron microscopy showed no structural changes in the glomerular basement membrane. Targeted sequencing of podocyte-related genes using next-generation sequencing was performed. As a result, previously reported biallelic pathogenic variants of the truncating variant (c.5073_5076dupCCAG) and a splice site variant (c.3797 + 5G > A) in the LAMB2 gene were detected, and the patient was diagnosed with LAMB2-associated renal disorder. Interestingly, a previously reported case with this splicing variant also showed an atypically mild phenotype. We suggest that clinicians should consider LAMB2-associated nephritis as an important differential diagnosis in children with asymptomatic proteinuria and microscopic hematuria if there is no structural change in the glomerular basement membrane. A comprehensive gene-screening system using next-generation sequencing is useful for diagnosing these atypical cases with isolated urine abnormalities.

Proliferative glomerulonephritis with monoclonal immunoglobulin G (IgG) deposits (PGNMID) is a rare kidney disease. The predominant pathological finding of PGNMID is the presence of monoclonal Ig deposits on the glomerular basement membrane (GBM). However, there is some variation in deposition pattern in this kidney disease. We report a case of steroid-sensitive recurrent mesangial proliferative type of PGNMID. A 40-year-old female noticed lower leg pitting edema and polyuria. Approximately 10 days prior to the first clinic visit, she was diagnosed with nephrotic syndrome based on the laboratory data of urine and blood. Immunological and hematological examination revealed no abnormality. However, kidney biopsy specimens showed mild mesangial cell proliferation and mesangial matrix accumulation on light microscopic findings. Regarding immunofluorescence staining, granular deposits of IgG, C1q, and β1c were observed on GBM and mesangial area. Granular deposits of IgG3 and λ were also observed on GBM and mesangial area. Moreover, negative results were obtained for the phospholipase A2 receptor antibody and thrombospondin type-1 domain-containing 7A. Electron microscopy revealed highly electron dense deposits mainly in the mesangial region. Kidney biopsy showed mesangial proliferative glomerulonephritis characterized by monoclonal Ig deposition of IgG3/λ. Steroid therapy was initiated, and complete remission was achieved on day 36. After the discontinuation of steroid therapy, proteinuria recurred and second kidney biopsy findings were almost similar to the first biopsy. However, complete remission was achieved with steroid therapy. This is a rare recurrent case of steroid-sensitive PGNMID. The pathological feature of this case was mesangial proliferative glomerulonephritis with Ig deposition of IgG3/λ.

We report a rare case of nephritic syndrome underlying dense deposit disease (DDD) with alternative complement pathway dysfunction explained with both C3 nephritic factor (C3NeF) antibodies and DDD associated polymorphism of factor H. A 8-year-old boy presented with macroscopic hematuria, hypertension and periorbital edema followed by persistently low C3 during the 8-week follow-up. Positive C3 staining on immunofluorescence microscopy, supported by dense deposits within the glomerular basement membrane on electron microscopy, confirmed the diagnosis of DDD. Preliminary tests for complement activation showed decreased classical pathway and deficient alternative complement pathway as well as slightly positive C3NeF, supporting the diagnosis of DDD. Genetic analysis revealed a polymorphism of the complement factor H gene with an increased risk of developing DDD. Supportive therapy has led to a satisfactory recovery of renal function and normalization of C3. Given the poor prognosis of the disease, the proper approach to such specific glomerulopathy is important to avoid or at least to slow the progression to end-stage renal disease

Diabetes-related complications are a significant source of morbidity and mortality worldwide. Diabetic kidney disease is a frequent microvascular complication and a primary cause of kidney failure in patients with diabetes. The glomerular filtration barrier is composed of 3 layers: the endothelium, glomerular basement membrane, and podocytes. Podocytes and the endothelium communicate through molecular crosstalk to maintain filtration at the glomerular filtration barrier. Chronic hyperglycemia affects all 3 layers of the glomerular filtration barrier, as well as the molecular crosstalk that occurs between the 2 cellular layers. One of the earliest events following chronic hyperglycemia is endothelial cell dysfunction. Early endothelial damage is associated with progression of diabetic kidney disease. However, current therapies are based in controlling glycemia and arterial blood pressure without targeting endothelial dysfunction. Disruption of the endothelial cell layer also alters the molecular crosstalk that occurs between the endothelium and podocytes. This review discusses both the physiologic and pathologic communication that occurs at the glomerular filtration barrier. It examines how these signaling components contribute to podocyte foot effacement, podocyte detachment, and the progression of diabetic kidney disease.

Objective The aim of this study was to investigate the role of prophylactic use of statin in venous thromboembolism (VTE) in patients with primary membranous nephropathy (PMN). Methods A total of 734 patients with PMN were consecutively enrolled in this retrospective study. 564 patients had received statins prescription, while 170 patients did not. Kaplan–Meier methods were used for cumulative incidence plots of thromboembolic events and Cox proportional hazards regression models were used to assess risk factors. Finally, the effects of different potency of statins were evaluated. Results In the cohort, 37 patients (5.0%) experienced VTE. In a univariate Cox proportional hazard model, the hazard ratio (HR) for VTE in statin users versus statin non-users was 0.5 (95% CI 0.3–0.8, p = .03). Multivariable model proportional-hazards analysis corrected for co-medications and risk factors revealed that adjusted HR was 0.4 (95% CI 0.1–0.7, p = .03). According to the type and dose, statin users were assigned into 3 groups: high-intensity group (n = 278), moderate-intensity group (n = 186), and low-intensity group (n = 49). In comparison, incidences of VTEs in the three groups were similar (2.9% vs 4.8% vs 2.0%, p = .45). Conclusions The prophylactic use of statins could effectively decrease the occurrence of VTE in patients with PMN, and the benefits have no difference in different potency of statins.

Background/Aim: Necrotizing crescentic glomerulonephritis (GN) associated with anti-neutrophil cytoplasmic antibodies (ANCA) against myeloperoxidase (MPO) is a devastating disease that quickly progresses to kidney failure. Current therapies are broadly immunosuppressive and associated with adverse effects. We wanted to set up a model that could be suitable for testing narrowly targeted therapies. Methods: The model was constructed in male Wistar Kyoto rats through injections of human MPO (hMPO) and pertussis toxin, followed by a sub-nephritogenic dose of sheep anti-rat glomerular basement membrane (GBM) serum to boost the disease. Rats were monitored for 35 days. Rats given hMPO alone, saline, or human serum albumin with or without anti-GBM serum were also studied. Results: Rats receiving hMPO developed circulating anti-hMPO and anti-rat MPO antibodies. Challenging hMPO-immunized rats with the anti-GBM serum led to more glomerular neutrophil infiltration and MPO release, and severe haematuria, heavy proteinuria, and higher blood urea nitrogen than hMPO alone. Pauci-immune GN developed with crescents, affecting 25% of glomeruli. The majority of crescents were fibrocellular. Necrotizing lesions and Bowman capsule ruptures were detected. Cells double positive for claudin-1 (a marker of parietal epithelial cells [PECs]) and neural cell adhesion molecule (NCAM; progenitor PECs) were present in crescents. Double staining for NCAM and Ki-67 established proliferative status of progenitor PECs. Podocyte damage was associated with endothelial and GBM changes by electron microscopy. Monocyte/macrophages and CD4+ and CD8+ T cells accumulated in glomeruli and the surrounding area and in the tubulointerstitium. Lung haemorrhage also manifested. Conclusion: This model reflects histological lesions of human ANCA-associated rapidly progressive GN and may be useful for investigating new therapies.

Membranous nephropathy (MN) with anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (ANCA-GN) is seen infrequently. Previous reports of patients with ANCA-GN with MN showed that the most frequent ANCA subtype was myeloperoxidase-ANCA. We herein present a 73-year-old woman with scleritis, hematuria, proteinuria, and positive serum proteinase 3 (PR3)-ANCA. She underwent a renal biopsy and was diagnosed with MN and ANCA-GN. Immunofluorescence staining for PR3 colocalized with IgG along the glomerular basement membrane were observed. Oral prednisolone and intravenous rituximab therapy immediately improved her symptoms and urinalysis abnormalities. PR3-ANCA may be involved in the pathogenesis of MN via the formation of immune complexes.

We report a case of nail-patella syndrome (NPS) with unusual thinning of the glomerular basement membrane (GBM) associated with a novel heterozygous variant in the LMX1B gene. A 43-year-old female patient with a previous diagnosis of NPS, referred to our hospital for persistent proteinuria, underwent a renal biopsy, which revealed minor glomerular abnormalities. She underwent a second renal biopsy at the age of 56 owing to the presence of persistent proteinuria and decline in serum albumin, meeting the diagnostic criteria for nephrotic syndrome. Light microscopy demonstrated glomerulosclerosis and cystic dilatation of the renal tubules. Notably, electron microscopy revealed unusual thinning of the GBM, which is quite different from typical biopsy findings observed in patients with NPS, characterized by thick GBM with fibrillary material and electron-lucent structures. Comprehensive genetic screening for 168 known genes responsible for inherited kidney diseases using a next-generation sequencing panel identified a novel heterozygous in-frame deletion-insertion (c.723_729delinsCAAC: p.[Ser242_Lys243delinsAsn]) in exon 4 of the LMX1B gene, which may account for the disrupted GBM structure. Further studies are warranted to elucidate the complex genotype-phenotype relationship between LMX1B and proper GBM morphogenesis.

Background Modern guidelines recommend sodium-glucose cotransporter-2 (SGLT2) inhibitors as the preferred antihyperglycemic agents for patients with type 2 diabetes and chronic kidney disease. However, the mechanisms underlying the renal protective effect of SGLT2 inhibitors are not fully understood. Aim To estimate the effect of the SGLT2 inhibitor, empagliflozin (EMPA), on the structure of podocytes and nephrin expression in glomeruli in db/db diabetic mice. Methods We treated 8-wk-old male db/db mice with EMPA (10 mg/kg/d) or vehicle for 8 wk. Age-matched male db/+ mice were included as non-diabetic controls. Parameters of body composition, glycemic and lipid control, and plasma concentrations of leptin, insulin and glucagon were assessed. We evaluated renal hypertrophy as kidney weight adjusted to lean mass, renal function as plasma levels of creatinine, and albuminuria as the urinary albumin-to-creatinine ratio (UACR). Renal structures were studied by light and transmission electron microscopy with a focus on mesangial volume and podocyte structure, respectively. Glomerular nephrin and transforming growth factor beta (TGF-β) were assessed by immunohistochemistry. Results Severe obesity and hyperglycemia developed in db/db mice prior to the start of the experiment; increased plasma concentrations of fructosamine, glycated albumin, cholesterol, leptin, and insulin, and elevated UACR were detected. Mesangial expansion, glomerular basement membrane thickening, and increased area of TGF-β staining in glomeruli were revealed in vehicle-treated mice. Podocytopathy was manifested by effacement of foot processes; nephrin-positive areas in glomeruli were reduced. EMPA decreased the levels of glucose, fructosamine and glycated albumin, UACR, kidney hypertrophy, mesangial expansion, glomerular basement membrane thickening, and glomerular TGF-β staining, alleviated podocytopathy and restored glomerular staining of nephrin. Conclusion These data indicate that EMPA attenuates podocytopathy in experimental diabetic kidney disease. The anti-albuminuric effect of EMPA could be attributed to mitigation of podocyte injury and enhancement of nephrin expression.

Alport syndrome (AS) is a progressive inherited kidney disease characterized by hearing loss and ocular abnormalities. There are three forms of AS depending on inheritance mode: X-linked Alport syndrome (XLAS), autosomal recessive AS (ARAS), and autosomal dominant AS (ADAS). XLAS is caused by pathogenic variants in COL4A5, which encodes type IV collagen α5 chain, while ADAS and ARAS are caused by variants in COL4A3 or COL4A4, which encode type IV collagen α3 or α4 chain, respectively. In male XLAS or ARAS cases, end-stage kidney disease (ESKD) develops around a median age of 20 to 30 years old, while female XLAS or ADAS cases develop ESKD around a median age of 60 to 70 years old. The diagnosis of AS is dependent on either genetic or pathological findings. However, determining the pathogenicity of the variants detected by gene tests can be difficult. Recently, we applied the following molecular investigation tools to determine pathogenicity: 1) in silico and in vitro trimer formation assay of α345 chains to assess triple helix formation ability, 2) kidney organoids constructed from patients' induced pluripotent stem cells to identify α5 chain expression on the glomerular basement membrane, and 3) in vitro splicing assay to detect aberrant splicing to determine the pathogenicity of variants. In this review article, we discuss the genetic background and novel assays for determining the pathogenicity of variants. We also discuss the current treatment approaches and introduce exon skipping therapy as one potential treatment option.

Oligomeganephronic hypoplasia, commonly referred to as oligomeganephronia (OMN), is a rare pediatric disorder characterized by small kidneys. Histologically a paucity of nephrons is observed which show compensatory enlargement. Hyperfiltration injury leads to end-stage kidney disease. Here we report a 23-year-old Caucasian female patient who presented with a 7-year history of nonnephrotic proteinuria, slow worsening of renal function, normal-sized kidneys, normal blood pressure, healthy weight, and normoglycemia. Evaluation of a kidney biopsy specimen revealed sparsely distributed and markedly enlarged glomeruli (glomerular density 0.63/mm2, glomerular diameter 268 µm), focal segmental glomerulosclerosis (FSGS), and 70% effacement of the foot processes. The glomerular basement membrane was normal (mean thickness 285 nm). The genetic analysis of 19 genes known to cause FSGS identified a heterozygous de novo nonsense mutation of PAX2 in exon 4 (NM_003990.3:c.430C>T and NP_003981.2:p.Gln144Ter). Clinical investigations ruled out optic nerve coloboma, hearing loss, and vesicoureteral reflux. Magnetic resonance imaging of the urogenital tract found the uterus to be bicornuate. Based on these data, OMN in nonhypoplastic kidneys and adaptive FSGS related to PAX2 mutation was diagnosed. Her kidney function worsened during the 30-month follow-up (last visit: eGFR-EPI 32 mL/min/1.73 m2) despite angiotensin-converting enzyme inhibitor treatment. To our best knowledge, our patient is the seventh in the English-language literature with a biopsy diagnosis of OMN in an adult, the first observed with normal-sized kidneys, and the first in whom a specific etiologic genetic diagnosis was established. Nonsense PAX2 mutations between the paired domain and the octapeptide domain appear to manifest in renal-limited phenotype.

X-linked Alport syndrome (XLAS) is a progressive kidney disease caused by genetic abnormalities of COL4A5. Lack of collagen IV α5 chain staining and “basket-weave” by electron microscopy (EM) in glomerular basement membrane (GBM) are its typical pathology. However, the causal relationship between GBM defects and progressive nephropathy is unknown. We analyzed sequential pathology in a mouse model of XLAS harboring a human nonsense mutation of COL4A5. In mutant mice, nephropathy commenced from focal GBM irregularity by EM at 6 weeks of age, prior to exclusive crescents at 13 weeks of age. Low-vacuum scanning EM demonstrated substantial ragged features in GBM, and crescents were closely associated with fibrinoid exudate, despite lack of GBM break and podocyte depletion at 13 weeks of age. Crescents were derived from two sites by different cellular components. One was CD44 + cells, often with fibrinoid exudate in the urinary space, and the other was accumulation of α-SMA + cells in the thickened Bowman’s capsule. These changes finally coalesced, leading to global obliteration. In conclusion, vulnerability of glomerular and capsular barriers to the structural defect in collagen IV may cause non-necrotizing crescents via activation of PECs and migration of interstitial fibroblasts, promoting kidney disease in this model.

Membranous nephropathy results from subepithelial antigen-antibody complex deposition along the glomerular basement membrane. Although PLA2R, THSD7A, and NELL-1 account for a majority (about 80%) of the target antigens, the target antigen in the remaining cases is not known. Using laser microdissection of PLA2R-negative glomeruli of patients with membranous nephropathy followed by mass spectrometry we identified a unique protein, Semaphorin 3B, in three cases. Mass spectrometry failed to detect Semaphorin-3B in 23 PLA2R-associated cases of membranous nephropathy and 88 controls. Semaphorin 3B in all three cases was localized to granular deposits along the glomerular basement membrane by immunohistochemistry. Next, an additional eight cases of Semaphorin 3B-associated membranous nephropathy were identified in three validation cohorts by immunofluorescence microscopy. In four of 11 cases, kidney biopsy also showed tubular basement membrane deposits of IgG on frozen sections. Confocal microscopy showed that both IgG and Semaphorin 3B co-localized to the glomerular basement membrane. Western blot analysis of five available sera showed reactivity to reduced Semaphorin 3B in four of four patients with active disease and no reactivity in one patient in clinical remission; there was also no reactivity in control sera. Eight of the 11 cases of Semaphorin 3B-associated membranous nephropathy were pediatric cases. Furthermore, in five cases, the disease started at or below the age of two. Thus, Semaphorin 3B-associated membranous nephropathy appears to be a distinct type of disease; more likely to be present in pediatric patients.

A 28-year-old woman was admitted during the eighth week of her pregnancy because her clinical course was consistent with rapid progressive glomerulonephritis (RPGN). Anti-glomerular basement membrane antibody (anti-GBM Ab) and myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) were positive, and the anti-GBM Ab titer being extremely high. She was treated with hemodialysis, plasma exchange and prednisolone. She survived the illness; however, neither the fetus nor her kidney function could be rescued. She had human leukocyte antigen (HLA)-DRB1*1502:01, which differs from the DRB1*1501 associated with anti-GBM GN. When patients have particular symptoms, we should check the urine and serum creatinine to exclude RPGN, even in cases of pregnancy.

The glomerular basement membrane (GBM) is a key component of the glomerular capillary wall and is essential for kidney filtration. The major components of the GBM include laminins, type IV collagen, nidogens and heparan sulfate proteoglycans. In addition, the GBM harbours a number of other structural and regulatory components and provides a reservoir for growth factors. New technologies have improved our ability to study the composition and assembly of basement membranes. We now know that the GBM is a complex macromolecular structure that undergoes key transitions during glomerular development. Defects in GBM components are associated with a range of hereditary human diseases such as Alport syndrome, which is caused by defects in the genes COL4A3, COL4A4 and COL4A5, and Pierson syndrome, which is caused by variants in LAMB2. In addition, the GBM is affected by acquired autoimmune disorders and metabolic diseases such as diabetes mellitus. Current treatments for diseases associated with GBM involvement aim to reduce intraglomerular pressure and to treat the underlying cause where possible. As our understanding about the maintenance and turnover of the GBM improves, therapies to replace GBM components or to stimulate GBM repair could translate into new therapies for patients with GBM-associated disease. The glomerular basement membrane (GBM) is essential for kidney filtration. This Review describes how studies of GBM composition and structure have provided insights into GBM assembly, its developmental transitions and its role in glomerular filtration. The authors also discuss GBM-associated diseases and current and potential future treatments for these disorders.

Background: Crescentic Glomerulonephritis (CGN) is produced by many factors like Antineutrophilic Cytoplasmic Antibody (ANCA), Anti Glomerular Basement Membrane Antibodies (Anti GBM Ab) or immune complexes (IC). Aim of the study was to see prevalence of ANCA in CGN and subtypes of CGN. Methods: Total 50 cases of CGN were studied from February 2016 to July 2017. All auto antibodies (ANCA, ANA, DNA) were performed by ELISA method. Formalin fixed, paraffin embedded tissue was used for histopathology. Result: In 50 cases of CGN (26 males, 24 females) age range was 13 – 86 years. ANCA was positive in 72%. About 60% cases were of Type III (Pauci-immune) followed by Type IV (combined type 1 and type 3), Type V (ANCA, immune-complex and anti GBM negative) (12% each), Type I (Anti GBM Ab mediated) and Type II (immune complex mediated) (8% each). About 14% patients were below 14 years of age, 52% were between 21 to 40 years, 24% were between 41 to 60 years and 10% were above 61 years of age. In Type III CGN, 53.33% were MPO positive, 40% were PR3 positive and 6.7% were both MPO and PR3 positive, while in Type IV CGN, 83.33% were MPO positive and 16.66% were PR3 positive. Small vessel vasculitis found in 83.3% of the patients of Type V, 69.9% patients of Type III and 50% of patients of Type I and Type IV and 25% of patients of Type II CGN. Vasculitis of medium sized blood vessels was seen in 50% of Type IV, 20% of Type III CGN, 25% of Type I and 16.7% of Type V CGN. About 41 cases of CGN, suspected highly for small vessel vasculitis, were subjected for CD34 staining. In HE but after CD 34 staining, all cases showed arteriolitis and peritubular capillaritis. About 33.33% of Type IV and 26.6% of Type III had granulomas in glomeruli; while 26.6% of Type III, 25% of Type I and IV each, 16% of Type IV and V each had granulomas in interstitium. Two cases (66.6%) of Type III had granulomas in blood vessel

Metabolic syndrome (MetS) represents a cluster of related metabolic abnormalities, including central obesity, hypertension, dyslipidemia, hyperglycemia, and insulin resistance. These metabolic derangements present significant risk factors for chronic kidney disease that carries to loss of essential micronutrients, which accelerates comorbidity apparition. The work aimed was to evaluate the trace element homeostasis regarding morphological adaptations and renal function in MetS early-onset. Fifty male Wistar rats were divided into two groups: (a) control group and (b) hypercaloric diet group that developed MetS early-onset after 3 months. Classical zoometric parameters do not show changes; however, biochemical modifications were observed such as hyperglycemia, protein glycation, insulin resistance, dyslipidemia, hyperinsulinemia, and hypoadiponectinemia. MetS early-onset group observed renal structural modifications, but no functional changes. The structural modifications observed were minimal glomerular injury, glomerular basement membrane thickening, as well as mesangial and tubular cells that showed growth and proliferation. In serum and kidney (cortex and medulla), the concentrations of Zn, Fe, Cr, Mg, Mn, Cu, Co, and Ni were no differences between the experimental groups, but excretory fractions of these were lower in the hypercaloric diet group. In conclusion, MetS early-onset coexist renal structural modification and a hyperreabsorptive activity of essential trace elements that avoid its loss; thus, the excretory fraction of oligo-elements could be used a biomarker of early renal injury caused by metabolic diseases in the clinical practice.

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.

Background Alport syndrome (AS) is a kind of progressive hereditary nephritis induced by mutations of different genes that encode collagen IV. The affected individuals usually develop hematuria during childhood, accompanying with gradual deterioration of renal functions. In this study, the multi-pronged approach was employed to improve the diagnosis of AS. Methods Twenty-two children were diagnosed and treated at the Department of Pediatric Nephrology of Jilin University First Hospital between January 2017 and January 2020 using the multi-pronged approach. The following information was collected from patients, including age of onset, age at diagnosis, clinical manifestations, family history, renal pathology and genotype. Results All these 22 children were diagnosed with Alport syndrome according to the diagnostic criteria formulated by the Japanese Society of Nephrology (2015), among them, only 13 children met the diagnostic criteria released in 1988. All the 22 patients presented with hematuria, and proteinuria to varying degrees was observed in some patients. Three children suffered from hearing loss, but no child in the cohort had any visual problem or renal failure. Meanwhile, five patients were estimated to be at Stage 2, whereas the remaining 17 cases were at Stage 0. Renal biopsies were performed in 18 patients, including 14 showing glomerular basement membranes (GBM)-specific abnormalities. Moreover, 13 children were detected with mutations of genes encoding collagen IV. Conclusions The multi-pronged approach helps to improve the diagnosis of AS. Most patients do not have renal failure during childhood, but close assessment and monitoring are necessary. Also, the advancements in treatment are reviewed.

Diabetic kidney disease (DKD) is among the most common and serious complications of both type 1 and type 2 diabetes. In this study, we used KK/Ta‐Ins2Akita (KK‐Akita) mice as a model of DKD and KK/Ta (KK) mice as controls to identify novel factors related to the development/progression of DKD. Capillary electrophoresis coupled with mass spectrometry analysis revealed that circulating Asp (l‐aspartic acid) levels in diabetic KK‐Akita mice tend to be lower than those in control KK mice. Therefore, we evaluated the effect of Asp supplementation to prevent the progression of DKD in KK‐Akita mice. Mice were divided into three groups: (a) untreated KK mice (Control group), (b) untreated KK‐Akita mice (DKD group), and (c) treated (double‐volume Asp diet) KK‐Akita mice (Tx group). Kidney sections were stained with fluorescein isothiocyanate‐labeled lectins, wheat germ agglutinin (WGA), and anti‐endothelial nitric oxide synthase (eNOS) antibody for evaluation of endothelial surface layer (ESL) and NO synthesis. The mesangial area and glomerular size in the DKD group were significantly larger than those in the Control group; however, there was no significant difference in those between the DKD and Tx groups. Albuminuria, the ratio of foot process effacement, and thickness of glomerular basement membrane in the Tx group were significantly lower than those in the DKD group. Furthermore, the expression levels of glomerular WGA and microvascular eNOS in the Tx group improved significantly and approached the level in the Control group. In conclusion, the improvement of albuminuria in the Tx group may be caused by the reduction of oxidative stress in the kidneys, which may lead to the subsequent improvement of glomerular ESL., Serum aspartic acid (Asp) levels in KK‐Akita mice were lower than those in KK mice. Albuminuria was decreased, and the expression of glomerular wheat germ agglutinin and microvascular endothelial nitric oxide synthase was improved after Asp supplementation in KK‐Akita mice. These results may be caused by the reduction of oxidative stress in the kidneys, which may lead to the subsequent improvement of glomerular endothelial surface layer.

Background Schimke immuno-osseous dysplasia (SIOD) is a rare autosomal recessive disorder characterized by spondyloepiphyseal dysplasia, progressive renal insufficiency and defective cellular immunity. Podocytic infolding glomerulopathy (PIG) is a newly proposed disease entity characterized by microspheres or microtubular structures associated with podocytes infolding into the glomerular basement membrane (GBM) on electron microscopy (EM). Case presentation A 4-year-old boy was admitted to our ward due to proteinuria and edema lasting 1 month. He had a short trunk and demonstrated subtle dysmorphology, with a triangular shape, a broad nasal bridge and a bulbous nasal tip. The laboratory findings were as follows: lymphocytes, 0.5 × 109/L; urine protein, 3.67 g/d; albumin, 9.8 g/L; and cholesterol, 11.72 mmol/L. Skeletal X rays showed small iliac wings, small ossification centers of the capital femoral epiphyses, shallow dysplastic acetabular fossae and mildly flattened vertebrae. The specimen for light microscopy (LM) suggested focal segmental glomerulosclerosis (FSGS). EM revealed a focal thickness of the GBM with some cytoplasmic processes of podocyte infolding into the GBM. Gene sequencing showed novel compound heterozygous mutations in the SMARCAL1 gene (c.2141 + 5G > A; c.2528 + 1G > A) that were inherited from his parents. Finally, we established the diagnosis of SIOD and treated him with diuretics and angiotensin-converting enzyme inhibitors (ACEIs). Conclusion The pathogenic mechanism of PIG has not been clarified. Further studies are required to understand whether gene mutations, especially those related to podocytes, contribute to the pathogenesis of podocytic infolding.

Purpose of review Crescents are classical histopathological lesions found in severe forms of rapidly progressive glomerulonephritis, also referred to as crescentic glomerulonephritis (CGN). Crescent formation is a consequence of diverse upstream pathomechanisms and unraveling these mechanisms is of great interest for improving the management of patients affected by CGN. Thus, in this review, we provide an update on the latest insight into the understanding on how crescents develop and how they resolve. Recent findings Cellular crescents develop from activated parietal epithelial cells (PECs) residing along Bowman's capsule and their formation has as a consequence the decline in glomerular filtration rate (GFR). Cellular crescents can be reversible, but when multilevel growth of PECs associate with an epithelial--mesenchymal transition-like change in cell phenotype, fibrous crescents form, and crescents become irreversible also in terms of GFR recovery. Different molecular pathways trigger the activation of PECs and are a prime therapeutics target in CGN. First, crescent formation requires also vascular injury causing ruptures in the glomerular basement membrane that trigger plasmatic coagulation within Bowman's space. This vascular necrosis can be triggered by different upstream mechanisms, such as small vessel vasculitides, immune complex glomerulonephritis, anti-GBM disease, and C3 glomerulonephritis, that all share complement activation but involve diverse upstream immune mechanisms outside the kidney accessible for therapeutic intervention. Summary Knowing the upstream mechanisms that triggered crescent formation provides a tool for the development of therapeutic interventions for CGN.

Goodpasture’s disease is the term for a pulmonary-renal syndrome associated with rapidly progressive glomerulonephritis* and anti-glomerular basement (GBM) membrane antibodies and is used alongside the term anti-GBM disease. The eponym was coined by Stanton and Tange in 1958 after their report of patients with the condition and their recognition that they were similar to the cases published 37 years earlier by Ernest Goodpasture, an American pathologist who described the clinical constellation of pulmonary haemorrhage and renal failure, during the 1918–1919 influenza pandemic. In the USA, Goodpasture’s syndrome is often used to refer to any cause of pulmonary-renal syndrome while Goodpasture’s disease is limited to those patients with anti-GBM antibodies.

Alport syndrome (AS) is a genetic disorder caused by mutations in type IV collagen that lead to defective glomerular basement membrane, glomerular filtration barrier (GFB) damage, and progressive chronic kidney disease. While the genetic basis of AS is well known, the molecular and cellular mechanistic details of disease pathogenesis have been elusive, hindering the development of mechanism-based therapies. Here, we performed intravital multiphoton imaging of the local kidney tissue microenvironment in a X-linked AS mouse model to directly visualize the major drivers of AS pathology. Severely distended glomerular capillaries and aneurysms were found accompanied by numerous microthrombi, increased glomerular endothelial surface layer (glycocalyx) and immune cell homing, GFB albumin leakage, glomerulosclerosis, and interstitial fibrosis by 5 months of age, with an intermediate phenotype at 2 months. Renal histology in mouse or patient tissues largely failed to detect capillary aberrations. Treatment of AS mice with hyaluronidase or the ACE inhibitor enalapril reduced the excess glomerular endothelial glycocalyx and blocked immune cell homing and GFB albumin leakage. This study identified central roles of glomerular mechanical forces and endothelial and immune cell activation early in AS, which could be therapeutically targeted to reduce mechanical strain and local tissue inflammation and improve kidney function.

International audience; Primary membranous nephropathy (MN) is an autoimmune glomerular disease in which autoantibodies are directed against podocyte proteins. In about 80% of cases the main targeted antigen is the phospholipase A2 receptor 1 (PLA2R1). Anti-PLA2R1 antibodies are mainly immunoglobulin G type 4 (IgG4). However, the antigenic target remains to be defined in 20% of cases. MN can be associated with chronic inflammatory demyelinating polyneuropathy, an autoimmune disease of the peripheral nervous system where a common antigenic target has yet to be identified. To ascertain a possible novel target antigen, we analyzed kidney biopsies from five patients positive for anti-contactin 1 antibodies and presenting with MN combined with chronic inflammatory demyelinating polyneuropathy. Eluted IgG from biopsy sections against contactin 1 and nerve tissue were screened. Western blot revealed contactin 1 expression in normal kidney glomeruli. Confocal microscopic analysis showed the presence and colocalization of contactin 1 and IgG4 on the glomerular basement membrane of these patients. Glomerular contactin 1 was absent in patients with anti-PLA2R1-associated MN or membranous lupus nephritis or a healthy control. The eluted IgG from contactin 1-positive biopsy sections but not the IgG eluted from patients with PLA2R1 MN bound conactin 1 with the main eluted subclass IgG4. Eluted IgG could bind paranodal tissue (myelinated axon) and colocalized with commercial anti-conactin 1 antibody. Thus, contactin 1 is a novel common antigenic target in MN associated with chronic inflammatory demyelinating polyneuropathy. However, the precise pathophysiology remains to be elucidated.

Kidney disease is characterized by loss of glomerular function with clinical manifestation of proteinuria. Identifying the cellular and molecular changes that lead to loss of protein in the urine is challenging due to the complexity of the filtration barrier, constituted by podocytes, glomerular endothelial cells, and glomerular basement membrane. In this review, we will discuss how technologies like single cell RNA sequencing and bioinformatics-based spatial transcriptomics, as well as in vitro systems like kidney organoids and the glomerulus-on-a-chip, have contributed to our understanding of glomerular pathophysiology. Knowledge gained from these studies will contribute toward the development of personalized therapeutic approaches for patients affected by proteinuric diseases.