Membranous Glomerulonephropathy Research Articles

Deciphering three predominant biopsy-proven phenotypes of IgG4-associated kidney disease: a retrospective study.

IgG4-associated kidney disease (IgG4-RKD) encompasses a spectrum of disorders, predominantly featuring tubulointerstitial nephritis (TIN) and membranous glomerulonephropathy (MGN). The limited understanding of the co-occurrence of IgG4-RD-TIN with anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) poses a diagnostic and therapeutic challenge. We examined 49 cases, comprising 21 cases of IgG4-RD-TIN (group A), 10 cases of IgG4-RD-TIN accompanied with MGN (group B), and 18 cases of IgG4-RD-TIN concurrent with AAV (group C), at the First Affiliated Hospital of Zhejiang University, China, from June 2015 to December 2022. The mean age and gender of the three IgG4-RKD subtypes were not statistically significant. IgG4-RD-TIN exhibited higher serum creatinine and a higher incidence of hypocomplementemia (group A 47.6%, group B 30%, group C 16.7%). IgG4-RD-TIN-MGN was characterized by proteinuria (group A 0.3g/d, group B 4.0g/d, group C 0.8g/d, P<0.001) and hypoalbuminemia. IgG4-RD-TIN-AAV exhibited hypohemoglobinemia (group A 103.45g/l, group B 119.60g/l, group C 87.94g/l, P<0.001) and a high level of urine erythrocytes. The primary treatment for IgG4-RD-TIN was steroids alone, whereas IgG4-RD-TIN-MGN and IgG4-RD-TIN-AAV necessitated combination therapy. Group A experienced two relapses, whereas groups B and C had no relapses. There was no significant difference in patient survival among the three groups, and only two cases in group C suffered sudden death. This study provides valuable insights into clinical manifestations, auxiliary examination features, pathological characteristics, and prognosis of IgG4-RD-TIN, IgG4-RD-TIN-MGN, and IgG4-RD-TIN concurrent AAV. Large-scale studies are required to validate these findings.

German Shorthaired Pointer dogs with exfoliative cutaneous lupus erythematosus develop immune-complex membranous glomerulonephropathy.

German Shorthaired Pointer (GSHP) dogs with a UNC93B1 gene mutation develop exfoliative cutaneous lupus erythematosus (ECLE) and kidney disease resembling lupus nephritis in humans. The objective of this study was to characterize the kidney disease by light microscopy, immunofluorescence, and electron microscopy in a population of GSHP dogs with ECLE. Medical records were reviewed, and light microscopy of kidneys from 7 GSHP dogs with a previous histologic diagnosis of ECLE was performed. Immunofluorescence of fresh-frozen kidney from 1 dog and transmission electron microscopy of kidney from that dog and 2 additional dogs were performed. Five of 7 dogs had proteinuria diagnosed by urinalysis or urine protein-to-creatinine ratio. Two of 7 dogs were intermittently hypoalbuminemic, and none were azotemic. Histologic findings included early (2 dogs) to late (5 dogs) membranous glomerulonephropathy characterized by mild-to-severe glomerular capillary loop thickening and tubular proteinosis. In all 7 cases, trichrome staining revealed red granular immune deposits on the subepithelial surface of the glomerular basement membrane. Immunofluorescence revealed strong granular labeling for immunoglobulins and complement protein C3. Electron microscopy demonstrated subepithelial electron-dense immune deposits encircled by the remodeled glomerular basement membrane. These findings are diagnostic of immune-complex membranous glomerulonephropathy and are similar to class V lupus in humans. This cohort of GSHP dogs with ECLE developed immune-complex membranous glomerulonephropathy, which we hypothesize is a manifestation of systemic lupus erythematosus. GSHP dogs with ECLE should undergo clinical evaluation of renal function for early identification and treatment.

Dysentery and leg ulcer as an atypical presentation of systemic lupus erythematosus: A case report

Due to heterogeneity in the organs involved and a variety of influencing factors, a wide range of clinical manifestations are possible in systemic lupus erythematosus (SLE). In our knowledge, a combination of leg ulcer and dysentery as presenting symptoms of SLE has never been reported previously. A 13-year-old female child presented with a chronic wound over right medial malleolus for 6 months, and passing of watery stool, later mixed with blood, for 4 days. On examination, she had a fever of 38.5°C. Lab reports revealed anemia, thrombocytopenia, proteinuria, and features of urinary tract infection. Renal biopsy showed membranous glomerulonephropathy. She was positive for antinuclear antibodies (ANA) and antidouble stranded DNA (anti-dsDNA). Immunofluorescence revealed reduced C4 and C3 levels. Abdominal ultrasound showed symmetrical circumscribed thickening, and edematous cecum and ascending colon. The patient was diagnosed with SLE based on the Systemic Lupus International Collaborating Clinics classification criteria. The patient was treated with prednisolone, hydroxychloroquine, metronidazole, ciprofloxacin, trypsin-chymotrypsin, zinc, calcium, and calcitriol tablets. Fever subsided within 3 days of treatment. Gastrointestinal symptoms subsided within 1 week of treatment. On 31 day of treatment, the wound had been reduced and showed features of healing. Dysentery and leg ulcers can be the manifestations of SLE. Therefore, SLE should also be considered when a patient presents with such symptoms. Any suspicion of infection in SLE should be treated aggressively with antibiotics.

ODP581 Rapid Onset Autoimmune (non-type 1) Lean Diabetes Causing Severe Insulin Resistance and Pseudo-Cushing State

Abstract Introduction Type B insulin resistance syndrome (TBIRS) is a rare life-threatening disorder caused by autoantibodies to the insulin receptor. Suggestive clinical features include profound insulin resistance, concurrent autoimmune disease, acanthosis nigricans in lean individuals. Clinical Case 59 year old male (BMI = 21) diagnosed with diabetes 1 year prior (A1c was 8%) presents to the hospital in DKA (A1c 16.7%, pH 7.17, bicarb 8, anion gap 21, +++ketones). GAD, IA2, Islet cell, insulin antibodies were negative. Prior to admission his doctor increased his insulin (Detemir 30 units twice daily and Lispro 15 units with meals), notably high for his 60 kg frame. In the ICU an insulin drip at 8 units/h for 20 hours closed the anion gap. Glucose remained &amp;gt;250 mg/dL the entire time so dextrose was never required. After aggressive attempts at increasing his insulin doses over 10 days, he was discharged home on metformin, pioglitazone, U500 concentrated insulin 450 units per day (divided amongst 3 meals) and close follow up. 12 months after presentation his U500 dose peaked to 660 units per day. Spontaneously, 6 months later hypoglycemia ensued, A1c improved to 10.2%, weight increased and insulin doses were reduced. Interestingly, because he endorsed hyperpigmentation and weight loss, ACTH (RR= 6-50 pg/mL) and cortisol (RR 6-22 ug/dL) were checked and were high-normal at 8AM (53, 17.3, respectively). 8AM cortisol (RR &amp;lt;1.8 ug/dL) after low dose dexamethasone was not suppressed at 9.44 and 24 hour urine free cortisol (RR &amp;lt;50) was elevated to 114. 8AM ACTH and cortisol were trended at 6 months and peaked at 65 and 20. However, a year after his initial presentation, they spontaneously normalized to 30 and 8 as his insulin requirements decreased suggesting resolution of Pseudo-Cushings due to uncontrolled diabetes. Workup for TBIRS included: fasting insulin level (RR 1.9-23) before his AM dose = 685 uIU/mL, fasting triglycerides = 91 mg/dL, +ANA, +Ribonucleoprotein/Smith, adiponectin 34 u/mL (high), mild pancytopenia. Because of 2 grams of proteinuria after only 1 year with diabetes renal biopsy was performed which demonstrated membranous glomerulonephropathy. Proteinuria improved as A1c decreased. Patient declined immunosuppression because he wanted to see if he would continue to improve spontaneously. Discussion The prevalence of TBIRS is unknown because confirmation testing for antibodies to the insulin receptor is limited to select research laboratories (none that we are aware of in the United States). To avoid delaying treatment, diagnosis can be made clinically on the basis of high fasting insulin levels, extremely high insulin doses with refractory hyperglycemia, autoimmunity, normal triglycerides, high adiponectin and hyperpigmentation. The mortality rate is high because of sporadic hypoglycemia that develops during treatment or as spontaneous remission occurs. Close follow up and counseling can decrease morbidity and morality. Presentation: No date and time listed

Leishmania (L.) infantum BH401 strain induces classic renal lesions in dogs: Histological and confocal microscopy study

Extracellular matrix (ECM) alterations in visceral leishmaniasis are related mainly to collagen deposition (fibropoiesis). In canine visceral leishmaniasis (CVL), an intense fibrosis associated to chronic inflammation in organs such as kidneys is described. However, renal fibropoiesis has not been described in natural or experimental infections with L. (L.) infantum. We aimed to characterize renal nephropathies by histology and confocal microscopy comparing renal lesions in dogs naturally and experimentally infected with L. (L.) infantum. Sixty-two mixed-breed symptomatic dogs naturally infected with L. (L.) infantum, sixteen beagles experimentally infected with two strains of L. infantum (eleven dogs with the BH400 strain and five dogs with the BH401 strain), and five uninfected beagles (controls) were used. Samples were stained with hematoxylin & eosin for routine histology. Congo red was used to visualize amyloid protein deposits, periodic acid-Schiff to identify glomerular basal membrane anomalies, Masson's trichrome for collagen deposits, and Jones' methenamine silver to reveal membranous glomerulonephropathy. Immunohistochemistry was used to identify Leishmania amastigotes, and confocal microscopy was used for macrophage characterization (L1/calprotectin and CD163 antigen receptors). The most common lesions were chronic glomerular and interstitial nephritis, which was found in all naturally infected dogs and dogs experimentally infected with L. infantum strain BH401 but not with the BH400 strain. Glomeruloesclerosis was the main lesion presented in all BH401 group. Morphometric analysis revealed positive correlation of renal glomeruli tufts with cellular expression of L1/calprotectin and CD163 antigens. Leishmania infantum strain BH401 shows pathogenicity that may be sufficient to induce classic chronic visceral renal leishmaniasis.

IGG4-RELATED DISEASE: A CHALLENGING DIAGNOSIS

TOPIC: Pulmonary Manifestations of Systemic Disease TYPE: Medical Student/Resident Case Reports INTRODUCTION: IgG4-Related Disease (IgG4-RD) is a recently recognized chronic fibroinflammatory disease that can be difficult to diagnose. We present a case of a fifty-one-year-old female diagnosed with IgG4-RD despite normal serum IgG4 levels. CASE PRESENTATION: A fifty-one-year-old female with history of chronic kidney disease stage 2, membranous glomerulonephropathy (MGN), Type 2 Diabetes Mellitus, Hypertension, and Rheumatoid Arthritis was referred to pulmonology for evaluation of abnormal findings on CT. She was diagnosed with MGN three years prior to presentation and her renal function improved with cyclophosphamide 50mg and prednisone 60mg daily. Two years later she was admitted to an outside hospital for acute hypoxic respiratory failure secondary to presumed PNA, resulting in intubation. She recovered and the decision was made to discontinue her cyclophosphamide due to concerns of pneumonia. Six months later her kidney function began to worsen resulting in a repeat kidney biopsy. Pathology showed glomeruli positive for IgG4 and negative for PLA2-R. During this time, she lost 20 pounds within 3 months and had CT C/A/P done to rule out malignancy. The CT showed diffuse ground glass infiltrates, for which she was referred to pulmonology. Repeat high resolution CT showed thickening of the interstitium mainly in the subpleural areas of the bilateral lungs with lower lung predominance, consistent with ILD. Of note, serum IgG4 levels returned normal. DISCUSSION: IgG4-Related disease (IgG4-RD) is a rare immune-mediated disease that can affect multiple organs. Clinical presentation may include any of the following: autoimmune pancreatitis, head/neck gland tumors, retroperitoneal fibrosis, glomerulonephropathy, and ILD. Diagnosis of IgG4-RD should not be solely based on serum IgG4 levels since the levels can be normal in up to 30% of cases. Diagnosis can be established with clinical suspicion and histopathological analysis of tissue biopsy. IgG4-RD has no established incidence or prevalence as there are no reliable studies likely due to disease being recently recognized or under diagnosed. CONCLUSIONS: IgG4-RD should be considered as a differential diagnosis in patients with ILD and nephropathy, despite a normal serum IgG4 level. Delay of diagnosis and treatment could be life-threatening as in our patient with multiple episodes of acute hypoxic respiratory failure requiring intubation. REFERENCE #1: Opriţă R, Opriţă B, Berceanu D, Diaconescu IB. Overview of IgG4 - Related Disease. J Med Life. 2017;10(4):203-207. REFERENCE #2: Legatowicz-Koprowska M. IgG4-related disease: why is it so important?. Central European Journal of Immunology. 2018;43(2):204-208. doi:10.5114/ceji.2018.77391. DISCLOSURES: No relevant relationships by Prangthip Charoenpong, source=Web Response No relevant relationships by Cesar Davila-Chapa, source=Web Response No relevant relationships by Diana Song, source=Web Response

MO011PODOCYTE NEPHRONECTIN IS REGULATED BY TRANSFORMING GROWTH FACTOR BETA VIA THE CANONICAL AND NON-CANONICAL PATHWAYS

Abstract Background and Aims The glomerular basement membrane (GBM), podocytes and glomerular endothelial cells (GEC) are composing the glomerular filtration barrier (GFB) within the glomerulus. Both podocytes and GEC are essential components for the synthesis of the extracellular matrix (ECM) of the GBM. One ECM protein of the GBM, which is mainly produced by podocytes is nephronectin (NPNT). An altered expression pattern of NPNT has been observed in different kidney diseases. While NPNT was shown to be down regulated in membranous glomerulonephropathy, its expression was elevated in diabetic glomerulopathy, compared to healthy controls. Using a morpholino-induced knockdown of npnt in zebrafish larvae, proteinuria, podocyte foot process effacement and thickening of the lamia rara interna of the GBM were observed. Mice that were intra peritoneally injected with a microRNA 378a (miR-378a) mimic showed a decrease in NPNT expression in the kidneys on both mRNA and protein level, suggesting a regulatory effect of miR-378a on NPNT. In addition, in cultured human podocytes treatment with transforming growth factor beta (TGFβ), as well as transfection with miR-378a mimic down regulated NPNT mRNA and protein expression. By blocking different parts of the TGFβ pathway, we want to further investigate the mechanisms by which TGFβ mediates the regulation of NPNT in podocytes. Method Our main model for this study are immortalized human podocytes, which are proliferating at 33°C and differentiating at 37°C due to a temperature sensitive SV40 large T antigen. Ten to 12 days differentiated podocytes were used for experiments. Differentiated cells were either transfected with a miR-192 or control miR mimic or pre-incubated with different inhibitors for components of both the canonical and the non-canonical TGFβ signaling pathways, followed by culture with or without additional TGFβ. Cell lysates were prepared to be used for Western Blot or qPCR analyses. Results Treatment of immortalized human podocytes with TGFβ decreased NPNT expression on mRNA and protein level. After transfecting immortalized human podocytes with a miR-192 mimic, a GEC-derived miR up regulated by TGFβ stimulation, we observed reduced NPNT expression, compared to control miR transfection. Blocking TGFβ receptor I signaling with the specific inhibitor SD208, caused higher NPNT protein abundance, while NPNT mRNA expression remained unchanged. Targeting downstream parts of both the canonical and non-canonical TGFβ pathways by using inhibitors for single molecules of the respective arms of the intricate TGFβ pathway showed ambiguous results. Suppression of either Smad2 and/or Smad3 tended to enhance NPNT protein levels, accompanied by mostly unaltered mRNA expression. Blockade of different parts of the non-canonical TGFβ pathway also up regulated protein expression of NPNT. However, NPNT mRNA expression was more variable. Therefore, regulation of podocyte NPNT might not be due to changes in mRNA transcription, but to modifications on posttranscriptional level. Conclusion Treating immortalized human podocytes with TGFβ or TGFβ-induced miR-192 reduced NPNT expression on both the mRNA and protein level. More detailed analysis with inhibition of different parts of the canonical and non-canonical TGFβ pathways hint that both pathways are involved in NPNT expression. Therefore, we suggest that the regulation of podocyte NPNT by TGFβ is fine-tuned via both the canonical and non-canonical pathways with additional modulation through TGFβ dependent miRs.

MicroRNAs as Biomarkers for Nephrotic Syndrome.

Nephrotic syndrome represents the clinical situation characterized by presence of massive proteinuria and low serum protein caused by a variety of diseases, including minimal change nephrotic syndrome (MCNS), focal segmental glomerulosclerosis (FSGS) and membranous glomerulonephropathy. Differentiating between diagnoses requires invasive renal biopsies in general. Even with the biopsy, we encounter difficulties to differentiate MCNS and FSGS in some cases. There is no other better option currently available for the diagnosis other than renal biopsy. MicroRNAs (miRNAs) are no-coding RNAs of approximately 20 nucleotides in length, which regulate target genes in the post-transcriptional processes and have essential roles in many diseases. MiRNAs in serum and urine have been shown as non-invasive biomarkers in multiple diseases, including renal diseases. In this article, we summarize the current knowledge of miRNAs as the promising biomarkers for nephrotic syndrome.

Renal involvement in voltage‐gated potassium channel complex antibody–associated diseases

AbstractBackgroundVoltage‐gated potassium channel (VGKC) complex antibody–associated diseases are characterized by peripheral nerve hyperexcitability, autonomic disturbance, and encephalopathy. We report three patients of this disease with some unusual as well as novel findings.Case presentationCase 1 was a 36‐year‐old male who presented with painful cramps in legs and proximal weakness along with involuntary twitching in calves for a duration of 2 months. He also had associated insomnia, irritability, and hyperhidrosis. Electromyographic (EMG) study revealed features characteristic of VGKC antibody–associated diseases. His serology was positive for the components of VGKC, LGI1, and CASPR2. Case 2 was a 23‐year‐old male and Case 3 was a 26‐year‐old female who also had similar clinical presentations, EMG findings, and serologic status. Both male patients had a history of hydrocele with surgical aspiration and sclerosant injection, nearly 2 months prior to symptom onset. Routine evaluation of all the three patients revealed gross proteinuria. Histology performed in two patients revealed membranous glomerulonephropathy (MGN). Apart from symptomatic pharmacotherapy, all patients were initially given intravenous methylprednisolone to which only Case 3 responded while Cases 1 and 2 required one and two courses of intravenous immunoglobulins, respectively. Drug response included considerable resolution of proteinuria.ConclusionsImmune mechanisms in VGKC antibody associated disease may sometimes cause renal involvement (MGN) with nephrotic‐range proteinuria. As all our patients with renal involvement had antibodies against both components of VGKC; this association needs further exploration.

SUN-379 ASSOCIATION BETWEEN USE OF BIOLOGIC THERAPY FOR NON-NEPHROLOGICAL DISEASE AND ONSET OF NEPHROTIC SYNDROME IN A LARGE TERTIARY UK RENAL UNIT COHORT

The use of tumour necrosis factor-α (TNF-α) inhibitors in the management of refractory autoimmune inflammatory conditions including Rheumatoid Arthritis and Inflammatory Bowel Disease (IBD) has become increasingly prevalent overtime. TNF-α promotes inflammation through variable mechanisms, including cytokine and chemokine expression with suppression of regulatory T cells. The main factor limiting use is the serious adverse side-effect profile of these agents including infection, cardiac failure, haematological malignancies and neurological disease. Isolated case reports suggest a link between biologics and the Nephrotic Syndrome (NS). We examine a large local cohort to determine the incidence of new onset NS following use of biologic therapy. This retrospective observational study collected data from 2 large UK centres, including a tertiary renal unit with catchment population of 2.2 million. Records and histopathology reports were available from February 1995 to March 2019 at centre 1, centre 2 from November 2012 to September 2018. Clinical notes and laboratory data including histopathology were reviewed across 3 specialities (aside from nephrology) at both centres more frequently using biologics in disease management; Dermatology, Rheumatology and Gastroenterology. We noted use of any biologic therapy for patients within these specialities during this time period in each respective centre and whether patients subsequently developed clinical and histological evidence of NS, cross-referencing to renal data across both sites. 685 patients reviewed across both centres; 392 patients identified in centre 1, 20 (5%), received biologic therapy at some stage and more specifically 9 of these received TNF-α inhibition. 293 patients identified as having biopsy-proven NS at centre 2, 10 (3%) received biologic therapy and specifically 2 had received a TNF-α inhibitor during the time periods stated. Overall, 3 patients developed NS directly following targeted TNF-α therapy, 2 were female, median age of 30 (range 21-67). 1 patient received TNF-α inhibition and developed NS however biopsy was consistent with diabetic nephropathy in a long-standing diabetic and so was excluded in the final outcomes. All 3 patients had IBD. 1 patient received both Infliximab and Adalimumab, 1 received Infliximab and Vedolizumab and 1 patient Infliximab alone. Histopathology revealed 1 case of Membranous Glomerulonephropathy, 1 Minimal Change Disease (MCD) and 1 MCD / IgA nephropathy crossover. We believe this to be the largest case series to date of patients developing NS following use of biologic therapy. Interestingly, all 3 cases related to biologics targeting TNF-α in patients with pre-existing IBD. This large cohort analysis suggests overall incidence of NS following biologics is very small, however the subset identified displayed common features; patients with IBD receiving treatment with infliximab or adalimumab. From our data, causality cannot be attributed and more mechanistic work is required to determine whether this represents coincidence or a rarer adverse effect. Despite this, as biologic use becomes more widespread, it is prudent for healthcare professionals monitoring patients on biologic agents to be aware of potential nephrological adverse outcomes with these agents, adopting prospective monitoring practices such as routine urinalysis accordingly.

Factors affecting the distribution of glomerulonephropathies among adult Saudi patients: A single-center, biopsy-based clinico-pathological study

Introduction: Glomerulonephropathies (GNs) have high burden of morbidity and mortality worldwide. The distribution GNs varies significantly due to several factors. Materials and Methods: This retrospective clinico-pathological study estimates the biopsy-proven distribution of primary and secondary GNs and detect s the predominant patterns among adult patients who underwent renal biopsy at Nephrology Centre, King Abdul-Aziz Specialist Hospital, Taif City, Kingdom of Saudi Arabia (KSA) from 2008 to 2013 with comparing data to other KSA studies and to other countries. Analysis of possible contributing factors for variation is provided. Relevant patients’ data were collected from hospital records. Renal biopsies stained with H&E, Periodic Acid Schiff (PAS), Gomori Methenamine Silver (GMS), Masson Trichrome (MT) and immunofluorescence (IF) were examined and categorized according to the World Health Organization (WHO) classification of glomerular diseases. Comparisons to other studies were set. Results: Primary and secondary GNs comprised 59.4% and 40.6%. Focal segmental glomerulosclerosis (FSGS) was the commonest primary GN (29.3%), followed by minimal change disease (MCD, 22%) then membranous glomerulonephropathy (MGN, 19.5%). IgA nephropathy was the least frequent (IgAN, 2.4%). Lupus nephritis (LN) was the commonest secondary GN (75%), followed by diabetic and vascular nephropathies (DN, 17.9% ; VN, 7.1%). Spatial and temporal variations in GNs distribution existed locally and worldwide. Conclusion: Factors including selection criteria; biopsy rate and indications; local facilities; demographic distribution; racial, ethnic and genetic differences; and prevalence of etiological factors contribute to the variations of GNs distribution. National renal biopsy registry is recommended for obtaining correct distribution of GNs leading to proper prevention and treatment. Keywords: Distribution, Glomerulonephropathy, Renal biopsy, FSGS, Lupus nephritis.

Immune-complex glomerulonephritis in cats: a retrospective study based on clinico-pathological data, histopathology and ultrastructural features

BackgroundChronic kidney disease (CKD) has typically a non-immune mediated origin in cats and immune-complex glomerulonephritis (ICGN) is scarcely described. Aims of this study were to characterize ICGN by light and electron microscopy and identify associations with clinico-pathological findings. In addition, comparisons between cats with ICGN and non immune-complex glomerulonephritis (non-ICGN) were performed.Renal samples examined between 2010 and 2019 were considered if both light and electron microscopy were performed. Signalment, feline immunodeficiency virus (FIV) and leukemia virus (FeLV) status, serum creatinine concentration, urine protein-to-creatinine (UPC) ratio, systolic blood pressure (SBP) and International Renal Interest Society (IRIS) stage were retrieved and used for comparisons.ResultsSixty-eight client-owned cats were included. Thirty-seven cats (54.4%) had ICGN and 31 (45.6%) non-ICGN. Eighteen (48.6%) with ICGN had membranous glomerulonephropathy (MGN), 14 (37.8%) membranoproliferative glomerulonephritis (MPGN), and 5 (13.5%) mesangioproliferative glomerulonephritis (MeGN). Clinico-pathological data were not associated with any type of ICGN. Among cats with non-ICGN, 11 (35.5%) had end-stage CKD, 9 (29%) focal segmental glomerulosclerosis, 6 (19.4%) global and multifocal mesangiosclerosis, 2 (6.5%) glomerular atrophy, 2 (6.5%) renal dysplasia and 1 (3.1%) amyloidosis. Eight (25.8%) cats with non-ICGN had chronic interstitial nephritis (CIN) grade 1, 13 (41.9%) grade 2 and 10 (32.3%) grade 3; creatinine and UPC ratio increased with CIN grades (p = 0.001, p < 0.001). Cats with ICGN were more frequently FIV or FeLV-infected (OR:11.4; 95%CI:1.4–94.4; p = 0.024), had higher UPC ratio (OR:6.8; 95%CI:2.5–18.2; p < 0.001) and were younger (OR:0.9; 95%CI:0.7–1.0; p = 0.042) than cats with non-ICGN.ConclusionsMGN and MPGN were the most common morphological diagnoses of ICGN in cats. Unfortunately, none of the investigated findings differentiated ICGN morphological diagnoses. Serum creatinine concentration and UPC ratio were directly associated with grades of CIN (p = 0.001 and p < 0.001, respectively), confirming previous literature. More ICGN than non-ICGN was observed in cats with retroviral infections, younger cats and higher UPC ratio.

Incidence, management, and outcomes of autoimmune nephropathies following alemtuzumab treatment in patients with multiple sclerosis

Background: Autoimmune disorders including nephropathies have been reported more frequently in alemtuzumab-treated multiple sclerosis (MS) patients than in the general population. Objective: Describe instances of autoimmune nephropathy in alemtuzumab-treated MS patients. Methods: Cases were identified from safety monitoring within the alemtuzumab relapsing-remitting multiple sclerosis (RRMS) clinical development program (CDP) or post-marketing, or following off-label use. Results: As of 16 June 2017, 16 autoimmune nephropathies have occurred following alemtuzumab treatment for MS. The incidence of autoimmune nephropathies was 0.34% within the CDP (5/1485 patients). The five CDP cases (one of anti-glomerular basement membrane (anti-GBM) disease, two of membranous glomerulonephropathy, and two of serum anti-GBM antibody without typical anti-GBM disease) were identified early, responded to conventional therapy (where needed), and had favorable outcomes. Three of 11 cases outside the CDP occurred following off-label alemtuzumab use prior to approval for RRMS and were all anti-GBM disease. Diagnosis was delayed in one of these three cases and another did not receive appropriate treatment; all three cases resulted in end-stage renal failure. All anti-GBM disease cases with documented urinalysis demonstrated prior microscopic hematuria. Conclusion: Close monitoring of alemtuzumab-treated MS patients facilitates diagnosis and treatment early in the nephropathy course when preservation of renal function is more likely.

Upregulated microRNAs in membranous glomerulonephropathy are associated with significant downregulation of IL6 and MYC mRNAs.

Membranous glomerulonephropathy (MGN) is a glomerulopathy characterized by subepithelial deposits of immune complexes on the extracapillary side of the glomerular basement membrane. Insertion of C5b-9 (complement membrane-attack complex) into the membrane leads to functional impairment of the glomerular capillary wall. Knowledge of the molecular pathogenesis of MGN is actually scanty. MicroRNA (miRNA) profiling in MGN and unaffected tissues was performed by TaqMan Low-Density Arrays. Expression of miRNAs and miRNA targets was evaluated in Real-Time polymerase chain reaction (PCR). In vitro transient silencing of miRNAs was achieved through transfection with miRNA inhibitors. Ten miRNAs (let-7a-5p, let-7b-5p, let-7c-5p, let-7d-5p, miR-107, miR-129-3p, miR-423-5p, miR-516-3p, miR-532-3p, and miR-1275) were differentially expressed (DE) in MGN biopsies compared to unaffected controls. Interleukin 6 (IL6) and MYC messenger RNAs (mRNAs; targets of DE miRNAs) were significantly downregulated in biopsies from MGN patients, and upregulated in A498 cells following let-7a-5p or let-7c-5p transient silencing. Gene ontology analysis showed that DE miRNAs regulate pathways associated with MGN pathogenesis, including cell cycle, proliferation, and apoptosis. A significant correlation between DE miRNAs and mRNAs and clinical parameters (i.e., antiphospholipid antibodies, serum creatinine, estimated glomerular filtration, proteinuria, and serum cholesterol) has been detected. Based on our data, we propose that DE miRNAs and their downstream network may be involved in MGN pathogenesis and could be considered as potential diagnostic biomarkers of MGN.

Allogenic Peripheral Blood Stem Cell Transplant-Induced Membranous Glomerulonephropathy as Chronic Graft-Versus-Host Disease

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De novo immune complex deposition in kidney allografts: a series of 32 patients

Immune complex deposition in kidney allografts can include both recurrent and de novo processes. Recurrent glomerulonephritis is a well-recognized phenomenon and has been shown to be a common cause of allograft failure. De novo immune complex-mediated disease remains relatively poorly characterized, likely owing to the less frequent use of immunofluorescence and electron microscopy in the transplant setting. We performed a retrospective review of kidney allograft biopsies showing glomerular immune complex deposition. Cases with de novo deposits were identified and further organized into two groups depending on whether the immune complex deposition could be clinically and/or histologically classified. Thirty-two patients with de novo immune complex deposition were identified over a 7-year period. A broad range of immune complex-mediated injuries were observed, the majority (63%) of which could be readily classified either clinically or histologically. These included cases of membranous glomerulonephropathy, IgA nephropathy, infection-related glomerulonephritis and glomerulonephritis related to an underlying autoimmune process. A smaller subset of patients (37%) demonstrated immune complex deposition that was difficult to histologically or clinically classify. These patients typically showed mild mesangial immune complex deposition with co-dominant IgG and IgM staining by immunofluorescence microscopy. The presence of concurrent antibody-mediated rejection and donor-specific antibody positivity was significantly higher in the unclassifiable group. The significance of these deposits and their possible relationship to allograft rejection deserves further investigation.

Immunoglobulin G4-related kidney disease: Pathogenesis, diagnosis, and treatment

Immunoglobulin G4-related disease (IgG4-RD) is a recently recognized clinical entity that often involves multiple organs; it is characterized by high levels of serum immunoglobulin G4 (IgG4), dense infiltration of IgG4+ cells, and storiform fibrosis. Cellular immunity, particularly T cell-mediated immunity, has been implicated in the pathogenesis of IgG4-RD. The most frequent renal manifestations of IgG4-RD are IgG4-related tubulointerstitial nephritis, membranous glomerulonephropathy (MGN), and obstructive nephropathy secondary to urinary tract obstruction due to IgG4-related retroperitoneal fibrosis, prostatitis, or ureter inflammation. Kidney function impairment can be acute or chronic. In IgG4-MGN, proteinuria can be in the nephrotic range. The diagnosis of IgG4-related kidney disease should not be based solely on serum IgG4 levels or the number of tissue-infiltrating IgG4+ plasma cells. Diagnosis should be based on specific histopathological findings, confirmed by tissue immunostaining and an appropriate clinical context. Steroid treatment is the first-line therapy. For relapsing or refractory cases, immunosuppressants could be combined with steroids. In hydronephrosis patients, appropriate immunosuppressive therapy could preclude the implantation of a double J ureteral catheter.

Podocytes regulate the glomerular basement membrane protein nephronectin by means of miR-378a-3p in glomerular diseases

The pathophysiology of many proteinuric kidney diseases is poorly understood, and microRNAs (miRs) regulation of these diseases has been largely unexplored. Here, we tested whether miR-378a-3p is a novel regulator of glomerular diseases. MiR-378a-3p has two predicted targets relevant to glomerular function, the glomerular basement membrane matrix component, nephronectin (NPNT), and vascular endothelial growth factor VEGF-A. In zebrafish (Danio rerio), miR-378a-3p mimic injection or npnt knockdown by a morpholino oligomer caused an identical phenotype consisting of edema, proteinuria, podocyte effacement, and widening of the glomerular basement membrane in the lamina rara interna. Zebrafish vegf-A protein could not rescue this phenotype. However, mouse Npnt constructs containing a mutated 3'UTR region prevented the phenotype caused by miR-378a-3p mimic injection. Overexpression of miR-378a-3p in mice confirmed glomerular dysfunction in a mammalian model. Biopsies from patients with focal segmental glomerulosclerosis and membranous nephropathy had increased miR-378a-3p expression and reduced glomerular levels of NPNT. Thus, miR-378a-3p-mediated suppression of the glomerular matrix protein NPNT is a novel mechanism for proteinuria development in active glomerular diseases.

Paraneoplastic Glomerulopathy in a Case of Collecting Duct Renal Cell Carcinoma

Paraneoplastic glomerulopathy has been described in established cases of the solid tumors of lung, gastrointestinal system, breast, etc., and rarely in patients with Renal Cell Carcinoma (RCC). Studies on secondary glomerular diseases have described a higher incidence of IgA nephropathy in patients with RCC compared to membranous glomerulopathy, which are commonly reported in malignancies of the lung and gastrointestinal tract. Collecting Duct Carcinoma (CDC), a rare high grade adenocarcinoma accounts for <1% of all renal malignancies. It arises from the cells of the collecting ducts of Bellini. We report a case of an elderly male who was diagnosed to have a disseminated CDC during his evaluation for nephrotic syndrome. Renal biopsy was suggestive of a secondary membranous glomerulonephropathy.

Membranous glomerulonephropathy in a patient with bullous pemphigoid.

Bullous pemphigoid (BP) is a common autoimmune blistering disease that can be complicated by autoimmune disorders. We describe a patient with BP who developed membranous glomerulonephropathy (MN). Proteinuria decreased during the clinical course as anti-BP180 antibody titers decreased. This finding suggested an association between the pathogenesis of these two diseases in terms of immunological disorders.