Case series of idiopathic intracranial hypertension in three patients with immune-complex glomerulonephritis.

BACKGROUND: Idiopathic intracranial hypertension (IIH) is defined by an increased cerebrospinal fluid pressure in the absence of inflammation, structural obstructions, or mass lesions. Although the underlying pathogenesis of IIH is not fully understood, associations with specific risk factors as obesity, obstruction of cerebral venous sinuses, medications, endocrine or systemic conditions and chronic kidney disease have been described. Immune-complex glomerulonephritis as IgA-nephropathy is a frequent cause of chronic kidney failure, which was reported previously in one IIH patient. To date, there is no knowledge about the variable relation of immune-complex nephritis, kidney function and the course of IIH. CASE PRESENTATION: We report three cases (two females) of concurrent diagnosis of IIH and immune-complex glomerulonephritis. All patients presented with typical IIH symptoms of headache and visual disturbances. Two patients had been diagnosed with IgA-nephropathy only few weeks prior to IIH diagnosis. The third patient had been diagnosed earlier with terminal kidney failure due to a cryoglobulin glomerulonephritis. CONCLUSION: We propose a possible link between renal deposition of immune-complexes and increased cerebrospinal fluid pressure. Pathophysiological hypotheses and clinical implications are discussed. We recommend clinical awareness and further systematic research to obtain more information on the association of IIH and immune-complex glomerulonephritis.

Demographic, clinical and laboratory characteristics of rapidly progressive glomerulonephritis in Turkey: Turkish Society of Nephrology-Glomerular Diseases (TSN-GOLD) Working Group.

BACKGROUND: In our study, diagnostic and demographic characteristics of patients diagnosed with RPGN by biopsy, clinical and laboratory findings in our country were investigated. METHODS: Data were obtained from the Turkish Society of Nephrology Glomerular Diseases (TSN-GOLD) Working Group database. Demographic characteristics, indications for biopsy, diagnosis of the glomerular diseases, comorbidities, laboratory and biopsy findings of all patients were recorded. According to their types, RPGN patients were classified as type 1 (anti-GBM related), type 2 (immuncomplex related) and type 3 (pauci-immune). RESULTS: Of 3875 patients, 200 patients with RPGN (mean age 47.9 ± 16.7 years) were included in the study which constitutes 5.2% of the total glomerulonephritis database. Renal biopsy was performed in 147 (73.5%) patients due to nephritic syndrome. ANCA positivity was found in 121 (60.5%) patients. Type 1 RPGN was detected in 11 (5.5%), type 2 RPGN in 42 (21%) and type 3 RPGN in 147 (73.5%) patients. Median serum creatinine was 3.4 (1.9-5.7) mg/dl, glomerular filtration rate was 18 (10-37) ml/min/1.73m2 and proteinuria 2100 (1229-3526) mg/day. The number of crescentic glomeruli ratio was ratio 52.7%. It was observed that urea and creatinine increased and calcium and hemoglobin decreased with increasing crescentic glomerular ratio. CONCLUSIONS: Our data are generally compatible with the literature. Advanced chronic histopathological findings were prominent in the biopsy of 21 patients. Early biopsy should be performed to confirm the diagnosis of RPGN and to avoid unnecessary intensive immunosuppressive therapy. In addition to the treatments applied, detailed data, including patient and renal survival, are needed.

Dynamic gut microbiome-metabolome in cationic bovine serum albumin induced experimental immune-complex glomerulonephritis and effect of losartan and mycophenolate mofetil on microbiota modulation.

Dynamic changes in gut dysbiosis and metabolomic dysregulation are associated with immune-complex glomerulonephritis (ICGN). However, an in-depth study on this topic is currently lacking. Herein, we report an ICGN model to address this gap. ICGN was induced via the intravenous injection of cationized bovine serum albumin (c-BSA) into Sprague-Dawley (SD) rats for two weeks, after which mycophenolate mofetil (MMF) and losartan were administered orally. Two and six weeks after ICGN establishment, fecal samples were collected and 16S ribosomal DNA (rDNA) sequencing and untargeted metabolomic were conducted. Fecal microbiota transplantation (FMT) was conducted to determine whether gut normalization caused by MMF and losartan contributed to their renal protective effects. A gradual decline in microbial diversity and richness was accompanied by a loss of renal function. Approximately 18 genera were found to have significantly different relative abundances between the early and later stages, and Marvinbryantia and Allobaculum were markedly upregulated in both stages. Untargeted metabolomics indicated that the tryptophan metabolism was enhanced in ICGN, characterized by the overproduction of indole and kynurenic acid, while the serotonin pathway was reduced. Administration of losartan and MMF ameliorated microbial dysbiosis and reduced the accumulation of indoxyl conjugates in feces. FMT using feces from animals administered MMF and losartan improved gut dysbiosis by decreasing the Firmicutes/Bacteroidetes (F/B) ratio but did not improve renal function. These findings indicate that ICGN induces serous gut dysbiosis, wherein an altered tryptophan metabolism may contribute to its progression. MMF and losartan significantly reversed the gut microbial and metabolomic dysbiosis, which partially contributed to their renoprotective effects.

Pathophysiology and system biology of rat c-BSA induced immune complex glomerulonephritis and pathway comparison with human gene sequencing data.

Immune-complex glomerulonephritis (ICGN) is a major cause of nephrotic syndrome in adults and children. Cationic BSA (c-BSA) intravenous injection could produce significant albuminuria within a short time, and is a suitable in vivo experimental animal model to investigate the pathophysiology of ICGN and for drug screening, but lack of thorough study to clarify its dynamic pathophysiological alteration so far, as well as detailed changes in mRNA and LncRNA levels. The purpose of this study is to investigate the dynamic alteration in renal function, lipid metabolism and histopathology during the progress of c-BSA induced ICGN. RNA sequencing was used to identified differentially expressed mRNA and LncRNA in kidney cortex of ICGN. Results demonstrated that c-BSA induced ICGN model could completely exhibit clinical features of immune-mediated nephrotic syndrome with gradual declining renal function, and increased albuminuria and deteriorated histopathological injuries. The correlation analysis suggested that complement activation was the most key element in mediating of ICGN. RNA sequencing using rat kidney tissues combined with Gene Expression Omnibus (GEO) data of human glomerulonephritis showed the most enriched KEGG pathways in ICGN were Toll-like receptor signaling pathway, B cell receptor and Focal adhesion. The differential lncRNAs in ICGN rats were also screened, and the lncRNA-mRNA co-expression network was constructed to clarify lncRNA role in molecular mechanism of ICGN progression. Their human homogenous lncRNAs were also identified, such as ST3GAL5-AS1 and DIO3OS, which provide the potential lncRNA targets to treat ICGN. All the differential LncRNAs in ICGN kidneys caused by MMF were also identified and provided another possible pharmacological mechanism of MMF through lncRNA regulation. In summary, the current study firstly described the dynamic physiological changes of c-BSA induced ICGN, identified most key KEGG pathways, and provided lncRNA-mRNA regulatory network in ICGN.

Clinicopathologic and pathologic characteristics of feline proteinuric kidney disease.

OBJECTIVES: The aim of this study was to describe the causes, clinicopathologic features and outcomes of feline protein-losing nephropathy (proteinuria secondary to glomerular disease [PLN]). METHODS: Kidney biopsy/necropsy samples from proteinuric cats submitted to the International Veterinary Renal Pathology Service were retrospectively reviewed. Diagnoses based on histopathology were categorized by primary disease compartment. Clinicopathologic variables at diagnosis, development of hypoalbuminemia, anemia, hypertension, azotemia and effusion/edema, and survival were compared between cats with immune-complex glomerulonephritis (ICGN) and other causes of PLN. RESULTS: Fifty-eight percent (n = 31/53) of proteinuric cats had ICGN and 74% (n = 31/42) of cats with PLN had ICGN. Cats with glomerular diseases other than ICGN had a higher median urine protein:creatinine ratio than ICGN cats (14.5 vs 6.5; P <0.001). Onset of PLN occurred at a young age; median age at diagnosis was 3.5 years in ICGN cats vs 1.3 years in cats with other glomerular diseases (P = 0.026). Development of complications such as hypoalbuminemia, anemia, hypertension, azotemia and effusion/edema were common, regardless of the cause of PLN, and were not different between ICGN and cats with other glomerular diseases. Male cats were over-represented in the ICGN group (P = 0.003). Median survival time (MST) for all cats with PLN was 94 days (range 3-1848 days). Survival was not different between cats with ICGN and cats with other glomerular diseases. MST in ICGN cats that developed effusion was shorter (94 days) than cats that did not (700 days; P = 0.035). MST in IGCN cats that received immunosuppressive medications was longer (244 days) than cats that did not (17 days, P = 0.039). CONCLUSIONS AND RELEVANCE: Taken together, these data suggest that clinical suspicion for glomerular proteinuria should increase in young, male cats with higher degrees of proteinuria, and immune-mediated disease is common. Further studies are needed to determine the effect of immunosuppression on morbidity and mortality in cats with ICGN.

Educational Case: Necrotizing and Crescentic Glomerulonephritis With Anti-Glomerular Basement Membrane Antibodies (Anti-Gbm).

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040.1.

Crescentic glomerulonephritis: what's different in South Asia? A single center observational cohort study.

Background: The spectrum and outcomes of crescentic glomerulonephritis (Cr.GN) in South Asia is vastly different from that reported worldwide and there is a paucity of information. The aim of the study was to study the demography, clinical presentation, histology and predictors of longitudinal outcomes of Cr.GN in this population. Methods: An observational cohort study of renal biopsies was performed in the largest tertiary center in South India over a period of 10 years (January 2006 to December 2015) with ≥50% crescents on renal histology indicating Cr.GN. Results: A total of 8645 kidney biopsies were done; 200 (2.31%) were Cr.GN. Patients were categorized into three etiological groups: anti-glomerular basement membrane (type I), immune complex (type II), and pauci-immune (type III). Type II was the most common (96, 46.5%), followed by type III (73, 38%) and type I (31, 15.5%). Female preponderance was seen across all types. About half of all patients presented with recent onset hypertension. Type II had the highest median proteinuria (4.2 (2.1-6) g/day, p=0.06) and the median estimated glomerular filtration rate was lowest in type I (5 (4-8) ml/min/1.73m 2, p<0.001). Among type III, anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis was seen only in ~50% of patients. Nearly one third of patients with type I were also positive for ANCA making them 'double positive'. Acute glomerular insults like tuft necrosis and chronic changes as evidenced by moderate to severe interstitial fibrosis, was a predominant feature of type I. Conclusions: ANCA-negative pauci-immune vasculitis, as well as double positive Cr.GN, are reported for the first time in South-Asia. Renal survival was significantly worse in type I/III compared to type II. Types I/III, moderate to severe interstitial fibrosis and tubular atrophy, presence of oliguria/anuria and increasing percentage of crescents in renal biopsy were significant predictors of end stage kidney disease in our cohort.

Clinicopathological Characteristics and Outcomes of Diffuse Crescentic Glomerulonephritis - A Single Center Experience from Southern India.

INTRODUCTION: Diffuse Crescentic glomerulonephritis (CrGN) is characterized by rapidly progressive renal failure and has grave prognosis. There is significant regional and temporal variation in aetiology, prevalence and prognosis of diffuse crescentic glomerulonephritis (CrGN) with limited data available in adult Indian population. AIM: This study aims to identify the aetiology, clinico-pathological features and outcomes of diffuse CrGN in south Indian population. MATERIALS AND METHODS: In this retrospective study, clinical records of all adults (>18 years) over a 5-year period (2010-2014) with a histopathological diagnosis of diffuse CrGN (>50% crescents) were reviewed. Clinical, serological, biochemical and histopathological data were collected. Follow-up data at six months including renal outcome and mortality were studied. Data was analysed using SPSS version 15. RESULTS: There were 29 cases of diffuse CrGN accounting for an incidence of 2.9% among 1016 non-transplant kidney biopsies. The most common cause was pauci-immune crescentic GN. The median creatinine at admission was 7.2 mg/dl {(interquartile range (IR) 3.3 - 10.4)} and 75.9% of patients required haemodialysis at admission. Complete/partial recovery was seen in 34.5%. At the end of six months 31% were dialysis dependent and the mortality was 27.6%. On univariate analysis, the significant predictors of renal loss and mortality were oliguria (p=0.02), requirement of haemodialysis and serum creatinine (p=0.001) at admission (>5.5mg/dl) (p=0.003). Histopathological features did not influence the outcome in our study. CONCLUSION: In our cohort, the most common cause for diffuse CrGN is pauci-immune CrGN. Diffuse CrGN carries a poor prognosis. Patients with pauci-immune and AntiGBM disease have worst prognosis compared to immune complex CrGN. The presence of oliguria, high serum creatinine and requirement of haemodialysis at admission are associated with poor outcomes.

Histologic regression of fibrillary glomerulonephritis: the first report of biopsy-proven spontaneous resolution of disease.

Fibrillary glomerulonephritis (FGN) is a rare immune complex type glomerulonephritis characterized by glomerular deposition of randomly oriented fibrils measuring 10-30 nm in thickness, and typically presents with proteinuria with or without renal insufficiency and hematuria. We present a case in which a patient initially presented at age 41 years with nephrotic-range proteinuria and hypertension; a kidney biopsy showed FGN. The patient was treated with angiotensin receptor blockage only, without immunosuppression as per patient preference, and the level of protein in the urine improved. During the follow-up period of 17 years, the patient developed type 2 diabetes mellitus. The patient re-presented with nephrotic-range proteinuria 17 years later, at the age of 58 years. A kidney biopsy was performed and showed diffuse diabetic glomerulosclerosis with secondary focal segmental glomerulosclerosis and related vascular changes. There was no evidence of FGN by immunofluorescence or electron microscopy. Although FGN has been rarely reported to regress clinically, this is the first documented case of histologic regression of FGN. The potential for FGN fibrils to regress spontaneously is important in the management of FGN patients considering that currently available immunosuppressive agents have limited efficacy, and is an encouraging finding for future studies aiming to find a cure for the disease.

Clinical spectrum and outcomes of crescentic glomerulonephritis: A single center experience.

There is limited data on the etiology, clinical and histopathological spectrum and outcomes of crescentic glomerulonephritis (CrGN) in adult Indian population. This prospective study was done to evaluate the etiology, clinicohistological patterns and predictors of outcome of CrGN in South Indian population. All the patients received standard protocol based immunosuppression in addition to supportive care. Immune-complex glomerulonephritis (ICGN) was the most common etiology (n = 31; 77.5%) followed by pauci-immune glomerulonephritis (PauciGN; n = 8; 20%) and anti-glomerular basement membrane disease (n = 1; 2.5%). The most common etiology of ICGN was IgA nephropathy (n = 11; 27.5%) followed by lupus nephritis (n = 7; 17.5%) and post-infectious glomerulonephritis (PIGN) (n = 7; 17.5%). The patients with PauciGN were significantly older compared to those with ICGN (44.5 ± 15 years vs. 31.8 ± 11 years; P = 0.01). The patients with PauciGN presented with significantly higher serum creatinine (9.7 ± 4.4 vs. 6.6 ± 3.3 mg/dl; P = 0.03). The histopathologic parameters of ICGN and PauciGN were comparable except for a higher proportion of sclerosed glomeruli in ICGN. At the end of 3 months follow-up, only two patients went into complete remission (5.4%). Majority of the patients had end-stage renal failure (48.6%) and were dialysis dependent and seven patients (18.9%) expired. There was no signifi difference in the renal survival (10.9 ± 1.9 vs. 9.6 ± 3.3 months) or patient survival (17.5 ± 2.1 vs. 17.3 ± 4.3 months). The parameters associated with adverse outcomes at 3 months were hypertension (odds ratio [OR]: 0.58; confidence interval [CI]: 0.36-0.94), need for renal replacement therapy (OR: 0.19; CI: 0.04-0.9), serum creatinine at admission (P = 0.019), estimated glomerular filtration rate (P = 0.022) and percentage of fibrocellular crescents (P = 0.022).

Fraternal twins with job's syndrome and immune complex nephritis.

Job's syndrome or autosomal dominant hyperimmunoglobulin E syndrome (Hyper-IgE) is a rare disorder that results from a STAT3 gene mutation, which results in the absence of T-helper 17 (Th17) cells and manifests as a severe immunodeficiency. Affected individuals suffer recurrent soft tissue and pulmonary infections among other manifestations, and the spectrum of the disease is still being characterized. We describe 2 sisters with Job's syndrome each with variable expressivity. However, both patients developed proteinuric kidney disease and had biopsies confirming the presence of immune complex glomerulonephritis with staining for immunoglobulins and complement components. Previous reports link Job's syndrome and the development of systemic lupus erythematosus (SLE), but proliferative immune complex glomerulonephritis has not been described. We speculate that continual internal and external antigen exposure may induce an autoimmune process similar to SLE, which in turn may account for the immune complex disease in the kidney.

Clinicopathologic and Histopathologic Renal Abnormalities in Dogs with Coccidioidomycosis.

BACKGROUND: We observed evidence of protein-losing nephropathy in some dogs with coccidioidomycosis, suggestive of immune complex glomerulonephritis (ICGN). The goal of this study was to understand the prevalence of renal histopathologic lesions and proteinuria in dogs with coccidioidomycosis. HYPOTHESIS: Biochemical and histopathological evidence of glomerular lesions is present in dogs with coccidioidomycosis. ANIMALS: Hundred and fifty-six dogs with naturally occurring coccidioidomycosis. METHODS: Retrospective case series. Clinical information and results of clinicopathologic testing were retrieved from the University of California, Davis Veterinary Medical Teaching Hospital (VMTH). Microscopic sections of renal tissue procured from necropsy of dogs with coccidioidomycosis were examined to evaluate the nature and distribution of lesions. RESULTS: A total of 156 dogs with coccidioidomycosis were identified; 87 dogs had serum biochemistry and a urinalysis performed, 17 had urine protein:creatinine ratios (UPCs), and 24 had renal tissue available for histopathology. Eleven (13%) of the 87 dogs were azotemic, 55 (63%) were proteinuric (of which 14 [25%] had clinically relevant proteinuria defined as ≥3+ or ≥500 mg/dL), and 14 dogs had UPC ≥0.5 (range, 0.5-21.5, median 4.2). Thirteen (54%) of 24 dogs had renal histopathologic lesions suggestive of ICGN. Seven of these dogs had urinalyses performed; 5 (71%) had clinically relevant proteinuria as described above. Two dogs (33%) with normal glomeruli had granulomatous nephritis, 1 of which had intralesional Coccidioides spherules. CONCLUSIONS AND CLINICAL IMPORTANCE: Coccidioidomycosis should be considered as a possible contributor to glomerular disease in dogs. Whether similar lesions occur in other mammalian hosts, including humans, warrants further investigation.

Non-immunoglobulin A mesangial immune complex glomerulonephritis in kidney transplants.

We have observed a predominantly mesangial non-immunoglobulin A immune complex mesangial glomerulopathy (MG) in renal transplants with mesangial deposits by immunofluorescence and electron microscopy. Clinicopathological features of 28 patients with MG were analyzed and compared with 28 transplant controls, matched for age, sex, ethnicity, donor type, estimated glomerular filtration rate, and interval from transplant to biopsy. Indications for biopsy in the MG group were allograft dysfunction in 64%, allograft dysfunction/proteinuria in 29%, and proteinuria in 7%. Biopsy indications in controls were allograft dysfunction (61%), allograft dysfunction/proteinuria (18%), proteinuria (14%), and delayed graft function (7%). Most MG cases had mild mesangial hypercellularity with endocapillary proliferation in 2 and crescents in 2 without fibrinoid necrosis. Immunoglobulin M-dominant deposits were present in 83%, and immunoglobulin G was dominant in 17% with mesangial deposits in 93% of cases by electron microscopy. Compared with controls, MG had higher Banff interstitial inflammation score (i) (P = .036) and was associated with concurrent acute T-cell-mediated rejection (P = .023), but not with acute or chronic antibody-mediated rejection. MG patients and controls had similar prevalence of polyomavirus nephropathy and Epstein-Barr virus infection. At follow-up, most MG patients had stable estimated glomerular filtration rate with no or stable proteinuria. Disease-specific graft survival was not different in MG versus controls. We conclude that, in view of the apparent self-limited nature of this lesion, additional treatment may not be required in these patients. Awareness of this lesion may thus spare patients unwarranted further intervention.