Immune Complex Glomerulonephritis Research Articles

Clinical characteristics and outcomes of immune-complex membranoproliferative glomerulonephritis and C3 glomerulopathy in Japanese children.

Membranoproliferative glomerulonephritis (MPGN) can be divided into immune-complex MPGN (IC-MPGN) and C3 glomerulopathy (C3G), which includes dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). These conditions result from abnormalities in different complement pathways and may lead to different prognoses. However, there are limited studies describing the respective clinical courses. In this study, Japanese pediatric patients diagnosed with MPGN based on kidney biopsies conducted between February 2002 and December 2022 were reclassified as having IC-MPGN or C3G (DDD or C3GN). We retrospectively analyzed the clinical characteristics and outcomes of these patients. Out of 25 patients with MPGN, three (12.0%) were diagnosed with DDD, 20 (80.0%) with C3GN, and two (8.0%) with IC-MPGN. There were 13 (65.0%) patients and one (33.3%) patient in remission after treatment for C3GN and DDD, respectively, and no patients with IC-MPGN achieved remission. The median follow-up period was 5.3 (2.5-8.9) years, and none of the patients in either group progressed to an estimated glomerular filtration rate < 15ml/min/1.73m2. Patients with C3GN presenting mild to moderate proteinuria (n = 8) received a renin-angiotensin system inhibitor (RAS-I) alone, and these patients exhibited a significant decrease in the urinary protein creatinine ratio and a notable increase in serum C3 levels at the last follow-up. Most patients with MPGN were diagnosed with C3GN. The remission rate for C3GN was high, and no patients developed kidney failure during the approximately 5-year follow-up. Additionally, patients with C3GN with mild to moderate proteinuria had good outcomes with RAS-I alone, but continued vigilance is necessary to determine long-term prognosis.

Recurrent disease after pediatric renal transplantation.

Recurrent disease after kidney transplant remains an important cause of allograft failure, accounting for 7-8% of graft loss and ranking as the fifth most common cause of allograft loss in the pediatric population. Although the pathophysiology of many recurrent diseases is incompletely understood, recent advances in basic science and therapeutics are improving outcomes and changing the course of several of these conditions. Review of the literature. We discuss the diagnosis and management of recurrent disease. We highlight new insights into the pathophysiology and treatment of post-transplant primary hyperoxaluria, focal segmental glomerulosclerosis, immune complex glomerulonephritis, C3 glomerulopathy, lupus nephritis, atypical hemolytic uremic syndrome, and IgA nephropathy.

Do we really need cyclophosphamide for lupus nephritis?

A 14-year-old patient presents with hematuria and proteinuria. Clinical evaluation reveals a positive anti-nuclear antibody titer, positive anti-double stranded DNA antibody and hypocomplementemia. Systemic lupus erythematosus (SLE) is diagnosed based on the 2019 EULAR/ACR (European League Against Rheumatism/American College of Rheumatology) classification criteria (Aringer et al. Arthritis Rheumatol 71:1400-1412, 2019). A kidney biopsy is performed that confirms the presence of immune complex glomerulonephritis, ISN-RPS (International Society of Nephrology/Renal Pathology Society) class IV (Bajema et al. Kidney Int 93:789-796, 2018). According to the latest clinical practice guidelines (Rovin et al. Kidney Int 100:753-779, 2021; Fanouriakis et al. Ann Rheum Dis 83:15-29, 2023), there are alternatives to treating this patient with cyclophosphamide. But what if this patient also presented with oliguria and volume overload requiring intensive care and dialysis? What if this patient also presented with altered mental status and seizures, and was diagnosed with neuropsychiatric lupus? What if this patient was also diagnosed with a pulmonary hemorrhage and respiratory failure? The clinical practice guidelines do not address these scenarios that are not uncommon in patients with SLE. Moreover, in some countries worldwide, patients do not have the privilege of access to biologics or more expensive alternatives. The purpose of this review is to evaluate the contemporary options for initial treatment of nephritis in patients with SLE.

378 A Case of Antineutrophilic Cytoplasmic Antibody (ANCA) Associated Vasculitis with Immune Complex Glomerulonephritis (GN) on Kidney Biopsy

378 A Case of Antineutrophilic Cytoplasmic Antibody (ANCA) Associated Vasculitis with Immune Complex Glomerulonephritis (GN) on Kidney Biopsy

Four Cases of Kidney Transplants With Donor HCV-Derived Immune Complex Glomerulonephritis

Four Cases of Kidney Transplants With Donor HCV-Derived Immune Complex Glomerulonephritis

Kidney Histopathology of Patients with Hepatitis C Infection and Diabetes Mellitus before and after Availability of Direct-Acting Antiviral Therapy.

Type 2 diabetes mellitus (DM) and diabetic kidney disease are increasing. Hepatitis C infection (HCV) occurs in 1% of the world population and can induce several kidney diseases. DM prevalence is increased in individuals with HCV; however, kidney diseases in those with both DM and HCV have not been assessed. Direct-acting antiviral agents (DAAs) became available for HCV treatment in 2014; it is unknown if DAAs altered the spectrum of kidney disease in patients with DM and HCV. Case review identifying patients with kidney biopsy and clinical history of DM and HCV between 2009-2013 (pre-DAA) and 2016-2020 (post-DAA), excluding kidney transplant, hepatitis B, HIV, and inadequate biopsy, identified 245 biopsies. Biopsies were evaluated for diabetic glomerulosclerosis (DGS) class, global and focal segmental glomerulosclerosis (FSGS), other glomerular diseases, interstitial fibrosis/tubular atrophy (IFTA), interstitial nephritis, acute tubular injury and degree of arterial and arteriolar sclerosis. Kidney disease differences in pre-DAA versus post-DAA eras and in mild versus severe DGS were assessed by χ2 and Fisher's exact tests. The most common non-DGS lesions were non-collapsing FSGS (41%), HCV-related IgM dominant immune complex glomerulonephritis (IgM-ICGN, 18%), IgA nephropathy (9%), and membranoproliferative glomerulonephritis (MPGN, 7%). Collapsing FSGS was more common pre-DAA versus post-DAA (8% vs. 1%, p = 0.03). Biopsies from patients with HCV and DM were reduced in post-DAA (0.7%) versus pre-DAA (1.3%) (p < 0.0001). Post-DAA there were less MPGN (2% vs. 10%, p = 0.02) and more advanced DGS (85% vs. 61%, p = 0.0002), non-collapsing FSGS (57% vs. 31%, p < 0.0001), IFTA (2.0 vs. 1.6, p = 0.0002), and vascular sclerosis (2.1 vs. 1.6, p < 0.0001). Post-DAA there were reduced biopsies and MPGN, with more severe DGS class, non-collapsing FSGS, IFTA, and chronic vascular changes. This suggests a modulating effect of DAAs on HCV-related kidney pathology with DM and chronic changes driving indications for kidney biopsy.

Anti-factor B antibodies in atypical hemolytic uremic syndrome.

The etiology of atypical hemolytic uremic syndrome (aHUS) is unknown in 30-40% of patients. Anti-factor B (FB) antibodies are reported in C3 glomerulopathy (C3G) and immune-complex membranoproliferative glomerulonephritis (IC-MPGN), though not in aHUS. We screened patients < 18-year-old from cohorts of aHUS and C3G/idiopathic IC-MPGN. Anti-FB IgG antibodies were measured by ELISA and confirmed by Western blot. Normative levels were based on antibody levels in 103 healthy blood donors. Prevalence of anti-FB antibodies was 9.7% (95% CI 6.1-14.5%; n = 21) in 216 patients with aHUS, including 11.5% (95% CI 6.4-18.5%; n = 14) in anti-FH associated aHUS and 11.8% (95% CI 4.4-23.9%; n = 6) in patients without a definitive genetic or autoimmune etiology. Patients with significant genetic variants did not show anti-FB antibodies. In patients with concomitant anti-FB and anti-FH antibodies, median anti-FH titers were higher (11,312 AU/mL vs. 4920 AU/mL; P = 0.04). Anti-FB antibody titer correlated with disease severity (hemoglobin and platelets; P < 0.05), declined following plasma exchange and increased during relapse. While 4/64 patients with C3G (6.3%) and 1/17 with IC-MPGN showed anti-FB antibodies, titers were higher in aHUS (544.8 AU/mL vs. 1028.8AU/mL; P = 0.003). Anti-FB antibodies are present in 6-10% of patients with aHUS and C3G/IC-MPGN, with higher titers in the former. The diagnostic and therapeutic implication of anti-FB antibodies in aHUS needs confirmation and further studies. The study shows propensity for autoantibody generation and co-existence of multiple risk factors for aHUS in Indian children.

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.

Podocyte Infolding Glomerulopathy: A Special Morphology of Podocyte Injury Caused by Heterogeneous Diseases

Podocyte infolding glomerulopathy (PIG) is a newly recognized rare glomerular injury. The clinical significance and mechanism of this injury pattern remains unclear. We conducted a retrospective study of renal biopsies from January 2018 to December 2020 in Kingmed Diagnostics. The renal biopsy features and clinical data were reviewed. Laser scanning microdissection and mass spectrometry (LMD/MS) was conducted to analyze the potential mechanism. A total of 116 (0.092%) out of 126,086 biopsies were diagnosed as PIG during the period. Of these, 89 (76.7%) cases were found to have PIG coexisting with immune-complex associated glomerulonephritis (IC-PIG) whereas 27 (23.3%) were identified as isolated PIG without immunoglobulin or complement deposition. Systemic lupus erythematosus (SLE), especially with membranous lupus nephritis (LN), was diagnosed in most (70.8%) IC-PIG cases. Of the isolated PIG cases, 51.9% had no known underlying conditions; however, a relatively high positive rate (42.1%) of antinuclear antibody (ANA) was detected. Nearly half (47.5%) of the patients presented with nephrotic syndrome (NS). PIG grade was associated with proteinuria in isolated PIG (P= 0.035). LMD/MS revealed dysregulated cytoskeletal protein α-actinin4 (ACTN4) and tubulin beta-4 chain in PIG compared with normal donor kidney and minimal change disease (MCD). The displacement of ACTN4 into the glomerular basement membrane (GBM) was confirmed by the confocal microscope. PIG is a rare podocyte injury that can exist alone without underlying disease or be concurrent with various diseases, especially SLE. Podocyte cytoskeletal protein ACTN4 and tubulin beta-4 chain were dysregulated, which may be involved in the mechanism of PIG.

Correlation of Red Blood Cell Casts With Renal Dysfunction in Patients With Infection-Related Glomerulonephritis.

Infection-related glomerulonephritis (IRGN) usually manifests as a proliferative immune-complex glomerulonephritis. The degree of renal dysfunction at presentation can vary. Association with histologic features on kidney biopsy remains unknown. To study the correlation between renal function in IRGN at the time of biopsy and the severity of histologic features. Culture-proven IRGN cases at our facility were included and divided based on estimated glomerular filtration rate (eGFR) 15 ml/min/1.73 m2. Patients' demographic and pathologic findings were obtained from electronic medical records and kidney biopsy reports. In total, 104 cases were diagnosed with IRGN on biopsy (mean age, 55.6 ± 15.6 years; male, n = 79 [76%]; median eGFR, 14.5 mL/min/1.73 m2), and 51 of 104 showed eGFR <15 mL/min/1.73 m2. Among all the histologic features assessed, only percent tubules with red blood cell (RBC) casts showed statistical difference, being significantly higher in the lower-eGFR group (P = .004). Multivariable logistic regression analysis also showed that %tubules with RBC casts were associated with lower eGFR (odds ratio, 1.12; 95% CI, 1.01-1.24; P = .01). Patients with 5% or more RBC casts (n = 31) showed a lower eGFR (P = .02) and a higher %cellular crescent (P < .001) compared with those with less than 5% RBC casts. Patients with concomitant anticoagulant therapy (n = 11) showed higher percentages of RBC casts than those without anticoagulants (P = .02). Particular attention to the extent of RBC casts on kidney biopsy is recommended in patients with IRGN because these portend worse renal dysfunction, more so in patients requiring anticoagulation (including for hemodialysis) because they are especially vulnerable to developing anticoagulant-related nephropathy.

Diagnosis and therapy of membranous nephropathy-2023

Membranous nephropathy (MN) is an immune-complex glomerulonephritis and is one of the most common causes of nephrotic syndrome in adults and is also one of the autoimmune kidney diseases with the highest rate of spontaneous remission. The most common autoantigen (> 70% of cases) is directed against the phospholipase A2 receptor (PLA2-R) and, with its detection and clinical course, allows for excellent diagnostics as well as optimal therapy monitoring. Other autoantigens are constantly being published and will enable an autoantigen-based diagnostic and therapeutic algorithm for MN in the future. In the absence of spontaneous remission, aspecific B‑cell-directed therapy, especially with rituximab, is the initial therapy of choice. Calcineurininhibitors or cyclophosphamide should only be used if they are carefully indicated in the respective clinical context and if there are serious clinical consequences both from the nephrotic syndrome and from loss of kidney function. Since immune complexes within the kidney often require along time to be degraded, proteinuria response can follow the immunological remission after many months. The therapy of MN represents the favorable case of aprecision medicine-based therapy in nephrology, whereby new therapeutic B‑cell antibodies for the rare but difficult forms of MN will find their way into clinical routine in the not-too-distant future.

#4574 ATYPICAL CHEMOKINE RECEPTOR 4 IS EXPRESSED IN GLOMERULAR PARIETAL EPITHELIAL CELLS AND MITIGATES THE SEVERITY OF EXPERIMENTAL GLOMERULONEPHRITIS

Abstract Background and Aims Cell migration contributes to the innumerable physiological and pathological processes driven and directed by chemotactic cytokines (chemokines), small structurally homologous proteins signaling via their cognate GPCRs on motile cells. In addition to GPCRs, chemokines importantly interact with atypical chemokine receptors (ACKRs) that are characterized by expression in various stromal cells and distinctive ligand specificities. ACKR4 binds CCL19, CCL20, CCL21, CCL22 and CCL25, chemokines involved primarily in adaptive immune responses. Accordingly, ACKR4 is prominently expressed in the primary and secondary lymphoid organs, thymus, bone marrow, lymph nodes and spleen where it regulates distinct cell migratory steps driven by its cognate ligands. Furthermore, ACKR4 is expressed by dissimilar cell types in multiple parenchymal organs, the heart, the liver and the gut. Currently it is not entirely clear how chemokine scavenging by ACKR4 in these organs might affect their pathophysiology. Here we investigated the expression of ACKR4 in murine kidney and assessed its contribution to nephrotoxic serum nephritis (NTSN), an experimental murine model of immune complex glomerulonephritis. The pathomechanisms in NTSN are known to rely on the contribution of multiple chemokines and their receptors and functions of Th1 cells, Th17 cells, neutrophils and macrophages exerting pathogenic effects in both lymphoid organs and the kidney. Method The expression of renal ACKR4 was evaluated in healthy ACKR4-eGFP reporter mice as well as after the induction of NTSN. To investigate the contribution of ACKR4 to NTSN, ACKR4-deficient mice and WT controls were subjected to an anti-basal membrane immunization protocol and the parameters of immunopathogenesis and the ensuing kidney disease were evaluated at 7 and 14 days after the immunization. Results Multicolour immunofluorescence confocal microscopy revealed that ACKR4 is expressed in the kidney exclusively in the glomeruli by a discrete subset of parietal epithelial cells localizing adjacently to the vascular glomerular pole. In mice with NTSN, the overall proportion of ACKR4 expressing cells in glomeruli at the vascular pole did not change as compared to healthy mice, however ACKR4+ cells were not detected in glomeruli corresponding with the increased abundance of alpha-SMA, a marker of renal fibrosis. The ACKR4-deficient mice showed delayed antibody response following immunization and reduced readouts of cellular immunity. However, despite this, disease parameters of NTSN, including albuminuria, PAS-score and crescent formation were significantly increased in ACKR4-deficient mice as compared to the WT controls. Renin, a hormone secreted by the cells adjacent to ACKR4+ cells in the kidney was significantly increased in serum of nephritic ACKR4-/- mice. Conclusion We report for the first time that ACKR4 is expressed in the kidney by a small subpopulation of parietal epithelial cells. Reduced parameters of humoral and cellular immunity in ACKR4-deficient mice contrast with a more severe manifestations of NTSN seen in these mice, suggesting a tissue-specific functional bias of ACKR4 in the kidney that limits the development of NTSN. Furthermore, the immediate proximity of ACKR4 expressing cells to the juxtaglomerular apparatus and the observed increased renin secretion in ACKR4-/- mice suggest a potential contribution of ACKR4 to the regulation of renin-driven pathways, by a yet unclear mechanism.

Resolution of IgA vasculitis nephritis in patient with activated PI3Kdelta syndrome after treatment with leniolisib

IntroductionActivated PI3K-delta syndrome is a combined immunodeficiency disease with a heterogenous immune phenotype. Common clinical manifestations include recurrent respiratory infections, persistent herpesvirus infections, lymphoproliferative disease, and autoimmunity. We describe the case of a patient with APDS who developed IgA vasculitis nephritis that responded to steroids, plasmapheresis, rituximab, and initiation of a new selective PI3Kdelta inhibitor, leniolisib. Case description19-year-old male with APDS (pathogenic variant in PI3KCD, p.E81K) complicated by recurrent ear and sinus infections, marginal zone B-cell hyperplasia, and EBV lymphadenitis who presented to the hospital with hematuria and fatigue. Initial work-up revealed acute kidney injury (Cr 1.72 mg/dL) with gross hematuria and nephrotic range proteinuria. A renal biopsy was performed which demonstrated IgA dominant immune complex glomerulonephritis (10% focal cellular crescents). The patient was started on empiric high-dose steroids. However, due to worsening renal injury (Cr peak to 4.1 mg/dL) and proteinuria, plasmapheresis and rituximab were administered. Additionally, leniolisib, a new oral PI3Kdelta inhibitor, was initiated at 70 mg twice daily. The patient’s renal function began to stabilize after administration of these therapies, and he was discharged on daily prednisone and leniolisib. On outpatient follow-up over the course of six months, he demonstrated normalization of his creatinine and improvement of his proteinuria. ConclusionsGlomerulonephritis has been reported as an autoimmune renal manifestation in APDS. This case highlights the first reported instance of treatment response to leniolisib and immunomodulatory agents in an APDS patient with IgA vasculitis nephritis. While leniolisib is an unapproved selective PI3K-delta inhibitor, its use should be considered in the management of APDS patients with significant autoimmune complications.

Focal Segmental Glomerulosclerosis and Renal Failure Secondary to Protein Kinase C Delta Deficiency in an Adolescent Male

Introduction: The autoimmune lymphoproliferative syndrome (ALPS)-like condition, Protein Kinase C-delta (PRKCD) deficiency, is associated with a lupus-like presentation, recurrent infections, and reduced B-cell function with hypogammaglobulinemia in addition to prominent lymphadenopathy and splenomegaly. Renal manifestations previously reported include nephrotic syndrome and glomerulonephritis. Focal segmental glomerulosclerosis (FSGS) and significant end-stage renal disease requiring dialysis have not been previously described in those with PRKCD deficiency.Case Study: We describe a now 21-year-old male of Palestinian descent with consanguineous parents who initially presented at 15 months of age with arthritis, splenomegaly, neutrophilic rash, and recurrent fevers. At 7 years of age, the patient was hospitalized with hepatosplenomegaly, diffuse adenopathy, and post-obstructive pneumonitis secondary to hilar adenopathy. He was subsequently given a diagnosis of presumed ALPS, although FAS mutation testing was negative, and started on mycophenolate with improvement in symptomology. He underwent additional comprehensive genetic testing when he was 18 years old with results revealing a novel homozygous PRKCD variant (c. 1872 1 G > A) leading to a presumed donor splice site defect. [Display omitted] Starting at 19 years of age, the patient was noted to have a steadily rising serum creatinine and profound proteinuria. Kidney biopsy revealed chronic immune complex glomerulonephritis with capillary loop and mesangial immune deposits and changes consistent with secondary FSGS. (Figure 1A&B). He was started on an angiotensin-converting enzyme (ACE) inhibitor for antiproteinuric effects, though this was discontinued due to persistent hyperkalemia. A subsequent renal biopsy performed 5 months later in the clinical setting of rapid deterioration of GFR and worsening proteinuria showed worsening FSGS with prominent podocytopathy (Figure 1 C&D). Mycophenolate and IVIG therapy were discontinued given a lack of efficacy and to preserve renal function. Unfortunately, his creatinine continued to rise, and he progressed to end-stage renal disease necessitating dialysis. He is currently being considered for kidney transplantation. ConclusionSevere FSGS leading to renal failure is an uncommon diagnosis in adolescents and has not previously been described in those with PRKCD deficiency. Our case thus broadens the phenotypic and pathologic renal manifestations of the disorder and emphasizes the need for comprehensive multidisciplinary care of individuals affected by ALPS-like conditions.

Immune Complex Glomerulonephritis and Elevated p-ANCA Overlap Syndrome in a 58-Year-Old Patient with Rapidly Progressive Kidney Failure

Immune Complex Glomerulonephritis and Elevated p-ANCA Overlap Syndrome in a 58-Year-Old Patient with Rapidly Progressive Kidney Failure

Kidney tubular epithelial cell ferroptosis links glomerular injury to tubulointerstitial pathology in lupus nephritis

Ferroptosis is a druggable, iron-dependent form of cell death that is characterized by lipid peroxidation but has received little attention in lupus nephritis. Kidneys of lupus nephritis patients and mice showed increased lipid peroxidation mainly in the tubular segments and an increase in Acyl-CoA synthetase long-chain family member 4, a pro-ferroptosis enzyme. Nephritic mice had an attenuated expression of SLC7A11, a cystine importer, an impaired glutathione synthesis pathway, and low expression of glutathione peroxidase 4, a ferroptosis inhibitor. Lipidomics of nephritic kidneys confirmed ferroptosis. Using nephrotoxic serum, we induced immune complex glomerulonephritis in congenic mice and demonstrate that impaired iron sequestration within the proximal tubules exacerbates ferroptosis. Lupus nephritis patient serum rendered human proximal tubular cells susceptibility to ferroptosis which was inhibited by Liproxstatin-2, a novel ferroptosis inhibitor. Collectively, our findings identify intra-renal ferroptosis as a pathological feature and contributor to tubular injury in human and murine lupus nephritis.

Immune Complex Glomerulonephritis in a Patient with Myelodysplastic Syndrome with Ring Sideroblasts Treated with Luspatercept

Myelodysplastic syndromes (MDS) are a group of clonal myeloid disorders distinguished by dysplastic bone marrow and peripheral blood cells, ineffective hematopoiesis, and an increased risk of developing acute myeloid leukemia (AML). MDS with ring sideroblasts (MDS-RS) is a favorable outcome subtype with a lower frequency of AML transformation. The FDA recently approved luspatercept for the treatment of patients with very-low-, low-, and intermediate-risk MDS-RS who have failed to correct anemia with an erythropoiesis-stimulating agent (ESA) and require two units of red blood cells over an eight-week period. This drug's pharmacology is based on the critical role of the transforming growth factor-beta (TGF-β) pathway in regulating erythropoiesis. In this case report, we describe for the first time an acute kidney injury caused by membranoproliferative glomerulonephritis (MPGN) in a patient with MDS-RS who was treated with luspatercept. We propose that a multi-hit hypothesis could explain the immunopathogenesis. A first unknown hit may stimulate IgA immune complex production, whereas luspatercept administration acts as a second hit, causing Smad1-5-8 phosphorylation. This intriguing case report on immune-complex-mediated proliferative glomerulonephritis following luspatercept treatment generates hypotheses and stimulates further research in this area.

Successful treatment of infectious endocarditis-associated glomerulonephritis during active hepatitis C infection: a case report

BackgroundHepatitis C virus (HCV) may play a pathogenic role in several forms of immune complex glomerulonephritis (GN). We present a patient whose initial clinical presentation instilled suspicion of HCV-related renal involvement. Yet, histopathologic data oriented towards a different diagnosis.Case presentationA 68-year old man presented with kidney dysfunction, cryoglobulins, low C4 level, high HCV—RNA and cutaneous vasculitis. The first hypothesis was a hepatitis C-related cryoglobulinemic glomerulonephritis. Renal biopsy revealed endocapillary and mesangial cells hypercellularity with complement C3 and IgM deposits. The echocardiography showed an infectious endocarditis (IE) on aortic valve. Appropriate antibiotic therapy and a prosthetic valve replacement were performed, obtaining recovery of renal function.ConclusionHCV infection may be linked to multiple renal manifestations, often immune-complex GN such as cryoglobulinemic membrano-proliferative GN. Renal disease due to IE is usually associated to focal, segmental or diffuse proliferative GN, with prominent endocapillary proliferation. The most common infectious agents are Staphylococcus aureus and Streptococcus species.This case report may be relevant because the renal dysfunction was highly suggestive of a cryoglobulinemic GN on a clinical ground, but the histologic pattern after performing the renal biopsy oriented towards a different cause of the underlying disease, that required a specific antibiotic treatment. The renal biopsy is always required to confirm a clinical suspicious in patients affected by multiple comorbidities.

Genetic analysis of CFH and MCP in Egyptian patients with immune-complex proliferative glomerulonephritis.

Glomerulonephritis (GN) is a complex disease with intricate underlying pathogenic mechanisms. The possible role of underlying complement dysregulation is not fully elucidated in some GN subsets, especially in the setting of autoimmunity or infection. In the current study, diagnosed cases of lupus nephritis (LN) and post-infectious GN (PIGN) were recruited for molecular genetic analysis and targeted next-generation DNA sequencing was performed for two main complement regulating genes: in the fluid phase; CFH, and on tissue surfaces; MCP. Three heterozygous pathogenic variants in CFH (Q172*, W701*, and W1096*) and one likely pathogenic heterozygous variant in MCP (C223R) have been identified in four of the studied LN cases. Additionally, among the several detected variants of uncertain significance, one novel variant (CFH:F614S) was identified in 74% of the studied LN cases and in 65% of the studied PIGN cases. This variant was detected for the first time in the Egyptian population. These findings suggest that subtle mutations may be present in complement regulating genes in patients with immune-complex mediated category of GN that may add to the disease pathogenesis. These findings also call for further studies to delineate the impact of these gene variants on the protein function, the disease course, and outcome.

Triple-threat quantitative multiplexed plasma proteomics analysis on immune complex disease MRL-lpr mice.

Systemic lupus erythematosus is a common autoimmune inflammatory disease which is associated with increases in autoantibodies and immune complexes that deposit in the kidney. The MRL-lpr mouse is a common mouse model used for the study of lupus and immune complex glomerulonephritis but very little is known about the plasma proteome changes in this model. We performed in-depth quantitative proteome profiling on MRL-lpr and control (strain MpJ) mice to investigate the changes in the proteome, immunoglobulins and their glycoproteome as well as protein and immune complexes. Methodologies used included immunohistochemistry, immunoglobulin isotyping, multiplexed proteome profiling, immunoglobulin immunoprecipitation with glycoproteome profiling, and size exclusion chromatography (SEC) profiling to enable a comprehensive proteome profiling of proteins and protein complexes. We also used a novel native multiplexed plasma proteome profiling (NativeMP3) method that relies on native enrichment of plasma proteins enabling ultra-deep single shot profiling where we identified 922 plasma proteins at 1% false discovery rate (FDR) in a single shot mass spectrometry run. We observed many large plasma protein differences between the MRL-lpr and control strain including differences in the immunoglobulins, immunoglobulins against specific antigens, chemokines, and proteases as well as changes in protein complexes such as the immunoproteasome.