抗糸球体基底膜腎炎

INTRODUCTION: Pediatric rapidly progressive glomerulonephritis (RPGN) encompasses heterogeneous serology-based subtypes, including anti-glomerular basement membrane (anti-GBM), immune-complex-associated, and ANCA-associated (pauci-immune) RPGN. Although these subtypes differ in their underlying immune mechanisms, their ability to predict early renal recovery in children remains uncertain. This study aimed to evaluate the association between serology-based RPGN subtypes and early changes in renal function and tubular injury markers. METHODS: This prospective cohort study included 30 children with newly diagnosed RPGN treated at Dr. Soetomo General Hospital. Patients were classified into anti-GBM, immune-complex-associated, or ANCA-associated RPGN based exclusively on serologic criteria. Estimated glomerular filtration rate (eGFR) and serum kidney injury molecule-1 (KIM-1) were measured at baseline and at 3 months after induction therapy. Primary outcomes were changes in eGFR (ΔeGFR) and serum KIM-1 (ΔKIM-1). Differences among subtypes were assessed using multivariate analysis of variance. RESULTS: Of the 30 patients, 67% had immune-complex-associated RPGN, 20% had ANCA-associated RPGN, and 13% exhibited anti-GBM disease. The median age was 15 years. No statistically significant differences in ΔeGFR or ΔKIM-1 were observed among subtypes (MANOVA, p = 0.506), although numerical improvements varied across groups. CONCLUSION: Serology-based RPGN subtype was not associated with early improvement in glomerular filtration or reduction in tubular injury markers in pediatric RPGN. Early renal recovery may be influenced more by baseline disease severity and therapeutic responsiveness than by serologic subtype classification alone.

Melanocortin-based therapies have demonstrated protective effects in experimental membranous nephropathy (MN). However, existing evidence is derived exclusively from passive immunization models that lack direct involvement of human MN-associated autoimmunity, limiting translational relevance. A clinically relevant model is essential to more precisely define melanocortin efficacy and mechanisms in MN. To address this gap, we established an active immunization model of THSD7A-associated MN by immunizing mice with recombinant THSD7A antigen. This clinically relevant and accessible model recapitulated cardinal features of human MN, including insidious onset, progressive proteinuria, and characteristic histopathology such as subepithelial immune deposition, complement fixation along glomerular tufts, glomerular basement membrane thickening, and podocyte injury with foot process effacement and loss of homeostatic markers. Rescue treatment with the pan-melanocortin receptor agonist NDP-MSH significantly reduced proteinuria and mitigated glomerular damage and podocyte injury. This was accompanied by a marked reduction in circulating anti-THSD7A autoantibody levels, reduced glomerular immune deposition, and diminished complement activation. Mechanistically, ex vivo treatment of primed B cells isolated from diseased mice demonstrated that NDP-MSH directly inhibited plasma cell differentiation and autoantibody production. This suppression was accompanied by increased expression of microphthalmia-associated transcription factor (MITF) and downregulation of interferon regulatory factor 4 (IRF4), indicating activation of the MITF/IRF4 signaling axis, a pathway implicated in negative regulation of B cell differentiation. Collectively, these findings extend the therapeutic potential of melanocortin signaling to a preclinical model that closely mirrors human MN and provide mechanistic insight into its immunomodulatory actions. These results support further investigation of targeted melanocortin-based therapies for MN.

Alport syndrome (AS) is characterised by progressive chronic kidney disease (CKD) leading to kidney failure, sensorineural hearing loss and eye abnormalities. AS patients have reduced or no expression of the α3α4α5 triple helix, a major component of the kidney glomerular basement membrane (GBM), due to pathogenic variants in COL4A3, COL4A4 and COL4A5. Post-transplant anti-GBM nephritis continues to be seen in AS patients and is immunological distinct from 'traditional' anti-GBM (Goodpasture's) disease. Post-transplant anti-GBM nephritis is reported to affect 5% of AS patients. There is also an isolated immunological anti-GBM disease counterpart, where despite the production of anti-GBM antibodies, the AS patient does not ever develop clinical nephritis post-transplant. The pathophysiology of anti-GBM nephritis post-transplant relates to the presentation of non-tolerised antigen to the immune system. The intact donor GBM is immunogenic, specifically the α3α4α5(IV) triple helix, which leads to the production of anti-GBM antibodies that can initiate a crescentic glomerulonephritis in the allograft. The target alloantigen most often implicated in X-linked dominant AS patients with post-transplant anti-GBM nephritis is α5(IV), whereas for autosomal recessive AS patients it is α3(IV). There is no agreed protocol for the treatment or prophylaxis of post-transplant anti-GBM nephritis in AS patients. Immunosuppressive strategies vary including steroids in combination with tacrolimus, azathioprine and ciclosporin. Plasmapheresis can be used to remove pathogenic anti-GBM antibodies. On initial transplantation, allograft failure due to anti-GBM nephritis may occur within weeks-to-months, and not usually beyond the first year post-renal transplant. Progression to graft loss secondary to diagnosed anti-GBM nephritis is often rapid. The recurrence of anti-GBM nephritis and accelerated allograft rejection (occurring within days-to-weeks) is reported in multiple AS patients who underwent retransplantation, having lost their first renal transplant to the same immune phenomenon. Improved diagnostics and disease registries are needed to document these immune phenomena and optimise personalised patient management.

Immunoglobulin A vasculitis (IgAV), formerly known as Henoch-Schönlein purpura, is a small‑vessel vasculitis characterized by immunoglobulin A-predominant immune complex deposition in vessel walls and the glomerular mesangium. Although most commonly observed in children, adult‑onset disease is less frequent and is associated with a higher risk of significant renal involvement and poorer clinical outcomes. We report the case of a 56‑year‑old man with alcoholic cirrhosis and chronic methicillin‑sensitive Staphylococcus aureus prosthetic joint infection who presented with progressive anasarca and a diffuse non‑blanching petechial rash. Laboratory evaluation demonstrated elevated inflammatory markers and acute kidney injury with a serum creatinine of 1.9 mg/dL (baseline approximately 1.0 mg/dL one month prior). Urinalysis revealed 3+ proteinuria and microscopic hematuria. Serologic testing, including antinuclear antibodies, antineutrophil cytoplasmic antibodies, anti‑glomerular basement membrane antibodies, complement levels, cryoglobulins, hepatitis panel, human immunodeficiency virus testing, and rheumatoid factor, was negative or non‑reactive. Renal biopsy demonstrated immunoglobulin A-dominant glomerulonephritis with mesangial hypercellularity and crescent formation. Skin biopsy demonstrated leukocytoclastic vasculitis. Culture obtained from the prosthetic hip abscess grew methicillin‑sensitive Staphylococcus aureus. These findings support a diagnosis of suspected infection‑associated IgAV occurring in the setting of chronic prosthetic joint infection. This case highlights the importance of recognizing chronic infections as potential triggers of immunoglobulin A-mediated vasculitic disease in adults and emphasizes the need to differentiate systemic IgAV from infection‑associated immunoglobulin A-dominant glomerulonephritis.

BACKGROUND: Anti-glomerular basement membrane (GBM) glomerulonephritis (GN) is a severe crescentic GN causing rapid renal failure. Despite extensive study of leukocyte-mediated injury, effective therapies that suppress inflammation and promote immunoregulation remain limited. YS-1301, a non-prostanoid prostacyclin receptor agonist and thromboxane synthase inhibitor, enhances tissue-protective factor release and modulates immune responses in other disease models. This study investigated whether YS-1301 ameliorates anti-GBM GN via immunomodulatory mechanisms. METHODS: Crescentic GN was induced in WKY rats by intravenous injection of anti-GBM antibody clone TF78. YS-1301 (10 mg/kg/day) was administered intravenously after disease induction on days 0-2. Renal function and histologic injury were assessed on day 3, and additional cohorts were evaluated on day 7, the latest time point within the rapidly progressive GN phase of this model. Leukocyte infiltration and monocyte/macrophage phenotypes were evaluated by immunohistochemistry and flow cytometry. RESULTS: YS-1301 significantly reduced day-3 and day-7 blood urea nitrogen (BUN), serum creatinine, proteinuria, and crescent formation without altering initial glomerular antibody deposition. Total glomerular CD68+ cell numbers were unchanged, whereas glomerular CD163+ and CD206+ cell numbers increased. Flow cytometry confirmed that YS-1301 promoted enrichment of immunoregulatory/pro-resolving monocyte/macrophage populations, thereby shifting leukocytes toward an immunoregulatory state. CONCLUSIONS: When administered as an early post-induction intervention, YS-1301 ameliorated anti-GBM GN and was associated with localized accumulation of glomerular immunoregulatory macrophages rather than reduced total macrophage infiltration. These data support further evaluation of YS-1301 as an early immunomodulatory strategy for rapidly progressive GN.