An Unusual Case of Anti-Glomerular Basement Membrane Disease and Phospholipase A2 Receptor-Associated Membranous Nephropathy After Exposure to Hydrocarbons.

We present a rare case of a patient with toluene exposure manifesting as anti-glomerular basement membrane (GBM) disease on a background of phospholipase A2 receptor (PLA2R)-associated membranous nephropathy. A 23-year-old man presented to the emergency department with hypertension, headache, hemoptysis, anemia, acute kidney injury, glomerular hematuria, and proteinuria. He endorsed repeated exposure to toluene-containing products while repairing dirt bikes. Serologies were positive for anti-GBM antibodies. Kidney biopsy showed crescentic glomerulonephritis with linear immunoglobulin G and granular PLA2R staining by immunofluorescence. He was initially treated with high-dose steroids, plasmapheresis, and hemodialysis for pulmonary-renal syndrome followed by oral cyclophosphamide and prednisone, which were discontinued after 3 months when follow-up biopsies confirmed little chance for renal recovery. He remained on dialysis 1 year later. This case exhibits a unique presentation of anti-GBM syndrome and underlying membranous nephropathy following repeated hydrocarbon exposure. Inhaled toxins promote recurrent localized inflammation, unmasking previously hidden epitopes. Early diagnosis and appropriate use of immunosuppressive and extracorporeal therapies are necessary to prevent morbidity and to improve survival in this rare condition.

Relapse of treated anti-GBM disease following hair dye use.

An 18-year-old woman was treated for acute kidney injury (AKI) secondary to antiglomerular basement membrane (GBM) disease with prednisolone, cyclophosphamide and plasma exchange. She also had epistaxis at initial presentation with no other organ involvement and achieved good recovery of her kidney function. Two weeks after completing induction treatment, she re-presented with further AKI and pulmonary haemorrhage. She was recommenced on plasma exchange and steroids and was given rituximab. She recovered from her illness with significant improvement to her kidney function. The cause of her relapse was thought to be possibly due to the use of hair dye. This case highlights the importance of acknowledging potential environmental exposures to prevent relapses of disease. We were also able to demonstrate a case of successful treatment of anti-GBM disease with rituximab.

Histological diagnosis of immune checkpoint inhibitor induced acute renal injury in patients with metastatic melanoma: a retrospective case series report.

BACKGROUND: Immune checkpoint inhibitors (ICI) have become the standard of care in many oncological conditions but are associated with a spectrum of renal immune-related adverse events (IrAEs). We aimed to describe the spectrum, histology, management and outcomes of renal IrAE in patients with metastatic melanoma undergoing ICI therapy. METHODS: We conducted a retrospective review of 23 patients with a diagnosis of metastatic melanoma treated with ICI between January 2017 and April 2019 who developed a renal IrAE. Baseline demographic data, biochemical and histopathological results, management and outcomes were analyzed. RESULTS: The majority of patients who developed renal irAE were male and received combination immunotherapy. The median time of onset from initiation of ICI therapy to renal IrAE was 4 months. 52% of the treated renal IrAE had histopathologically confirmed renal IrAE. The most common histological pattern of injury was acute tubulo-interstitial nephritis (92%). One patient developed anti-GBM disease with non-dialysis dependent stage 5 CKD. In tubulointerstitial injury, there was no association between peak creatinine, renal recovery and histologically reported inflammation or fibrosis. Patients with renal IrAE demonstrated persisting renal dysfunction at 3, 6 and 12 months with a mean baseline, 3 and 12 month creatinine of 90.0 µmol/L, 127.0 µmol/L and 107.5 µmol/L respectively. CONCLUSION: Renal IrAE is most commonly attributable to steroid responsive acute tubulointerstitial nephritis. The outcome of rarer pathologies such as anti-GBM disease may be adversely affected by a delayed diagnosis. There is persisting renal dysfunction following an episode of renal IrAE that may have impact on future renal and overall survival outcomes.

Anti-glomerular basement membrane glomerulonephritis following nintedanib for idiopathic pulmonary fibrosis: a case report.

BACKGROUND: We report a previously unrecognized and unreported case of a patient with anti-glomerular basement membrane glomerulonephritis following nintedanib, an orally active small molecule tyrosine kinase inhibitor. CASE PRESENTATION: A 59-year-old Caucasian woman with a history of idiopathic pulmonary fibrosis presented with severe acute kidney injury (creatinine 285 umol/L) secondary to anti-glomerular basement membrane glomerulonephritis disease 4 months after commencement of nintedanib. She had hematuria with red blood cell casts, nephrotic range proteinuria (3.5g/24 hours) and significantly elevated anti-glomerular basement membrane glomerulonephritis titers at 860 chemiluminescent units. A kidney biopsy confirmed severe crescentic glomerulonephritis with linear immunoglobulin G deposition in glomerular basement membrane. Despite the commencement of treatment with plasma exchange and cyclophosphamide, she remained dialysis dependent. Nintedanib was discontinued. CONCLUSIONS: Onset of acute anti-glomerular basement membrane glomerulonephritis was found to be associated with recent nintedanib use suggesting that nintedanib may be a potential trigger for anti-glomerular basement membrane glomerulonephritis. This case highlights the importance of close monitoring of patients receiving new targeted therapies. Management of novel targeted agents in patients receiving dialysis is challenging because of the scarcity of specific data.

Human anti-α3(IV)NC1 antibody drug conjugates target glomeruli to resolve nephritis.

Current therapies to limit kidney disease progression lack specificity and often have systemic toxicity. To approach this problem, we postulated that a human monoclonal antibody (F1.1), directed against the noncollagenous-1 domain (NC1) of α3(IV) collagen that localizes in glomeruli, could serve as a vehicle for targeted drug delivery. Given enhanced exposure of the NC1 domain of α3(IV) during glomerular diseases, with limited epitope expression in other organs, α3(IV)NC1 provides an ideal target for delivery of disease-modifying agents. As a potential disease-modifying agent, we initially took advantage of recent observations that PGE2 promoted recovery after established injury during the course of nephrotoxic nephritis. To address the general applicability of the approach, the efficacy of glomerular delivery of dexamethasone was also examined. To achieve glomerular targeted therapy, PGE2 and dexamethasone were coupled to F1.1. After confirmation of the composition and activity of the conjugates, both glomerular localization and the capacity of the conjugates to modify disease were evaluated. After injection into mice with established nephritis, resolution of disease was enhanced with both agents, with normalization of histology and improved blood urea nitrogen levels in conjugate-treated mice compared with untreated mice. The results provide a novel means of targeting glomeruli during nephritis, irrespective of cause, by providing efficient drug delivery, with the potential of limiting systemic effects.

Successful treatment of experimental glomerulonephritis with IdeS and EndoS, IgG-degrading streptococcal enzymes.

BACKGROUND: Anti-glomerular basement membrane (anti-GBM) disease often results in end-stage renal failure despite therapy with plasma exchange and immunosuppressive drugs. The newly discovered streptococcal enzymes IgG-degrading enzyme of S.pyogenes (IdeS) and endoglycosidase S (EndoS) act with remarkable specificity on circulating IgG. In this study, we investigate their ability in vivo to prevent damage mediated by kidney-bound antibodies in a mouse model of anti-GBM disease. METHODS: Anti-GBM disease was induced in mice by injection of subnephritogenic doses of rabbit anti-mouse GBM, followed a week later by injection of monoclonal mouse anti-rabbit IgG antibodies. By administrating IdeS or EndoS as fusion partners with GST between these antibody injections, we tested their ability to prevent damage by acting on kidney-bound rabbit anti-GBM. Control animals received placebo injections. RESULTS: All animals in the positive control groups developed severe albuminuria immediately after the second antibody injection (mean, 2.51 mg/24 h; range, 0.13-8.20). This was significantly diminished by EndoS (1.3 +/- 1.3 mg/24 h) and completely prevented by IdeS (0.017 +/- 0.014 mg/24 h). Immunofluorescence studies showed that IdeS treatment effectively removed the Fc fragments of the rabbit IgG. This was accompanied by a significant reduction of the deposition of the complement components C3 and C1q, and this diminished the recruitment of leukocytes to the glomeruli. CONCLUSION: IdeS degrades IgG bound to the GBM in vivo, thereby preventing renal damage in this animal model. Most likely, IdeS would degrade both circulating and kidney-bound anti-GBM in patients with Goodpasture's disease. Whether this would lead to a halt in disease progression and a better prognosis remains to be determined.

An unusual non-immunological cause of renal pulmonary syndrome.

A 38-year-old Caucasian male presented with a 4-week history of nose bleeds, gross hematuria and blurred vision. He was a smoker, who had used cannabis and cocaine previously. At presentation, he had features of malignant hypertension (blood pressure 220/120 mmHg), was hypoxic on room air, with no signs of fluid overload or heart failure. He had acute renal failure with radiological evidence of alveolar hemorrhage. Renal biopsy showed extensive ischemic collapse of glomeruli and severe fibrointimal thickening of the arteries with fibrinoid deposits in the wall. Auto-immune screen was negative. Serum creatinine peaked at 749 micromol/l. Adequate control of blood pressure and supportive oxygen therapy lead to a complete clinical and radiological resolution of the pulmonary hemorrhage and he did not need dialysis. Eighteen months on, his serum creatinine is stable at 279 micromol/l with good blood pressure control. Malignant hypertension is not a recognized cause of the renal-pulmonary syndrome and physicians should be aware of the possibility, if only to avoid inappropriate treatments like plasmapheresis and immunosuppression. History of cocaine use is important in the setting of an acute vascular event.

Involvement of MCP-1 in tubulointerstitial fibrosis through massive proteinuria in anti-GBM nephritis induced in WKY rats.

We investigated participation of monocyte chemoattractant protein-1 (MCP-1) in tubulointerstitial fibrosis and correlation between MCP-1 and proteinuria in Wistar-Kyoto (WKY) rats with glomerulonephritis induced by anti-glomerular basement membrane (anti-GBM) antibody. WKY rats showed marked proteinuria and severe glomerular crescent formation at 7 days post antibody injection. At 28 days, tubulointerstitial fibrotic lesions were observed, followed by sustained heavy proteinuria and severe tubulointerstitial fibrosis at 56 days. Histological examination revealed that the overlapped immunoreactivities of MCP-1, rat albumin, and p65NF-kappaB were detected in the same tubular segments of nephritic kidney, and a significant positive correlation was observed between proteinuria and MCP-1 expression in the tubulointerstitial fibrosis. ED-1- and CD8-positive cells were also abundant, and there was a good correlation between monocyte/macrophage recruitment and MCP-1 expression in the tubulointerstitial area. These results suggest that MCP-1 participates in the progression of tubulointerstitial fibrosis, through massive albuminuria, which is accompanied by marked monocyte/macrophage recruitment.

Protective effect of ligustrazine on accelerated anti-glomerular basement membrane antibody nephritis in rats is based on its antioxidant properties.

Ligustrazine has a renoprotective effect against nephritis. In this study, we further characterized the renoprotective properties of ligustrazine in an experimental model using accelerated anti-glomerular basement membrane antibody (AGBM-Ab). Ligustrazine was given i.p. once daily at 50, 100 mg/kg for 15 days after singly giving i.v. of rabbit anti-rat glomerular basement membrane serum, and showed dose-dependent inhibition the elevation of urinary protein, serum creatinine and blood urea nitrogen as well as the development of glomerular histological changes. Ligustrazine (50 mg/kg) had no affect on glutathione (GSH) content, glutathione peroxidase and catalase activities, but decreased the malondialdehyde (MDA) content and increased superoxide dismutase (SOD) activity in nephritis induced by AGBM-Ab. Ligustrazine (100 mg/kg) significantly decreased MDA content while significantly increased GSH content and SOD, glutathione peroxidase, catalase activities of kidney tissues in the rats treated with AGBM-Ab alone. In conclusion, our results show that ligustrazine has protective activity against accelerated AGBM-Ab nephritis, and its renoprotective effect may be due to its antioxidant properties and inhibition reactive oxygen species (ROS).

Calpain activation and secretion promote glomerular injury in experimental glomerulonephritis: evidence from calpastatin-transgenic mice.

Glomerular injury and albuminuria in acute glomerulonephritis are related to the severity of inflammatory process. Calpain, a calcium-activated cysteine protease, has been shown to participate in the development of the inflammatory process. Therefore, for determination of the role of calpain in the pathophysiology of acute glomerulonephritis, transgenic mice that constitutively express high levels of calpastatin, a calpain-specific inhibitor protein, were generated. Wild-type mice that were subjected to anti-glomerular basement membrane nephritis exhibited elevated levels of calpain activity in kidney cortex at the heterologous phase of the disease. This was associated with the appearance in urine of calpain activity, which originated potentially from inflammatory cells, abnormal transglomerular passage of plasma proteins, and tubular secretion. In comparison with nephritic wild-type mice, nephritic calpastatin-transgenic mice exhibited limited activation of calpain in kidney cortex and limited secretion of calpain activity in urine. This was associated with less severe glomerular injury (including capillary thrombi and neutrophil activity) and proteinuria. There was a reduction in NF-kappaB activation, suggesting that calpain may participate in inflammatory lesions through NF-kappaB activation. There also was a reduction in nephrin disappearance from the surface of podocytes, indicating that calpain activity would enhance proteinuria by affecting nephrin expression. Exposure of cultured podocytes to calpain decreased nephrin expression, and, conversely, exposure of these cells to calpastatin prevented TNF-alpha from decreasing nephrin expression, demonstrating a role for the secreted form of calpain. Thus, both activation and secretion of calpains participate in the development of immune glomerular injury.

Goodpasture-like syndrome induced by D-penicillamine in a patient with systemic sclerosis: report and review of the literature.

We report a case of Goodpasture-like syndrome developing in a patient who was treated with D-penicillamine for the diffuse form of systemic sclerosis. This unusual pulmonary-renal syndrome has been described on rare occasions in patients receiving D-penicillamine. This complication appeared to be uniformly fatal unless treated with aggressive immunotherapy. We review the cases reported to date in the literature and describe the clinical characteristics, therapy, and outcome of this group of patients.

Outcomes in patients with Goodpasture's syndrome and hydrocarbon exposure.

Goodpasture's Syndrome has been associated with hydrocarbon exposure. No study has examined outcomes in these patients. All reported cases of Goodpasture's Syndrome and hydrocarbon exposure were identified using MEDLINE and was analyzed for factors related to outcomes. A total of 43 cases were identified since 1969. The mean age of patients was 28 years old. There was a slight predilection for males (60%) when analyzing gender. Various types of hydrocarbons were identified and the duration of exposure varied from minutes to years. A majority of patients (86%) had pulmonary hemorrhage and antiglomerular basement membrane antibodies (AGBM) (92%). Patients were treated with immunosuppressive agents. The only significant statistical correlation was female patients with hydrocarbon exposure were younger. There was no correlation between age, gender, duration of exposure, presence of pulmonary hemorrhage or AGBM, or other risk factors and outcome. The relationship between hydrocarbon exposure and Goodpasture's Syndrome remains unclear since only 6% of cases in the literature had exposure. Even though most patients survived, no factor studied affected outcome making it difficult to predict prognosis in these patients.

Protection and injury: the differing roles of complement in the development of glomerular injury.

The role of complement in autoimmune glomerulonephritis (as in other autoimmune diseases) is paradoxical, in that complement activation mediates acute inflammatory injury, yet inherited deficiency of complement may predispose to immune complex disease in particular immune complex glomerulonephritis. We have investigated the role of complement in experimentally induced glomerulonephritis in C3-deficient mice, using antibodies against the mouse glomerular basement membrane (GBM). In the acute phase of the disease, which is initiated by binding of heterologous antibody to the GBM, we confirmed that the inflammatory injury was positively complement dependent, with C3-deficient mice developing less severe injury. In contrast, in the autologous phase of the disease, mediated by the immune response against the heterologous antibody fixed in the GBM, the disease was negatively complement dependent. That is, by 14 days after disease induction the C3-deficient mice had heavier proteinuria and more severe uremia (p < 0.001) compared to the complement sufficient mice. The C3-deficient mice also showed a greater accumulation of electron-dense deposits in the GBM. These findings were reproduced in an accelerated model of this disease in which C3-deficient mice also develop more severe functional disturbance and demonstrate a higher rate of immune complex deposition. These data illustrate the potential for the net effect of complement to switch from a detrimental to a protective mode at different stages of autoimmune injury.

Antiglomerular basement membrane antibody-mediated glomerulonephritis after intranasal cocaine use.

We report a case of rapidly progressive glomerulonephritis due to antiglomerular basement membrane (anti-GBM) antibodies that progressed to end-stage renal disease in a 35-year-old man who used intranasal cocaine on an occasional basis. In contrast to many prior reports of acute renal failure occurring with cocaine-associated rhabdomyolysis, this patient did not have any evidence of acute muscle damage and myoglobin release. Circulating anti-GBM antibodies and renal biopsy with linear IgG and C3 deposits confirmed the diagnosis of anti-GBM disease. The possibility of anti-GBM must be considered in the differential diagnosis of acute renal failure in cocaine addicts. This unusual combination raises complex questions regarding the pathogenesis of this type of renal injury.

Pulmonary hemorrhage and antiglomerular basement membrane antibody-mediated glomerulonephritis after exposure to smoked cocaine (crack): a case report and review of the literature.

A case of Goodpasture's syndrome with a negative immunofluorescence examination of the lung biopsy in a 32-year-old man is described. The patient was a 40 cigarettes per day smoker, who had been smoking cocaine (crack) up to 3 weeks before hospital admission. He developed a diffuse alveolar hemorrhage with extremely acute respiratory distress, followed by renal failure with anuria. Transjugular renal biopsy, immunofluorescence and serum antiglomerular basement membrane antibody titer studies confirmed the diagnosis of Goodpasture's syndrome without linear immunoglobulin G deposits as determined by immunofluorescence examination of the alveolar basement membranes. The case illustrates the potentially complex interrelations between an autoimmune disease and exposure to substances with possible antigenic properties, besides the imperative necessity for an early, accurate diagnosis and treatment for the potential for threatening life. Moreover, the association of Goodpasture's syndrome with crack has not been previously reported.

Goodpasture's syndrome. Unusual presentation after exposure to hard metal dust.

An unusual case of Goodpasture's syndrome in a 26-year-old man with occupational exposure to hard metal dust is described. The patient developed a life-threatening interstitial lung disease that was followed by a rapidly progressive glomerulonephritis two months later. To our knowledge, association of Goodpasture's syndrome and hard metal exposure has not been reported previously.

Binding of anti-basement membrane antibody to alveolar basement membrane after intratracheal gasoline instillation in rabbits.

A possible causal relationship has been suggested between hydrocarbon (gasoline, solvents, etc.) exposure and development of anti-basement membrane antibody-associated Goodpasture's syndrome in man. The authors evaluated the effect of hydrocarbons on pulmonary capillary permeability and binding of heterologous anti-basement membrane antibodies in the lungs after intratracheal instillation of minute amounts of unleaded gasoline into rabbits. The anti-glomerular basement membrane (GBM) antibodies used reacted with the alveolar basement membrane (ABM) in vitro by indirect immunofluorescence. The gasoline treatment altered pulmonary capillary permeability, judging from the increased accumulation of systemically administered radioiodinated bovine serum albumin in the alveolar and extravascular spaces of lungs; it also induced focal macroscopic and microscopic pulmonary histologic lesions. The gasoline caused focal in vivo binding of the anti-GBM antibodies to the ABM detectable by immunofluorescence microscopy. No binding was observed in lungs from control rabbits given saline instillations when assayed by immunofluorescence. The paired label radioisotope technique confirmed the increased antibody binding to lungs injured with gasoline (1.08 +/- 0.03 micrograms) versus 0.37 +/- 0.07 microgram after saline (P less than 0.001). These results indicate that gasoline exposure damages a pulmonary barrier that normally prevents binding of anti-GBM/ABM antibody to ABM and suggest that hydrocarbon exposure may be one of perhaps several pneumotoxic events that contribute to the episodic pulmonary hemorrhage in Goodpasture's syndrome by temporarily allowing ABM binding of anti-basement membrane antibodies.