Have We Made "Rapid Progress" Understanding the Pathogenesis in Rapidly Progressive Glomerulonephritis?
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ABSTRACT:
SUBMITTER: Palmer ND
PROVIDER: S-EPMC6177289 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Rapidly progressive glomerulonephritis (RPGN) results from severe crescentic damage to glomeruli and leads to irreversible kidney failure if not diagnosed and managed in a timely fashion. Traditional treatment has relied on glucocorticoids and cyclophosphamide, with additional plasmapheresis for certain conditions. Here we describe updates in the management of RPGN, according to the underlying renal pathology. However, there remains a paucity of trials that have enrolled patients with more advanced renal disease, dialysis dependence or with RPGN, and we are therefore still reliant on extrapolation of data from studies of patients with a less severe form of disease. In addition, reporting bias results in publication of cases or cohorts showing benefit for newer agents in advanced disease or RPGN, but it remains unclear how many unsuccessful outcomes in these circumstances take place. Since clinical trials specifically in RPGN are unlikely, use of biologic registries or combination of sufficient sized cohort series may provide indications of benefit outside of a clinical trial setting and should be encouraged, in order to provide some evidence for the efficacy of therapeutic regimens in RPGN and advanced renal disease.
| S-EPMC4370308 | biostudies-literature
Project description:BackgroundPlasma exchange may be effective adjunctive treatment for renal vasculitis. We performed a systematic review and meta-analysis of randomized controlled trials of plasma exchange for renal vasculitis.Study designSystematic review and meta-analysis of articles identified from electronic databases, bibliographies, and studies identified by experts. Data were abstracted in parallel by 2 reviewers.Setting & populationAdults with idiopathic renal vasculitis or rapidly progressive glomerulonephritis.Selection criteria for studiesRandomized controlled trials that compared standard care with standard care plus adjuvant plasma exchange in adult patients with either renal vasculitis or idiopathic rapidly progressive glomerulonephritis.InterventionAdjuvant plasma exchange.OutcomeComposite of end-stage renal disease or death.ResultsWe identified 9 trials including 387 patients. In a fixed-effects model, the pooled RR for end-stage renal disease or death was 0.80 for patients treated with adjunctive plasma exchange compared with standard care alone (95% CI, 0.65-0.99; P = 0.04). No significant heterogeneity was detected (P = 0.5; I(2) = 0%). The effect of plasma exchange did not differ significantly across the range of baseline serum creatinine values (P = 0.7) or number of plasma exchange treatments (P = 0.8). The RR for end-stage renal disease was 0.64 (95% CI, 0.47-0.88; P = 0.006), whereas the RR for death alone was 1.01 (95% CI, 0.71-1.4; P = 0.9).LimitationsAlthough the primary result was statistically significant, there is insufficient statistical information to reliably determine whether plasma exchange decreases the composite of end-stage renal disease or death.ConclusionsPlasma exchange may decrease the composite end point of end-stage renal disease or death in patients with renal vasculitis. Additional trials are required given the limited data available.
| S-EPMC3062650 | biostudies-literature
Project description:We experienced a case of a 36-year-old female with rapidly progressive glomerulonephritis (RPGN) due to anti-neutrophil cytoplasmic antibody (ANCA)-associated nephritis and systemic lupus erythematosus (SLE) nephritis. Chiral amino acid metabolomics revealed a prominent profile of D-serine in this patient. At the fulminant period of RPGN, the level of plasma D-serine, a potential biomarker in CKD that reflects actual glomerular filtration ratio (GFR), was extremely high. On the other hand, urinary fractional excretion (FE) of D-serine, which was usually much higher than that of L-isoform, was 0% in this patient. These abnormal D-serine profiles normalized in response to the intensive treatment. Normalizations of blood D-serine levels were in parallel with those of blood creatinine levels and potentially reflect the recovery of GFR. FE of D-serine increased transiently before the normalization of D-serine profile, suggesting that kidney promotes urinary excretion of D-serine for the normalization of plasma D-serine level. These unexplored clinical features of D-serine well reflected the clinical course of this patient. Blood D-serine level can also serve as a biomarker in acute kidney injury (AKI) or RPGN, and, in combination with FE of D-serine, may render the clinical practitioners to judge the efficacy of intensive treatments.
| S-EPMC6820815 | biostudies-literature
Project description:Rapidly progressive glomerulonephritis (RPGN) is a life-threatening clinical syndrome and a morphological manifestation of severe glomerular injury that is marked by a proliferative histological pattern ('crescents') with accumulation of T cells and macrophages and proliferation of intrinsic glomerular cells. We show de novo induction of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in intrinsic glomerular epithelial cells (podocytes) from both mice and humans with RPGN. HB-EGF induction increases phosphorylation of the epidermal growth factor receptor (EGFR, also known as ErbB1) in mice with RPGN. In HB-EGF-deficient mice, EGFR activation in glomeruli is absent and the course of RPGN is improved. Autocrine HB-EGF induces a phenotypic switch in podocytes in vitro. Conditional deletion of the Egfr gene from podocytes of mice alleviates the severity of RPGN. Likewise, pharmacological blockade of EGFR also improves the course of RPGN, even when started 4 d after the induction of experimental RPGN. This suggests that targeting the HB-EGF-EGFR pathway could also be beneficial in treatment of human RPGN.
| S-EPMC3198052 | biostudies-literature
Project description:Background/aimSteroidal mineralocorticoid receptor antagonists (MRAs) are effective in the treatment of kidney disease; however, the side effect of hyperkalaemia, particularly in the context of renal impairment, is a major limitation to their clinical use. Recently developed non-steroidal MRAs have distinct characteristics suggesting that they may be superior to steroidal MRAs. Therefore, we explored the benefits of a non-steroidal MRA in a model of rapidly progressive glomerulonephritis.MethodsAccelerated anti-glomerular basement membrane (GBM) glomerulonephritis was induced in groups of C57BL/6J mice which received no treatment, vehicle or a non-steroidal MRA (BR-4628, 5mg/kg/bid) from day 0 until being killed on day 15 of disease. Mice were examined for renal injury.ResultsMice with anti-GBM glomerulonephritis which received no treatment or vehicle developed similar disease with severe albuminuria, impaired renal function, glomerular tuft damage and crescents in 40% of glomeruli. In comparison, mice which received BR-4628 displayed similar albuminuria, but had improved renal function, reduced severity of glomerular tuft lesions and a 50% reduction in crescents. The protection seen in BR-4628 treated mice was associated with a marked reduction in glomerular macrophages and T-cells and reduced kidney gene expression of proinflammatory (CCL2, TNF-?, IFN-?) and profibrotic molecules (collagen I, fibronectin). In addition, treatment with BR-4626 did not cause hyperkalaemia or increase urine Na+/K+ excretion (a marker of tubular dysfunction).ConclusionsThe non-steroidal MRA (BR-4628) provided substantial suppression of mouse crescentic glomerulonephritis without causing tubular dysfunction. This finding warrants further investigation of non-steroidal MRAs as a therapy for inflammatory kidney diseases.
| S-EPMC4689384 | biostudies-literature
Project description:Langerhans cell histiocytosis (LCH), the most common histiocytic disorder, is characterized by the accumulation of CD1A(+) /CD207(+) mononuclear phagocytes within granulomatous lesions that can affect nearly all organ systems. Historically, LCH has been presumed to arise from transformed or pathologically activated epidermal dendritic cells called Langerhans cells. However, new evidence supports a model in which LCH occurs as a consequence of a misguided differentiation programme of myeloid dendritic cell precursors. Genetic, molecular and functional data implicate activation of the ERK signalling pathway at critical stages in myeloid differentiation as an essential and universal driver of LCH pathology. Based on these findings, we propose that LCH should be re-defined as an inflammatory myeloid neoplasia. Increased understanding of LCH pathogenesis will provide opportunities to optimize and personalize therapy through improved risk-stratification, targeted therapy and assessment of therapy response based on specific molecular features and origin of the pathological myeloid cells.
| S-EPMC5193221 | biostudies-literature
Project description:BACKGROUND:Rapidly progressive glomerulonephritis (RPGN) is a syndrome characterized by a rapid decline in renal function that often causes end-stage renal disease. Although it is important to predict renal outcome in RPGN before initiating immunosuppressive therapies, no simple prognostic indicator has been reported. The aim of this study was to investigate the associations of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) to renal outcomes in patients with RPGN. METHODS:Forty-four patients with a clinical diagnosis of RPGN who underwent renal biopsy were enrolled. The relationships between NLR and PLR and renal outcome after 1 year were investigated. RESULTS:NLR and PLR were significantly higher in patients with preserved renal function in comparison to patients who required maintenance hemodialysis (p < 0.05 and p < 0.01, respectively). An NLR of 4.0 and a PLR of 137.7 were the cutoff values for renal outcome (area under the curve, 0.782 and 0.819; sensitivity, 78.4% and 89.2%; specificity, 71.4% and 71.4%, respectively). Furthermore, an NLR of 5.0 could predict recovery from renal injury in patients requiring hemodialysis (area under the curve, 0.929; sensitivity, 83.3%; specificity, 85.7%). CONCLUSION:NLR and PLR could be candidates for predicting renal outcomes in patients with RPGN.
| S-EPMC7230792 | biostudies-literature
Project description:BACKGROUND:Dermatomyositis (DM) with rapidly progressive interstitial lung disease (DM RP-ILD) is a life-threatening condition. Serum cytokine levels are potentially suitable biomarkers for DM RP-ILD. However, the relationships among cytokine levels, lung imaging findings, and lung pathology have not been investigated. The aim of the present retrospective study was to determine the association between hypercytokinemia and lung inflammation in patients with DM RP-ILD. METHODS:The study subjects were nine patients with life-threatening DM RP-ILD and severe hypoxemia (partial arterial oxygen pressure (PaO2)/fraction of inspired oxygen (FiO2) ratio???200) before receiving intensive care management, who were admitted to our hospital between 2006 and 2015. The controls included 10 patients with DM without RP-ILD and 19 healthy subjects. We assessed the association between serum cytokine levels and computed tomography (CT) scores of the lung (ground glass opacity-score, G-score; fibrosis-score, F-score). Lung, hilar lymph nodes, and spleen from two autopsies were examined by hematoxylin-eosin (H&E) staining and immunostaining. RESULTS:Serum interferon (IFN)-?, interleukin (IL)-1? and IL-12 levels were significantly higher in patients with DM RP-ILD than in the other two groups, whereas serum IL-6 levels were elevated in the two patient groups but not in the healthy subjects. Serum levels of IL-2, IL-4, IL-8, IL-10, IFN-?, and TNF (tumor necrosis factor)-? were not characteristically elevated in the DM RP-ILD group. Serum IFN-? levels correlated with G-scores in patients with DM RP-ILD, while IL-1? was negatively correlation with F-scores. Immunohistochemical staining showed infiltration of numerous IFN-?-positive histiocytes in the lung and hilar lymph nodes; but not in the spleen. Serum IL-6 levels did not correlate with the CT scores. Numerous IL-6-positive plasma cells were found in hilar lymph nodes, but not in the lungs or spleen. CONCLUSIONS:Our results suggest strong IFN-?-related immune reaction in the lungs and hilar lymph nodes of patients with life-threatening DM RP-ILD, and potential IFN-? involvement in the pathogenesis of DM, specifically in the pulmonary lesions of RP-ILD.
| S-EPMC6235206 | biostudies-other
Project description:Rapidly progressive dementias are conditions that typically cause dementia over weeks or months. They are a particular challenge to neurologists as the differential diagnosis often is different from the more typical, slowly progressive dementias. Early and accurate diagnosis is essential, as many of the etiologies are treatable. The information in this review is in part based on experience through our rapidly progressive dementia program at the University of California San Francisco, Memory and Aging Center. As treatment of a rapidly progressive dementia is entirely dependent on the diagnosis, we present a comprehensive, structured, but pragmatic approach to diagnosis, including key clinical, laboratory, and radiologic features. For the 2 most common causes of rapid dementia, treatment algorithms for the autoimmune encephalopathies and symptomatic management for the neurodegenerative causes are discussed.
| S-EPMC3613204 | biostudies-literature
Project description:Melanoma, like most cancers, is a disease that wreaks havoc mostly through its propensity to spread and establish secondary tumors at sites that are anatomically distant from the primary tumor. The consideration of models of cancer progression is therefore important to understand the essence of this disease. Previous work has suggested that melanoma may propagate according to a cancer stem cell (CSC) model in which rare tumorigenic and bulk non-tumorigenic cells are organized into stable hierarchies within tumors. However, recent studies using assays that are more permissive for revealing tumorigenic potential indicate that it will not be possible to cure patients by focusing research and therapy on rare populations of cells within melanoma tumors. Studies of the nature of tumorigenic melanoma cells reveal that these cells may gain a growth, metastasis and/or therapy resistance advantage by acquiring new genetic mutations and by reversible epigenetic mechanisms. In this light, efforts to link the phenotypes, genotypes and epigenotypes of melanoma cells with differences in their in vivo malignant potential provide the greatest hope of advancing the exciting progress finally being made against this disease.
| S-EPMC3033805 | biostudies-other