In 2021 new KDIGO (Kidney Disease: Improving Global Outcomes) guidelines for the management of glomerular diseases were published.For ANCA-associated glomerulonephritis the new recommendations ...comprise a more rapid steroid taper during induction treatment with cyclophosphamide or rituximab, the advice against routine use of plasma exchange, the choice of drug for and duration of maintenance treatment in accordance with predictors of relapse. A kidney transplant should be performed after at least 6 months of remission irrespective of the ANCA titer in ANCA-associated disease, and 6 months after absence of anti-GBM-antibodies in anti-GBM-disease.
Objective
Antineutrophil cytoplasmic antibodies (ANCA) are believed to play a pathogenetic role in necrotizing small‐vessel vasculitis. While the involvement of neutrophils in this disease has been ...extensively studied in vitro, we undertook to analyze thoroughly the contribution of monocytes to tissue destruction in systemic vasculitis.
Methods
Monocytes obtained from normal human individuals were stimulated by ANCA isolated from patients with active vasculitis. The formation of oxygen radicals was measured by a fluorometric assay using 2′,7′‐dichlorofluorescin diacetate.
Results
ANCA induced monocytes to produce oxygen radicals, resulting in a mean 43% increase (range 21–84%) in oxygen radical formation compared with normal IgG. The formation of reactive oxygen species was time and concentration dependent and was also induced by ANCA F(ab′)2 fragments. Normal nonspecific IgG or their corresponding F(ab′)2 fragments induced no release or very little release of oxygen radicals. Preincubation of monocytes with the Fcγ receptor type II–blocking monoclonal antibody IV.3 before addition of ANCA greatly reduced formation of oxygen radicals. Using ligand affinity chromatography with proteinase 3 (PR3) and myeloperoxidase (MPO), ANCA were further purified by depletion of patient IgG. The stimulation of monocytes with these pure PR3‐ and MPO‐ANCA confirmed that cellular activation was specifically induced by ANCA.
Conclusion
These results show that ANCA induce the formation of reactive oxygen species in human monocytes. These findings support the notion that ANCA specifically activate monocytes by several mechanisms to participate in the inflammatory process of ANCA‐associated vasculitis.
The Wilms' tumor suppressor gene WT1 encodes a zinc-finger DNA-binding protein that functions as a transcriptional repressor.
WT1 is expressed in a dramatic spatial and temporal pattern during kidney ...development and is thought to be critical during
mesenchymal-epithelial conversion. The WT1 protein bound multiple sites in the WT1 promoter and functioned as a powerful transcriptional
repressor of its gene in vivo (> 50-fold). The WT1 protein carrying an NH2-terminal 17-amino acid insertion and a 3-amino
acid insertion (KTS) between zinc fingers 3 and 4, arising from the most abundant of four alternatively spliced transcripts,
was the most powerful repressor. Of importance, a subset of WT1-binding sites differs from the Egr-1 consensus sequence, which
has been shown to bind one splice variant of the WT1 protein (WT1(-KTS)). We characterized two of these sites and show that
they bind both -KTS and +KTS forms of the WT1 zinc-finger protein and can confer repression on a heterologous promoter construct.
Our data demonstrate that WT1, in addition to its known effects on insulin-like growth factor II, platelet-derived growth
factor A, and Pax-2 transcription, is a powerful repressor of its own gene. These observations emphasize its critical role
as a transcriptional regulatory protein during normal kidney development.
Specific interactions between cells and components of the surrounding extracellular matrix (ECM) or underlying basement membrane have been shown to modulate cell behaviour, in culluro and in vivo. ...There is evidence that extensive 'cross-talk' occurs between glomerular mesangial cells (MCs), ECM molecules, and soluble mediator substances affecting the proliferative and synthetic-secretory phenotype of MCs. This is likely to be relevant for the behaviour of MCs during embryonic development, disease processes of glomeruli, and tissue repair. The potential biologic and clinical relevance of cell-matrix interactions in the glomerulus are discussed in this brief review of selected aspects of recent investigations concerning the mesangial matrix and its interactions with MCs.
Background. IgA nephropathy (IgAN) is the most common chronic glomerular disease in adults. End-stage renal disease (ESRD) develops in about 30% of the patients. Early intervention and consequent ...therapy may prevent or at least delay the development of ESRD in these patients. Up to now, the diagnosis could only be achieved with a renal biopsy. Methods. The urine of 45 patients with IgAN was collected and screened for protein-polypeptide patterns with a novel high throughput method, capillary electrophoreses on-line coupled to a mass spectrometer (CE-MS). CE-MS allows the fast and accurate evaluation of up to 2000 polypeptides in one urine sample. The results in IgAN were compared to findings in 13 patients with membranous nephropathy (MN) and 57 healthy individuals. Results. In the patients with IgAN, even when urinary protein excretion was within the normal range of regular tests, the polypeptide pattern in urine differed significantly from that of healthy controls and patients with MN, indicating a specific 'IgAN' pattern of polypeptide excretion. Classification regarding discrimination of IgAN from healthy controls and from MN had a sensitivity of 100% and 77%, respectively. Specificity was 90% and 100%, respectively. Compared to patterns established earlier in patients with minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), or diabetic nephropathy (DN), sensitivity and specificity were 100%. Treatment of the patients was associated with changes of the pattern, possibly indicating a therapeutic effect. Conclusion. Proteomic analysis with CE-MS coupling permits fast and accurate identification and differentiation of polypeptide patterns in the urine of patients with IgAN, allowing differentiation from healthy controls and, probably, other renal diseases.
Cell-matrix interactions in the glomerular mesangium. Specific interactions between cells and components of the surrounding extracellular matrix (ECM) or underlying basement membrane have been shown ...to modulate cell behavior, including cellular responses to soluble regulator molecules. In addition to the long-recognized role of such interactions in cell localization, anchoring and differentiation during embryogenesis, they are also involved in diverse processes such as maintenance of tissue integrity, response of cells to mechanical stress, inflammatory response, wound healing, tumor cell growth and metastasis as well as apoptosis. Over the last several years, evidence has been reported that extensive “cross-talk” between glomerular mesangial cells (MCs), ECM molecules and soluble mediator substances also affects the proliferative and synthetic phenotype of MCs. This is likely to be relevant for the behavior of MCs during embryonic development, tissue repair and disease processes of glomeruli. The potential biologic and clinical relevance of cell-matrix interactions in the glomerulus makes their elucidation a challenging goal in current kidney research. In this brief review, we present selected aspects of recent investigations concerning the mesangial matrix and its interactions with MCs. In addition to results from cell culture studies, descriptive findings on abnormalities of the ECM and their potential role for the altered MC behavior in glomerular disease will also be discussed.
A 26-year-old man had sudden fever and chills with severe muscle pain and weakness in his legs and pectoral muscles while mountaineering in the Andes. He was brought to a local hospital, where he ...received hemodialysis three times because of anuria and a rapid rise in the serum creatinine level before being transferred to our unit.
TGF-β1-induced cell cycle arrest in renal mesangial cells involves inhibition of cyclin E-cdk 2 activation and retinoblastoma protein phosphorylation. In glomerular disease, transforming growth ...factor-β1 (TGF-β1) has been demonstrated to exert anti-mitogenic and anti-inflammatory as well as fibrogenic effects. To better understand the TGF-β1 action on glomerular cells at the molecular level, we investigated mechanisms of TGF-β1-induced growth suppression in primary cultures of rat mesangial cells (MCs). TGF-β1 (5 ng/ml) markedly inhibited proliferation of MCs incubated with PDGF, endothelin-1, bFGF, serotonin, or EGF, indicating that TGF-β1 interferes with post-receptor signals of mitogenesis. TGF-β1 did not affect mitogen-stimulated induction of the immediate early genes, c-fos, c-jun, and Egr-1 in MCs that occurred transiently at 30 to 120 minutes. Time-course studies revealed that TGF-β1 inhibited DNA synthesis and MC replication when added up to six to eight hours after MC stimulation with PDGF. FACS analysis demonstrated that MCs had reached middle to late G1 phase of cell cycle progression at this timepoint. PDGF stimulation of MCs induced protein expression of the G1 phase cyclin Dl as well as the cyclin-dependent kinases cdk 4 and cdk 2. This was not significantly altered when MCs were coincubated with both, PDGF and TGF-β1. However, TGF-β1 prevented PDGF-elicited phosphorylation of the retinoblastoma tumor suppressor (pRb), a negative cell cycle regulator. Moreover, TGF-β1 significantly reduced cyclin E-associated histone H1 kinase activity in the presence of PDGF. These results indicate that TGF-β1 inhibits mitogen-stimulated MC growth by causing cell cycle arrest in late G1 phase. While TGF-β1 does not alter the mitogen-induced expression and abundance of G1 phase cyclin D1 and cdks 4 and 2 in MCs, it inhibits cyclin E-cdk 2 activity, thus preventing mitogen-elicited phosphorylation and inactivation of pRb in G1 phase and transition to S phase.
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