Urinary Transforming Growth Factor-beta 1 as a marker of response to immunosuppressive treatment, in patients with crescentic nephritis

BACKGROUND: Crescentic nephritis is characterized by formation of cellular crescents that soon become fibrotic and result in irreversible damage, unless an effective immunosuppressive therapy is rapidly commenced. TGF-β(1 )is involved in the development of crescents through various pathways. The aim of this study was to identify whether the determination of urinary TGF-β(1 )levels in patients with crescentic nephritis could be used as a marker of response to treatment. METHODS: Fifteen patients with crescentic nephritis were included in the study. The renal expression of TGF-β(1 )was estimated in biopsy sections by immunohistochemistry and urinary TGF-β(1 )levels were determined by quantitative sandwich enzyme immunoassay (EIA). TGF-β(1 )levels were determined at the time of renal biopsy, before the initiation of immunosuppressive treatment (corticosteroids, cyclophosphamide and plasma exchange). Twelve patients with other types of proliferative glomerulonephritis and ten healthy subjects were used as controls. RESULTS: Improvement of renal function with immunosuppressive therapy was observed in 6 and stabilization in 4 patients (serum creatinine from 3.2 ± 1.5 to 1.4 ± 0.1 mg/dl and from 4.4 ± 1.2 to 4.1 ± 0.6 mg/dl, respectively). In 5 patients, with severe impairment of renal function who started on dialysis, no improvement was noted. The main histological feature differentiating these 5 patients from others with improved or stabilized renal function was the percentage patients with poor response to treatment were the percentage of glomeruli with crescents and the presence of ruptured Bowman's capsule and glomerular necrosis. Urinary TGF-β(1 )levels were significantly higher in patients who showed no improvement of renal function with immunosuppressive therapy (930 ± 126 ng/24 h vs. 376 ± 84 ng/24 h, p < 0.01). TGF-β(1 )was identified in crescents and tubular epithelial cells, whereas a significant correlation of TGF-β(1 )immunostaining with the presence of fibrocellular cresents was observed (r = 0.531, p < 0,05). CONCLUSION: Increased TGF-β(1 )renal expression and urinary excretion that is related to the response to immunosuppressive therapy was observed in patients with crescentic nephritis. Evaluation of urinary TGF-β(1 )levels may be proved a useful marker of clinical outcome in patients with crescentic nephritis

Cognitive disorders in patients with chronic kidney disease: Approaches to prevention and treatment

Background: Cognitive impairment is common in patients with chronic kidney disease (CKD), and early intervention may prevent the progression of this condition. Methods: Here, we review interventions for the complications of CKD (anemia, secondary hyperparathyroidism, metabolic acidosis, harmful effects of dialysis, the accumulation of uremic toxins) and for prevention of vascular events, interventions that may potentially be protective against cognitive impairment. Furthermore, we discuss nonpharmacological and pharmacological methods to prevent cognitive impairment and/or minimize the latter's impact on CKD patients' daily lives. Results: A particular attention on kidney function assessment is suggested during work-up for cognitive impairment. Different approaches are promising to reduce cognitive burden in patients with CKD but the availabe dedicated data are scarce. Conclusions: There is a need for studies assessing the effect of interventions on the cognitive function of patients with CKD

Staphylococcus Aureus Osteomyelitis as an Inducer of Tolerance to Escherichia Coli Pyelonephritis: an Experimental Study

The high incidence of osteomyelitis in vulnerable populations like those with multiple injuries or elderly undergoing joint arthroplasties generates the question what may be their responses to subsequent infection by high virulent isolates. Rabbits were subject to two operations at three week intervals; sham osteomyelitis and sham pyelonephritis (group S); sham osteomyelitis and Escherichia coli pyelonephritis (group P); and Staphylococcus aureus osteomyelitis and E. coli pyelonephritis (group OP). Survival was recorded; cytokine stimulation of circulating mononuclear cells (PBMCs) and tissue myeloperoxidase (MPO) activity and bacterial growth were monitored. In some experiments, dalbavancin treatment was given before pyelonephritis. Healthy PBMCs were pre-treated with bone homogenate, S. aureus or both. Mortality of groups S, P and OP after induction of pyelonephritis was 0%, 50% and 8.3% respectively. Tumour necrosis factor-alpha (TNFα) production by PBMCs was significantly lower in the OP group at 48 hours. E. coli bacterial load was similar in groups P and OP at death or sacrifice whereas the MPO activity of group OP was decreased. Production of TNFα was further decreased among dalbavancin treated rabbits; in these rabbits tissue MPO was increased. TNFα production decreased when healthy PBMCs pre-treated with bone homogenate, S. aureus (HKSA) or both were stimulated with E. coli (HKEC); production was further decreased in the presence of anti-TLR4 and anti-TLR9. It is concluded that staphylococcal osteomyelitis modulated the innate immune responses of the host leading to protection from death by highly virulent E. coli. Tolerance to TLR ligands is the most likely mechanism of action. © 2020, The Author(s)

T helper (Th)-cytokines in the urine of patients with primary glomerulonephritis treated with immunosuppressive drugs: Can they predict outcome?

Background: Glomerulonephritides (GNs) represent common causes of chronic kidney disease associated with a wide spectrum of clinical and histological features. Various factors that activate the inflammatory cascade are involved in the development of kidney injury. The aim of this study was to estimate the urinary excretion of pro-inflammatory (IL-2, INF-γ, TNF-α, IL-6, IL-17) and anti-inflammatory (IL-4, IL-10, TGF-β1) cytokines, as well as the chemokine MCP-1 in patients with various types of GN treated by immunosuppressive drugs and to identify any prognostic value of excreted cytokines for future renal function. Patients and methods: Ninety-seven patients (62. M/35. F, age 53.1. ±. 15.6. years) with primary glomerulonephritis and 32 healthy controls were studied. The original diagnoses were membranous nephropathy (MN, n = 36), IgA nephropathy (IgAN, n = 31) and minimal changes disease or focal segmental glomerulosclerosis (MCD/FSGS, n = 30). All patients had been treated with immunosuppressive drugs and, at the time of measurement of urinary cytokine excretion, were either in clinical remission or still had active disease with persistent proteinuria. Results: GN patients had significantly higher levels of all cytokines and MCP-1 compared to healthy controls. A strong positive correlation between TGF-β1 and MCP-1 concentrations was observed in all GN patients. Increased urinary excretion of all tested cytokines apart from TNF-α and TGF-β1 was observed even in patients with clinical remission. The main difference between patients with proteinuria and those in clinical remission was the level of MCP-1 urinary excretion. The urinary excretion of MCP-1 and TGF-β1 was significantly higher in patients with MN who showed deterioration of renal function over a follow-up period of five years. Conclusions: Increased levels of cytokines are observed in the urine of patients with different types of glomerulonephritis, even after the achievement of clinical remission with the administration of immunosuppressive drugs. Urinary excretion of MCP-1 and TGF-β1 indicates the ongoing inflammatory and fibrotic processes in the kidney and is probably related to unfavourable outcomes. © 2015 Elsevier Ltd

Myofibroblasts and the progression of crescentic glomerulonephritis

Background. The cellular and humoral factors involved in the pathogenesis of glomerulosclerosis and renal fibrosis following a crescentic glomerulonephritis have not been fully elucidated. Myofibroblasts and transforming growth factor-beta (TGF-beta) have been implicated in the development of experimental and clinical renal fibrosis. We have attempted to identify these mediators in crescentic glomerulonephritis and determine their role in the progression of the disease. Patients and methods, We studied retrospectively 21 patients With crescentic and necrotizing glomerulonephritis (CNG) with emphasis on the renal expression (detected by immunohistochemistry) of myofibroblasts (alpha-smooth muscle actin(+) cells), TGF-beta and collagen (III and TV) as well as their relationship with the clinical outcome of these patients. In situ hybridization histochemistry was applied to determine the site of synthesis of TGF-beta 1 and collagen III. All the patients Were I-reared by immunosuppression and followed up for a median pet-led of 14 months. Results, Myofibroblasts and TGF-beta were detected in the crescents as well as in the periglomerular and tubulointerstitial areas in CNG biopsies. TGF-beta 1 was also detected within renal tubular cells. The percentage of glomeruli with fibrotic and fibrocellular crescents was positively correlated with the severity of Bowman’s capsule disruption (r=0.631, P&lt;0.01) and with the intensity of myofibroblast expression in the interstitium (r=0.504, P&lt;0.05). Strong interstitial immunostain for myofibroblasts and TGF-beta was also noted in association with interstitial fibrosis. In situ hybridization revealed the site of synthesis of TGF-beta 1 to be the renal tubular cells of patients with CNG. By contrast, the site of synthesis of collagen III appeared to be confined to interstitial cells surrounding vessels, tubules and the glomeruli in a distribution identical to that of myofibroblasts. There was a significant positive correlation between the number of interstitial alpha-SMA(+) cells and both interstitial TGF-beta (r=0,591, P&lt;0.01) and interstitial collagen IV (r=0.588, P&lt;0.01). In addition. the number of interstitial alpha-SMA(+) cells and the extent of immunostain for collagen IV were positively correlated with the final serum creatinine (r=0.517, P&lt;0.05 and r=0.612, P&lt;0.01 respectively) and partially predicted functional outcome (R-2=26,7% and 37.5% respectively) as well as the response to treatment. An association was observed between periglomerular myofibroblasts and the generation of fibrotic and fibrocellular crescents. Conclusion. These observations suggest a causal link. between myofibroblasts and fibrotic crescent formation. Mie also believe that interstitial myofibroblasts are actively involved in the pathogenesis of interstitial fibrosis in CNG

Nephrology: achieving sustainability

International audienc