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S J Chadban

Publications and source records attributed to S J Chadban.

11 recordsLinked to original sources
PubMed2005

Chronic kidney disease in the general population.

End-stage kidney disease (ESKD), defined as the need for dialysis, receipt of a transplant, or death from chronic kidney failure, generally affects fewer than 1% of the population. However ESKD is the end result of chronic kidney disease (CKD), a widely prevalent but often silent condition with elevated risks of cardiovascular morbidity and mortality and a range of metabolic complications. A recently devised classification of CKD has facilitated prevalence estimates that reveal an "iceberg" of CKD in the community, of which dialysis and transplant patients are the tip. Hypertension, smoking, hypercholesterolemia, and obesity, currently among the World Health Organization's (WHO's) top 10 global health risks, are strongly associated with CKD. The factors, together with increasing diabetes prevalence and an aging population, will result in significant global increases in CKD and ESKD patients. Treatments now available effectively reduce the rate of progression of CKD and the extent of comorbid conditions and complications. The challenges are (1) to intervene effectively to reduce the excess burden of cardiovascular morbidity and mortality associated with CKD, (2) to identify those at greatest risk for ESKD and intervene effectively to prevent progression of early CKD, and (3) to ultimately introduce cost-effective primary prevention to reduce the overall burden of CKD. The vast majority of the global CKD burden will be in developing countries, and policy responses must be both practical and sustainable in these settings.

Disease Progression↗
PubMed2004

Treatment for lupus nephritis.

BACKGROUND: Lupus nephritis is the renal manifestation of systemic lupus erythematosus (SLE) - a disease mainly affecting young women with substantial morbidity and mortality. It is classified by the World Health Organization (WHO) criteria I - VI based on histology. WHO Class IV is a diffuse proliferative glomerulonephritis which has the worst prognosis without treatment, with a reported 17% five year survival in the era 1953-1969. This survival was 82% in the early 1990's and continues to improve. An important factor behind this has been the use of cytotoxics such as cyclophosphamide in addition to steroids. OBJECTIVES: To assess the benefits and harms of different treatments in biopsy-proven proliferative lupus nephritis (LN). SEARCH STRATEGY: We searched the Cochrane Renal Group's specialised register (January 2003), the Cochrane Central Register of Randomised Controlled Trials (CENTRAL - The Cochrane Library issue 1, 2003), MEDLINE (1966 - 31 January 2003), EMBASE (1980 - 31 January 2003) and handsearched reference lists of retrieved articles. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs comparing treatments for PLN in both adult and paediatric patients with Class III, IV, Vc, Vd lupus nephritis were included. All treatments were considered. DATA COLLECTION AND ANALYSIS: Data was extracted and quality assessed independently by two reviewers, with differences resolved by discussion. Dichotomous outcomes are reported as relative risk (RR) and measurements on continuous scales are reported as weighted mean differences (WMD) with 95% confidence intervals. Subgroup analysis by study quality, drug type and drug route have been performed where possible to explore reasons for heterogeneity. MAIN RESULTS: Of 920 articles identified, 25 were RCTs suitable for inclusion, which enrolled 915 patients. The majority compared cyclophosphamide or azathioprine plus steroids versus steroids alone. Cyclophosphamide plus steroids reduced the risk of doubling of serum creatinine (RR 0.59, 95% CI 0.40 to 0.88) compared to steroids alone but had no impact on mortality (RR 0.98, 95% CI 0.53 to 1.82). The risk of ovarian failure was significantly increased (RR 2.18, 95% CI 1.10 to 4.34). Azathioprine plus steroids reduced the risk of all cause mortality compared to steroids alone (RR 0.60, 95% CI 0.36 to 0.99), but did not alter renal outcomes. Neither therapy was associated with increased risk of major infection. No benefit was found with addition of plasma exchange to cyclophosphamide or azathioprine plus steroids for mortality ( RR 0.71, 95% CI 0.50 to 1.02), doubling of serum creatinine (RR 0.17, 95% CI 0.02 to 1.26) or end-stage renal failure (RR 1.24, 95% CI 0.60 to 2.57). There was also no increased risk of major infection (RR 0.69, 95% CI 0.35 to 1.37). REVIEWER'S CONCLUSIONS: Until future RCTs of newer agents are completed, the current use of cyclophosphamide combined with steroids remains the best option to preserve renal function in proliferative LN. The smallest effective dose and shortest duration of treatment should be used to minimise gonadal toxicity, without compromising efficacy.

Azathioprine↗
PubMed2002

IL-10 induces mesangial cell proliferation via a PDGF-dependent mechanism.

Interleukin-10 (IL-10) is a mesangial cell growth factor in vivo and in vitro. However, the mechanism by which IL-10 exerts its mitogenic activity is not known. The aim of this study was to determine whether IL-10 induces mesangial cell proliferation in a PDGF-dependent or independent fashion. A well--characterized rat mesangial cell line (1097) was used in a series of cell proliferation experiments in which cells were serum-starved and then incubated with recombinant IL-10 in the presence or absence of STI 571 (a specific inhibitor of signalling via the PDGF-alpha and beta receptors) or a neutralizing anti-PDGF-AB antibody. IL-10 induced significant mesangial cell proliferation at 24 and 48 h after cytokine addition. This response was inhibited totally by the addition of STI-571, demonstrating that IL-10 mitogenic activity has an absolute requirement for signalling through the PDGF receptor. In further studies, it was found that STI-571 could be added 24 h after IL-10 stimulation and still exert a profound inhibition of IL-10 mitogenic activity. The ability of a neutralizing anti-PDGF-AB antibody to inhibit completely IL-10-induced mesangial cell proliferation confirmed that IL-10 acts via induction of an autocrine PDGF response rather than the possibility that IL-10 may transactivate the PDGF receptor in a PDGF-independent fashion. In conclusion, this study has demonstrated that IL-10 induces mesangial cell proliferation via an autocrine PDGF-mediated mechanism. Thus, therapies which antagonize PDGF signalling will also inhibit any contribution of IL-10 to mesangial proliferation.

Animals↗
PubMed2001

Urine macrophage migration inhibitory factor concentrations as a diagnostic tool in human renal allograft rejection.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that is a potent activator of macrophages and T cells. Previous studies have shown that local MIF production is increased in acute renal allograft rejection, suggesting that it may play an important role in the rejection process. AIMS: To determine if urine and serum MIF concentrations: (1) are increased in acute rejection, and (2) can be used as noninvasive tools to discriminate between acute rejection (AR) and cyclosporine nephrotoxicity (CyA toxicity). METHODS: In a prospective study of nine renal allograft patients (five acute rejection and four stable), serial urine MIF concentrations were measured by ELISA in the first 14 days after transplantation. In a retrospective study, MIF concentrations in urine and serum were measured in 24 patients who were biopsied for acute renal transplant dysfunction (11 AR, 13 CyA toxicity). Urine and serum MIF were also measured in 23 stable renal transplant patients and 10 normals. RESULTS: MIF was readily detected in the urine of normal healthy controls (106+/-61 pg/micromol creatinine). In the prospective study, the urinary MIF concentration was increased substantially on day 1 posttransplantation and subsequently fell in parallel with the serum creatinine. However, urine MIF increased before episodes of biopsy proven acute rejection. The retrospective study showed that urine MIF concentrations in patients with AR were increased 5-fold compared to normal controls (439+/-313 pg/micromol Cr; P<0.01). In contrast, urine MIF concentrations in CyA toxicity were not significantly different to normal controls (145+/-119 pg/micromol Cr; P=NS). A marked increase in MIF immunostaining was seen in biopsies of AR, but not in CyA toxicity. No significant differences were evident in serum MIF levels between normals and any transplant patient group. CONCLUSIONS: These results suggest that measurement of urine MIF concentration may be useful in monitoring renal transplant patients for acute rejection and as a discriminator from cyclosporine nephrotoxicity.

Adult↗
PubMed2000

Autoimmune-prone mice share a promoter haplotype associated with reduced expression and function of the Fc receptor FcgammaRII.

Human autoimmune diseases thought to arise from the combined effects of multiple susceptibility genes include systemic lupus erythematosus (SLE) and autoimmune diabetes. Well-characterised polygenic mouse models closely resembling each of these diseases exist, and genetic evidence links receptors for the Fc portion of immunoglobulin G (FcR) with their pathogenesis in mice and humans [1] [2] [3]. FcRs may be activatory or inhibitory and regulate a variety of immune and inflammatory processes [4] [5]. FcgammaRII (CD32) negatively regulates activation of cells including B cells and macrophages [6]. FcgammaRII-deficient mice are prone to immune-mediated disease [7] [8] [9]. The gene encoding FcgammaRII, Fcgr2, is contained in genetic susceptibility intervals in mouse models of SLE such as the New Zealand Black (NZB) contribution to the (NZB x New Zealand White (NZW)) F1 strain [1] [10] [11] and the BXSB strain [12], and in human SLE [1] [2] [3]. We therefore sequenced Fcgr2 and identified a haplotype defined by deletions in the Fcgr2 promoter region that is present in major SLE-prone mouse strains (NZB, BXSB, SB/Le, MRL, 129 [13]) and non-obese diabetic (NOD) mice but absent in control strains (BALB/c, C57BL/6, DBA/2, C57BL/10) and NZW mice. The autoimmune haplotype was associated with reduced cell-surface expression of FcgammaRII on macrophages and activated B cells and with hyperactive macrophages resembling those of FcgammaRII-deficient mice, and is therefore likely to play an important role in the pathogenesis of SLE and possibly diabetes.

Animals↗
PubMed1998

Interleukin-10 differentially modulates MHC class II expression by mesangial cells and macrophages in vitro and in vivo.

Inhibition of major histocompatibility complex (MHC) class II expression by macrophages is the primary mechanism by which interleukin-10 (IL-10) exerts immune suppression. Little, however, is known of the effects of IL-10 on other types of cells which can be induced to express MHC class II during an inflammatory response. We therefore studied the effects of IL-10 treatment on the expression of MHC class II molecules in a rat model of immunologically induced glomerulonephritis. MHC class II mRNA levels in whole kidney were increased in saline-treated (control) animals with glomerulonephritis (2.6-fold increase versus normal, P = 0.028) and this was partially inhibited by treatment with IL-10 (P = NS). Double immunostaining of tissue sections was used to compare MHC class II expression by infiltrating macrophages and resident glomerular cells. IL-10 treatment reduced the proportion of glomerular macrophages which expressed detectable MHC class II (70% reduction, P = 0.03). In contrast, IL-10 treatment was associated with an increase in the number of resident glomerular cells expressing MHC class II, particularly within mesangial areas. Therefore, the effects of IL-10 on macrophages and mesangial cells were compared in vitro. IL-10 reduced constitutive MHC class II mRNA and cell surface expression by peritoneal macrophages. In contrast, IFN-gamma-stimulated mesangial cells (1097 cell line) cultured with IL-10 for 24 hr showed increased MHC class II mRNA (26% increase) and surface expression (72% increase in percentage MHC II+ by flow cytometry, P = 0.04) as compared with cells stimulated with IFN-gamma alone. IL-10 also directly up-regulated expression of ICAM-1 by 1997 cells. In conclusion, IL-10 was found to have contrasting effects on the production and cell surface expression of MHC class II molecules by mesengial cells and by macrophages, both in vitro and in vivo. The implications of these findings for IL-10-mediated immunosuppression are discussed.

Animals↗
PubMed1997

Effect of interleukin-10 treatment on crescentic glomerulonephritis in rats.

This study examined the utility of interleukin-10 (IL-10), a cytokine with potent anti-macrophage and anti-Th1 activity, in the treatment of experimental anti-glomerular basement membrane (GBM) nephritis in the rat. Accelerated anti-GBM disease was induced in Sprague-Dawley rats by immunization with rabbit IgG, followed five days later by an i.v. injection of anti-GBM serum. Groups of four rats received daily s.c. injections of recombinant mouse IL-10 (500, 10 or 0.2 microgram/kg/day) or saline (control) from the time of anti-GBM serum administration until being killed on day 14. IL-10 treatment suppressed the skin DTH response as measured by skin thickness (44 to 62% decrease vs. control, p < 0.05). Compared to saline controls, IL-10 treatment had no beneficial effect on renal function, proteinuria or histological damage (including crescent formation) at any dose examined. A detailed analysis of high dose IL-10 (500 micrograms/kg/day) and saline treated animals was undertaken. Saline controls had marked glomerular macrophage accumulation and proliferation, which was augmented by IL-10 treatment (46 to 99% increases and 44 to 143% increases, respectively; p < 0.05). Immunohistochemical staining found no difference in the state of macrophage activation between the groups, as determined by the percentage of macrophages expressing IL-1 beta protein. Northern blot analysis of whole kidney RNA demonstrated an 830% increase in IL-1 beta mRNA expression in saline controls compared to normal rat kidney. High dose IL-10 treatment reduced IL-1 beta mRNA levels by 60% compared to controls (P < 0.05), but did not significantly reduce glomerular IL-1 beta protein expression. IL-10 treatment increased serum levels of rat anti-rabbit IgG, induced a rat anti-mouse IL-10 response and augmented glomerular deposition of rat C3. In conclusion, IL-10 was not an effective treatment for rat crescentic anti-GBM glomerulonephritis. This may have been due to the failure of IL-10 to achieve a sufficient reduction in IL-1 beta expression and macrophage participation in disease, or promotion of the Th2 immune response.

Animals↗
PubMed1997

Intrinsic renal cells are the major source of interleukin-1 beta synthesis in normal and diseased rat kidney.

BACKGROUND: A number of studies have demonstrated a pathological role for interleukin-1 (IL-1) in experimental models of glomerulonephritis, but the cellular pattern of renal IL-1 production remains poorly characterized. The aim of this study, therefore, was to identify the cell types expressing IL-1 in normal and diseased rat kidney. METHODS: Renal IL-1 beta expression was examined in normal rats and during a 21-day time course of rat accelerated anti-GBM glomerulonephritis by northern blotting, in situ hybridization and double immunohistochemistry. RESULTS: Interleukin-1 beta mRNA expression was readily detectable in normal rat kidney by northern blot analysis and in situ hybridization. Immunohistochemistry staining demonstrated constitutive IL-1 beta expression by glomerular endothelial cells and cortical tubular epithelial cells. There was a marked increase in whole kidney IL-1 beta mRNA in rat anti-GBM glomerulonephritis. Glomerular IL-1 beta immunostaining was upregulated, being expressed by podocytes, mesangial cells and infiltrating macrophages, and was particularly prominent within glomerular crescents. Double staining with the ED1 antibody showed IL-1 beta expression in up to 13% of glomerular macrophages, whereas 48% of macrophages within crescents stained for IL-1 beta. However, the most marked increase in IL-1 beta expression was seen in cortical tubular epithelial cells, particularly in areas of tubular damage. In situ hybridization confirmed that tubular IL-1 beta staining was due to local cytokine synthesis rather than protein absorption. CONCLUSIONS: This study has identified constitutive IL-1 beta expression by glomerular endothelium and tubular epithelial cells in normal rat kidney. In addition, the marked upregulation of IL-1 beta expression by intrinsic glomerular cells and tubules in rat anti-GBM disease suggests an important role for these cells in IL-1 dependent crescent formation and tubulointerstitial injury.

Animals↗
PubMed1997

Interleukin-10 is a mesangial cell growth factor in vitro and in vivo.

Macrophages are involved in the pathogenesis of mesangioproliferative glomerulonephritis. As macrophages are known to produce interleukin-10 (IL-10), we investigated the effect of recombinant murine IL-10 (rIL-10) on mesangial cell growth. In vitro studies were performed using the rat 1097 mesangial cell line. These cells exhibited a dose-dependent proliferative response to rIL-10 (23% to 70% increases at 80 ng/mL; p < 0.01), as assessed by both 3H-thymidine uptake and cell count. This effect was inhibited by preincubation of rIL-10 with a neutralizing anti-IL-10 antibody. When added to cultures of growth-arrested 1097 cells, IL-10 induced dose-dependent proliferation that paralleled the effects of platelet-derived growth factor. Incubation with a neutralizing anti-IL-10 Ab for 48 hours reduced 3H-thymidine uptake (median, 27% decreases; range, 2% to 56% decreases) versus a control Ab; p < 0.05). Rat mesangial cells were also shown to express IL-10 mRNA and protein, as determined by Northern blotting and immunostaining, thereby suggesting a role for IL-10 in autocrine mesangial cell growth. To examine the effects of IL-10 in vivo, inbred male Sprague-Dawley rats were given subcutaneous rIL-10 (0.5 mg/kg) for 3 (n = 6), 7 (n = 3), or 14 days (n = 4), or vehicle control, then killed. IL-10 administration induced a transient reduction in creatinine clearance of 35% at Day 3 (p < 0.01). Following IL-10 administration, an increase in glomerular cellularity was seen, which was maximal at Day 3 (82.7 +/- 5.9 nuclei/glomerular cross section versus control 64.6 +/- 4.6, 28% increases; p < 0.001) and maintained at Day 14 (23% increases; p < 0.01). Immuno-histochemical staining for proliferating cell nuclear antigen demonstrated an increased number of proliferating cells per glomerular cross section at day 3 (48% increases versus controls; p < 0.05). Staining for alpha-smooth-muscle actin showed significant labeling only in the glomeruli of IL-10-treated animals; double-labeling with an anti-proliferating cell nuclear antigen Ab demonstrated that some of these mesangial cells were proliferating. Collectively, these results suggest that IL-10 is a growth factor for rat mesangial cells both in vitro and in vivo.

Actins↗
PubMedDate not supplied

Glomerulonephritis.

The term glomerulonephritis encompasses a range of immune-mediated disorders that cause inflammation within the glomerulus and other compartments of the kidney. Studies with animal models have shown the crucial interaction between bone-marrow-derived inflammatory cells and cells intrinsic to the kidney that is both fundamental and unique to the pathogenesis of glomerulonephritis. The mechanisms of interaction between these cells and the mediators of their coordinated response to inflammation are being elucidated. Despite these pathophysiological advances, treatments for glomerulonephritis remain non-specific, hazardous, and only partly successful. Glomerulonephritis therefore remains a common cause of end-stage kidney failure worldwide. Molecule-specific approaches offer hope for more effective and safer treatments in the future.

Glomerulonephritis↗