Serum D-dimer concentrations in nephrotic syndrome track with albuminuria, not estimated glomerular filtration rate.

BACKGROUND: The nephrotic syndrome is associated with an increased risk of venous and arterial thrombosis. There are little published data on the distribution, interpretation or determinants of serum D-dimer levels in patients with the nephrotic syndrome. We aimed to describe this relationship. METHODS: This was a cross-sectional study of 100 patients with the nephrotic syndrome. Multivariate linear regression was used to evaluate for independent predictors of elevated D-dimer levels. Patients were observed for a period of 2 years after the baseline measurement of D-dimer level to assess for subsequent clinically evident thrombosis. RESULTS: On univariate linear regression, D-dimer elevation was associated with age in years ß (95% CI) 0.02 (0.016, 0.03), log-transformed urinary protein:creatinine ratio in g/g 0.439 (0.32, 0.558) and inversely with serum albumin in g/l -0.05 (-0.073, -0.035) and estimated glomerular filtration rate (eGFR) in ml/min/1.73 m(2) -0.01 (-0.016, -0.003). On multivariate linear regression, age in years ß (95% CI) 0.019 (0.012, 0.026), serum albumin in g/l -0.023 (-0.043, -0.003), and log-transformed urinary protein:creatinine ratio in g/g 0.266 (0.124, 0.408) were independently associated with elevated D-dimer levels. CONCLUSION: D-dimer levels are commonly raised in the nephrotic syndrome in the absence of clinically evident thrombosis, and are independently associated with age, degree of proteinuria and serum albumin, but not with eGFR. Baseline levels of D-dimer did not predict subsequent episodes of clinically evident thrombosis after 2 years of follow-up.

New insights in CD28-independent allograft rejection.

CD28 costimulatory blockade induces tolerance in most murine transplant models but fails to do so in stringent transplant models, such as skin transplantation. The precise immunological mechanisms of CD28-independent rejection remain to be fully defined. Using two novel mouse strains in which both CD28 and either CD4 or CD8 are knocked out (CD4(-/-)CD28(-/-) or CD8(-/-)CD28(-/-) mice), we examined mechanisms of CD28-independent CD4(+) or CD8(+) T-cell-mediated allograft rejection. CD4(-/-)CD28(-/-) and CD8(-/-)CD28(-/) deficient mice rejected fully allogeneic skin allografts at a tempo comparable with that in wild-type mice. Rejection proceeded despite significant reduction in alloreactive T-cell clone sizes suggesting the presence of a subset of T cells harnessing alternate CD28-independent costimulatory pathways. Blockade of CD40-CD154 and CD134-CD134L, but not ICOS-B7h pathways in combination significantly prolonged allograft survival in CD8(-/-)CD28(-/-) recipients and to a lesser extent in CD4(-/-)CD28(-/-) recipients. Prolongation in allograft survival was associated with reduced effector-memory T-cell generation, decreased allospecific Th1 cytokine generation and diminished alloreactive T-cell proliferation in vivo. In aggregate, the data identify these two pathways as critical mediators of CD28-independent rejection by CD4(+) and to a lesser extent CD8(+) T cells, and provide novel mechanistic insights into functions of novel T-cell co-stimulatory pathways in vivo.

Impaired renal allograft, but not patient survival, in patients with antibodies to hepatitis C virus.

BACKGROUND: The impact of hepatitis C virus (HCV) infection in renal transplant patients is controversial and there are no data on the outcome of renal transplantation in this sub-group of Irish patients. AIM: To examine the outcome of renal transplantation in patients with hepatitis C. METHODS: We examined the outcome of first grafts from renal transplant patients with hepatitis C antibody positive and compared them to a control group. During this period, 24 HCV positive patients received 33 grafts. All were treated with standard immunosuppression. RESULTS: Graft survival rate was less in the HCV positive cases (p=0.0087). Graft survival at 1 year was 75% in the HCV positive group versus 85% in the HCV negative group, 40% versus 62% at 5 years and 14% compared with 40% at 10 years. Patient survival was similar in both groups (p=0.78). Patient survival at 1 year was 96% versus 94%, 87% versus 80% at 5 years and 70% in both groups at 10 years. CONCLUSION: In the Irish renal transplant population, the presence of hepatitis C antibodies, before or after transplantation is associated with worse long-term graft, but not patient survival.

Connective tissue growth factor: potential role in glomerulosclerosis and tubulointerstitial fibrosis.

Transforming growth factor beta (TGF-beta) is a pivotal driver of glomerulosclerosis and tubulointerstitial fibrosis in renal diseases. Because TGF-beta also plays important anti-inflammatory and antiproliferative roles in mammalian systems, there has been a recent drive to elucidate downstream mediators of TGF-beta's pro-fibrotic effects with the ultimate goal of developing new anti-fibrotic strategies for treatment of chronic diseases. Connective tissue growth factor (CTGF) belongs to the CCN family of immediate early response genes. Several lines of evidence suggest that CTGF is an important pro-fibrotic molecule in renal disease and that CTGF contributes to TGF-beta bioactivity in this setting. CTGF expression is increased in the glomeruli and tubulointerstium in a variety of renal disease in association with scarring and sclerosis of renal parenchyma. In model systems in vitro, mesangial cell CTGF expression is induced by high extracellular glucose, cyclic mechanical strain and TGF-beta. Recombinant human CTGF augments the production of fibronectin and type IV collagen by mesangial cells and the effects of high glucose on mesangial cell CTGF expression and matrix production are attenuated, in part, by anti-TGF-beta antibody. In aggregate, these observations identify CTGF as an attractive therapeutic target in fibrotic renal diseases.

Leukotrienes and lipoxins: lipoxygenase-derived modulators of leukocyte recruitment and vascular tone in glomerulonephritis.

With the gradual elucidation of the cellular and molecular events that underpin the inflammatory process, the pathogenetic complexities of glomerulonephritis are slowly being unravelled. Lipoxygenase-derived eicosanoids play important counter-regulatory roles within inflamed glomeruli. Leukotrienes, derived from the 5-lipoxygenase pathway, are potent stimuli for leukocyte infiltration, intrarenal vasoconstriction, and mesangial cell contraction in many forms of experimental glomerulonephritis and probably in human disease. The recruitment of 12- and 15-lipoxygenase pathways, particularly during cell-cell interactions, promotes the formation of lipoxins. The latter compounds antagonize many leukotriene effects, attenuate neutrophil recruitment, and are potential 'braking signals' within the inflammatory cascade that promote resolution of inflammation. The generation and metabolism of leukotrienes and lipoxins is regulated independently, and each family of eicosanoids mediates its biological activities through distinct cell surface receptors and signal transduction pathways. Leukotriene biosynthesis inhibitors and leukotriene receptor antagonists are protective in several experimental models of glomerulonephritis. Initial studies with lipoxins and synthetic lipoxin stable analogues suggest that it may be possible to harness this and other putative anti-inflammatory system for therapeutic gain [3,22,92].