Search

AT1R blockade reduces IFN-γ production in lymphocytes in vivo and in vitro.BackgroundType 1 angiotensin II (Ang II) receptor (AT1R) signaling induces proinflammatory responses. Recent studies suggest that T lymphocytes express AT1R; yet the effects of Ang II binding to AT1R on T cells are poorly understood. We examined the effect of AT1R blockade on release of the proinflammatory cytokine, interferon-gamma (IFN-γ) by human lymphocytes in vivo and in vitro.MethodsWe used an AT1R blocker losartan in a randomized clinical trial in kidney transplant recipients over a 12-month period [AT1R blocker (N = 11) and control (N = 10)]. Peripheral blood lymphocytes, isolated from both cohorts, were analyzed by enzyme-linked immunosorbent spot assays (ELISPOT) analyses and real-time reverse transcription-polymerase chain reaction (RT-PCR) to enumerate IFN-γ producing T cells and IFN-γ mRNA levels. The effects of AT1R blockade in vitro were assessed using human alloreactive T cells and an IFN-γ producing human cytotoxic T-lymphocyte line. Alloreactive T cells were treated with losartan or candesartan and enzyme-linked immunosorbant assay (ELISA) was used to measure IFN-γ protein release. The cytotoxic T-lymphocyte line also was AT1R blocker–treated prior to determining IFN-γ producing cells by intracellular cytokine staining.ResultsThe AT1R blocker cohort had a significant decrease in IFN-γ producing peripheral blood lymphocytes (P≤ 0.05 for each time point) and IFN-γ mRNA levels (P = 0.01 vs. control patients). Losartan also decreased IFN-γ production (P < 0.001) in purified alloreactive T cells in vitro as did candesartan. Moreover, Ang II amplified IFN-γ generation (P < 0.05) in alloreactive T cells while AT1R blocker treatment inhibited Ang II's effect (P < 0.04). AT1R blocker treatment furthermore also inhibited IFN-γ production in the cytotoxic T-lymphocyte line.ConclusionAT1R blockers may have a clinically relevant immunomodulatory role by blocking IFN-γ production in T cells.

Simultaneous pancreas-kidney transplantation reduces excess mortality in type 1 diabetic patients with end-stage renal disease. Background Diabetic renal disease continues to be the most significant cause of end-stage renal disease (ESRD) in the United States. Renal transplantation improves diabetic ESRD patient survival; however, the diabetic state remains associated with poor patient survival. Simultaneous pancreas-kidney (SPK) transplantation can restore normoglycemia and thus may improve outcomes. Methods We assessed the impact of SPK on age-range–matched type 1 diabetic patients who underwent renal transplantation at a single center. The observed/expected life span and annual mortality rates (AMRs) were used as measures of survival. A Cox proportional hazards analysis was used to analyze the impact of potential variables on mortality in SPK recipients. Results SPK transplantation ( N = 335) increased the observed/expected life span compared with diabetic cadaveric (DM-Cad, N = 147) and live-donor (DM-Live, N = 160) transplant recipients ( P = 0.004) and significantly reduced the AMRs (SPK, 1.5%; DM-Cad, 6.27%; DM-Live, 3.65%, P = 0.008, SPK vs. other DM). Moreover, the SPK observed/expected life span and AMR were not significantly different from that of age-range–matched nondiabetic transplant recipients ( N = 492). The only variable that was significantly associated with patient survival was discharge serum creatinine (relative risk 1.16, P ≤ 0.0154). Conclusion These data demonstrate that SPK improves the ability for type 1 diabetic patients to live more of their expected life span. This suggests that glycemic control, even as a late intervention in a diabetic patient's lifetime, may beneficially affect survival.

Effect of glucose, pyruvate, and insulin on type 1 angiotensin II receptor expression in SV40-immortalized rabbit proximal tubule epithelial cells. Ambient glucose concentrations alter type 1 angiotensin II receptor (AT1R) expression in renal tissues. The direction of change in AT1R density may depend on the specific cell type and the capacity for that cell type to use glucose as an energy substrate. Given the effects of angiotensin II (Ang II) in proximal tubule epithelia, glucose-mediated fluctuations in AT1R expression could significantly alter tubular Na+-H+ exchange and volume reabsorption. To determine if glucose influenced AT1R expression in cultured proximal tubule epithelial cells, SV40-immortalized rabbit proximal tubule epithelial cells (RPTEC) were exposed to 25mmol (hi-glc) or 5mmol glucose-containing serum-free medium (lo-glc) for seven to nine days, with or without an alternative energy substrate, pyruvate. AT1R expression, assessed by quantitative reverse-transcription polymerase chain reaction and specific 125I-Ang II binding, decreased in lo-glc medium (% reduction AT1R mRNA expression: 52 ± 8%; N = 6; P < 0.005 vs. hi-glc; % reduction specific 125I-Ang II binding: 48 ± 12%; N = 12; P < 0.03 vs. hi-glc). AT1R mRNA expression and specific 125I-Ang II binding recovered to hi-glc levels following the addition of pyruvate [60 mmol] to lo-glc cells. To ascertain if a growth factor that increases glucose uptake in vivo also altered AT1R expression, RPTEC were cultured in hi-glc medium with or without exogenous insulin [100 nM], Insulin addition increased AT1R mRNA expression and specific 125I-Ang II binding in a concentration-dependent manner. However, insulin (100 nM) addition to lo-glc cells did not significantly increase specific 125I-Ang II binding. These results suggest that AT1R expression in SV40-immortalized rabbit proximal tubule cells is significantly affected by the availability of energy substrate. Ultimately, changes in proximal tubule AT1R expression, mediated by elevated glucose concentrations and insulin, could contribute to sodium-dependent hypertension in the setting of hyperinsulinemia and hyperglycemia.

The paper entitled "Endothelium in the allograft" by Bryan N Becker et al, which was published online on 9 September 2009, has been withdrawn at the authors' request. Kidney International advance online publication, 9 September 2009; doi:10.1038/ki.2009.333.

Type 1 angiotensin II (Ang II) receptor (AT(1)R) signaling induces proinflammatory responses. Recent studies suggest that T lymphocytes express AT(1)R; yet the effects of Ang II binding to AT(1)R on T cells are poorly understood. We examined the effect of AT(1)R blockade on release of the proinflammatory cytokine, interferon-gamma (IFN-gamma) by human lymphocytes in vivo and in vitro.We used an AT(1)R blocker losartan in a randomized clinical trial in kidney transplant recipients over a 12-month period [AT(1)R blocker (N= 11) and control (N= 10)]. Peripheral blood lymphocytes, isolated from both cohorts, were analyzed by enzyme-linked immunosorbent spot assays (ELISPOT) analyses and real-time reverse transcription-polymerase chain reaction (RT-PCR) to enumerate IFN-gamma producing T cells and IFN-gamma mRNA levels. The effects of AT(1)R blockade in vitro were assessed using human alloreactive T cells and an IFN-gamma producing human cytotoxic T-lymphocyte line. Alloreactive T cells were treated with losartan or candesartan and enzyme-linked immunosorbant assay (ELISA) was used to measure IFN-gamma protein release. The cytotoxic T-lymphocyte line also was AT(1)R blocker-treated prior to determining IFN-gamma producing cells by intracellular cytokine staining.The AT(1)R blocker cohort had a significant decrease in IFN-gamma producing peripheral blood lymphocytes (Por = 0.05 for each time point) and IFN-gamma mRNA levels (P= 0.01 vs. control patients). Losartan also decreased IFN-gamma production (P0.001) in purified alloreactive T cells in vitro as did candesartan. Moreover, Ang II amplified IFN-gamma generation (P0.05) in alloreactive T cells while AT(1)R blocker treatment inhibited Ang II's effect (P0.04). AT(1)R blocker treatment furthermore also inhibited IFN-gamma production in the cytotoxic T-lymphocyte line.AT(1)R blockers may have a clinically relevant immunomodulatory role by blocking IFN-gamma production in T cells.

Disease progression and outcomes in chronic kidney disease and renal transplantation.BackgroundIt is unknown whether renal transplant recipients (RTR) have better outcomes and disease progression rates compared to patients with chronic kidney disease (CKD) when matched for the level of kidney function.MethodsWe analyzed data on 1762 patients with CKD (N = 872) and RTR (N = 890) over 16years, applying the new Kidney/Disease Outcomes Quality Initiative (K/DOQI) staging system for CKD in a single center retrospective study. Patients were further divided based their native kidney disease. We determined disease progression by the slope of creatinine clearance decline and patient and kidney survival rates adjusted for age, gender and stage of kidney function, using Cox proportional hazards models.ResultsThe overall rate of creatinine clearance decline in patients with CKD was -6.6 ± 8.7mL/min/year compared to -1.9 ± 4.7mL/min/year in RTR (P < 0.0001). The rate of decline per stage of CKD was also significantly lower in RTR. Whereas overall kidney survival was higher in RTR compared to patients with CKD (49.6% vs. 17.2%, respectively, P < 0.001), patient survival was not statistically different between the two groups (74.7% vs. 80.3%, respectively, P = 0.25).ConclusionRTR had similar mortality rates compared to patients with CKD despite enjoying slower rates of disease progression and better kidney survival rates. These data suggest that RTR are a unique subset of patients with CKD whose comorbid conditions likely offset the potential benefits of slower rates of progression.

Renal disease and hypertension in non–insulin-dependent diabetes mellitus. Recent epidemiologic data demonstrate a dramatic increase in the incidence of end-stage renal disease (ESRD) in patients with non-insulin-dependent diabetes mellitus (NIDDM), thus dispelling the mistaken belief that renal prognosis is benign in NIDDM. Currently, the leading cause of ESRD in the United States, Japan, and in most industrialized Europe is NIDDM, accounting for nearly 90% of all cases of diabetes. In addition to profound economic costs, patients with NIDDM and diabetic nephropathy have a dramatically increased morbidity and premature mortality. NIDDM–related nephropathy varies widely among racial and ethnic groups, genders and lifestyles; and gender may interact with race to affect the disease progression. While the course of insulin-dependent diabetes mellitus (IDDM) progresses through well-defined stages, the natural history of NIDDM is less well characterized. NIDDM patients with coronary heart disease have a higher urinary albumin excretion rate at the time of diagnosis and follow-up. This greater risk may also be associated with hypertension and hyperlipidemia, and genes involved in blood pressure are obvious candidate genes for diabetic nephropathy. Hyperglycemia appears to be an important factor in the development of proteinuria in NIDDM, but its role and the influence of diet are not yet clear. Tobacco smoking can also be deleterious to the diabetic patient, and is also associated with disease progression. Maintaining euglycemia, stopping smoking and controlling blood pressure may prevent or slow the progression of NIDDM-related nephropathy and reduce extrarenal injury. Treatment recommendations include early screening for hyperlipidemia, appropriate exercise and a healthy diet. Cornerstones of management should also include: (1) educating the medical community and more widely disseminating data supporting the value of early treatment of microalbuminuria; (2) developing a comprehensive, multidisciplinary team approach that involves physicians, nurses, diabetes educators and behavioral therapists; and (3) intensifying research in this field.

Donor genomics influence graft events: The effect of donor polymorphisms on acute rejection and chronic allograft nephropathy.BackgroundOrgans procured from deceased donors emanate from individuals with diverse genetic backgrounds. Donor organs, therefore, may vary in their response to injury and immune stimuli in a genetically determined manner. We assessed polymorphisms from 244 renal allograft donors to better understand the impact of donor polymorphisms on selected transplant outcomes.MethodsDonor genomic DNA restriction fragment length polymorphisms were assayed for evidence of common cytokine [interleukin (IL)-2, IL-6, IL-10, tumor necrosis factor (TNF)-α, TGF-β, interferon (IFN)-γ] and chemokine (CCR2, CCR5) polymorphisms. Associations between donor polymorphisms and graft events were determined using chi-square, linear regression, and Kaplan-Meier analyses.ResultsSeveral genotypic polymorphisms demonstrated a modest association with acute rejection, including the transforming growth factor (TGF)-β T/C codon 10 (P = 0.027) and the CCR5 G/A 59029 (P = 0.039) genes by chi-square analysis. Notably, the presence of the T allele in the IFN-γ gene (+874) demonstrated a highly significant association with biopsy-proven chronic allograft nephropathy (P < 0.008). This association remained highly significant in a multiple linear regression model that incorporated biopsy-proven acute rejection as a covariate.ConclusionThese data suggest that many of the donor polymorphisms studied in this analysis may influence a recipient's immune response to a renal allograft. However, their greatest impact may be demonstrated in long-term outcomes.