Showing papers by "Anil Chandraker published in 2004"

Pharmacoepidemiology of Anemia in Kidney Transplant Recipients

Abstract: . Anemia has long been known to be a complication of end-stage renal disease (ESRD), and it has been linked to cardiovascular morbidity and mortality. Although kidney transplant recipients (KTR) are prone to experiencing cardiovascular outcomes, little is known about the epidemiology of anemia in this population. With few exceptions, studies to date have not fully evaluated the associations between posttransplant anemia (PTA) and medications commonly used in KTR, particularly immunosuppressant drugs, angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB). The authors aimed to specifically investigate possible associations between these drugs and PTA. Detailed medical information was retrospectively collected on 374 consecutive KTR from our transplant clinic. Univariate/multivariate linear regression models were used to test for associations between hematocrit (HCT) and other covariates, and logistic regression models were used to detect independent predictors of PTA, defined as HCT <33%. The mean time since transplantation was 7.7 yr, and mean creatinine was 2.2 mg/dl. The prevalence of PTA was 28.6%. Ten percent of all patients were on erythropoietin therapy, but only 41.6% of patients whose HCT was <30 received this treatment. From multivariate analyses, the authors found that female gender and lower renal function were associated with lower HCT (both P < 0.001). Patients on ACEI had significantly lower HCT (P = 0.005) compared with patients without such treatment. In addition, a significant curvilinear dose-response relationship was found between ACEI dose and HCT. Among the immunosuppressant drugs, mycophenolate mofetil (P = 0.05) and tacrolimus (P = 0.02) were associated with a lower HCT. The authors conclude that PTA is prevalent and undertreated in KTR. Several medications that are possibly modifiable correlates of PTR deserve further study.

Neural stem/progenitor cells express costimulatory molecules that are differentially regulated by inflammatory and apoptotic stimuli.

Abstract: Increased expression of the costimulatory molecule CD80 (B7–1) was noted in the subventricular zone of the brain during the course of experimental autoimmune encephalomyelitis (EAE). This area of the brain is a neural stem cell (NSC) niche in the adult. We show that isolated NSCs from adult brain express CD80 and CD86 (B7–2) and this expression is increased after exposure to IFN-γ or TNF-α, the prototypical Th1 cytokines expressed during EAE. CD80 and CD86 expressed by NSCs are functional and can costimulate allogeneic cells in a mixed lymphocyte reaction. Furthermore, cross-linking of CD80 on the surface of NSCs results in apoptosis of NSCs. In vitro, we show that T cells can interact with NSCs and form conjugates with redistribution of CD3 on the surface of T cells to the area of contact. These data raise the possibility that during CNS inflammatory diseases such as EAE, NSCs may express immune molecules and interact with the inflammatory environment potentially resulting in injury to the NSCs, which may have implications for repair mechanisms in the central nervous system.

Fasting Plasma Total Homocysteine Levels and Mortality and Allograft Loss in Kidney Transplant Recipients: A Prospective Study

Abstract: Homocysteine is implicated to be an atherogenic amino acid and has been associated with increased risk of adverse cardiovascular outcomes. The prognostic significance of plasma total homocysteine (tHcy) levels for mortality and allograft loss in kidney transplant recipients has not been established. A total of 733 kidney transplant recipients who were seen for a routine visit at this transplant clinic in 1996 to 1998 were studied prospectively. During that visit, clinical information was collected and blood was drawn for laboratory evaluation. Information on the previous transplant procedure and the organ donor was obtained from the Eurotransplant Foundation database. Patients were followed prospectively using the Austrian Dialysis and Transplant Registry. With the use of proportional-hazards regression, the independent relations of fasting plasma tHcy levels to the risk of death from any cause and kidney allograft loss were examined. During a median follow-up of 6.1 yr, 154 participants died and 260 kidney allografts were lost. After adjustment for several important risk factors, elevated tHcy levels (≥12 μmol/L) were associated with 2.44 times the mortality risk of patients with normal tHcy levels (hazards ratio 2.44; 95% confidence interval 1.45 to 4.12; P P = 0.02). In this single-center sample, baseline fasting plasma tHcy levels were independently associated with the risk of death and kidney allograft loss. The clinical utility of homocysteine-lowering therapy, such as multivitamin therapy, to reduce the rates of these end points needs to be studied.

Efficacy and safety of low-dose valganciclovir for prevention of cytomegalovirus disease in renal transplant recipients: a single-center, retrospective analysis.

Abstract: Study Objective. To evaluate the safety and efficacy of valganciclovir 450 mg/day for 6 months for cytomegalovirus (CMV) prophylaxis in renal transplant recipients. Design. Single-center, retrospective analysis. Setting. Urban, academic medical center. Patients. Fifty-eight patients who received de novo renal transplants from August 1, 2001–November 21, 2002. Intervention. Valganciclovir 450 mg/day was administered to all renal transplant recipients at risk for CMV disease. Therapy was begun postoperatively and was dose adjusted to renal function. Measurements and Main Results. Data collected from renal transplant recipients were demographics, immunosuppressive and antiviral drug therapy, and occurrence of CMV disease, acute rejection, allograft loss, and hematologic adverse events. Donor (D)/recipient (R) CMV serostatus was 37.9% D+/R+, 29.3% D-/R+, 17.3% D+/R-, and 15.5% D-/R-. Antithymocyte globulin (ATG) was administered to 62.1% of patients. Most of the transplant recipients received triple immunosuppression as maintenance therapy. Median follow-up was 20 months. The frequency of CMV disease was 1.7% within 6 months after transplantation and 5.2% at any point after transplantation. All patients who developed CMV disease were D+/R- and had received ATG. Leukopenia and thrombocytopenia associated with valganciclovir were seen in 28% and 24% of patients, respectively. One patient developed acute cellular rejection. No graft losses or deaths occurred. Early discontinuation of valganciclovir occurred in 20% of patients secondary to severe, persistent leukopenia, thrombocytopenia, and/or diarrhea. None of these patients developed CMV disease. Conclusion. A high rate of CMV disease was noted among the D+/R-population. Administration of ATG as an induction agent also increased the frequency of CMV disease. Despite the low dosage of valganciclovir, hematologic adverse events were common. However, valganciclovir, administered at 450 mg/day for 6 months, was effective and relatively safe for prophylaxis of CMV disease in renal transplant recipients.

The antagonism of calcineurin inhibitors and costimulatory blockers: fact or fiction?

Abstract: Blockade of T-cell costimulatory pathways has proven to be a useful approach in inhibiting allograft rejection and/or inducing tolerance in some experimental models of transplantation, and clinical development of B7 blockade by CTLA4Ig in kidney transplant recipients is under way. Although calcineurin inhibitors are clinically effective immunosuppressive agents in their own right, conflicting findings have been reported as to whether concomitant use of these drugs with costimulatory blockade has a beneficial or adverse effect on preventing rejection and promoting long-term allograft survival or transplant tolerance. Here, we summarize the current understanding of the interaction between calcineurin inhibitors and T-cell costimulatory blockade strategies in transplantation.

Chronic Rejection: Insights from a Novel Immunosuppressive-Free Model of Kidney Transplantation

Abstract: The use of immunosuppressive drugs in models of chronic rejection may limit their usefulness for mechanistic studies. We have developed a new minor histocompatibility-mismatched rat kidney transplant model without the need for immunosuppression. Kidneys from LEW (RT1(l)) donors were transplanted to congenic WF.1L (RT1(l)) recipients and compared with the reversed strain combination and isogenic controls. Urinary protein excretion was measured serially in all recipients; kidneys were harvested 90, 120, and 180 d after transplantation for morphologic analysis and cytokine gene expression. In vitro lymphocytic reactivity and cytokine analysis of mixed lymphocyte reaction (MLR) culture supernatants by ELISA was also carried out. LEW into WF.1L kidney grafts developed proteinuria starting 120 d after transplantation and were associated with morphologic changes of focal segmental glomerulosclerosis together with interstitial cell infiltrates, upregulated gene expression of IL-1beta, IL-2, and TNF-alpha/-beta, as well as IL-2, IFN-gamma, and TNF-alpha production by lymphocytes in MLR culture supernatants. WF.1L kidneys transplanted into LEW recipients did not develop chronic rejection and had upregulation of Th2 cytokines, both within the allograft and in MLR supernatant of recipient lymphocytes cultured with WF.1L cells. Furthermore, these lymphocytes produced both Th1 and Th2 cytokines when cultured with WF cells, unlike lymphocytes from the LEW isografts, which produced Th1 cytokines when challenged with WF cells. These studies show that indirect allorecognition can cause strain-dependent chronic rejection associated with Th1-like cytokine production, whereas production of Th2 cytokines is associated with protection from the development of chronic rejection.

NEPHROLOGY Rounds AS PRESENTED IN THE ROUNDS OF

Abstract: Cardiovascular disease (CVD) is the leading cause of death among patients with end-stage renal disease (ESRD) and the risk of cardiovascular events is increased among all patients with chronic kidney disease (CKD). The excess risk of CVD may be attributed to well-known cardiovascular risk factors (eg, diabetes mellitus, hypertension, hyperhomocysteinemia, cigarette smoking, and hyperlipidemia), as well as factors unique to the underlying CKD process (eg, proteinuria, anemia, hyperparathyroidism, inflammation, and malnutrition). While the importance of treatment of hyperlipidemia in the primary and secondary prevention of CVD has long been recognized in the general population, the treatment of hyperlipidemia in the dialysis population has been more controversial. The controversy regarding treatment of hyperlipidemia in patients with ESRD is largely based on the observation that, in some studies, higher cholesterol levels in dialysis patients have been associated with lower mortality. This is in marked contrast to the general population, in whom higher cholesterol levels are clearly associated with higher cardiovascular risk for mortality. This issue of Nephrology Rounds focuses on the epidemiology and management of lipid disorders in patients with ESRD. Epidemiology of dyslipidemias in ESRD Lipid disorders are common in ESRD as a consequence of both systemic metabolic derangements (as in diabetes mellitus) and the uremic milieu itself. Estimates of dyslipidemia vary, based on the type of lipid disturbance, the definition of dyslipidemia, and the type of dialysis modality, but hypertriglyceridemia is the most commonly observed lipid abnormality in ESRD. 1 In a European study of lipid disorders in dialysis patients, two-thirds had low-density lipoprotein cholesterol (LDL-C) levels >100 mg/dL and high-density lipoprotein cholesterol (HDL-C) levels 180 mg/dL. 2 In the CHOICE cohort of incident dialysis patients in the United States, 47% of HD patients and 72% of PD patients had LDL-C levels >100 mg/dL. 3 In addition to elevations in plasma cholesterol and/or triglycerides, the dyslipidemia of ESRD is also characterized by an abnormal apolipoprotein (apo) profile with decreased concentrations of apo-A containing lipoproteins in HDL and increased concentrations of triglyceride-rich apo-B containing lipoproteins in very low density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and LDL. 4 Triglycerides are further enriched with apoC-III, such that the ratio of apoA-I to apoC-III is markedly reduced between the early stages of CKD and ESRD. 4 Reduced activity of the enzymes, lipoprotein lipase and hepatic lipase, as well as increased levels of apoC-III in VLDL, may explain the reduced clearance of these lipoproteins. 5