Association of pretransplant glycemic control with posttransplant outcomes in diabetic kidney transplant recipients

OBJECTIVE

Observational studies have yielded inconsistent findings regarding the association of hemoglobin A_1c (HbA_1c) with survival in diabetic patients on dialysis. The association between pretransplant glycemic control and short- and long-term posttransplant outcomes in kidney transplant recipients is not clear.

RESEARCH DESIGN AND METHODS

Linking the 5-year patient data of a large dialysis organization (DaVita) to the Scientific Registry of Transplant Recipients, we identified 2,872 diabetic dialysis patients who underwent first kidney transplantation. Mortality or graft failure and delayed graft function (DGF) risks were estimated by Cox regression (hazard ratio [HR]) and logistic regression (odds ratio), respectively.

RESULTS

Patients were 53 ± 11 years old and included 36% women and 24% African Americans. In our fully adjusted model, allograft failure–censored, all-cause death HR and 95% CI for time-averaged pretransplant HbA_1c categories of 7 to <8%, 8 to <9%, 9 to 10%, and ≥10%, compared with 6 to <7% (reference), were 0.89 (0.59–1.36), 2.06 (1.31–3.24), 1.41 (0.73–2.74), and 3.43 (1.56–7.56), respectively; and graft failure–censored cardiovascular death HR was 0.38 (0.13–1.05), 1.78 (0.69–4.55), 1.59 (0.44–5.76), and 4.28 (0.85–21.64), respectively. We did not find any difference in risk of death-censored graft failure or DGF with different pretransplant HbA_1c levels.

CONCLUSIONS

Poor pretransplant glycemic control appears associated with decreased posttransplant survival in kidney transplant recipients, whereas allograft outcomes may not be affected.Diabetes is a potent cardiovascular risk factor in the general population as well as in those undergoing maintenance dialysis and kidney transplant recipients (1,2). Clinical trials have shown that tight glycemic control decreases the risk of developing retinopathy, nephropathy, and neuropathy in the general population (3,4). Furthermore, glycemic control, as measured by glycosylated hemoglobin (HbA_1c), is a predictor of cardiovascular complications, including myocardial infarctions and hospitalizations for coronary artery disease (2). Expert groups have recommended that diabetic dialysis patients should follow the American Diabetes Association (ADA) guidelines; however, there is no consistent evidence to support these recommendations for patients with end-stage renal disease (5–7). In concordance with the ADA guidelines, the Kidney Disease Outcomes Quality Initiative (K-DOQI) recommendations, last updated in 2007, state that “Target HbA_1c for people with diabetes should be <7%, irrespective of presence or absence of CKD” (8).Large observational studies with differing methodologies reached somewhat contrasting conclusions regarding the association of glycemic control with survival in diabetic maintenance hemodialysis and peritoneal dialysis patients. Recently, a large randomized trial has indicated that intensive glucose lowering in patients with type 2 diabetes did not reduce the risks of cardiovascular disease, the most common source of end-stage renal disease mortality (9). Additionally, Williams et al. (10) reported a higher risk for death only in type 2 diabetic hemodialysis patients with HbA_1c levels >11% (11). Shurraw et al. (12) found higher casual glucose and HbA_1c levels were not associated with mortality in maintenance hemodialysis patients with or without diabetes. In contrast, we reported that after adjusting for potential confounders, higher HbA_1c values were incrementally associated with higher death risks in patients on maintenance dialysis (13). Furthermore, in peritoneal dialysis patients, only poor glycemic control (HbA_1c ≥8% and/or glucose ≥300 mg/dL) was incrementally associated with lower survival (14). Alas, mortality is only one measure of the deleterious impact of poor glycemic control. Other potential benefits of glycemic control include slowing the rate of progression of micro- and macrovascular disease, decreasing the presence of nonfatal strokes and myocardial infarctions, and slowing the rate progression of neuropathy. These factors have a strong impact on survival in kidney transplant recipients.To the best of our knowledge, no study has examined the association between pretransplant glycemic control and either short-term outcome, such as delayed graft function (DGF), or long-term outcomes, such as mortality and graft failure after kidney transplantation. We hypothesized that higher pretransplant HbA_1c during the dialysis period prior to kidney transplantation is associated with worse posttransplant patient and graft survival and with DGF in a large prospective cohort of incident kidney transplant recipients across the U.S.     

The Angiotensin-converting enzyme inhibitor captopril inhibits poly(adp-ribose) polymerase activation and exerts beneficial effects in an ovine model of burn and smoke injury

We investigated the effect of the angiotensin-converting enzyme (ACE) inhibitor captopril in a clinically relevant ovine model of smoke and burn injury, with special reference to oxidative stress and activation of poly(ADP-ribose) polymerase, in the lung and in circulating leukocytes. Female, adult sheep (28-40 kg) were divided into three groups. After tracheostomy and under deep anesthesia, both vehicle-control-treated (n = 5) and captopril-treated (20 mg/kg per day, i.v., starting 0.5 h before the injury) (n = 5) groups were subjected to 2 × 20%, third-degree burn injury and were insufflated with 48 breaths of cotton smoke. A sham group not receiving burn/smoke was also studied (n = 5). Animals were mechanically ventilated and fluid resuscitated for 24 h in the awake state. Burn and smoke injury resulted in an upregulation of ACE in the lung, evidenced by immunohistochemical determination and Western blotting. Burn and smoke injury resulted in pulmonary dysfunction, as well as systemic hemodynamic alterations. Captopril treatment of burn and smoke animals improved PaO2/FiO2 ratio and pulmonary shunt fraction and reduced the degree of lung edema. There was a marked increase in PAR levels in circulating leukocytes after burn/smoke injury, which was significantly decreased by captopril. The pulmonary level of ACE and the elevated pulmonary levels of transforming growth factor β in response to burn and smoke injury were significantly decreased by captopril treatment. Our results suggest that the ACE inhibitor captopril exerts beneficial effects on the pulmonary function in burn/smoke injury. The effects of the ACE inhibitor may be related to the prevention of reactive oxygen species-induced poly(ADP-ribose)polymerase overactivation. Angiotensin-converting enzyme inhibition may also exert additional beneficial effects by inhibiting the expression of the profibrotic mediator transforming growth factor β.     

Chemical Imaging of Cardiac Cell and Tissue by Using Secondary Ion Mass Spectrometry

Purpose  

Identification and localization of biomolecules in cells and tissue samples are important for understanding of subcellular structures and can be helpful in biomedical and pharmaceutical research.     

Polymer-based oral peptide nanomedicines

Oral peptide delivery has been one of the major challenges of pharmaceutical sciences as it could lead to a great improvement of classical therapies, such as insulin, alongside making an important number of new therapies feasible. Successful oral delivery needs to fulfill two key tasks: to protect the macromolecules from degradation in the GI tract and to shuttle them across the intestinal epithelium in a safe and efficient fashion. Over the last decade, there have been numerous approaches based on the chemical modification of peptides and on the use of permeation enhancers, enzyme inhibitors and drug-delivery systems. Among the approaches developed to overcome these restrictions, the design of nanocarriers seems to be a particularly promising approach. This article is an overview on the state of the art of oral-peptide formulation strategies, with special attention to insulin delivery and the use of polymeric nanocarriers as delivery systems.     

Low-density lipoprotein cholesterol and high-sensitivity C-reactive protein lowering with atorvastatin in patients of South Asian compared with European origin: insights from the Achieve Cholesterol Targets Fast with Atorvastatin Stratified Titration (ACTFAST) study

The aim of this study was to determine the effects of atorvastatin in patients of South Asian versus European origin who participated in the Achieve Cholesterol Targets Fast with Atorvastatin Stratified Titration (ACTFAST) study. ACTFAST was a 12-week prospective, open-label study in patients at high risk for atherosclerosis (European origin, n = 1978; South Asian origin, n = 64). Compared with patients of European origin, patients of South Asian origin were younger, were less likely to smoke, and had lower body mass index, systolic blood pressure, low-density lipoprotein cholesterol (LDL-C) and triglycerides. Because significant differences were observed in baseline characteristics between patient groups, case control propensity scores were used. In the unmatched analysis, South Asians had greater LDL-C response to atorvastatin than patients of European origin. However, after propensity matching, atorvastatin lowered LDL-C and high-sensitivity C-reactive protein (hs-CRP) to a similar degree in both groups, with no differences in safety profile. The authors observed no correlation between change in hs-CRP and LDL-C concentrations in either population. In conclusion, atorvastatin lowered both LDL-C and hs-CRP to a similar degree in patients of South Asian or European origin, suggesting usual starting doses of atorvastatin (with appropriate monitoring), rather than lower starting doses as has been advocated by some, may be used in patients of South Asian origin.     

AT-1001: A High Affinity and Selective α3β4 Nicotinic Acetylcholine Receptor Antagonist Blocks Nicotine Self-Administration in Rats

Genomic and pharmacologic data have suggested the involvement of the α3β4 subtype of nicotinic acetylcholine receptors (nAChRs) in drug seeking to nicotine and other drugs of abuse. In order to better examine this receptor subtype, we have identified and characterized the first high affinity and selective α3β4 nAChR antagonist, AT-1001, both in vitro and in vivo. This is the first reported compound with a Ki below 10 nM at α3β4 nAChR and >90-fold selectivity over the other major subtypes, the α4β2 and α7 nAChR. AT-1001 competes with epibatidine, allowing for [³H]epibatidine binding to be used for structure-activity studies, however, both receptor binding and ligand-induced Ca²⁺ flux are not strictly competitive because increasing ligand concentration produces an apparent decrease in receptor number and maximal Ca²⁺ fluorescence. AT-1001 also potently and reversibly blocks epibatidine-induced inward currents in HEK cells transfected with α3β4 nAChR. Importantly, AT-1001 potently and dose-dependently blocks nicotine self-administration in rats, without affecting food responding. When tested in a nucleus accumbens (NAcs) synaptosomal preparation, AT-1001 inhibits nicotine-induced [³H]dopamine release poorly and at significantly higher concentrations compared with mecamylamine and conotoxin MII. These results suggest that its inhibition of nicotine self-administration in rats is not directly due to a decrease in dopamine release from the NAc, and most likely involves an indirect pathway requiring α3β4 nAChR. In conclusion, our studies provide further evidence for the involvement of α3β4 nAChR in nicotine self-administration. These findings suggest the utility of this receptor as a target for smoking cessation medications, and highlight the potential of AT-1001 and congeners as clinically useful compounds.