Plasma Branched-Chain Amino Acid Concentrations and Glucose Homeostasis in Kidney Transplant Recipients and Candidates.

Background: Post-transplant diabetes mellitus (PTDM) encompasses new-onset and previously unrecognized type 2 diabetes. Kidney failure masks type 2 diabetes. Branched-chain amino acids (BCAA) are closely associated with glucose metabolism. Therefore, understanding BCAA metabolism both in kidney failure and after kidney transplantation may inform PTDM mechanisms. Objective: To understand the impact of present or absent kidney function on plasma BCAA concentrations. Design: Cross-sectional study of kidney transplant recipients and kidney transplant candidates. Setting: Large kidney transplant center in Toronto, Canada. Measurements: We measured plasma BCAA and aromatic amino acid (AAA) concentrations in 45 pre-kidney transplant candidates (15 with type 2 diabetes, 30 without type 2 diabetes) and 45 post-kidney transplant recipients (15 PTDM, 30 non-PTDM), along with insulin resistance and sensitivity by 75 g oral glucose loading for those in each group without type 2 diabetes. Methods: Plasma AA concentrations were analyzed using MassChrom AA Analysis and compared between groups. The insulin sensitivity for oral glucose tolerance tests or Matsuda index (a measure of whole-body insulin resistance), Homeostatic Model Assessment for Insulin Resistance (a measure of hepatic insulin resistance), and Insulin Secretion-Sensitivity Index-2 (ISSI-2, a measure of pancreatic ß-cell response) was calculated from fasting insulin and glucose concentrations, and compared with BCAA concentrations. Results: Each BCAA concentration was higher in post-transplant subjects than pre-transplant subjects (P < .001 for leucine, isoleucine, valine). In post-transplant subjects, each BCAA concentration was higher in PTDM versus non-PTDM (odds ratio for PTDM 3-4 per 1 SD increase in BCAA concentration, P < .001 for each). Tyrosine concentrations were also higher in post-transplant subjects than pre-transplant subjects, but tyrosine did not differ by PTDM status. By contrast, neither BCAA nor AAA concentrations were different in pre-transplant subjects with or without type 2 diabetes. Whole-body insulin resistance, hepatic insulin resistance, and pancreatic ß-cell response did not differ between nondiabetic post-transplant and pre-transplant subjects. Branched-chain amino acid concentrations correlated with the Matsuda index and Homeostatic Model Assessment for Insulin Resistance (P < .05 for each) only in nondiabetic post-transplant subjects-not in nondiabetic pre-transplant subjects. Branched-chain amino acid concentrations did not correlate with ISSI-2 in either pre-transplant or post-transplant subjects. Limitations: The sample size was small, and subjects were not studied prospectively for the development of type 2 diabetes. Conclusions: Plasma BCAA concentrations are higher post-transplant in type 2 diabetic states, but do not differ by diabetes status in the presence of kidney failure. The association of BCAA with measures of hepatic insulin resistance among nondiabetic post-transplant patients is consistent with impaired BCAA metabolism as a characteristic of kidney transplantation.

Contexte: Le diabète post-transplantation (DPT) englobe les nouvelles manifestations du diabète de type 2 nouveau et le diabète précédemment non reconnu. L'insuffisance rénale masque le diabète de type 2. Les acides aminés à chaîne ramifiée (AACR) sont étroitement liés au métabolisme du glucose. Par conséquent, la compréhension du métabolisme des acides aminés à chaîne ramifiée (AACR) à la fois dans l'insuffisance rénale et après la transplantation rénale peut informer les mécanismes de DPT. Objectifs: Comprendre l'impact de la présence ou de l'absence de fonction rénale sur les concentrations plasmatiques d'AACR. Type d'étude: Étude transversale portant sur des receveurs d'une greffe rénale et des candidats à une transplantation de rein. Cadre: Un grand centre de transplantation rénale de Toronto (Canada). Mesures: Nous avons mesuré les concentrations plasmatiques d'AACR et d'AA aromatiques (AAA) chez 45 candidats pré-transplantation rénale (15 atteints de diabète de type 2; 30 non-diabétiques) et 45 patients ayant reçu une greffe rénale (15 DPT, 30 non-DPT). Les patients des groupes non-diabétiques ont en outre subi un test de résistance et de sensibilité à l'insuline à la suite de l'administration orale de 75 g de glucose. Méthodologie: Les concentrations plasmatiques d'AA ont été analysées à l'aide de l'appareil Mass Chrom AA Analysis et comparées entre les groupes. La sensibilité à l'insuline pour les tests oraux de tolérance au glucose ou l'indice Matsuda (mesure de la résistance à l'insuline dans tout l'organisme), l'évaluation du modèle homéostatique de la résistance à l'insuline (mesure de la résistance hépatique à l'insuline) et l'indice de sensibilité à la sécrétion d'insuline-2 (mesure de la réponse des cellules ß pancréatiques) ont été calculés à partir des concentrations d'insuline et de glucose à jeun, et comparés aux concentrations d'AACR. Résultats: Chacune des concentrations en AACR était plus élevée chez les sujets post-transplantation que chez les sujets pré-transplantation (p < 0,001 pour la leucine, l'isoleucine, la valine). Chez les sujets post-transplantation, chaque concentration d'AACR était plus élevée chez les sujets DPT que chez le cas des sujets non-DPT (RC pour DPT: entre 3 et 4 pour chaque augmentation de l'écart-type; p < 0,001 pour chacun). Les concentrations de tyrosine étaient également plus élevées chez les sujets post-transplantation que chez les sujets pré-transplantation, mais ne différaient pas selon le statut du DPT. En revanche, ni les concentrations d'AACR ni les concentrations d'AAA n'étaient différentes chez les sujets pré-transplantation qu'ils soient ou non atteints de diabète de type 2. La résistance de tout l'organisme à l'insuline, la résistance hépatique à l'insuline et la réponse des cellules ß pancréatiques ne différaient pas entre les sujets non-diabétiques avant ou après la transplantation. Les concentrations d'AACR étaient corrélées avec l'indice Matsuda et l'évaluation du modèle homéostatique de la résistance à l'insuline (p<0,05 pour chacun) uniquement chez les sujets non-diabétiques après la transplantation, et non chez les sujets non-diabétiques avant la transplantation. Les concentrations d'AACR n'étaient pas en corrélation avec l'ISSI-2, que ce soit chez les sujets avant ou après la transplantation. Limites: L'échantillon était de petite taille et les sujets n'ont pas été étudiés prospectivement pour le développement du diabète de type 2. Conclusion: Les concentrations plasmatiques d'AACR sont plus élevées après la transplantation chez les sujets diabétiques de type 2, mais ne diffèrent pas selon le statut du diabète en présence d'une insuffisance rénale. Les associations entre les AACR et les mesures de la résistance hépatique à l'insuline chez les patients non-diabétiques post-transplantation sont cohérentes avec une altération du métabolisme des AACR comme caractéristique de la transplantation rénale.

Pre-transplantation glucose testing for predicting new-onset diabetes mellitus after renal transplantation.

AIM: New-onset diabetes after renal transplantation (NODAT) adversely affects graft and patient survival. However, NODAT risk based on pre-transplant blood glucose (BG) levels has not been defined. Our goal was to identify the best pre-transplant testing method and cut-off values. MATERIALS AND METHODS: We performed a case-control analysis of non-diabetic recipients who received a live donor allograft with at least 6 months post-transplant survival. Pre-transplant glucose abnormalities were excluded through 75 g oral glucose tolerance testing (OGTT) and random BG (RBG) measurement. NODAT was defined based on 2003 Canadian Diabetes Association criteria. Multivariate logistic and Cox regression analysis was performed to determine independent predictor variables for NODAT. Receiver-operating-characteristic (ROC) curves were constructed to determine threshold BG values for diabetes risk. RESULTS: 151 recipients met initial entry criteria. 12 had pre-transplant impaired fasting glucose and/or impaired glucose tolerance, among who 7 (58%) developed NODAT. In the remaining 139, 24 (17%) developed NODAT. NODAT risk exceeded 25% for those with pre-transplant RBG > 6.0 mmol/l and 50% if > 7.2 mmol/l. Pre-transplant RBG provided the highest AUC (0.69, p = 0.002) by ROC analysis. Increasing age (p = 0.025), acute rejection (p = 0.011), and RBG > 6.0 mmol/l (p = 0.001) were independent predictors of NODAT. CONCLUSION: Pre-transplant glucose testing is a specific marker for NODAT. Patients can be counseled of their incremental risk even within the normal BG range if the OGTT is normal.

Role of dietary salt intake in posttransplant hypertension with tacrolimus-based immunosuppression.

Dietary salt is an important contributor to hypertension in the general population. While its role in cyclosporine-induced hypertension is minimal, its role in tacrolimus-based immunosuppression has not been defined. We measured the 24-hour urine sodium excretion as an estimate of intake in a group of stable renal transplant recipients on tacrolimus (N = 143) who had serum creatinine fluctuations <20% during the preceding 3 months. Average clinic-measured blood pressure (BP) from before and after the 24-hour urine collection was computed. Patients with recent changes in antihypertensive medications were excluded. Average systolic BP was 126 +/- 14 and diastolic BP 76 +/- 7 mm Hg. Urine sodium was 162.6 +/- 70 mmol/d (range 50 to 351), and the sodium/creatinine ratio was 15.4 +/- 6.4. There was no correlation between urine sodium excretion and either systolic or diastolic BP (R = 0.07 and R = 0.05, P = NS) or the sodium/creatinine and systolic/diastolic BP (R = 0.13, R = 0.11, P = NS). By multiple linear regression only weight and urine protein were independently associated with both systolic BP (P < .0001 for each) and diastolic BP (P < .05 for each). In conclusion, there is no appreciable influence of dietary salt intake on BP under tacrolimus-based immunosuppression. Restricting dietary salt intake in these patients cannot be recommended at the current time.

Efficacy of azithromycin in the treatment of cyclosporine-induced gingival hyperplasia in renal transplant recipients.

BACKGROUND: Gingival hyperplasia (GH) is a common side effect of cyclosporine . Azithromycin (Zithromax; AZI) is a macrolide antibiotic reported in case studies to reduce cyclosporine-induced gingival hyperplasia (CIGH) in renal transplant recipients (RTR). METHODS: The efficacy of AZI to treat CIGH in RTR was examined in a double-blind, randomized crossover trial. Patients (n=17) with CIGH were randomized to receive AZI and a matching placebo in alternate order for 5 days, separated by a 2-week washout period. Follow-up visits were conducted at week 6 and week 12. Changes in GH were evaluated by measuring the clinical gingival sulcus depths, tooth length, and the length of the interdental papillae to the cementum-enamel junction of two teeth in each of the four quadrants. RESULTS: Significant improvements were observed in all three types of periodontal measurements, representing reductions of gingival tissue above the medial aspect of the tooth, of the gingival sulcus depth, and of the length of the interdental papillae. Patients reported an improvement in gum bleeding. AZI was well tolerated, and 67% of the patients reported that the treatment was at least somewhat useful. CONCLUSIONS: AZI should be considered for RTR with CIGH.

Seasonal variation in outpatient blood pressure in stable renal transplant recipients.

Seasonal variation in blood pressure (BP) has been described in the general and dialysis populations, with higher recordings noted in the winter than in the summer. This difference has been attributed to changes in weight, ambient temperature, and length of daylight. In this study, we sought to determine whether such seasonal differences exist in renal transplant recipients, a group with a high prevalence of hypertension. We reviewed our outpatient population of 652 adult renal transplant recipients and identified primary allograft recipients with graft survival >1 year, stable renal function, on both cyclosporine and prednisone, and who had >1 pair of post-first year "winter" (defined as the months of January and February) plus "summer" (defined as the months of July and August) outpatient BP measurements from the same year. One hundred sixty-three patients met entry criteria, from whom 432 BP pairs were obtained. When the most recent pair from each patient was analyzed (n=163), diastolic and mean BP were found to be higher in winter than summer (by 2.5 and 2.3 mmHg, respectively, P<0.01 for each) by a paired Student t test. In a separate analysis using all BP pairs (n=432), systolic, diastolic, and mean BP were found to be significantly higher in winter (by 5.3, 2.7, and 3.5 mmHg, respectively, P<0.001 for each). An effect of season was confirmed in a multiple regression model of common predictors for hypertension, controlling for number of BP pairs per patient. In conclusion, renal transplant recipients demonstrate higher BP in the winter than in the summer. This effect is independent of known predictors of hypertension in this population and may be, at least, partly related to changes in length of daylight and temperature.

Corneal Langerhans cell dynamics after herpes simplex virus reactivation.

PURPOSE: The authors investigated the progressive changes in the distribution of corneal Langerhans cells (LC) after reactivation of latent herpes simplex virus type 1 (HSV-1) in mice. METHODS: After corneal inoculation of National Institutes of Health inbred mice with HSV-1 and the establishment of latency, viral reactivation was induced by irradiating the ocular surface with 250 mJ/cm2 of ultraviolet B (UV-B) light. RESULTS: Subsequent viral replication in the cornea was followed by the migration of the LC toward the paracentral and central corneal epithelium. These areas are normally devoid of LC. The number of LC in the paracentral and central regions of the eye reached a peak at day 14 post-UV-B irradiation. After UV-B irradiation of mice latently infected with HSV-1, the development of corneal stromal opacification and neovascularization closely followed the migration of LC toward the central cornea and paralleled the influx of T-cells into the corneal stroma. This pattern was not observed in irradiated uninfected mice. CONCLUSIONS: LC migrate centrally in the corneal epithelium after viral reactivation. There is a direct correlation between the number of LC in the cornea and the degree of persistent stromal opacification.