Stable Renal Recipients Research Articles

Antiphospholipid Syndrome in Renal Allograft Recipients-A Long-Term Multicenter Analysis.

The aim of the study was to assess renal allograft function and survival in recipients with APS. Retrospective, multicenter study included 19 adult renal recipients with definite APS (primary or lupus-related) from three Polish transplant centers. Renal allograft function was assessed using serum creatinine concentration (SCr1) at 3rd month post-transplant and at the end of the observation (SCr2) and glomerular filtration rate (GFR) was estimated based on modification of diet in renal disease (MDRD) formula. General linear model was used to assess 12 month GFR change over time. Kaplan-Meier curves and restricted mean survival time were used for allograft survival. Matched control group consisted of 21 stable renal recipients without history of thrombosis and without anticoagulation/antiplatelet treatment. The study group differs in induction therapy (p = 0.019), high-urgency procedure (p = 0.04), proteinuria (p = 0.0058), primary disease (lupus) (p < 0.0001), re-transplantation in primary APS (p = 0.0046) and shorter time since engraftment to SCr2 (p = 0.016). Primary APS was more often diagnosed post-transplant (p = 0.0005). Allograft biopsy revealed thrombotic microangiopathy (TMA) with acute rejection (AR) or isolated AR vs AR or chronic rejection in controls but did not reach significance (p = 0.054). Renal allograft function was inferior in the study group but did not reach significance: mean SCr2 (mg/dL) was 2.18 ± 1.41 and 1.5 ± 0.68 in controls, respectively, p = 0.27; mean GFR2 (ml/min/1.73m2) was 39.9 ± 20.83 and 51.23 ± 19.03, respectively, p = 0.102. Renal allograft duration was inferior in patients with APS and was (in years) 11.22 ± 1.44 vs. 14.36 ± 0.42, respectively, p = 0.037, in patients with primary APS (p = 0.021), in patients with APS diagnosed post-transplant (p = 0.012) but not in lupus-related APS (p = ns). Fifteen year renal allograft survival was inferior in APS vs. controls (73,86% vs. 90.48%, respectively, p = 0.049). Recipients with APS are at higher risk for allograft loss due to immune and non-immune causes. Renal allograft survival was inferior in recipients with APS and renal function remains impaired but stable.

Tacrolimus Can Be Reliably Measured With Volumetric Absorptive Capillary Microsampling Throughout the Dose Interval in Renal Transplant Recipients.

Therapeutic drug monitoring is standard practice for the immunosuppressant tacrolimus (Tac). Venous blood sampling at outpatient clinics is time-consuming and impractical with regard to obtaining trough concentrations on clinical visit days. Home-based blood sampling may be patient friendly and pave the way for limited sampling strategies for the prediction of total drug exposure. The aim was to establish a Tac assay for dried capillary microsamples, ensuring reliable measurements during the full dose interval in renal transplant recipients. An assay based on volumetric absorptive microsampling and liquid chromatography tandem mass spectrometry was validated. The agreement between capillary microsamples and liquid venous samples was investigated in stable renal recipients on twice-daily Tac dosing. Sampling throughout the 12-hour dose interval was examined at 2 separate days, at least 1 week apart, for each participant. Two sets of samples were obtained at each time point, one delivered directly to the laboratory and one sent through mail. Twenty-seven renal transplant recipients were included, of whom 26 were investigated twice. Tac was efficiently extracted from the dried microsamples (mean recovery 94%-103%). The between-series mean accuracy was 88%-98% with coefficients of variation ≤5.0% (≤11% at the lower limit of quantification), measurement range 0.70-60 mcg/L. The mean difference between parallel microsamples was 5%-7%. Overall, the mean differences between dried microsamples and liquid samples were -3.1% when mailed (n = 679) and -4.2% when directly delivered (n = 682). Less than 8% were outside ±20%. The microsamples were stable for 1 month at ambient temperature. The microsample method demonstrated acceptable performance. Tac concentrations can be reliably quantified throughout the dose interval by using volumetric absorptive microsampling in renal transplant recipients, and the results are not influenced by postal shipment.

A Single Center, Open-label, Randomized Pilot Study to Evaluate the Safety and Efficacy of Tacrolimus Modified Release, ADVAGRAF, Versus Tacrolimus Twice Daily, PROGRAF, in Stable Renal Recipients (SINGLE)

BackgroundCompliance with immunosuppressive regimens may affect clinical outcomes in renal transplant recipients. The aim of this study was to assess the safety and efficacy of standard-dose tacrolimus modified-release (TAC-MR) once daily versus tacrolimus (TAC) twice daily in stable renal transplant recipients. MethodsNinety-nine stable renal transplant recipients were randomized to receive standard-dose tacrolimus twice daily or standard-dose modified-release tacrolimus once daily on a 1:1 (mg:mg) basis. The primary end point was the incidence of adverse events (AEs) in both groups. Secondary end points included biopsy-proven acute rejection, graft survival, patient survival, clinical indicators, and change in score of questionnaire. ResultsThe incidence of AEs was not different between the TAC and TAC-MR groups (56.0% vs 53.1%, P > .05). There were no significant differences in mean calculated glomerular filtration rate, blood pressure, glycosylated hemoglobulin (HbA1c), blood concentration of tacrolimus, and drug compliance. The scores of all items in the 36-item short form health survey (SF-36) were not different between groups, except for vitality. With respect to the subject questionnaire, there was no difference in question scores between the two treatment groups. ConclusionA regimen of TAC-MR once daily can be considered as an effective and safe alternative formulation of tacrolimus in stable renal transplant patients.

Short-term efficacy and safety of sitagliptin treatment in long-term stable renal recipients with new-onset diabetes after transplantation

New-onset diabetes after transplantation (NODAT) is a common complication after renal transplantation. There are limited available oral drugs to treat hyperglycaemia in this population owing to reduced renal function, potential interactions with immunosuppressive drugs and adverse effects such as hypoglycaemic events that may increase the cardiovascular risk. This study was initiated to investigate efficacy and safety of sitagliptin treatment that may represent a novel alternative in renal transplant recipients. Nineteen long-term stable renal transplant recipients with NODAT were included in a controlled, cross-over study and randomized to first receive either sitagliptin 50-100 mg/day or a sitagliptin-free period of 4 weeks. Median age (interquartile range, IQR) was 67 (62-72) years (12 males/7 females), all studied 1 (1-3) year after transplantation. The immunosuppressive regimen was a triple calcineurin inhibitor-based therapy. Oral glucose tolerance test (OGTT) with insulin and C-peptide responses and laser Doppler (LD) flowmetry assessment of endothelial function were performed at baseline and after each treatment period. Home measurements of plasma glucose were performed daily during the study. The median (IQR) first- and second-phase insulin secretion responses increased significantly by 56.3% (45.2-112.6%, P = 0.005) and 39.3% (26.5-81.0%, P = 0.006), respectively, following sitagliptin treatment as compared with no sitagliptin treatment. Fasting and 2-h plasma glucose concentrations fell significantly {0.9 mmol/L [0.5-1.7 mmol/L (16.2 mg/dL), P = 0.003] and 2.9 mmol/L [0.5-6.4 mmol/L (52.3 mg/dL), P = 0.004], respectively}, as did also home measurements of plasma glucose. Endothelial function and plasma markers of cardiovascular risk were unaffected. No serious adverse events were observed. Two mild and asymptomatic hypoglycaemic episodes were observed in combination with glipizide. Sitagliptin increases insulin secretion and reduces fasting and postprandial plasma glucose in renal transplant recipients with NODAT. The short-term treatment was well tolerated, and sitagliptin seems safe in this population.

Predictors of New Onset of Diabetes after Transplantation in Stable Renal Recipients

Background: Several groups identified pre-transplant factors which contribute to the development of new onset of diabetes after transplantation (NODAT). Aim: To identify post-transplant risk factors for NODAT. Methods: 55 stable renal transplant patients were divided into group A of 34 recipients with normoglycemia and group B of 21 recipients with impaired fasting glucose. Markers including insulin, pro-insulin, soluble receptors for advanced glycated end products (sRAGE), adiponectin, malondialdehyde, homeostasis model assessment of insulin resistance (HOMA-IR), and β-cell function were calculated at the outset and correlated, thereafter, with the later development of NODAT after a follow-up duration of 14.98 ± 3.97 months. Results: 11.8 and 19% of groups A and B respectively developed NODAT. Insulin, sRAGE, HOMA-IR and basal fasting plasma glucose correlated with the development of NODAT in univariate analysis. A baseline insulin level of 54.54 mU/l predicted the development of NODAT with a specificity of 95.45% and was the only significant factor in the multivariate analysis. β-Cell function was not different among the three groups. Conclusions: A long prodrome of insulin resistance (IR) exists prior to development of NODAT. 50% of patients with NODAT will remit to a normoglycemic state. IR, rather than β-cell dysfunction, precedes the development of NODAT. Serum insulin in stable non-diabetic renal transplant patients can be used as a confirmatory test to the development of future NODAT.

Glucose metabolism before and after conversion from cyclosporine microemulsion to tacrolimus in stable renal recipients

Tacrolimus is more diabetogenic than cyclosporine. However, this difference is only discernible in the first few months after renal transplantation. In randomized trials, investigating the effects of immunosuppression after renal transplantation, no increase in diabetes mellitus has been reported. However, no sensitive technique was used in these trials, so subclinical alteration of glucose metabolism cannot be excluded. We, therefore, decided to use an intravenous glucose tolerance test (IV-GTT), to investigate whether conversion from cyclosporine-based immunosuppression, with a median trough level of 120 microg/l, to tacrolimus-based immunosuppression with a median trough level of 6.5 microg/l influences glucose metabolism and whether patients on steroids behave differently from those not on steroids. Thirty stable, non-diabetic patients, transplanted 10 or more years earlier, were converted from cyclosporine to tacrolimus without changing their concomitant medication. IV-GTT's were performed before and 2.5 months after the conversion. Before conversion, 40% of the patients had an abnormal glucose disappearance rate (kG): in 7%, kG was below 0.8 (abnormal range) and in 34%, kG was between 0.8 and 1.2 (indeterminate range). After conversion, stimulated insulin production, kG, HbA1C and fasting glucose did not change significantly. Insulin resistance (HOMA-R) of the whole group increased significantly, mainly due to a rise in HOMA-R in patients on steroids (n = 18). None of these patients developed overt diabetes mellitus. Some 40% of long-term cyclosporine-treated patients had an abnormal glucose metabolism. Conversion from cyclosporine to tacrolimus does not negatively influence stimulated glucose metabolism or insulin resistance in stable, steroid-free renal transplant recipients. However, in patients receiving steroids, conversion leads to an increase in insulin resistance while insulin output remains the same.

The Impact of Renal Allograft Function on Exposure and Elimination of Mycophenolic Acid (MPA) and Its Metabolite MPA 7-O-glucuronide

Previous studies have shown that total-body clearance of mycophenolic acid (MPA) is increased and total MPA exposure decreased in renal allograft recipients with severe renal dysfunction. In contrast to these studies, other studies have associated renal impairment with higher MPA exposure. The reason for these inconsistencies is not clear. In 120 renal allograft recipients with stable graft function and treated with a combination of mycophenolate mofetil, tacrolimus, and corticosteroids, clinical determinants of exposure to total MPA and its glucuronide metabolite MPA 7-O-glucuronide (MPAG) were investigated in a multivariate regression model at 3 (n=118) and 12 (n=63) months after transplantation. Almost 50% of total MPA exposure could be explained by the final model, in which proteinuria, glomerular filtration rate, diabetes mellitus, and the mycophenolate mofetil dose were independent determinants of total MPA exposure. Lower glomerular filtration rate (GFR) was independently associated with higher MPA exposure both at 3 and 12 months after transplantation. GFR, alanine aminotransferase, and serum albumin levels and mycophenolate mofetil dose explained 69% of total MPAG exposure variability. In stable renal recipients, total MPA exposure negatively associates with renal function, through accumulation of both MPA and MPAG in patients with moderately reduced renal allograft function. This is in contrast to severe graft dysfunction, where MPA clearance is higher due to increased free fraction of MPA, as shown in previous studies. The duality in the effect of graft function on MPA pharmacokinetics is of clinical importance, adjusting mycophenolate mofetil dose according to renal function might help to avoid side effects and improve efficacy.

Assessment of the Bioequivalence of a Generic Cyclosporine A by a Randomized Controlled Trial in Stable Renal Recipients

The aim of this study was to determine the bioequivalence of Cysporin, a generic cyclosporine A, compared with Neoral in stable renal transplant recipients. Study design consisted of an open label, two-way crossover, randomized controlled trial of Cysporin versus Neoral in stable renal transplant recipients. In all, 33 patients were enrolled; 31 were randomized and 28 were evaluable. AUCs(0-12) were done on day 14 and 28; C(0) and C(2) were done on days 0, 7, 21 and 35. Dose conversion was 1:1. Outcome measures for serum cyclosporin A concentrations expressed as the mean+/-SD were AUC(0-12) (microg x hr/L), C(max) (microg/L), C(2) (microg/L), T(max) (hr) and T(1/2) (hr). Mean and 90% CI of the ratio Cysporin/Neoral of log-transformed data were calculated using a general linear model. The main pharmacokinetic features were: AUC(0-12): Cysporin 3495+/-1319, Neoral 3853+/-1378 (P<0.05); C(max): Cysporin 755+/-301, Neoral 881+/-368 (P<0.05); C(2): Cysporin 613+/-235, Neoral 672+/-255 (P>0.05); T(max): Cysporin 1.9+/-0.8, Neoral 1.4+/-0.6 (P<0.005); and T1/2: Cysporin 8.8+/-4.3, Neoral 8.7+/-6.2 (P>0.05). Estimated ratios of Cysporin/Neoral were: AUC 0.93 (90% CI 0.88-0.98; P<0.05); C(max) 0.88 (90% CI 0.80-0.97; P<0.05); and T(max) 1.32 (90% CI 1.14-1.53; P<0.005). Both the extent and rate of absorption of Cysporin are significantly less than those of Neoral. The 90% CI for the ratios of Cysporin/Neoral for AUC and C(max) lie within 0.80-1.25. Hence in this clinical context Cysporin is pharmacologically bioequivalent with Neoral. This study illustrates the importance of testing bioequivalence of generic cyclosporine A products in transplant recipients not healthy volunteers.

Do Blood Pressure and Arterial Wall Properties Change After Conversion From Cyclosporine to Tacrolimus?

Cardiovascular disease is the leading cause of death in renal transplant recipients. Arterial wall properties are surrogate markers for arteriosclerosis. Previous investigations have shown that the cardiovascular risk profile is better with tacrolimus compared to cyclosporine. Renal function, blood pressure, and lipid levels improve. The hypothesis is that arterial wall properties will improve after conversion from cyclosporine to tacrolimus. Thirty-four stable renal recipients were converted from cyclosporine microemulsion to tacrolimus without changing concomitant medication. Before and after conversion we performed wall track ultrasounds of the carotid and the brachial arteries; pulse wave velocity (PWV); laboratory investigations; 24-hour ABPM; estimates of renal function; and Framingham risk scores. After conversion the 24-hour ambulatory blood pressure monitoring (ABPM) did not change. Total cholesterol, LDL cholesterol, and triglycerides improved significantly. Renal function (Cockroft) improved. There were no significant changes in arterial wall properties, or in PWV. Framingham comparative risk scores improved only significantly in patients not receiving statins. In conclusion, 3 months after conversion from cyclosporine to tacrolimus total cholesterol, LDL cholesterol, and triglycerides were significantly decreased and renal function significantly improved. Contrary to expectation, ABPM did not change, probably due to prolonged use (>10 years) of cyclosporine. There was also no difference in arterial wall properties.

Evaluating mechanisms of post-transplant diabetes mellitus

Post-transplant diabetes mellitus (PTDM) is a frequent complication in renal transplantation. While both tacrolimus and ciclosporin are known to be associated with PTDM, the mechanisms underlying this metabolic disturbance and the relative contribution of concomitant corticosteroids have been unclear. At the University Hospital Maastricht, a series of studies have been conducted to investigate these issues. Administering tacrolimus to non-diabetic, dialysis patients was shown to result in a dose-related reduction in insulin secretion without altering insulin resistance. The patients who developed diabetes after transplantation already had impaired glucose metabolism pre-transplant. In a second study, corticosteroid withdrawal from tacrolimus-based immunosuppression reduced insulin resistance without changing insulin secretion. Moreover, reducing tacrolimus blood levels by 30% within the therapeutic window increased both insulin and C-peptide secretion by 24 and 36%, respectively. Accordingly, the effects of tacrolimus on insulin secretion are both dose dependent and reversible. A comparison of the effects of tacrolimus and ciclosporin on glucose metabolism revealed reduced insulin release with tacrolimus at week 3 post-transplant, but for the remainder of the 3 year follow-up there were no significant differences between the two treatment arms. Also, no difference was reported in glucose metabolism following conversion of stable renal recipients from ciclosporin to tacrolimus. Therefore, replacing tacrolimus with ciclosporin in patients experiencing glucose metabolism disturbances is unlikely to be helpful. In a recent study, early corticosteroid withdrawal from tacrolimus-based therapy resulted in a significantly lower incidence of new-onset diabetes mellitus than that achieved with a corticosteroid dose-tapering regimen. In conclusion, corticosteroid minimization plus dose-optimized tacrolimus immunosuppression is likely to be the best option for patients at risk of developing PTDM.

DOES BLOODPRESSURE AND ARTERIAL WALL PROPERTIES CHANGE AFTER CONVERSION FROM CYCLOSPORIN TO TACROLIMUS

P205 Aims: Cardiovascular disease is the leading cause of death in renal transplant recipients. Previous investigations have shown that the cardiovascular risk profile is better in patients treated with tacrolimus: they have a higher creatinine clearance, lower blood pressure and lower lipids compared to patients treated with cyclosporin. The hypothesis is that also the arterial wall properties will improve after conversion from cyclosporin to tacrolimus. Methods: 25 stable renal recipients, > 1 year post renal transplant, were converted from cyclosporin to tacrolimus without changing concomitant medication. Before and 3 months after conversion the following investigations were performed: Wall track measurements (distensibility coefficient[DC] and intima media thickness [IMT]) at both carotid and brachial artery, Pulse Wave Velocity, 24-hours blood pressure measurements, Creatinine Clearance (Cockcroft), and serum LDL-cholesterol. Results: Data are shown in the table. Dipper = >10% decrease of MAP during night-time p <0.001FigureConclusions: Conversion from cyclosporin to tacrolimus resulted in a significant improvement of the median LDL-cholesterol and renal function. Blood pressure rhythm normalized. However in this cohort 24 hr blood pressure and arterial wall properties remained unchanged.

Feasibility of changing therapeutic cyclosporine monitoring from C 0 to C 2 in stable renal recipients: narrower coefficient of variation with C 2 monitoring

Feasibility of changing therapeutic cyclosporine monitoring from C 0 to C 2 in stable renal recipients: narrower coefficient of variation with C 2 monitoring