Richard Borrows

Mycophenolic acid 12-h trough level monitoring in renal transplantation: association with acute rejection and toxicity.

Studies of renal transplantation utilizing trough plasma level monitoring of mycophenolic acid (MPA) have shown inconsistent associations with toxicity and rejection.

Meta-Analysis of Calcineurin-Inhibitor-Sparing Regimens in Kidney Transplantation

Calcineurin-inhibitor-sparing strategies in kidney transplantation may spare patients the adverse effects of these drugs, but the efficacy of these strategies is unknown. Here, we conduct a meta-analysis to assess outcomes associated with reducing calcineurin inhibitor exposure from the time of transplantation. We search Medline, Embase, and Cochrane Register of Controlled Trials for randomized controlled trials published between 1966 and 2010 that compared de novo calcineurin-inhibitor-sparing regimens to calcineurin-inhibitor-based regimens. In this analysis, we include 56 studies comprising data from 11337 renal transplant recipients. Use of the contemporary agents belatacept or tofacitinib, in combination with mycophenolate, decreased the odds of overall graft failure (OR 0.61; 95% CI 0.39-0.96; P = 0.03). Similarly, minimization of calcineurin inhibitors in combination with various induction and adjunctive agents reduces the odds of graft failure (OR 0.73; 95% CI 0.58-0.92; P = 0.009). Conversely, the use of inhibitors of mammalian target of rapamycin (mTOR), in combination with mycophenolate, increases the odds of graft failure (OR 1.43; 95% CI 1.08-1.90; P = 0.01). Calcineurin-inhibitor-sparing strategies are associated with less delayed graft function (OR 0.89; 95% CI 0.80-0.98; P = 0.02), improved graft function, and less new-onset diabetes. The more contemporary protocols did not seem to increase rates of acute rejection. In conclusion, this meta-analysis suggests that reducing exposure to calcineurin inhibitors immediately after kidney transplantation may improve clinical outcomes.

Calcineurin inhibitor sparing with mycophenolate in kidney transplantation: a systematic review and meta-analysis

Background. Limiting the exposure of kidney transplant recipients to calcineurin inhibitors (CNIs) has potential merit, but there is no clear consensus on the utility of current strategies. In an attempt to aid clarification, we conducted a systematic review and meta-analysis of randomized trials that assessed CNI sparing (minimization or elimination) with mycophenolate as sole adjunctive immunosuppression. Methods. The search strategy identified trials where CNI sparing was accompanied by the continuation of, or conversion to, mycophenolate and compared with standard or higher dose CNI therapy. Two investigators independently examined each trial for eligibility, quality, and outcome measures. Additional subgroup analyses were assessed: (1) de novo CNI sparing; (2) elective CNI sparing beyond 2 months posttransplantation; and (3) CNI sparing for transplant dysfunction. Results. Nineteen randomized controlled trials met the inclusion criteria permitting analysis of 3312 renal transplant recipients with median follow-up of 12 months. CNI sparing significantly improved glomerular filtration rate (weighted mean difference 4.4 mL/min, 95% confidence interval [CI] 2.9–5.9, P<0.001); with some evidence, albeit weak, of improved graft survival (odds ratio 0.72, 95% CI 0.52–1.01, P=0.06). Acute rejection rates were only increased after elective CNI elimination (odds ratio 2.23, 95% CI 1.57–3.17, P<0.001). There were no significant differences in mortality, malignancy or incidence of infections. Conclusions. CNI sparing strategies with adjunctive mycophenolate may play an important role in kidney transplant recipients. Improvements in short-term graft function, and possibly graft survival, are achievable. Longer term studies are needed to substantiate the short-term benefits, and refining elective CNI elimination protocols may help to reduce the risk of rejection.

Donor ABCB1 Variant Associates with Increased Risk for Kidney Allograft Failure

The impact of variation within genes responsible for the disposition and metabolism of calcineurin inhibitors (CNIs) on clinical outcomes in kidney transplantation is not well understood. Furthermore, the potential influence of donor, rather than recipient, genotypes on clinical endpoints is unknown. Here, we investigated the associations between donor and recipient gene variants with outcome among 4471 white, CNI-treated kidney transplant recipients. We tested for 52 single-nucleotide polymorphisms (SNPs) across five genes: CYP3A4, CYP3A5, ABCB1 (MDR1; encoding P-glycoprotein), NR1I2 (encoding the pregnane X receptor), and PPIA (encoding cyclophilin). In a discovery cohort of 811 patients from Birmingham, United Kingdom, kidney donor CC genotype at C3435T (rs1045642) within ABCB1, a variant known to alter protein expression, was associated with an increased risk for long-term graft failure compared with non-CC genotype (hazard ratio [HR], 1.69; 95% confidence interval [CI], 1.20-2.40; P=0.003). No other donor or recipient SNPs were associated with graft survival or mortality. We validated this association in 675 donors from Belfast, United Kingdom (HR, 1.68; 95% CI, 1.21-2.32; P=0.002), and in 2985 donors from the Collaborative Transplant Study (HR, 1.84; 95% CI, 1.08-3.13; P=0.006). In conclusion, these data suggest that an ABCB1 variant known to alter protein expression represents an attractive candidate for future study and risk stratification in kidney transplantation.

Association of Caveolin-1 Gene Polymorphism With Kidney Transplant Fibrosis and Allograft Failure

CONTEXT Caveolin-1 (CAV1) is an inhibitor of tissue fibrosis. OBJECTIVE To study the association of CAV1 gene variation with kidney transplant outcome, using kidney transplantation as a model of accelerated fibrosis. DESIGN, SETTING, AND PATIENTS Candidate gene association and validation study. Genomic DNA from 785 white kidney transplant donors and their respective recipients (transplantations in Birmingham, England, between 1996 and 2006; median follow-up, 81 months) were analyzed for common variation in CAV1 using a single-nucleotide polymorphism (SNP) tagging approach. Validation of positive findings was sought in an independent kidney transplant donor-recipient cohort (transplantations in Belfast, Northern Ireland, between 1986 and 2005; n = 697; median follow-up, 69 months). Association between genotype and allograft failure was initially assessed by Kaplan-Meier analysis, then in an adjusted Cox model. MAIN OUTCOME MEASURE Death-censored allograft failure, defined as a return to dialysis or retransplantation. RESULTS The presence of donor AA genotype for the CAV1 rs4730751 SNP was associated with increased risk of allograft failure in the Birmingham group (donor AA vs non-AA genotype in adjusted Cox model, hazard ratio [HR], 1.97; 95% confidence interval [CI], 1.29-3.16; P = .002). No other tag SNPs showed a significant association. This finding was validated in the Belfast cohort (in adjusted Cox model, HR, 1.56; 95% CI, 1.07-2.27; P = .02). Overall graft failure rates were as follows: for the Birmingham cohort, donor genotype AA, 22 of 57 (38.6%); genotype CC, 96 of 431 (22.3%); and genotype AC, 66 of 297 (22.2%); and for the Belfast cohort, donor genotype AA, 32 of 48 (67%); genotype CC, 150 of 358 (42%); and genotype AC, 119 of 273 (44%). CONCLUSION Among kidney transplant donors, the CAV1 rs4730751 SNP was significantly associated with allograft failure in 2 independent cohorts.

Delayed Graft Function After Kidney Transplantation: The Clinical Perspective

Delayed graft function continues to pose a significant challenge to clinicians in the context of kidney transplantation. With the present disparity between supply and demand for organs, transplantation is proceeding with more marginal kidneys and therefore the problem of delayed graft function is likely to increase in the future. Although our understanding of the mechanism and risk factors for delayed graft function has improved, translation of this understanding into targeted clinical therapy to attenuate or manage established delayed graft function has been elusive. Based on current trends, the use of kidneys from expanded criteria or cardiac death donors will continue to expand, which will increase the prevalence of delayed graft function in the immediate postoperative setting. The aim of this article is to discuss and critique the available clinical evidence for targeted intervention in the prevention and management of delayed graft function and review emerging and experimental therapies.

Determinants of mycophenolic acid levels after renal transplantation.

There are data suggesting an association between mycophenolic acid (MPA) levels and acute rejection and toxicity in renal transplant recipients treated with mycophenolate mofetil (MMF), and therefore, knowledge of factors determining MPA levels may aid in accurate adjustment of MMF dosage. A total of 4970 samples taken 12 hours postdose were analyzed for MPA by immunoassay at regular intervals from the first week posttransplantation in 117 renal transplant patients immunosuppressed with MMF and tacrolimus in a steroid-sparing regimen (prednisolone for the first 7 days only). MPA levels rose in the first 3 months and stabilized thereafter; dose-normalized MPA levels rose throughout the first 12 months and subsequently stabilized. Multivariate analysis by means of a population-averaged linear regression showed positive associations between MPA level and total daily dose (P < 0.001) but not individual dose or total daily dose corrected for body weight. Positive associations were also seen with serum albumin (P = 0.01), tacrolimus trough level (P = 0.01), and female gender (P = 0.002). The association with tacrolimus levels diminished with time. Negative associations were seen between MPA level and higher estimated creatinine clearance (P < 0.001), and also with increasing alanine transaminase levels (P = 0.002), the use of oral antibiotics (P < 0.001), and infective diarrhea (P < 0.001). The latter findings may be related to changes in enterohepatic recirculation of MPA. Many clinical variables show associations with trough MPA levels. An understanding of these factors may aid therapeutic monitoring of MMF.

Transitional B lymphocytes are associated with protection from kidney allograft rejection: a prospective study.

Recent cross‐sectional studies suggest an important role for transitional B lymphocytes (CD19 + CD24hiCD38hi) in promoting transplant tolerance, and protecting from late antibody‐mediated rejection (ABMR). However, prospective studies are lacking. This study enrolled 73 de novo transplant recipients, and collected serial clinical, immunological and biochemical information over 48 ± 6 months. Cell phenotyping was conducted immediately prior to transplantation, and then on five occasions during the first year posttransplantation. When modeled as a time‐dependent covariate, transitional B cell frequencies (but not total B cells or “regulatory” T cells) were associated with protection from acute rejection (any Banff grade; HR: 0.60; 95% CI: 0.37–0.95; p = 0.03). No association between transitional B cell proportions and either de novo donor‐specific or nondonor‐specific antibody (dnDSA; dnNDSA) formation was evident, although preserved transitional B cell proportions were associated with reduced rejection rates in those patients developing dnDSA. Three episodes of ABMR occurred, all in the context of nonadherence, and all associated with in vitro anti‐HLA T cell responses in an ELISPOT assay (p = 0.008 versus antibody‐positive patients not experiencing ABMR). This prospective study supports the potential relevance of transitional (“regulatory”) B cells as a biomarker and therapeutic intervention in transplantation, and highlights relationships between humoral immunity, cellular immunity and nonadherence.

Validity of glycated haemoglobin to diagnose new onset diabetes after transplantation

Diagnosing new onset diabetes after transplantation (NODAT) by glycated haemoglobin (HbA1c) has not been validated against the gold‐standard oral glucose tolerance test (OGTT). We analysed the predictive and optimum value of HbA1c to diagnose NODAT amongst nondiabetic renal transplant recipients. Assessment of glucose metabolism (OGTT and HbA1c) was prospectively undertaken at 3 and 12 months post‐transplantation in 71 nondiabetic renal transplant recipients. Receiver operator characteristic (ROC) curve analyses were performed to determine accuracy, sensitivity, specificity and area under curve (c‐statistic). Incidence of NODAT at 3 and 12 months post‐transplantation was 14.3% and 9.5% respectively. At 3 months, optimum HbA1c cut‐off value for predicting NODAT based on fasting glucose was 7.35 [AUC 1.00 (sensitivity 100.0%, specificity 100.0%, P = 0.004)] and for postprandial glucose‐defined NODAT was 6.20 [AUC 0.98 (sensitivity 100.0%, specificity 88.9%, P < 0.001)]. At 12 months, optimum HbA1c cut‐off value for both fasting‐ and postprandial glucose‐defined NODAT was 6.45 [AUC 0.92 (sensitivity 100.0%, specificity 87.5%, P = 0.048) and AUC 0.84 (sensitivity 75.0%, specificity 89.5%, P = 0.026) respectively]. Concordance between diagnosis of NODAT (OGTT+, HbA1c+) and nondiagnosis of NODAT (OGTT−, HbA1c−) was 88.9% and 98.7% respectively. To conclude, HbA1c (≥6.5%) can be utilized to diagnose NODAT beyond 3 months post‐transplantation but the OGTT remains the gold‐standard tool.

Comparison of the Predictive Performance of eGFR Formulae for Mortality and Graft Failure in Renal Transplant Recipients

Background. To date, efforts have focused on assessing estimated glomerular filtration rate (eGFR) formulae against measured GFR. However, a more appropriate clinical gold standard is one conveying a defined clinical disadvantage. In renal transplantation, these measures are mortality and graft failure. Methods. The Long Term Efficacy and Safety Surveillance database was used to analyze 1344 renal transplant recipients. eGFR was assessed 6 months posttransplantation with the following formulae: Cockcroft-Gault; Walser; Nankivell; abbreviated modification of diet in renal disease (aMDRD); MDRD7; Rules refitted MDRD; and Mayo Clinic. The outcome measures were mortality and graft failure. Results. Although eGFR was statistically associated with subsequent mortality and graft failure in the Cox model (irrespective of which eGFR formula was used), the clinical utility of eGFR was moderate at best in predicting subsequent mortality and graft failure. No clinically relevant or statistically significant difference was discernable between formulae, with a maximum area under the receiver operating characteristic curve of 0.63 and 0.61 for 3- and 5-year mortality, respectively, and 0.66 and 0.60 for 3- and 5-year graft failure, respectively. Serum creatinine used in isolation displayed similar predictive utility, and no improvement was seen by investigating the change in creatinine or eGFR between 6 and 12 months. Conclusions. In summary, seven eGFR equations showed similar and limited utility in predicting mortality and graft failure after renal transplantation. This has important implications for the management of renal transplant recipients and the use of an eGFR as a surrogate endpoint in clinical trials.