Andrew Ready

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.

Comparison of microemulsion and conventional formulations of cyclosporine A in preventing acute rejection in de novo kidney transplant patients. The U.K. Neoral Renal Study Group.

Background. The microemulsion preconcentrate formulation of cyclosporine A (CsA) (Neoral) exhibits more uniform pharmacokinetics than the conventional formulation (Sandimmun; SIM). This randomized, open-label, U.K. multicenter study compared the efficacy, safety, and tolerability of Neoral and SIM in preventing acute rejection in de novo renal transplant recipients. Methods. Adult cadaveric kidney recipients (n=293) received Neoral or SIM twice daily for 12 months. Initially identical Neoral and SIM doses were titrated, maintaining trough CsA levels within locally defined therapeutic limits. Results. In the year after transplantation, acute rejection occurred in 34% of the Neoral and 47% of the SIM recipients (P=0.037). In the intent-to-treat population, fewer treatment failures (defined as acute rejection, graft loss, withdrawal, or death) occurred in the Neoral (45%) than the SIM recipients (58%) (P=0.015) and therapeutic CsA levels (≥250 μg/L) were reached faster with Neoral than SIM (P=0.0017). Antibody treatment of refractory rejection was used slightly less in the Neoral group (Neoral: 10%; SIM: 12%). One-year patient and graft survival rates (excluding deaths with functioning grafts) were 95% and 88%, respectively, for Neoral and 96% and 89% for SIM. Both formulations were well tolerated. No differences were observed between therapies in the nature, frequency, or severity of adverse events. Neoral use was not associated with increased nephrotoxicity or excessive immunosuppression. Conclusions. Neoral reduced the incidence of acute rejection compared with SIM, without significant increases in adverse events. This was achieved without altering existing SIM protocols and was attributed to improved absorption of CsA from Neoral and less variability in whole blood CsA concentrations.

Use of Neoral C2 monitoring: a European consensus

Large‐scale clinical trials using C2 monitoring of cyclosporine (CsA) microemulsion (Neoral) in renal transplant recipients have demonstrated low acute rejection rates and good tolerability with a low adverse event profile in a variety of settings: with or without routine induction therapy; in combination with mycophenolate mofetil; with standard‐exposure or low‐exposure Neoral; and in patients with immediate or delayed graft function. In liver transplantation, C2 monitoring significantly reduces the severity and incidence of acute rejection compared with C0 monitoring, without adverse consequences in terms of renal function or tolerability. Different C2 targets are appropriate depending on adjunctive immune suppression, level of immunologic risk, CsA tolerability, risk of renal toxicity and time since transplantation. CsA absorption may increase substantially in most patients during the first 1–2 weeks post‐transplant, and this should be taken into account to avoid overshooting C2 target range. A patient with a low C2 value may be either a low or a delayed absorber of CsA, or be a normal absorber who is receiving too low a dose of Neoral. C2 monitoring alone is insufficient to differentiate between these types of patients, and measurement of additional timepoints is recommended. Adopting C2 monitoring in maintenance transplant patients identifies those who are overexposed to CsA. In summary, randomized, prospective, multicenter studies and single‐center trials have evaluated Neoral C2 monitoring within a range of regimens in different organ types, providing a robust evidence base for the benefits of this sensitive monitoring technique.

ABO‐incompatible live donor renal transplantation using blood group A/B carbohydrate antigen immunoadsorption and anti‐CD20 antibody treatment

Abstract: Background: Blood group ABO‐incompatible live donor (LD) renal transplantation may provide a significant source of organs. We report the results of our first 14 cases of ABO‐incompatible LD renal transplantation using specific anti‐A/B antibody (Ab) immunoadsorption (IA) and anti‐CD20 monoclonal Ab (mAb) treatment.

Identification of the optimal donor quality scoring system and measure of early renal function in kidney transplantation.

Background. The early identification of kidney allografts at risk of later dysfunction has implications for clinical practice. Donor quality scoring systems (preoperative) and measures of early allograft function (first week postoperative) have previously shown practical utility. This study aimed to determine the optimal parameter(s) (preoperative and postoperative) with greatest predictive power for the development of subsequent allograft dysfunction. Methods. Consecutive deceased donor renal transplants (n=217) were studied. In each, the following measures were assessed: Preoperative donor quality scores: expanded criteria donor status; Deceased Donor Score (Nyberg et al., Am J Transplant 2003;3:715); Donor Risk Score (Schold et al., Am J Transplant 2005; 5(4 pt 1): 757); and delayed graft function (DGF) Nomogram (Irish et al., J Am Soc Nephrol 2003; 14: 2967). Postoperative early function measures: dialysis requirement and duration; extended DGF definition (Boom et al., Kidney Int 2000; 58: 859); creatinine at day 5 and day 7; creatinine reduction ratios at day 2 and day 7; and urine output posttransplantation. Primary outcome measures were creatinine at 12 months and the development of chronic kidney disease stage 4T. Results. Of donor scoring systems, Donor Risk Score was best associated with subsequent allograft function. Of early function measures: the extended definition of DGF, creatinine at day 5, and dialysis duration showed greatest predictive power in the patient population overall, those not requiring postoperative dialysis, and those requiring dialysis, respectively. No scores or early function measures were associated with change in creatinine between 6 and 12 months. Conclusions. This study validates and identifies the optimal early predictive parameter available for kidney transplant recipients, with implications for refining early postoperative management and potential utility in organ allocation policy.

Organ Trafficking for Live Donor Kidney Transplantation in Indoasians Resident in the West Midlands: High Activity and Poor Outcomes

Introduction. Some Indoasian (IA) patients with established renal failure travel abroad for commercial kidney transplantation. We compared the 1-year outcomes of IA patients from one UK region who received overseas transplants with IA patients receiving local living donor (LD) kidney transplantation, deceased donor (DD) transplantation, and dialysis. Methods. Between 1996 and 2006, 40 adults were transplanted overseas; 38 were IA, and follow-up data were available on 36 patients. Forty IA patients received LD transplants, and 156 patients received DD transplants locally. A cohort of 120 prospective dialysis patients was also used as a comparator group. Results. In the overseas cohort, 20 patients (56%) were not active in the UK transplant waiting list at the time of kidney transplantation overseas. One-year graft survival was 87%, and 1-year patient survival was 83%. Composite graft and patient survival was 69.5% at 1 year. In the local LD transplant recipients, patient survival was 97.5% (39 of 40; P=0.03), and graft survival was 97.5% (39 of 40; P=0.06). Composite graft and patient survival was 95% (P=0.003). In the overseas group, 42% had major infections compared with 15% in the local group (P=0.02). One-year graft survival for DD transplant was 84.6% (132 of 156), and 1-year patient survival was 93% (145 of 156; P=NS and P=0.06, respectively). In the dialysis group, 1-year patient survival was 96.7% (116 of 120; P=0.001). Conclusion. IA patients who choose to travel overseas for kidney transplantation have poor clinical outcomes and should be counseled accordingly.

Optical Clearing in Dense Connective Tissues to Visualize Cellular Connectivity In Situ

Visualizing the three-dimensional morphology and spatial patterning of cells embedded deep within dense connective tissues of the musculoskeletal system has been possible only by utilizing destructive techniques. Here we utilize fructose-based clearing solutions to image cell connectivity and deep tissue-scale patterning in situ by standard confocal microscopy. Optical clearing takes advantage of refractive index matching of tissue and the embedding medium to visualize light transmission through a broad range of bovine and whole mount murine tissues, including cartilage, bone, and ligament, of the head and hindlimb. Using non-destructive methods, we show for the first time intercellular chondrocyte connections throughout the bulk of cartilage, and we reveal in situ patterns of osteocyte processes and the lacunar-canalicular system deep within mineralized cortical bone. Optical clearing of connective tissues is expected to find broad application for the study of cell responses in normal physiology and disease pathology.

Metabolomic analysis of perfusate during hypothermic machine perfusion of human cadaveric kidneys.

Background The metabolic processes occurring within the preserved kidney during hypothermic machine perfusion (HMP) are not well characterized. The aim of this study was to use nuclear magnetic resonance (NMR) spectroscopy to examine the metabolomic profile of HMP perfusate from human cadaveric kidneys awaiting transplantation and to identify possible discriminators between the profiles of kidneys with delayed graft function (DGF) and immediate graft function (IGF). Methods Perfusates from HMP kidneys were sampled at 45 min and 4 hr of preservation with the LifePort Kidney Transporter 1.0 (Organ Recovery Systems, Chicago, IL) using KPS-1. Prepared samples underwent 1-D Proton-NMR spectroscopy, and resultant spectra were analyzed. Clinical parameters were collected prospectively. Results Perfusate of 26 transplanted cadaveric kidneys was analyzed; 19(73%) with IGF and 7(27%) with DGF. Glucose concentrations were significantly lower in DGF kidneys compared to those with IGF at both 45 min (7.772 vs. 9.459 mM, P = 0.006) and 4 hr (8.202 vs. 10.235 mM, P = 0.003). Concentrations of inosine and leucine were significantly different between DGF and IGF kidneys at 45 min (0.002 vs. 0.013 mM, P = 0.009 and 0.011 vs. 0.006 mM, P = 0.036), and gluconate levels were also significantly different between DGF and IGF kidneys at 4 hr (49.099 vs. 59.513 mM, P = 0.009). Conclusion Significant metabolic activity may be occurring in kidneys during HMP. The NMR spectroscopy of the perfusate can identify differences in the metabolomic profiles of DGF and IGF kidneys that might have a predictive role in viability assessment. Modification of harmful metabolic processes may improve outcomes for HMP kidneys.

The use of NGAL and IP‐10 in the prediction of early acute rejection in highly sensitized patients following HLA‐incompatible renal transplantation

Acute rejection is a significant problem for patients undergoing HLA‐incompatible renal transplantation, affecting between 12 and 53% of patients. Any mechanism of detecting rejection in advance of current methods would offer significant benefit. This study aimed to evaluate whether serum biomarkers could predict rejection in HLAi transplants recipients. Sera from 94 HLAi transplant recipients from a single centre were analysed for a panel of biomarkers including: NGAL, KIM‐1, IP‐10, cystatin C, cathepsin L and VEGF. Biomarker levels pre‐operatively, day 1 and at day 30 post‐transplant were correlated with the development of early rejection. Significantly higher levels of IP‐10 and NGAL were seen on day 1 following transplant in those patients who developed acute rejection (P < 0.001 and 0.005) and generated AUC of 0.73 and 0.67, respectively. No differences were seen for the other biomarkers or at the other time points. In this study cohort, IP‐10 and NGAL have demonstrated good predictive ability for the development of acute rejection at a very early time point. They may have a role in identifying patients at higher risk for rejection and stratifying immunosuppression or surveillance.

Urinary biomarkers of acute kidney injury in deceased organ donors--kidney injury molecule-1 as an adjunct to predicting outcome.

Deceased kidney donors are increasingly “marginal,” and many have risk factors for acute kidney injury (AKI) that may impact on subsequent renal transplant outcome. Despite this, determining the presence of AKI at the time of deceased organ donation remains difficult.