Graeme Russ

A Systematic Review of Conversion From Calcineurin Inhibitor to Mammalian Target of Rapamycin Inhibitors for Maintenance Immunosuppression in Kidney Transplant Recipients

This was a systematic review of randomized controlled trials comparing delayed conversion of mammalian target of rapamycin inhibitors (mTORi) for calcineurin inhibitors (CNIs) versus CNI continuation in kidney transplantation. Databases (2000–2012) and conference abstracts (2009–2012) were searched giving a total of 29 trials. Outcomes analyzed included GFR, graft loss, rejection and adverse events and were expressed as weighted mean differences (WMDs) or as risk ratios (RRs). Patients converted to mTORi up to 1 year posttransplant in intention‐to‐treat analysis had higher GFR compared with those remaining on CNI (WMD 0.28u2009mL/min/1.73u2009m2, 95% confidence interval [CI] 0.21–0.36; I2u2009=u200968%, pu2009<u20090.001). Stratifying trials by time posttransplant or type of mTORi did not change the overall heterogeneity. For on‐treatment population, mTORi was associated with higher GFR (14.21u2009mL/min/1.73u2009m2, 10.34–18.08; I2u2009=u20090%, pu2009=u20090.970) 2–5 years posttransplant. The risk of rejection at 1 year was higher in mTORi trials (RR 1.72, 1.34–2.22; I2u2009=u200912%, pu2009=u20090.330). Discontinuation secondary to adverse events was more common in patients on mTORi, whereas the incidence of skin cancers and cytomegalovirus infection was lower in patients on mTORi. Conversion from CNI to mTORi is associated with short‐term improvements in GFR in a number of studies but longer‐term follow‐up data of graft and patient survival are required.

A randomized, controlled trial of everolimus‐based dual immunosuppression versus standard of care in de novo kidney transplant recipients

Kidney transplant recipients receiving calcineurin inhibitor‐based immunosuppression incur increased long‐term risks of cancer and kidney fibrosis. Switch to mammalian target of rapamycin (mTOR) inhibitors may reduce these risks. Steroid or Cyclosporin Removal After Transplant using Everolimus (SOCRATES), a 36‐month, prospective, multinational, open‐label, randomized controlled trial for de novo kidney transplant recipients, assessed whether everolimus switch could enable elimination of mycophenolate plus either steroids or CNI without compromising efficacy. Patients received cyclosporin, mycophenolate and steroids for the first 14 days then everolimus with mycophenolate and CNIwithdrawal (CNI‐WD); everolimus with mycophenolate and steroid withdrawal (steroid‐WD); or cyclosporin, mycophenolate and steroids (control). 126 patients were randomized. The steroid WD arm was terminated prematurely because of excess discontinuations. Mean eGFR at month 12 for CNI‐WD versus control was 65.1 ml/min/1.73 m2 vs. 67.1 ml/min/1.73 m2 by ITT, which met predefined noninferiority criteria (P = 0.026). The CNI‐WD group experienced a higher rate of BPAR(31% vs. control 13%, P = 0.048) and showed a trend towards higher composite treatment failure (BPAR, graft loss, death, loss to follow‐up). The 12 month results from SOCRATES show noninferiority in eGFR, but a significant excess of acute rejection when everolimus was commenced at week 2 to enable a progressive withdrawal of mycophenolate and cyclosporin in kidney transplant recipients.

Efficacy of Sotrastaurin Plus Tacrolimus After De Novo Kidney Transplantation : Randomized, Phase II Trial Results

Sotrastaurin, a novel immunosuppressant, blocks early T cell activation through protein kinase C inhibition. Efficacy and safety of sotrastaurin with tacrolimus were assessed in a dose‐ranging non‐inferiority study in renal transplant recipients. A total of 298 patients were randomized 1:1:1:1 to receive sotrastaurin 100 (nu2009=u200977; discontinued in December 2011) or 200u2009mg (nu2009=u200973) b.i.d. plus standard tacrolimus (sTAC; 5–12u2009ng/mL), sotrastaurin 300u2009mg (nu2009=u200975) b.i.d. plus reduced tacrolimus (rTAC; 2–5u2009ng/mL) or enteric‐coated mycophenolic acid (MPA) plus sTAC (nu2009=u200973); all patients received basiliximab and corticosteroids. Composite efficacy failure (treated biopsy‐proven acute rejectionu2009≥u2009grade IA, graft loss, death or loss to follow up) rates at Month 12 were 18.8%, 12.4%, 10.9% and 14.0% for the sotrastaurin 100, 200 and 300u2009mg, and MPA groups, respectively. The median estimated glomerular filtration rates were 55.7, 53.3, 64.9 and 59.2u2009mL/min, respectively. Mean heart rates were faster with higher sotrastaurin doses and discontinuations due to adverse events and gastrointestinal adverse events were more common. Fewer patients in the sotrastaurin groups experienced leukopenia than in the MPA group (1.3–5.5% vs. 16.5%). Sotrastaurin 200 and 300u2009mg had comparable efficacy to MPA in prevention of rejection with no significant difference in renal function between the groups.

Human leukocyte antigen mismatches associated with increased risk of rejection, graft failure, and death independent of initial immunosuppression in renal transplant recipients

Human leukocyte antigen (HLA) mismatches have been shown to adversely affect renal allograft outcomes and remain an important component of the allocation of deceased donor (DD) kidneys. The ongoing importance of HLA mismatches on transplant outcomes in the era of more potent immunosuppression remains debatable. Using Australia and New Zealand Dialysis and Transplant Registry, live and DD renal transplant recipients between 1998 and 2009 were examined. The association between the number of HLA mismatches and HLA‐loci mismatches and outcomes were examined. Of the 8036 renal transplant recipients, 59% had between 2 and 4 HLA mismatches. Compared with 0 HLA mismatch, increasing HLA mismatches were associated with a higher risk of graft failure and patient death in the adjusted models. HLA mismatches were associated with an incremental risk of rejection although the relative risk was higher for live donor kidney transplants. Increasing HLA‐AB and HLA‐DR mismatches were associated with a greater risk of acute rejection, graft failure, death‐censored graft failure, and/or death. There was no consistent association between initial immunosuppressive regimen and outcomes. Our results corroborate and extend the previous registry analyses demonstrating that HLA mismatches are associated with poorer transplant outcomes independent of immunosuppression and transplant era.

Sotrastaurin in Calcineurin Inhibitor–Free Regimen Using Everolimus in De Novo Kidney Transplant Recipients

Sotrastaurin, a novel selective protein‐kinase‐C inhibitor, inhibits early T cell activation via a calcineurin‐independent pathway. Efficacy and safety of sotrastaurin in a calcineurin inhibitor—free regimen were evaluated in this two‐stage Phase II study of de novo kidney transplant recipients. Stage 1 randomized 131 patients (2:1) to sotrastaurin 300u2009mg or cyclosporine A (CsA). Stage 2 randomized 180 patients (1:1:1) to sotrastaurin 300 or 200u2009mg or CsA. All patients received basiliximab, everolimus (EVR) and prednisone. Primary endpoint was composite efficacy failure rate of treated biopsy‐proven acute rejection, graft loss, death or lost to follow‐up. Main safety assessment was estimated glomerular filtration rate (eGFR) by MDRD‐4 at Month 12. Composite efficacy failure rates at 12 months were higher in sotrastaurin arms (Stage 1: 16.5% and 10.9% for sotrastaurin 300u2009mg and CsA; Stage 2: 27.2%, 34.5% and 19.4% for sotrastaurin 200u2009mg, 300u2009mg and CsA). eGFR was significantly better in sotrastaurin groups versus CsA at most time points, except at 12 months. Gastrointestinal and cardiac adverse events were more frequent with sotrastaurin. Higher treatment discontinuation, deaths and graft losses occurred with sotrastaurin 300u2009mg. Sotrastaurin combined with EVR showed higher efficacy failure rates and some improvement in renal allograft function compared to a CsA‐based therapy.

KHA‐CARI guideline: KHA‐CARI adaptation of the KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients

The latest Caring for Australians with Renal Impairment (CARI) guideline detailing renal transplant care, developed as a local modification of the Kidney Disease Improving Global Outcomes (KDIGO) guidelines.

Evaluation of the Effect of Tofacitinib Exposure on Outcomes in Kidney Transplant Patients

Tofacitinib fixed‐dose regimens attained better kidney function and comparable efficacy to cyclosporine (CsA) in kidney transplant patients, albeit with increased risks of certain adverse events. This post‐hoc analysis evaluated whether a patient subgroup with an acceptable risk‐benefit profile could be identified. Tofacitinib exposure was a statistically significant predictor of serious infection rate. One‐hundred and eighty six kidney transplant patients were re‐categorized to above‐median (AME) or below‐median (BME) exposure groups. The 6‐month biopsy‐proven acute rejection rates in AME, BME and CsA groups were 7.8%, 15.7% and 17.7%, respectively. Measured glomerular filtration rate was higher in AME and BME groups versus CsA (61.2 and 67.9 vs. 53.9u2009mL/min) at Month 12. Fewer patients developed interstitial fibrosis and tubular atrophy (IF/TA) at Month 12 in AME (20.5%) and BME (27.8%) groups versus CsA (48.3%). Serious infections occurred more frequently in the AME group (53.0%) than in BME (28.4%) or CsA (25.5%) groups. Posttransplant lymphoproliferative disorder (PTLD) only occurred in the AME group. In kidney transplant patients, the BME group preserved the clinical advantage of comparable acute rejection rates, improved renal function and a lower incidence of IF/TA versus CsA, and with similar rates of serious infection and no PTLD.

Early conversion from calcineurin inhibitor- to everolimus-based therapy following kidney transplantation: Results of the randomized ELEVATE trial

In a 24‐month, multicenter, open‐label, randomized trial, 715 de novo kidney transplant recipients were randomized at 10–14 weeks to convert to everolimus (n = 359) or remain on standard calcineurin inhibitor (CNI) therapy (n = 356; 231 tacrolimus; 125 cyclosporine), all with mycophenolic acid and steroids. The primary endpoint, change in estimated glomerular filtration rate (eGFR) from randomization to month 12, was similar for everolimus versus CNI: mean (standard error) 0.3(1.5) mL/min/1.732 versus −1.5(1.5) mL/min/1.732 (p = 0.116). Biopsy‐proven acute rejection (BPAR) at month 12 was more frequent under everolimus versus CNI overall (9.7% vs. 4.8%, p = 0.014) and versus tacrolimus‐treated patients (2.6%, p < 0.001) but similar to cyclosporine‐treated patients (8.8%, p = 0.755). Reporting on de novo donor‐specific antibodies (DSA) was limited but suggested more frequent anti‐HLA Class I DSA under everolimus. Change in left ventricular mass index was similar. Discontinuation due to adverse events was more frequent with everolimus (23.6%) versus CNI (8.4%). In conclusion, conversion to everolimus at 10–14 weeks posttransplant was associated with renal function similar to that with standard therapy overall. Rates of BPAR were low in all groups, but lower with tacrolimus than everolimus.

HLA-DQ Mismatches and Rejection in Kidney Transplant Recipients

BACKGROUND AND OBJECTIVESnThe current allocation algorithm for deceased donor kidney transplantation takes into consideration HLA mismatches at the ABDR loci but not HLA mismatches at other loci, including HLA-DQ. However, the independent effects of incompatibilities for the closely linked HLA-DQ antigens in the context of HLA-DR antigen matched and mismatched allografts are uncertain. We aimed to determine the effect of HLA-DQ mismatches on renal allograft outcomes.nnnDESIGN, SETTING, PARTICIPANTS, & MEASUREMENTSnUsing data from the Australia and New Zealand Dialysis and Transplant Registry, we examined the association between HLA-DQ mismatches and acute rejections in primary live and deceased donor kidney transplant recipients between 2004 and 2012 using adjusted Cox regression models.nnnRESULTSnOf the 788 recipients followed for a median of 2.8 years (resulting in 2891 person-years), 321 (40.7%) and 467 (59.3%) received zero and one or two HLA-DQ mismatched kidneys, respectively. Compared with recipients who have received zero HLA-DQ mismatched kidneys, those who have received one or two HLA-DQ mismatched kidneys experienced greater numbers of any rejection (50 of 321 versus 117 of 467; P<0.01), late rejections (occurring >6 months post-transplant; 8 of 321 versus 27 of 467; P=0.03), and antibody-mediated rejections (AMRs; 12 of 321 versus 38 of 467; P=0.01). Compared with recipients of zero HLA-DQ mismatched kidneys, the adjusted hazard ratios for any and late rejections in recipients who had received one or two HLA-DQ mismatched kidneys were 1.54 (95% confidence interval [95% CI], 1.08 to 2.19) and 2.85 (95% CI, 1.05 to 7.75), respectively. HLA-DR was an effect modifier between HLA-DQ mismatches and AMR (P value for interaction =0.02), such that the association between HLA-DQ mismatches and AMR was statistically significant in those who have received one or two HLA-DR mismatched kidneys, with adjusted hazard ratio of 2.50 (95% CI, 1.05 to 5.94).nnnCONCLUSIONSnHLA-DQ mismatches are associated with acute rejection, independent of HLA-ABDR mismatches and initial immunosuppression. Clinicians should be aware of the potential importance of HLA-DQ matching in the assessment of immunologic risk in kidney transplant recipients.

Validation of an LC-MS/MS method for the quantification of mycophenolic acid in human kidney transplant biopsies

Mycophenolic acid (MPA) has a low therapeutic index and large inter-individual pharmacokinetic variability necessitating therapeutic drug monitoring to individualise dosing after transplantation. There is an ongoing discrepancy as to whether plasma MPA concentrations sufficiently predict kidney rejection or toxicity and whether immunosuppressant concentrations within the graft tissue may better predict transplant outcomes. The aim of the study was to develop an LC-MS/MS method for the quantification of MPA concentrations in human kidney biopsies taken as part of routine clinical procedures. A total of 4 surplus human kidney biopsies obtained from 4 different kidney transplant recipients were available to use for this study. MPA was also quantified in 2 kidney samples from rats administered MPA to assess tissue extraction reproducibility. Human kidney biopsies and rat kidneys were homogenised mechanically and underwent liquid-liquid extraction before analysis by LC-MS/MS. MPA-free human kidney tissue was used in calibrators and quality control samples. Analyte detection was achieved from multiple reaction monitoring of the ammonium adducts of both MPA (m/z 321.1→207.3) and N-phthaloyl-l-phenylalanine (PPA, internal standard, m/z 296.2→250.2) using positive electrospray ionisation. The method was linear (calibration curves R(2)>0.99, n=10), precise, and accurate with coefficients of variation and bias less than 15%. Extraction efficiencies for MPA and PPA were approximately 97% and 86%, respectively, and matrix effects were minimal. In 4 kidney transplant recipients, tissue MPA concentrations ranged from 1.3 to 7.7ng/mg of tissue, however, the correlation between blood (C0) and tissue MPA concentrations could not be established. The method was successfully applied to the quantification of MPA in human kidney biopsies without the need to alter current clinical protocols.