Graeme R. Russ

Sirolimus Therapy after Early Cyclosporine Withdrawal Reduces the Risk for Cancer in Adult Renal Transplantation

Sirolimus (SRL) is a mammalian target of rapamycin inhibitor that, in contrast to cyclosporine (CsA), has been shown to inhibit rather than promote cancers in experimental models. At 3 mo +/- 2 wk after renal transplantation, 430 of 525 enrolled patients were randomly assigned to remain on SRL-CsA-steroids (ST) or to have CsA withdrawn and SRL troughs increased two-fold (SRL-ST). Median times to first skin and nonskin malignancies were compared between treatments using a survival analysis. Mean annualized rates of skin malignancy were calculated, and the relative risk was determined using a Poisson model. Malignancy-free survival rates for nonskin malignancies were compared using Kaplan-Meier estimates and the log-rank test. At 5 yr, the median time to a first skin carcinoma was delayed (491 versus 1126 d; log-rank test, P = 0.007), and the risk for an event was significantly lower with SRL-ST therapy (relative risk SRL-ST to SRL-CsA-ST 0.346; 95% confidence interval 0.227 to 0.526; P < 0.001, intention-to-treat analysis). The relative risks for both basal and squamous cell carcinomas were significantly reduced. Kaplan-Meier estimates of nonskin cancer were 9.6 versus 4.0% (SRL-CsA-ST versus SRL-ST; P = 0.032, intention-to-treat analysis). Nonskin cancers included those of the lung, larynx, oropharynx, kidney, gastrointestinal tract, prostate, breast, thyroid, and cervix as well as glioma, liposarcoma, astrocytoma, leukemia, lymphoma, and Kaposis sarcoma. Patients who received SRL-based, calcineurin inhibitor-free therapy after CsA withdrawal at month 3 had a reduced incidence of both skin and nonskin malignancies at 5 yr after renal transplantation compared with those who received SRL therapy combined with CsA. Longer follow-up and additional trials are needed to confirm these promising results.

Early cyclosporine withdrawal from a sirolimus‐based regimen results in better renal allograft survival and renal function at 48 months after transplantation

We report the 48‐month results of a trial testing whether withdrawal of cyclosporine (CsA) from a sirolimus (SRL)‐CsA‐steroid (ST) regimen would impact renal allograft survival. Eligible patients receiving SRL‐CsA‐ST from transplantation were randomly assigned at 3 months to remain on triple therapy (SRL‐CsA‐ST, n = 215) or to have CsA withdrawn and SRL trough concentrations increased (SRL‐ST, n = 215). SRL‐ST therapy resulted in significantly better graft survival, either when including death with a functioning graft as an event (84.2% vs. 91.5%, P = 0.024) or when censoring it (90.6% vs. 96.1%, P = 0.026). Calculated glomerular filtration rate (43.8 vs. 58.3 ml/min, P < 0.001) and mean arterial blood pressure (101.3 vs. 97.1 mmHg, P = 0.047) were also improved with SRL‐ST. Differences in the incidences of biopsy‐proven acute rejection after randomization (6.5% vs. 10.2%, SRL‐CsA‐ST versus SRL‐ST, respectively) and mortality (7.9% vs. 4.7%) were not significant. SRL‐CsA‐ST‐treated patients had significantly higher incidences of adverse events generally associated with CsA, whereas those in the SRL‐ST group experienced greater frequencies of events commonly related to higher trough levels of SRL. In conclusion, early withdrawal of CsA from a SRL‐CsA‐ST regimen rapidly improves renal function and ultimately results in better graft survival.

The ORION study: comparison of two sirolimus-based regimens versus tacrolimus and mycophenolate mofetil in renal allograft recipients.

Safety and efficacy of two sirolimus (SRL)‐based regimens were compared with tacrolimus (TAC) and mycophenolate mofetil (MMF). Renal transplantation recipients were randomized to Group 1 (SRL+TAC; week 13 TAC elimination [n = 152]), Group 2 (SRL + MMF [n = 152]) or Group 3 (TAC + MMF [n = 139]). Group 2, with higher‐than‐expected biopsy‐confirmed acute rejections (BCARs), was sponsor‐terminated; therefore, Group 2 two‐year data were limited. At 1 and 2 years, respectively, graft (Group 1: 92.8%, 88.5%; Group 2: 90.6%, 89.9%; Group 3: 96.2%, 95.4%) and patient (Group 1: 97.3%, 94.4%; Group 2: 95.2%, 94.5%; Group 3: 97.0%, 97.0%) survival rates were similar. One‐ and 2‐year BCAR incidence was: Group 1, 15.2%, 17.4%; Group 2, 31.3%, 32.8%; Group 3, 8.2%, 12.3% (Group 2 vs. 3, p < 0.001). Mean 1‐ and 2‐year modified intent‐to‐treat glomerular filtration rates (mL/min) were similar. Primary reason for discontinuation was adverse events (Group 1, 34.2%; Group 2, 33.6%; Group 3, 22.3%; p < 0.05). In Groups 1 and 2, delayed wound healing and hyperlipidemia were more frequent. One‐year post hoc analysis of new‐onset diabetes posttransplantation was greater in TAC recipients (Groups 1 and 3 vs. 2, 17% vs. 6%; p = 0.004). Between‐group malignancy rates were similar. The SRL‐based regimens were not associated with improved outcomes for kidney transplantation patients.

Tubular expression of intercellular adhesion molecule-1 during renal allograft rejection.

Molecules responsible for adhesion between cells are known to play an important role in the immune response. The expression of one of these molecules, intercellular adhesion molecule-1 (ICAM-1), was examined on normal and allografted kidneys using a specific monoclonal antibody and an indirect immunoperoxidase technique. The expression of this molecule was compared to that of HLA class II antigens. On normal kidneys and most allograft biopsies taken immediately before implantation, ICAM-1 was expressed only on vascular endothelial cells (VEC) and parietal epithelium of Bowmans capsule. In the 11 kidneys where biopsies were available before and after transplantation, the appearance of rejection was associated with de novo expression of ICAM-1 on renal tubular epithelial cells that closely paralleled that of HLA class II antigens. In addition, an increase in endothelial cell expression of these molecules was also seen in rejection. In 23 random allograft biopsies, most of those with rejection showed tubular expression of both HLA class II antigens and ICAM-1. However, the presence of these molecules on tubules in several biopsies that did not show rejection limits the clinical usefulness of monitoring these antigens in posttransplant biopsies. The upregulation of these molecules is presumed to be secondary to the release of cytokines by cells infiltrating the allograft, although other mechanisms may be operating that explain the expression of these molecules in nonrejecting grafts.

Polyomavirus BK replication in de novo kidney transplant patients receiving tacrolimus or cyclosporine: a prospective, randomized, multicenter study.

Polyomavirus BK (BKV)‐associated nephropathy causes premature kidney transplant (KT) failure. BKV viruria and viremia are biomarkers of disease progression, but associated risk factors are controversial. A total of 682 KT patients receiving basiliximab, mycophenolic acid (MPA), corticosteroids were randomized 1:1 to cyclosporine (CsA) or tacrolimus (Tac). Risk factors were analyzed in 629 (92.2%) patients having at least 2 BKV measurements until month 12 posttransplant. Univariate analysis associated CsA‐MPA with lower rates of viremia than Tac‐MPA at month 6 (10.6% vs. 16.3%, p = 0.048) and 12 (4.8% vs. 12.1%, p = 0.004) and lower plasma BKV loads at month 12 (3.9 vs. 5.1 log10 copies/mL; p = 0.028). In multivariate models, CsA‐MPA remained associated with less viremia than Tac‐MPA at month 6 (OR 0.60; 95% CI 0.36–0.99) and month 12 (OR 0.33; 95% CI 0.16–0.68). Viremia at month 6 was also independently associated with higher steroid exposure until month 3 (OR 1.19 per 1 g), and with male gender (OR 2.49) and recipient age (OR 1.14 per 10 years) at month 12. The data suggest a dynamic risk factor evolution of BKV viremia consisting of higher corticosteroids until month 3, Tac‐MPA compared to CsA‐MPA at month 6 and Tac‐MPA, older age, male gender at month 12 posttransplant.

Acitretin for chemoprevention of non‐melanoma skin cancers in renal transplant recipients

A prospective, open randomized crossover trial was conducted to evaluate the efficacy of acitretin for chemoprevention of squamous cell carcinomas and basal cell carcinomas in renal allograft recipients. Analysis was performed according to the intention‐to treat principle. Twenty‐three patients with previous history of non‐melanoma skin cancer enrolled into the study and were randomly allocated into two groups. They crossed over at the end of 1 year. Eleven (47.8%) patients completed the 2‐year trial. Twelve (52.2%) patients withdrew from the trial. Nine of these withdrew because of side‐effects of acitretin. The majority of the patients who continued with the acitretin could tolerate 25 mg of acitretin daily or on alternate days. The number of squamous cell carcinomas (SCC) observed in patients while on acitretin was significantly lower than that in the drug‐free period (P = 0.002). A similar trend was observed in patients with basal cell carcinomas, but this was not significant and the numbers were small. Side‐effects were a major limiting factor. A severe rebound increase in SCC occurred in one patient after the acitretin was ceased.

Pharmacokinetics for once- versus twice-daily tacrolimus formulations in de novo kidney transplantation: a randomized, open-label trial.

Tacrolimus, a cornerstone immunosuppressant, is widely available as a twice‐daily formulation (Tacrolimus BID). A once‐daily prolonged‐release formulation (Tacrolimus QD) has been developed that may improve adherence and impart long‐lasting graft protection. This study compared the pharmacokinetics (PK) of tacrolimus in de novo kidney transplant patients treated with Tacrolimus QD or Tacrolimus BID. A 6‐week, open‐label, randomized comparative study was conducted in centers in Europe and Australia. Eligible patients received Tacrolimus QD or Tacrolimus BID. PK profiles were obtained following the first tacrolimus dose (day 1), and twice under steady‐state conditions. As secondary objectives, efficacy and safety parameters were also evaluated. Sixty‐six patients completed all PK profiles (34 Tacrolimus QD, 32 Tacrolimus BID). Mean AUC0–24 of tacrolimus on day 1 was approximately 30% lower for Tacrolimus QD than Tacrolimus BID (232 and 361 ng.h/mL, respectively), but was comparable by day 4. There was a good correlation and a similar relationship between AUC0–24 and Cmin for both formulations. Efficacy and safety data were also comparable over the 6‐week period. Tacrolimus QD can be administered once daily in the morning on the basis of the same systemic exposure and therapeutic drug monitoring concept as Tacrolimus BID.

Current incidence, treatment patterns and outcome of end‐stage renal disease among indigenous groups in Australia and New Zealand

SUMMARY: The changes in rates of treated end‐stage renal disease (ESRD) among indigenous populations have profound consequences for those individuals affected and for health‐care providers. By using data from the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry, we examined the current incidence, treatment and outcomes of ESRD among indigenous groups in Australia and New Zealand. All patients who began renal replacement therapy (RRT) in Australia or New Zealand between October 1991 and September 2000 were included. Rates of ESRD, RRT modalities, renal transplantation and mortality were the outcomes examined. End‐stage renal disease rates among indigenous groups in Australia and New Zealand exceeded non‐indigenous rates up to eightfold. The median age of indigenous ESRD patients was younger (51 vs 60 years, P < 0.0001), and there was an excess of comorbidities, particularly diabetes. For Australian Aboriginal and Torres Strait Islanders, and New Zealand Maori patients, mortality rates across all modalities of RRT were 70% higher than non‐indigenous rates. Indigenous people were less likely to receive a renal transplant prior to dialysis treatment, less likely to be accepted onto the cadaveric transplant waiting list, and less likely to receive a well‐matched transplant. The poorer outcomes among Australian Aboriginal and Torres Strait Islanders, and New Zealand Maori patients did not appear to be explained by the different comorbid conditions or age. Whether the outcomes reflect unmeasured differences in disease burden or treatment differences is not known. Tackling this problem will involve a spectrum of people and approaches, from tertiary care providers and RRT to local staff and preventative programs.

Kidney Transplant Rejection in Australia and New Zealand: Relationships Between Rejection and Graft Outcome

Although acute rejection rates have fallen over time, how this relates to graft outcomes is not known. Using data from the ANZDATA Registry, we examined associations of rejection within six months of transplantation with graft and patient outcomes among kidney‐only transplants performed between April 1997 and December 2004 in Australia and New Zealand. Associations of biopsy histology with outcomes of the rejection episode were also examined. Outcomes were examined among 4325 grafts with 1961 rejection episodes in total. Crude rejection rates have fallen by one‐third over that time, but rates of graft survival are constant. The occurrence of acute rejection was associated with an increased risk of graft loss after 6 months (HR, adjusted for donor and recipient characteristics, 1.69 [1.36–2.11], p < 0.001). Late rejection (first rejection ≥90 days) was associated with higher risk of graft loss (adjusted HR 2.46 [1.70–3.56], p < 0.001). Vascular rejection was also associated with a higher risk of graft loss 2.07 [95% CI 1.60–2.68], p < 0.001. The occurrence of acute rejection is associated with an ongoing increased risk of graft loss, particularly if that episode occurred late or included vascular rejection. The reduced rates of rejection have not been associated with improved graft survival.

Comparison of trough, 2-hour, and limited AUC blood sampling for monitoring cyclosporin (Neoral) at day 7 post-renal transplantation and incidence of rejection in the first month.

The use of alternative strategies to the traditional pre-dose/trough (C0) blood sampling for cyclosporine (CsA) therapeutic drug monitoring has the potential to revolutionize analytical practices which have, in many centers, been established for some 20 years. While the C0 sample has previously been recommended, current attitudes are increasingly proposing alternatives for assessing CsA exposure, including various limited sampling strategies of the AUC (lssAUC) in the early postdose period, or alternative single-point nontrough samples, such as a 2-hour postdose sample (C2). The present study has reviewed a series of consecutive renal transplant recipients over 18 months where CsA was the primary immunosuppressant. The lssAUC performed at around day 7 posttransplantation included drawing blood at 0, 2, and 4 hours postdose, giving AUC(0–4). The aim of this study was to review the occurrence of acute biopsy-proven rejection in the first month and consider which of (simultaneously measured) C0, C2 or AUC(0–4) was a better early indicator of this adverse outcome. The result was best described by comparing the data from rejectors (n = 13) and nonrejectors (n = 42) for these 3 indices of CsA exposure (i.e., C0, C2 or AUC(0–4)). There was no evidence that C0 predicted the likelihood of such adverse clinical outcomes. In contrast, rejectors tended to have lower mean C2 CsA concentrations, and the incidence of rejection was 0.0 when C2 exceeded 1200 &mgr;g/L (n = 10). While the data are limited in the higher C2 CsA concentration range, it is nevertheless consistent with more recent recommendations suggesting that the CsA at C2 should target 1700 &mgr;g/L in this first month posttransplantation. As 64% of the patients were also receiving a CsA-sparing agent (diltiazem [DTZ]), the relationships were also investigated to determine whether any affect of concomitant DTZ therapy could be demonstrated. However, in this small sample, no significant affect of DTZ was seen.