Brian Hutchison

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transplantation, 430 of 525 enrolled patients were randomly assigned to remain on SRL-CsA-steroids (ST) or to have CsA withdrawn and SRL troughs increased two-fold (SRL-ST).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.

Prevention of Tunneled Hemodialysis Catheter-Related Infections Using Catheter-Restricted Filling with Gentamicin and Citrate: A Randomized Controlled Study

Tunneled catheters are widely used for the provision of hemodialysis. Long-term catheter survival is limited by tunneled catheter-related infections (CRI). This study assesses the efficacy of catheter-restricted filling with gentamicin and citrate in preventing CRI in hemodialysis patients. A double-blind randomized study was conducted to compare heparin (5000 U/ml) with gentamicin/citrate (40 mg/ml and 3.13% citrate; ratio 2:1) as catheter-lock solutions. A total of 112 tunneled catheters in 83 patients were enrolled at the time of catheter insertion for commencement or maintenance of hemodialysis. The primary end point was CRI. Catheter malfunction, defined as blood flow rate of <200 ml/min for three consecutive dialyses and/or the use of urokinase, was also assessed as a secondary end point. Infection rates per 100 catheter-days were 0.03 in the gentamicin group versus 0.42 in the heparin group (P = 0.003). Kaplan-Meier survival analyses showed mean infection-free catheter survival of 282 d (95% CI, 272 to 293 d) in the gentamicin group versus 181 d (95% CI, 124 to 237 d) in the heparin group (log rank, 9.58; P = 0.002). Cox regression analyses showed a relative risk for infection-free catheter survival of 0.10 (95% CI, 0.01 to 0.92) in the gentamicin group when adjusted for gender, race, diabetes mellitus, catheter malfunction, and hemoglobin (P = 0.042). The incidence of catheter malfunction was not significantly different between groups. Predialysis gentamicin levels were significantly higher in patients randomized to gentamicin (gentamicin/citrate: median 2.8 mg/L [range, 0.6 to 3.5 mg/L], n = 5; heparin: median <0.2 mg/L [range <0.2 to 0.2 mg/L], n = 5; P = 0.008). Tunneled hemodialysis catheter-restricted filling with gentamicin and citrate is a highly effective strategy for prevention of CRI. Although citrate as a catheter-lock solution provides adequate anticoagulation for the interdialytic period, gentamicin levels suggest significant risk for chronic aminoglycoside exposure and associated ototoxicity. Before this technique is adopted, these preliminary observations warrant replication in future studies that will examine the efficacy and safety of lower doses of gentamicin or alternative agents with a reduced potential for toxicity.

Sirolimus‐Based Therapy Following Early Cyclosporine Withdrawal Provides Significantly Improved Renal Histology and Function at 3 Years

Graft function and histology are predictive of renal transplant survival. The Rapamune Maintenance Regimen study demonstrated that early cyclosporine (CsA) withdrawal from a sirolimus (SRL)‐CsA‐steroid (ST) regimen improved renal function and blood pressure. We report the protocol‐mandated biopsy findings from that study. Renal transplant patients (n = 430) receiving SRL‐CsA‐ST were randomized at 3 months after transplantation to remain on SRL‐CsA‐ST, or to have CsA withdrawn (SRL‐ST group). Protocol‐mandated biopsies were performed at engraftment and at 12 and 36 months. Two pathologists blindly evaluated 484 biopsies to obtain the Chronic Allograft Damage Index (CADI) scores. At 36 months among patients with serial biopsies (n = 63), the mean CADI score was significantly lower with SRL‐ST(4.70 vs. 3.20, p = 0.003), as was the mean tubular atrophy score (0.77 vs. 0.32, p < 0.001). All six components of the CADI score were numerically lower in SRL‐ST group; moreover, inflammation and the tubular atrophy scores decreased significantly in the SRL‐ST group between 12 and 36 months. The calculated glomerular filtration rate at 36 months was significantly better in the CsA‐withdrawal group (54.8 vs. 68.2 mL/min, p = 0.009). In conclusion, withdrawing CsA from the SRL‐CsA‐ST regimen resulted in improved renal histology and function.

Health-related quality-of-life outcomes of sirolimus-treated kidney transplant patients after elimination of cyclosporine A: results of a 2-year randomized clinical trial.

Background. This study compared 2-year health-related quality-of-life (HRQL) outcomes of sirolimus (SRL)-treated kidney transplant patients after elimination of cyclosporine A (CsA) to patients continuing on a combined CsA and SRL regimen. Methods. A randomized, open-label, clinical trial was performed in Europe, Australia, and Canada. Four hundred thirty kidney transplant patients were randomly assigned to sirolimus plus steroids (ST) (n=215) or SRL and CsA+ST (n=215) therapy after 3 months of combined SRL+CsA+ST treatment. HRQL was measured using the Kidney Transplant Questionnaire (KTQ) and the SF-36 Health Survey at month 3 (time of randomization) and months 12 and 24 after transplantation. Repeated-measures analysis of covariance was used to evaluate treatment differences in HRQL scores over the 2-year period. Results. HRQL scores were available for 361 (86%) eligible study patients. Statistically significant treatment-by-assessment time interactions, favoring SRL+ST, were found on KTQ Fatigue (P =0.0158) and Appearance scores (P =0.0007). No treatment differences were observed in KTQ Physical Symptom, Uncertainty-Fear, and Emotion scores. Statistically significant treatment-by-assessment time interactions were observed for SF-36 Vitality scores (P =0.0203) but not other SF-36 scores (P >0.05). For Vitality scores, the SRL+ST group remained stable (mean, 0.4-point change) from month 3 to month 24 compared with decreases in the SRL+CsA+ST group (mean, −6.5-point change). Conclusions. SRL-based therapy with early elimination of CsA results in fewer appearance-related problems, less fatigue, and better vitality compared with continuous treatment with SRL, CsA, and ST.

Atherosclerosis and folic acid supplementation trial in chronic renal failure: Baseline results

Background:  Atherosclerosis and Folic Acid Supplementation Trial (ASFAST) is a randomized placebo controlled trial assessing whether high‐dose folic acid can reduce cardiovascular events and atherosclerosis progression in patients with chronic renal failure (CRF). Here we report the baseline results and compare indices of arterial structure (carotid intima‐medial thickness (IMT)) and function (systemic arterial compliance (SAC)), pressure augmentation index (AIx) and pulse wave velocity (PWV a‐f and PWV f‐d)) to age‐ and sex‐matched controls.

Enteric-coated mycophenolate sodium in combination with full dose or reduced dose cyclosporine, basiliximab and corticosteroids in Australian de novo kidney transplant patients.

Cyclosporine (CsA), dosed to achieve C2 targets, has been shown to provide safe and efficacious immunosuppression when used with a mycophenolate and steroids for de novo kidney transplant recipients. This study examined whether use of enteric‐coated mycophenolate sodium (EC‐MPS) together with basiliximab and steroids would enable use of CsA dosed to reduced C2 targets in order to achieve improved graft function.

Pre-transplant pharmacokinetic profiling and tacrolimus requirements post-transplant

Aim:  To determine the proportion of patients achieving tacrolimus whole‐blood concentrations of ≥10 ng/mL within 3 days of kidney transplantation, after randomization either to standard dosing (control group) or post‐transplantation dosing guided by a 2‐hour (C2) level following a preoperative tacrolimus dose (T2 group).