Frank Pietruck

Everolimus-based, calcineurin-inhibitor-free regimen in recipients of de-novo kidney transplants: an open-label, randomised, controlled trial

BACKGROUND Non-nephrotoxic immunosuppressive strategies that allow reduction of calcineurin-inhibitor exposure without compromising safety or efficacy remain a goal in kidney transplantation. Immunosuppression based on the mammalian-target-of-rapamycin inhibitor everolimus was assessed as a strategy for elimination of calcineurin-inhibitor exposure and optimisation of renal-graft function while maintaining efficacy. METHODS In the ZEUS multicentre, open-label study, 503 patients (aged 18-65 years) who had received de-novo kidney transplants were enrolled. After initial treatment with ciclosporin, based on trough concentrations, and enteric-coated mycophenolate sodium (1440 mg/day, orally), corticosteroids (≥5 mg/day prednisolone or equivalent, orally), and basiliximab induction (20 mg, intravenously, on day 0 [2 h before transplantation], and on day 4), 300 (60%) patients were randomly assigned at 4·5 months in a 1:1 ratio to undergo calcineurin-inhibitor elimination (everolimus-based regimen that was based on trough concentrations [6-10 ng/mL] and enteric-coated mycophenolate sodium [1440 mg/day] with corticosteroids), or continue standard ciclosporin-based treatment. Randomisation was done by use of a central, validated system that automated the random assignment of treatment groups to randomisation numbers. The primary objective was to show better renal function (glomerular filtration rate [GFR]; Nankivell formula) with the calcineurin-inhibitor-free everolimus regimen at 12 months after transplantation. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00154310. FINDINGS 118 (76%) of 155 everolimus-treated patients and 117 (81%) of 145 ciclosporin-treated patients completed treatment with study drug up to 12 months after transplantation. At this timepoint, the everolimus regimen was associated with a significant improvement in GFR versus the ciclosporin regimen (71·8 mL/min per 1·73 m(2) vs 61·9 mL/min per 1·73 m(2), respectively; mean difference 9·8 mL/min per 1·73 m(2), 95% CI -12·2 to -7·5). Rates of biopsy-proven acute rejection were higher in the everolimus group than in the ciclosporin group after randomisation (15 [10%] of 154 vs five [3%] of 146; p = 0·036), but similar for the full study period (23 [15%] vs 22 [15%]). Compared with the ciclosporin regimen, higher mean lipid concentrations, slightly increased urinary protein excretion, and lower haemoglobin concentrations were noted with the everolimus regimen; thrombocytopenia, aphthous stomatitis, and diarrhoea also occurred more often in the everolimus group. A higher incidence of hyperuricaemia was noted with ciclosporin. INTERPRETATION Early elimination of calcineurin inhibitor by use of everolimus-based immunosuppression improved renal function at 12 months while maintaining efficacy and safety, indicating that this strategy may facilitate improved long-term outcomes in selected patients. FUNDING Novartis Pharma.

Cystatin C: Efficacy as Screening Test for Reduced Glomerular Filtration Rate

Serum cystatin C, a cysteine proteinase inhibitor, has been proposed as a marker of glomerular filtration rate (GFR). Serum cystatin C, serum creatinine and creatinine clearance were measured in 226 patients with various nephropathies, covering the entire range of renal function, to evaluate the efficacy of cystatin C as a screening test to detect reduced creatinine clearance in comparison to creatinine. Subgroups of 53 patients with glomerular and 26 patients with tubular impairment were compared to assess whether cystatin C performed differently in either glomerular or tubular impairment. Cystatin C detected reduced creatinine clearance with higher sensitivity (97 vs. 83%), and higher negative predictive value (96 vs. 87%) compared to creatinine. In parallel, 95% sensitivity of cystatin C as derived from receiver-operating characteristic plot was significantly higher (p < 0.05). In the subgroups with glomerular or tubular impairment, cystatin C and creatinine did not significantly differ with regard to efficacy. Serum cystatin C is as efficacious as serum creatinine to detect reduced GFR as measured by creatinine clearance. The efficacy of cystatin C as a screening test may even be superior compared to creatinine. In addition, the efficacy of cystatin C is independent of either glomerular or tubular impairment.

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.

The Impact of Living-Related Kidney Transplantation on the Donor's Life

Background. Living-donation kidney transplantation (LDKT) is increasingly performed for treatment of chronic renal failure. Recently, risks for the donor and problems in decision-making have been stressed. This study was conducted to illuminate the decision making-process and consequences of LDKT on family life, the financial and occupational situation. Moreover, quality of life (QOL) and mental distress were explored. Methods. All German residents at Essen University, who donated their kidney between 1999 and 2003, were included in the study. Donors filled out the questionnaire of the European Multicenter Study of Transplantation Using Living Donors, the Short Form 36-Health Survey, and the Brief Symptom Inventory. Results. Out of a total of 65 donors, 47 replied (72%) at an average 2.5 years postdonation. No fatalities occurred in the whole sample (n=65), medical complications were experienced by 28%. Most donors decided voluntarily (94%) and spontaneously (66%) to donate, after donation 96% stated that they would decide in the same way again. QOL was within the norm. On the other hand, 10% experienced family conflicts, every eighth donor suffered from clinically relevant distress, financial disadvantages were experienced by every fourth donor, with 25% not answering this question. Conclusion. Seen from the donor’s perspective, LDKT is a relatively safe procedure. However, increased rates of donors with mental distress and intra-familial conflicts emphasize the need for a careful selection process. Regular postdonation psychosocial screening and provision of specific interventions to those in need are recommended. Donors should not suffer from financial and occupational disadvantages resulting from donation.

Repaglinide in the Management of New‐Onset Diabetes Mellitus After Renal Transplantation

The purpose of this study was to investigate the use of the short‐acting insulin secretion drug repaglinide in new‐onset diabetes mellitus (NODM) after renal transplantation. Twenty‐three Caucasian patients with NODM after renal transplantation were selected to receive repaglinide therapy and were followed for at least 6 months. A control group treated with rosiglitazone was chosen for comparison. Successful repaglinide treatment was defined as a significant improvement of blood glucose concentrations and HbA1c <7% in the absence of glucosuria and without the need for the addition of further anti‐diabetic agents. After 6 months of treatment with repaglinide, 14 of the 23 patients were successfully treated. Mean HbA1c decreased from 7.6 ± 0.6% to 5.8 ± 0.6% in 14 patients treated successfully. In nine patients, hyperglycemia persisted, and they were switched to insulin treatment (HbA1c 8.5 ± 2.9% at the beginning to 7.4 ± 2.2%). Mean serum creatinine levels, cyclosporine A and tacrolimus blood levels did not change significantly following institution of repaglinide therapy. The rate of successful treatment and the degree of HbA1c decrease were similar compared to rosiglitazone‐treated control patients. The data from our observational study indicate that repaglinide can be an effective treatment option in Caucasian patients with NODM after renal transplantation.

Ezetimibe for the Treatment of Uncontrolled Hypercholesterolemia in Patients with High-Dose Statin Therapy After Renal Transplantation

We investigated prospectively the efficacy of ezetimibe in addition to statin therapy in stable renal transplant patients in whom hypercholesterolemia was not sufficiently treated. Eighteen renal transplant patients received 10 mg ezetimibe once daily in addition to high‐dose statin therapy for uncontrolled hypercholesterolemia. Total cholesterol, LDL‐cholesterol, HDL‐cholesterol, triglycerides, Tacrolimus (Tac)‐ and Cyclosporine A (CsA) blood levels, creatinine, urea, liver enzymes, electrolytes and creatinkinase (CK) were measured before initiation of ezetimibe therapy, after 7 days, 6 weeks and 3 months. Cholesterol concentrations decreased significantly (p < 0.005) from 264 ± 46 mg/dL at baseline to 205 ± 48 mg/dL after 1 week to 202 ± 48 mg/dL after 6 weeks and 212 ± 40 mg/dL after 3 months (reduction after 3 months 21 ± 10%). LDL‐concentrations decreased significantly (p < 0.005) from 178 ± 41 mg/dL at baseline to 129 ± 35 mg/dL after 1 week to 123 ± 25 after 6 weeks and to 117 ± 40 mg/dL after 3 months (reduction after 3 months 37 ± 14%). Two patients stopped ezetimibe therapy due to nausea and muscle pain without CK elevation. Significant changes of CsA and Tac blood levels, liver and muscle enzymes were not observed. Ezetimibe seems to be an effective therapy for uncontrolled hypercholesterolemia in renal transplant patients when combined with high‐dose statin therapy.

Tacrolimus-based, steroid-free regimens in renal transplantation: 3-year follow-up of the ATLAS trial.

Background Long-term use of corticosteroids is associated with considerable morbidity, including cardiovascular and metabolic adverse effects. Methods This study evaluated the long-term efficacy and safety of two steroid-free regimens compared with a triple immunosuppressive therapy in renal transplant recipients. This was a 3-year follow-up to a 6-month, open-label, randomized, multicenter study. Results Data from 3 years were available for 421 (93.3%) of 451 patients in the original intent-to-treat population (143 tacrolimus/basiliximab [Tac/Bas], 139 tacrolimus/mycophenolate mofetil [Tac/MMF], and 139 tacrolimus/MMF/steroids [triple therapy]). In the time interval from 6 months to 3 years after transplantation, the incidence of biopsy-proven acute rejection was low and similar (Tac/Bas, 2.1%; Tac/MMF, 2.2%; triple therapy, 2.2%); Most rejection episodes occurred during the first 6 months of the study. Graft survival was high (Kaplan-Meier estimates: 92.7%, 92.5%, and 92.5%), as was patient survival (93.1%, 96.4%, and 97.0%). There were 10 graft losses (n=2, 4, and 4) and 12 patient deaths (n=5, 2, and 5). Renal function was well preserved throughout the study and similar between groups. There was a trend toward improved cardiovascular risk factors in the Tac/Bas group, including reduced total and low-density lipoprotein cholesterol and lower new-onset insulin use. There were no between-group differences in the incidence or type of adverse events. Conclusion Higher rates of acute rejection early in treatment were seen with the steroid-free regimens, but this did not translate into poorer long-term outcomes, such as graft and patient survival and renal function. A trend for a more favorable cardiovascular risk profile was observed for steroid-free immunosuppression with Tac/Bas.

Efficacy and safety of enteric-coated mycophenolate sodium in renal transplant patients with diabetes mellitus: post hoc analyses from three clinical trials

Abstract:  To examine the efficacy and safety of enteric‐coated mycophenolate sodium (EC‐MPS, myfortic®) in renal transplant patients with diabetes mellitus, six‐ and 12‐month data from three clinical trials with EC‐MPS (Studies B301, B302, and myPROMS) were analyzed post hoc. Studies B301 (de novo patients) and B302 (maintenance patients) followed a randomized double‐blind design whereas myPROMS was an open‐label study in de novo and maintenance renal transplant patients in which all patients received EC‐MPS as part of their immunosuppressive regimen. In studies B301 and B302, diabetic patients were compared against mycophenolate mofetil (MMF, CellCept®), the reference drug. For myPROMS, data from diabetic and non‐diabetic patients were compared. In total, 246 diabetic patients receiving EC‐MPS were analyzed. In study B301, the efficacy failure rate [biopsy‐proven acute rejection (BPAR), graft loss, death or loss to follow‐up] in diabetics at 12 months was 17.6% (EC‐MPS) vs. 26.2% (MMF), and of BPAR alone 14.7% vs. 19.0% (both n.s.). In de novo patients from myPROMS, the treatment failure rate was similar in diabetic (20.3%) and non‐diabetic patients (27.1%), as was the incidence of BPAR (17.7% vs. 23.1%, both n.s.). The overall incidence, severity and pattern of AEs were comparable between EC‐MPS and MMF in de novo patients. This was supported by the safety results assessed in maintenance patients (B302) indicating no increased safety risk with the use of EC‐MPS in the diabetic patient population, if compared with MMF. Likewise, apart from a higher incidence of severe/serious infections in diabetics, the safety profile of EC‐MPS was not different to non‐diabetics in myPROMS. In conclusion, preliminary data suggest that EC‐MPS in combination with cyclosporine (± steroids) can be used efficiently and safely for the prophylaxis of organ rejection in diabetic renal transplant patients. Moreover, diabetic patients can apparently be safely converted from MMF to EC‐MPS. More data from prospective studies are needed to fully judge the efficacy and safety profile of EC‐MPS in the diabetic transplant population.

Tacrolimus combined with two different corticosteroid-free regimens compared with a standard triple regimen in renal transplantation : one year observational results

Krämer BK, Klinger M, Wlodarczyk Z, Ostrowski M, Midvedt K, Stefoni S, Citterio F, Pietruck F, Squifflet J‐Paul, Segoloni G, Krüger B, Sperschneider H, Banas B, Bäckman L, Weber M, Carmellini M, Perner F, Claesson K, Marcinkowski W, Vítko Š, Senatorski G, Salmela K, Nordström J. Tacrolimus combined with two different corticosteroid‐free regimens compared with a standard triple regimen in renal transplantation: one year observational results.
Clin Transplant 2010: 24: E1–E9.

Differential tissue distribution of the Invs gene product inversin

Nephronophthisis is a common genetic cause of end-stage renal disease in childhood. Recently, Invs was identified as the gene mutated in the infantile form of nephronophthisis. Humans with nephronophthisis develop a large number of extrarenal manifestations, including situs variations, anomalies of the hepatobiliary system, retinal degeneration and cerebellar ataxia. Mice homozygous for a mutation in the Invs gene (inv mouse) die during the first week after birth as a result of renal and liver failure. Although organ anomalies have been characterized in human nephronophthisis and the inv mouse, little is known about the tissue expression of the Invs gene product, inversin. We have used laser confocal microscopy of paraffin-embedded murine tissue sections to provide the first detailed characterization of the distribution of inversin in various organs. Our results show that inversin is localized to distal tubules in the kidney, hepatic bile ducts, acinar and ductal pancreatic cells, epithelial intestinal cells, splenic germinal centres, bronchiolar epithelial cells, dendrites of cerebellar Purkinje cells, retinal neural cells and spermatocytes and spermatids in the testis. The localization of inversin in distal tubules in the kidney and in extrarenal tissues suggests that the expression of this protein has an important function in a variety of organs. Further studies are required to understand the way in which mutations in the Invs gene lead to the multi-organ pathology of inv mouse and human nephronophthisis.