Ute Eisenberger

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.

Five-year outcomes in kidney transplant patients converted from cyclosporine to everolimus: the randomized ZEUS study.

ZEUS study was an open‐label, 12‐month, multicenter study in which 300 de novo kidney transplant recipients were randomized to continue receiving cyclosporine (CsA) or convert to everolimus at 4.5 months posttransplant. Five‐year follow‐up data were available for 245/269 patients (91.1%) who completed the core 12‐month study (123 everolimus, 109 CsA). At 5 years, adjusted estimated GFR was 66.2 mL/min/1.73 m2 with everolimus versus 60.9 mL/min/1.73 m2 with CsA; the mean difference was 5.3 mL/min/1.73 m2 in favor of everolimus (95% CI 2.4, 8.3; p < 0.001 [intent‐to‐treat population]). In a post hoc analysis of patients remaining on study drug at 5 years (everolimus 77, CsA 86), mean difference was 8.2 mL/min/1.73 m2 (95% CI 4.3, 12.1; p < 0.001) in favor of everolimus. The cumulative incidence of biopsy‐proven acute rejection postrandomization was 13.6% with everolimus versus 7.5% with CsA (p = 0.095), largely accounted for by grade I rejection (16/21 patients and 7/11 patients, respectively). Postrandomization, graft loss, mortality, serious adverse events and neoplasms were similar in both arms. In conclusion, conversion of kidney transplant patients to everolimus at 4.5 months posttransplant is associated with a significant improvement in renal function that is maintained to at least 5 years. The increase in early mild acute rejection did not affect long‐term graft function.

Conversion from cyclosporine to everolimus at 4.5 months posttransplant: 3-year results from the randomized ZEUS study.

The long‐term effect of conversion from calcineurin inhibitor (CNI) therapy to an mTOR inhibitor requires clarification. Following completion of the 12‐month, open‐label, multicenter ZEUS study, in which 300 kidney transplant recipients were randomized to continue cyclosporine (CsA) or convert to everolimus at 4.5 months posttransplant, outcomes were assessed at month 36 (n = 284; 94.7%). CNI therapy was reintroduced in 28.4% of everolimus patients by month 36. The primary efficacy endpoint, estimated glomerular filtration rate (Nankivell, ANCOVA) was significantly higher with everolimus versus the CsA group at month 24 (7.6 mL/min/1.73 m2, 95%CI 4.3, 11.0 mL/min/1.73 m2; p < 0.001) and month 36 (7.5 mL/min/1.73 m2, 95%CI 3.6, 11.4 mL/min/1.73 m2; p < 0.001). The incidence of biopsy‐proven acute rejection from randomization to month 36 was 13.0% in the everolimus arm and 4.8% in the CsA arm (p = 0.015). Patient and graft survival, as well as incidences of malignancy, severe infections and hospitalization, were similar between groups. Kidney transplant patients who are converted from CsA to everolimus at month 4.5 and who remain on everolimus thereafter may achieve a significant improvement in renal function that is maintained to 3 years. There was a significantly higher rate of rejection in the everolimus arm but this did not exert a deleterious effect by 3 years posttransplant.

Serum cytokine profile in patients with active lupus nephritis

PURPOSE Determination of disease activity of lupus nephritis remains challenging. Since cytokines play a role as inflammatory mediators extending renal injury, measuring serum cytokine levels might help in the clinical assessment of patients with lupus nephritis. Therefore, the aim of this study was to determine the diagnostic value of a panel of serum cytokines in patients with active lupus nephritis. METHODS In this prospective controlled multicenter trial, sera of 12 patients with active lupus nephritis were collected in a clinical routine setting at the time of renal biopsy and 6 months afterwards. Fourteen patients with inactive systemic lupus erythematosus (SLE), and 14 healthy subjects were used as controls. Eleven cytokines (IL-4, IL-5, IL-6, IL-10, IL-12(p40), IL-12(p70), IL-18, TNF-α, TGF-β1, IFN-α2, IFN-γ) and two soluble receptors (IL-1ra and TNF-RII) were measured by cytokine multiplex assay. RESULTS In inactive SLE patients, serum levels of IL-10, IL-12(p40), IL-18 and TNF-RII were increased compared to healthy controls. Active lupus nephritis was found to be associated with further increase of these cytokine levels. Follow-up measurements in clinical remission of lupus nephritis showed downregulation of increased cytokines to levels found in inactive SLE. Most strikingly, TNF-RII serum level were elevated in all patients with active lupus nephritis (p<0.001) and declined after clinical remission (p<0.0005). CONCLUSION The cytokine multiplex assay used in our study allowed a fast and stable analysis of a panel of serum cytokines in a clinical routine setting. In addition, serum cytokines, especially TNF-RII, might be excellent markers of active lupus nephritis.

Calcification Propensity and Survival among Renal Transplant Recipients

Calciprotein particle maturation time (T50) in serum is a novel measure of individual blood calcification propensity. To determine the clinical relevance of T50 in renal transplantation, baseline serum T50 was measured in a longitudinal cohort of 699 stable renal transplant recipients and the associations of T50 with mortality and graft failure were analyzed over a median follow-up of 3.1 years. Predictive value of T50 was assessed for patient survival with reference to traditional (Framingham) risk factors and the calcium-phosphate product. Serum magnesium, bicarbonate, albumin, and phosphate levels were the main determinants of T50, which was independent of renal function and dialysis vintage before transplant. During follow-up, 81 (12%) patients died, of which 38 (47%) died from cardiovascular causes. Furthermore, 45 (6%) patients developed graft failure. In fully adjusted models, lower T50 values were independently associated with increased all-cause mortality (hazard ratio, 1.43; 95% confidence interval, 1.11 to 1.85; P=0.006 per SD decrease) and increased cardiovascular mortality (hazard ratio, 1.55; 95% confidence interval, 1.04 to 2.29; P=0.03 per SD decrease). In addition to age, sex, and eGFR, T50 improved prognostication for all-cause mortality, whereas traditional risk factors or calcium-phosphate product did not. Lower T50 was also associated with increased graft failure risk. The associations of T50 with mortality and graft failure were confirmed in an independent replication cohort. In conclusion, reduced serum T50 was associated with increased risk of all-cause mortality, cardiovascular mortality, and graft failure and, of all tested parameters, displayed the strongest association with all-cause mortality in these transplant recipients.

Reference Values and Factors Associated With Renal Resistive Index in a Family-Based Population Study

Increased renal resistive index (RRI) has been recently associated with target organ damage and cardiovascular or renal outcomes in patients with hypertension and diabetes mellitus. However, reference values in the general population and information on familial aggregation are largely lacking. We determined the distribution of RRI, associated factors, and heritability in a population-based study. Families of European ancestry were randomly selected in 3 Swiss cities. Anthropometric parameters and cardiovascular risk factors were assessed. A renal Doppler ultrasound was performed, and RRI was measured in 3 segmental arteries of both kidneys. We used multilevel linear regression analysis to explore the factors associated with RRI, adjusting for center and family relationships. Sex-specific reference values for RRI were generated according to age. Heritability was estimated by variance components using the ASSOC program (SAGE software). Four hundred women (mean age±SD, 44.9±16.7 years) and 326 men (42.1±16.8 years) with normal renal ultrasound had mean RRI of 0.64±0.05 and 0.62±0.05, respectively (P<0.001). In multivariable analyses, RRI was positively associated with female sex, age, systolic blood pressure, and body mass index. We observed an inverse correlation with diastolic blood pressure and heart rate. Age had a nonlinear association with RRI. We found no independent association of RRI with diabetes mellitus, hypertension treatment, smoking, cholesterol levels, or estimated glomerular filtration rate. The adjusted heritability estimate was 42±8% (P<0.001). In a population-based sample with normal renal ultrasound, RRI normal values depend on sex, age, blood pressure, heart rate, and body mass index. The significant heritability of RRI suggests that genes influence this phenotype.

Medication Adherence Assessment: High Accuracy of the New Ingestible Sensor System in Kidney Transplants

Background This open-label single-arm exploratory study evaluated the accuracy of the Ingestible Sensor System (ISS), a novel technology for directly assessing the ingestion of oral medications and treatment adherence. Methods ISS consists of an ingestible event marker (IEM), a microsensor that becomes activated in gastric fluid, and an adhesive personal monitor (APM) that detects IEM activation. In this study, the IEM was combined to enteric-coated mycophenolate sodium (ECMPS). Twenty stable adult kidney transplants received IEM-ECMPS for a mean of 9.2 weeks totaling 1227 cumulative days. Results Eight patients prematurely discontinued treatment due to ECMPS gastrointestinal symptoms (n=2), skin intolerance to APM (n=2), and insufficient system usability (n=4). Rash or erythema due to APM was reported in 7 (37%) patients, all during the first month of use. No serious or severe adverse events and no rejection episode were reported. IEM detection accuracy was 100% over 34 directly observed ingestions; Taking Adherence was 99.4% over a total of 2824 prescribed IEM-ECMPS ingestions. ISS could detect accurately the ingestion of two IEM-ECMPS capsules taken at the same time (detection rate of 99.3%, n=2376). Conclusions ISS is a promising new technology that provides highly reliable measurements of intake and timing of intake of drugs that are combined with the IEM.

Three-year follow-up of human transplanted kidneys by diffusion-weighted MRI and blood oxygenation level-dependent imaging.

To prospectively determine the 3‐year stability and potential changes of functional parameters in renal allograft recipients obtained from diffusion‐weighted imaging (DWI) and blood oxygenation level‐dependent (BOLD) MRI.

Living Renal Allograft Transplantation: Diffusion-weighted MR Imaging in Longitudinal Follow-up of the Donated and the Remaining Kidney

PURPOSE To determine whether diffusion-weighted (DW) magnetic resonance (MR) imaging in living renal allograft donation allows monitoring of potential changes in the nontransplanted remaining kidney of the donor because of unilateral nephrectomy and changes in the transplanted kidney before and after transplantation in donor and recipient, respectively, and whether DW MR parameters are correlated in the same kidney before and after transplantation. MATERIALS AND METHODS The study protocol was approved by the local ethics committee; written informed consent was obtained. Thirteen healthy kidney donors and their corresponding recipients prospectively underwent DW MR imaging (multiple b values) in donors before donation and in donors and recipients at day 8 and months 3 and 12 after donation. Total apparent diffusion coefficient (ADCT) values were determined; contribution of microcirculation was quantified in perfusion fraction (FP). Longitudinal changes of diffusion parameters were compared (repeated-measures one-way analysis of variance with post hoc pairwise comparisons). Correlations were tested (linear regression). RESULTS ADCT values in nontransplanted kidney of donors increased from a preexplantation value of (188 ± 9 [standard deviation]) to (202 ± 11) × 10(-5) mm(2)/sec in medulla and from (199 ± 11) to (210 ± 13) × 10(-5) mm(2)/sec in cortex 1 week after donation (P < .004). Medullary, but not cortical, ADCT values stayed increased up to 1 year. ADCT values in allografts in recipients were stable. Compared with values obtained before transplantation in donors, the corticomedullary difference was reduced in allografts (P < .03). Cortical ADCT values correlated with estimated glomerular filtration rate in recipients (R = 0.56, P < .001) but not donors. Cortical ADCT values in the same kidney before transplantation in donors correlated with those in recipients on day 8 after transplantation (R = 0.77, P = .006). FP did not show significant changes. CONCLUSION DW MR imaging depicts early adaptations in the remaining nontransplanted kidney of donors after nephrectomy. All diffusion parameters remained constant in allograft recipients after transplantation. This method has potential monitoring utility, although assessment of clinical relevance is needed.

Comparison of physiological triggering schemes for diffusion‐weighted magnetic resonance imaging in kidneys

To determine the potential benefit of combined respiratory‐cardiac triggering for diffusion‐weighted imaging (DWI) of kidneys compared to respiratory triggering alone (RT).