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Aims The 2021 European Society of Cardiology (ESC) guideline on cardiovascular disease (CVD) prevention categorizes moderate and severe chronic kidney disease (CKD) as high and very-high CVD risk status regardless of other factors like age and does not include estimated glomerular filtration rate (eGFR) and albuminuria in its algorithms, systemic coronary risk estimation 2 (SCORE2) and systemic coronary risk estimation 2 in older persons (SCORE2-OP), to predict CVD risk. We developed and validated an ‘Add-on’ to incorporate CKD measures into these algorithms, using a validated approach. Methods In 3,054 840 participants from 34 datasets, we developed three Add-ons [eGFR only, eGFR + urinary albumin-to-creatinine ratio (ACR) (the primary Add-on), and eGFR + dipstick proteinuria] for SCORE2 and SCORE2-OP. We validated C-statistics and net reclassification improvement (NRI), accounting for competing risk of non-CVD death, in 5,997 719 participants from 34 different datasets. Results In the target population of SCORE2 and SCORE2-OP without diabetes, the CKD Add-on (eGFR only) and CKD Add-on (eGFR + ACR) improved C-statistic by 0.006 (95%CI 0.004–0.008) and 0.016 (0.010–0.023), respectively, for SCORE2 and 0.012 (0.009–0.015) and 0.024 (0.014–0.035), respectively, for SCORE2-OP. Similar results were seen when we included individuals with diabetes and tested the CKD Add-on (eGFR + dipstick). In 57 485 European participants with CKD, SCORE2 or SCORE2-OP with a CKD Add-on showed a significant NRI [e.g. 0.100 (0.062–0.138) for SCORE2] compared to the qualitative approach in the ESC guideline. Conclusion Our Add-ons with CKD measures improved CVD risk prediction beyond SCORE2 and SCORE2-OP. This approach will help clinicians and patients with CKD refine risk prediction and further personalize preventive therapies for CVD.

Purine metabolism is essential for all known living creatures, including humans in whom elevated serum concentration of purine break-down product uric acid (UA) is probably an independent risk factor for mortality, type 2 diabetes and cardiovascular events. An automated multiplex assay that measures several purine metabolites could therefore prove useful in many areas of medical, veterinary and biological research. The aim of the present work was to develop a sensitive LC-MS/MS method for simultaneous quantitation of xanthine, hypoxanthine, UA, allantoin, and creatinine in biobanked urine samples. This article describes details and performance of the new method studied in 55 samples of human urine. Archival sample preparation and effect of storage conditions on stability of the analytes are addressed. The intra-day and inter-day coefficients of variation were small for all the analytes, not exceeding 1% and 10%, respectively. Measurements of UA and creatinine in biobanked urine showed good agreement with values obtained using routine enzymatic assays on fresh urine. Spearman's correlation coefficients were 0.869 (p < .001) for creatinine and 0.964 (p < .001) for UA. Conclusion: the newly developed LC-MS/MS method allows reliable quantitative assessment of xanthine, hypoxanthine, allantoin, UA and creatinine. The proposed pre-analytical processing makes the method suitable for both fresh and biobanked urine stored frozen at -80 °C for at least 5.5 years. Keywords: Liquid chromatography; allantoin; biological specimen bank; creatinine; hydrophilic interaction; hypoxanthine; mass spectroscopy; purines; reference ranges; solubility; uric acid; urine; xanthine. The study has been funded by the following: 1. Helse Nord research foundation, 2017, project number: HNF1388-17. 2. Helse Nord research foundation, 2018, project number: HNF1430-18. 3. Familien Blix Fond, Project title: URIC ACID IN HEART AND KIDNEY DISEASE: development of new diagnostics and treatment. 4. UiT – The Arctic University of Norway and the Tromsø Research Foundation [Grant no. 311333/A22349].

BACKGROUND: A calcineurin inhibitor free immunosuppressive regimen has been demonstrated to improve renal function early after heart transplantation, but long-term outcome of such a strategy has not been well described.METHODS: In the randomized SCHEDULE trial, de novo heart transplant recipients received (1) everolimus with reduced-exposure calcineurin inhibitor (CNI, cyclosporine) followed by CNI withdrawal at weeks 7-11 post-transplant or (2) standard-exposure cyclosporine, both with mycophenolate mofetil and corticosteroids; 95/115 randomized patients were followed up at 5-7 years post-transplant.RESULTS: Mean measured GFR was 74.7mL/min and 62.4mL/min with everolimus and CNI, respectively. The mean difference was in favor of everolimus by 11.8 mL/min in the intent-to-treat population (P = 0.004) and 17.2 mL/min in the per protocol population (n = 75; P < 0.001). From transplantation to last follow-up, the incidence of biopsy-proven acute rejection (BPAR) was 77% (37/48) and 66% (31/47) (P = 0.23) with treated BPAR in 50% and 23% (P < 0.01), in the everolimus and CNI groups, respectively; no episode led to hemodynamic compromise. Coronary allograft vasculopathy (CAV) assessed by coronary intravascular ultrasound was present in 53% (19/36) and 74% (26/35) of everolimus- and CNI-treated patients, respectively (P = 0.037). Graft dimensions and function were similar between groups. Late adverse events were comparable.CONCLUSIONS: These results suggest that de novo heart transplant patients randomized to everolimus and low-dose CNI followed by CNI-free therapy maintain significantly better long-term renal function as well as significantly reduced CAV, than patients randomized to standard CNI treatment. Increased BPAR in the everolimus group during year 1 did not impair long-term graft function.

This is the pre-peer reviewed version of the following article: Norum, H.M., Michelsen, A.E., Lekva, T., Arora, S., Otterdal, K., Olsen, M.B. ... Ueland, T. (2018). Circulating delta‐like Notch ligand 1 is correlated with cardiac allograft vasculopathy and suppressed in heart transplant recipients on everolimus‐based immunosuppression. American journal of transplantation, 19(4), 1050-1060, which has been published in final form at https://doi.org/10.1111/ajt.15141. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. Cardiac allograft vasculopathy (CAV) causes heart failure after heart transplantation (HTx), but its pathogenesis is incompletely understood. Notch signaling, possibly modulated by everolimus (EVR), is essential for processes involved in CAV. We hypothesized that circulating Notch ligands would be dysregulated after HTx. We studied circulating delta‐like Notch ligand 1 (DLL1) and periostin (POSTN) and CAV in de novo HTx recipients (n = 70) randomized to standard or EVR‐based, calcineurin inhibitor‐free immunosuppression and in maintenance HTx recipients (n = 41). Compared to healthy controls, plasma DLL1 and POSTN were elevated in de novo (P < .01; P < .001) and maintenance HTx recipients (P < .001; P < .01). Use of EVR was associated with a treatment effect for DLL1. For de novo HTx recipients, a change in DLL1 correlated with a change in CAV at 1 (P = .021) and 3 years (P = .005). In vitro, activation of T cells increased DLL1 secretion, attenuated by EVR. In vitro data suggest that also endothelial cells and vascular smooth muscle cells (VSMCs) could contribute to circulating DLL1. Immunostaining of myocardial specimens showed colocalization of DLL1 with T cells, endothelial cells, and VSMCs. Our findings suggest a role of DLL1 in CAV progression, and that the beneficial effect of EVR on CAV could reflect a suppressive effect on DLL1.

The NOCTET study randomized 282 patients ≥1 year after heart or lung transplantation to continue conventional calcineurin inhibitor (CNI) therapy or to start everolimus with reduced-exposure CNI. Last follow-up, at ≥5 years post-randomization (mean 5.6 years) was attended by 72/140 everolimus patients (51.4%) and 91/142 controls (64.1%). Mean measured GFR remained stable in the everolimus group from randomization (51.3mL/min) to last visit (51.4mL/min) but decreased in controls (from 50.5mL/min to 45.3mL/min), and was significantly higher with everolimus at last follow-up (p=0.004). The least squares mean (SE) change from randomization was -1.5 (1.7)mL/min with everolimus versus -7.2 (1.7)mL/min for controls (difference 5.7 [95% CI 1.7; 9.6]mL/min; p=0.006). The difference was accounted for by heart transplant patients (difference 6.9 [95% 2.3; 11.5]mL/min; p=0.004). Lung transplant patients showed no between-group difference at last follow-up. Rates of rejection, death and major cardiac events were similar between groups, as was graft function. Pneumonia was more frequent with everolimus (18.3% versus 6.4%). In conclusion, introducing everolimus in maintenance heart transplant patients, with reduced CNI, achieves a significant improvement in renal function which is maintained for at least five years, but an early renal benefit in lung transplant patients was lost. Long-term immunosuppressive efficacy was maintained. This article is protected by copyright. All rights reserved.

The decline in glomerular filtration rate (GFR) associated with aging is one of the most important predisposing causes of kidney failure in old age. Identifying persons at risk for accelerated GFR decline is an essential first step in the development of preventive measures to preserve kidney function in the elderly. Heart rate (HR) has not yet been studied as a risk factor for GFR decline in the general population. In the RENIS-T6 (Renal Iohexol-Clearance Survey in Tromsø 6), we measured baseline ambulatory HR and GFR as iohexol clearance in a representative, middle-aged cohort of 1627 persons without self-reported diabetes mellitus, cardiovascular disease, or kidney disease. In the RENIS-FU (RENIS Follow-Up Study), we repeated the GFR measurements and calculated the rate of GFR decline in 81% of the participants after a median follow-up of 5.6 years. The unadjusted mean rate of GFR decline was 0.96 mL/min per year. In multivariable-adjusted linear mixed models, 10 bpm higher ambulatory 24-hour and daytime HRs and office HR were associated with steeper GFR decline rates of 0.20 to 0.21 mL/min per year ( P≤0.01). The odds ratio for predicting a rate of GFR decline twice that of the population mean in a fully adjusted model was 1.24 ( P=0.01) for ambulatory 24-hour HR. Office HR was also an independent predictor of a steeper rate of GFR decline. HR may be a useful biomarker to identify persons at risk of accelerated GFR decline.

Background Cardiac allograft vasculopathy (CAV) limits survival after heart transplantation, and the effect of different immunosuppressive regimens on CAV is not fully understood. The randomized SCHEDULE trial (Scandinavian Heart Transplant Everolimus De Novo Study With Early Calcineurin Inhibitors Avoidance) evaluated whether initiation of the proliferation signal inhibitor everolimus and early cyclosporine elimination can reduce CAV development. Methods and Results The SCHEDULE trial was a multicenter Scandinavian trial, where 115 de novo heart transplantation recipients were randomized to everolimus with complete cyclosporine withdrawal 7 to 11 weeks after heart transplantation or standard cyclosporine-based immunosuppression. Seventy-six (66%) patients had matched intravascular ultrasound examinations at baseline and 12 and 36 months. Intravascular ultrasound analysis evaluated maximal intimal thickness, percent atheroma volume, and total atheroma volume. Qualitative plaque analysis using virtual histology assessed fibrous, fibrofatty, and calcified tissue as well as necrotic core. Serum inflammatory markers were measured in parallel. The everolimus group (n=37) demonstrated significantly reduced CAV progression as compared with the cyclosporine group (n=39) at 36 months (Δ maximal intimal thickness, 0.09±0.05 versus 0.15±0.16 mm [ P =0.03]; Δ percent atheroma volume, 5.3±2.8% versus 7.6±5.9% [ P =0.03]; and Δ total atheroma volume, 33.9±71.2 versus 54.2±96.0 mm 3 [ P =0.34], respectively]. At 36 months the number of everolimus patients with rejection graded ≥2R was 15 (41%) as compared with 5 (13%) in the cyclosporine group ( P =0.01). Everolimus did not affect CAV morphology or immune marker activity during the follow-up period. Conclusions The SCHEDULE trial demonstrates that everolimus initiation and early cyclosporine elimination significantly reduces CAV progression at 12 months, and this beneficial effect is clearly sustained at 36 months. Clinical trial registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT01266148.

The Scandinavian heart transplant everolimus de novo study with early calcineurin inhibitors avoidance (SCHEDULE) trial was a 12 month, randomized, open-label, parallel-group trial that compared everolimus (EVR; n=56) to conventional CsA (n=59) immunosuppression. Previously, we reported that EVR outperformed CsA in improving renal function and coronary artery vasculopathy, despite a higher rejection rate with EVR. This study aimed to compare the effects of these treatments on quality of life (QoL). Within five post-operative days, patients (mean age 50±13 years, 27% women) were randomized to EVR or a standard CsA dosage (CsA group). This study assessed quality of life (QoL), based on the Short Form-36, EuroQol-5D, and Beck Depression Inventory (BDI). Assessments were performed pre-HTx and 12 and 36 months post-HTx. At 12 and 36 months, the groups showed similar improvements in Short Form-36 measures (at pre-HTx, 12 and 36 months the values were as follows: Physical component summary: EVR: 31.5±110.9, 49.1±9.7, and 47.9±10.6; P

Aim: Predictors of renal recovery following conversion from calcineurin inhibitor- to proliferation signal inhibitor-based therapy are lacking. We hypothesized that plasma NGAL (P-NGAL) could predict improvement in glomerular filtration rate (GFR) after conversion to everolimus. Patients & methods: P-NGAL was measured in 88 cardiac transplantation patients (median 5 years post-transplant) with renal dysfunction randomized to continuation of conventional calcineurin inhibitor-based immunosuppression or switching to an everolimus-based regimen. Results: P-NGAL correlated with measured GFR (mGFR) at baseline (R2 = 0.21; p < 0.001). Randomization to everolimus improved mGFR after 1 year (median [25–75 % percentiles]: ΔmGFR 5.5 [-0.5–11.5] vs -1 [-7–4] ml/min/1.73 m2; p = 0.006). Baseline P-NGAL predicted mGFR after 1 year (R2 = 0.18; p < 0.001), but this association disappeared after controlling for baseline mGFR. Conclusion: P-NGAL and GFR correlate with renal dysfunction in long-term heart transplantation recipients. P-NGAL did not predict improvement of renal function after conversion to everolimus-based immunosuppression.

In this 12-month multicenter Scandinavian study, 78 maintenance heart transplant (HTx) recipients randomized to everolimus with reduced calcineurin inhibitor (CNI) exposure or continued standard CNI-therapy underwent matched virtual histology (VH) examination to evaluate morphological progression of cardiac allograft vasculopathy (CAV). Parallel measurement of a range of inflammatory markers was also performed. A similar rate of quantitative CAV progression was observed in the everolimus (n = 30) and standard CNI group (n = 48) (plaque index 1.9 ± 3.8% and 1.6 ± 3.9%, respectively; p = 0.65). However, VH analysis revealed a significant increase in calcified (2.4 ± 4.0 vs. 0.3 ± 3.1%; p = 0.02) and necrotic component (6.5 ± 8.5 vs. 1.1 ± 8.6%; p = 0.01) among everolimus patients compared to controls. The increase in necrotic and calcified components was most prominent in everolimus patients with time since HTx >5.1 years and was accompanied by a significant increase in levels of von Willebrand (vWF) factor (p = 0.04) and vascular cell adhesion molecule (VCAM) (p = 0.03). Conversion to everolimus and reduced CNI is associated with a significant increase in calcified and necrotic intimal components and is more prominent in patients with a longer time since HTx. A significant increase in vWF and VCAM accompanied these qualitative changes and the prognostic implication of these findings requires further investigation.

BACKGROUND Everolimus reduces the progression of cardiac allograft vasculopathy (CAV) in de novo heart transplant (HTx) recipients, but the influence on established CAV is unknown. METHODS In this Nordic Certican Trial in Heart and lung Transplantation substudy, 111 maintenance HTx recipients (time post-HTx 5.8 ± 4.3 years) randomized to everolimus+reduced calcineurin inhibitor (CNI) or standard CNI had matching (intravascular ultrasound) examinations at baseline and 12 months allowing accurate assessment of CAV progression. RESULTS No significant difference in CAV progression was evident between the treatment groups (P = 0.30). When considering patients receiving concomitant azathioprine (AZA) therapy (n = 39), CAV progression was attenuated with everolimus versus standard CNI (Δmaximal intimal thickness 0.00 ± 0.04 and 0.04 ± 0.04 mm, Δpercent atheroma volume 0.2% ± 3.0% and 2.6% ± 2.5%, and Δtotal atheroma volume 0.25 ± 14.1 and 19.8 ± 20.4 mm(3), respectively [P < 0.05]). When considering patients receiving mycophenolate mofetil (MMF), accelerated CAV progression occurred with everolimus versus standard CNI (Δmaximal intimal thickness 0.06 ± 0.12 vs. 0.02 ± 0.06 mm and Δpercent atheroma volume 4.0% ± 6.3% vs. 1.4% ± 3.1%, respectively; P < 0.05). The levels of C-reactive protein and vascular cell adhesion molecule-1 declined significantly with AZA+everolimus, whereas MMF+everolimus patients demonstrated a significant increase in levels of C-reactive protein, vascular cell adhesion molecule-1, and von Willebrand factor. CONCLUSIONS Conversion to everolimus and reduced CNI does not influence CAV progression among maintenance HTx recipients. However, background immunosuppressive therapy is important as AZA+everolimus patients demonstrated attenuated CAV progression and a decline in inflammatory markers, whereas the opposite pattern was seen with everolimus+MMF. The different effect of everolimus when combined with AZA versus MMF could potentially reflect hitherto unknown interactions.

In a single-center study, 20 kidney transplant patients without prior rejection were abruptly converted from cyclosporine to everolimus at seven wk post-transplant. All patients received basiliximab induction with maintenance enteric-coated mycophenolate sodium and corticosteroids. Biopsy-proven acute rejection had occurred in three of 20 patients (15.0%) by the end of week seven post-conversion. All episodes were mild and reversible, with subsequent recovery of renal function. Calculated glomerular filtration rate (GFR) improved significantly (51 +/- 11 mL/min at time of conversion, 58 +/- 12 mL/min at week seven post-conversion, 57 +/- 17 mL/min at month six post-conversion; p = 0.001). No patient developed proteinuria in the nephrotic range. Twenty-two adverse events were reported in 10 patients, three of which had a suspected relationship to everolimus. Mean leukocyte and platelet count decreased significantly, and triglyceride level increased. This study suggests that kidney transplant patients without prior rejection can be converted abruptly from cyclosporine to everolimus at seven wk post-transplant, resulting in significantly improved renal function with no apparent increase, in risk of rejection and good tolerability.

Background. Immunosuppressive therapies have been associated with gastrointestinal (GI) side effects, which may impair health-related quality of life (HRQoL). Methods. In this survey, 4,232 renal transplant recipients from Denmark, Finland, Nor-way, and Sweden completed the Short-Form 36 (SF-36) questionnaire and the Gastrointestinal Symptom Rating Scale (GSRS). SF-36 scores were compared with country norm values. Multiple logistic regression analysis was used to identify immunosuppressants associated with GI symptoms. Results. The prevalence of troublesome GI symptoms (GSRS > 1) was 83% for indigestion, 69% for abdominal pain, 58% for constipation, 53% for diarrhea, 47% for reflux, and 92% for any GI symptom. Compared with the general population, HRQoL was most commonly meaningfully impaired in the general health dimension (53% of patients). The presence and severity of GI symptoms were associated with worse HRQoL. Tacrolimus showed a significant association with diarrhea (odds ratio [OR]: 1.7; 95% confidence interval [CI]: 1.4-2.0) and constipation (OR: 1.3; 95% Cl: 1.1-1.6), and sirolimus with indigestion (OR: 2.9; 95% Cl: 1.0-8.1) and abdominal pain (OR: 2.2; 95% Cl: 1.1-4.4). Conclusions. GI symptoms are associated with impaired HRQoL in the renal transplant population. Managing GI symptoms by careful choice of immunosuppressants should be a focus for improving HRQoL in renal transplant recipients (Less)

In a randomized, open-label trial, de novo heart transplant recipients were randomized to everolimus (3-6 ng/mL) with reduced-exposure calcineurin inhibitor (CNI; cyclosporine) to weeks 7-11 after transplant, followed by increased everolimus exposure (target 6-10 ng/mL) with cyclosporine withdrawal or standard-exposure cyclosporine. All patients received mycophenolate mofetil and corticosteroids. A total of 110 of 115 patients completed the 12-month study, and 102 attended a follow-up visit at month 36. Mean measured GFR (mGFR) at month 36 was 77.4 mL/min (standard deviation [SD] 20.2 mL/min) versus 59.2 mL/min (SD 17.4 mL/min) in the everolimus and CNI groups, respectively, a difference of 18.3 mL/min (95% CI 11.1-25.6 mL/min; p < 0.001) in the intention to treat population. Multivariate analysis showed treatment to be an independent determinant of mGFR at month 36. Coronary intravascular ultrasound at 36 months revealed significantly reduced progression of allograft vasculopathy in the everolimus group compared with the CNI group. Biopsy-proven acute rejection grade ≥2R occurred in 10.2% and 5.9% of everolimus- and CNI-treated patients, respectively, during months 12-36. Serious adverse events occurred in 37.3% and 19.6% of everolimus- and CNI-treated patients, respectively (p = 0.078). These results suggest that early CNI withdrawal after heart transplantation supported by everolimus, mycophenolic acid and steroids with lymphocyte-depleting induction is safe at intermediate follow-up. This regimen, used selectively, may offer adequate immunosuppressive potency with a sustained renal advantage.

Summary In a 36-month, open-label, multicenter trial, 202 kidney transplant recipients were randomized at week 7 post-transplant to convert to everolimus or remain on cyclosporine: 182 were analyzed to month 36 (92 everolimus, 90 controls). Mean (SD) change in measured GFR (mGFR) from randomization to month 36 was 1.3 (14.0) ml/min with everolimus versus −1.7 (15.4) ml/min in controls (P = 0.210). In patients who remained on treatment, mean mGFR improved from randomization to month 36 by 7.9 (11.5) ml/min with everolimus (n = 37) but decreased by 1.4 (14.7) ml/min in controls (n = 62) (P = 0.001). During months 12–36, death-censored graft survival was 100%, patient survival was 98.9% and 96.7% in the everolimus and control groups, respectively, and 13.0% and 11.1% of everolimus and control patients, respectively, experienced mild biopsy-proven acute rejection (BPAR). Protocol biopsies in a limited number of on-treatment patients showed similar interstitial fibrosis progression. Donor-specific antibodies were present at month 36 in 6.3% (2/32) and 18.0% (9/50) of on-treatment everolimus and control patients with available data (P = 0.281). During months 12-36, adverse events were comparable, but discontinuation was more frequent with everolimus (33.7% vs. 10.0%). Conversion from cyclosporine to everolimus at 7 weeks post-transplant was associated with a significant benefit in renal function at 3 years when everolimus was continued.

Early initiation of everolimus with calcineurin inhibitor therapy has been shown to reduce the progression of cardiac allograft vasculopathy (CAV) in de novo heart transplant recipients. The effect of de novo everolimus therapy and early total elimination of calcineurin inhibitor therapy has, however, not been investigated and is relevant given the morbidity and lack of efficacy of current protocols in preventing CAV. This 12-month multicenter Scandinavian trial randomized 115 de novo heart transplant recipients to everolimus with complete calcineurin inhibitor elimination 7-11 weeks after HTx or standard cyclosporine immunosuppression. Ninety-five (83%) patients had matched intravascular ultrasound examinations at baseline and 12 months. Mean (± SD) recipient age was 49.9 ± 13.1 years. The everolimus group (n = 47) demonstrated significantly reduced CAV progression as compared to the calcineurin inhibitor group (n = 48) (ΔMaximal Intimal Thickness 0.03 ± 0.06 and 0.08 ± 0.12 mm, ΔPercent Atheroma Volume 1.3 ± 2.3 and 4.2 ± 5.0%, ΔTotal Atheroma Volume 1.1 ± 19.2 mm(3) and 13.8 ± 28.0 mm(3) [all p-values ≤ 0.01]). Everolimus patients also had a significantly greater decline in levels of soluble tumor necrosis factor receptor-1 as compared to the calcineurin inhibitor group (p = 0.02). These preliminary results suggest that an everolimus-based CNI-free can potentially be considered in suitable de novo HTx recipients.

In a randomized, open-label trial, everolimus was compared to cyclosporine in 115 de novo heart transplant recipients. Patients were assigned within 5 days posttransplant to low-exposure everolimus (3–6 ng/mL) with reduced-exposure cyclosporine (n = 56), or standard-exposure cyclosporine (n = 59), with both mycophenolate mofetil and corticosteroids. In the everolimus group, cyclosporine was withdrawn after 7–11 weeks and everolimus exposure increased (6–10 ng/mL). The primary efficacy end point, measured GFR at 12 months posttransplant, was significantly higher with everolimus versus cyclosporine (mean ± SD: 79.8 ± 17.7 mL/min/1.73 m2 vs. 61.5 ± 19.6 mL/min/1.73 m2; p

s S129 Conclusion: Using a portable Freedom driver, TAH-t patients are increasingly mobile, allowing discharge from the hospital with successful bridge to transplantation, while residing in a home environment.

In an open-label, multicenter trial, de novo kidney transplant recipients at low to medium immunological risk were randomized at week 7 posttransplant to remain on CsA (n = 100, controls) or convert to everolimus (n = 102), both with enteric-coated mycophenolate sodium and corticosteroids. The primary endpoint, change in measured GFR (mGFR) from week 7 to month 12, was significantly greater with everolimus than controls: 4.9 (11.8) mL/min versus 0.0 (12.9) mL/min (p = 0.012; analysis of covariance [ANCOVA]). Per protocol analysis demonstrated a more marked difference: an increase of 8.7 (11.2) mL/min with everolimus versus a decrease of 0.4 (12.0) mL/min in controls (p

The NOCTET (NOrdic Certican Trial in HEart and lung Transplantation) trial demonstrated that everolimus improves renal function in maintenance thoracic transplant (TTx) recipients. Nevertheless, introduction of everolimus is not recommended for patients with advanced renal failure. We evaluated NOCTET data to assess everolimus introduction amongst TTx recipients with advanced renal failure.This 12-month multicenter Scandinavian study randomized 282 maintenance TTx recipients to everolimus introduction with calcineurin inhibitor (CNI) reduction or standard CNI therapy. The measured glomerular filtration rate (mGFR) was noted at baseline and after 1-year using Cr-ethylenediaminetetraacetic acid clearance.In 21 patients with a baseline mGFR of 20 to 29 ml/min/1.73 m(2), renal function improved in the everolimus group compared with the control group ((ΔmGFR 6.7 ± 9.0 vs -1.6 ± 5.1 ml/min/1.73 m(2); p = 0.03). Amongst 173 patients with moderate renal impairment (mGFR 30-59 ml/min/1.73 m(2)), renal function improvement was also greater amongst everolimus patients than in controls (ΔmGFR 5.1 ± 11.1 vs -0.5 ± 8.7 ml/min/1.73 m(2); p0.01). In 55 patients with mGFR 60 to 89 ml/min/1.73 m(2), mGFR did not change significantly in either group. Improvement in mGFR was limited to patients with a median time since TTx of less than 4.6 years and was also influenced by CNI reduction during the study period.Everolimus introduction and reduced CNI significantly improved renal function amongst maintenance TTx patients with pre-existing advanced renal failure. This beneficial effect was limited to patients undergoing conversion in less than 5 years after TTx, indicating a window of opportunity that is appropriate for pharmacologic intervention with everolimus.

Use of the mammalian target of rapamycin inhibitor everolimus with an accompanying reduction in calcineurin inhibitor (CNI) exposure has shown promise in preserving renal function in maintenance thoracic transplant patients, but robust, long-term data are required.In a prospective, open-label, multicenter study, thoracic transplant recipients more than or equal to 1 year posttransplant with mild-to-moderate renal insufficiency were randomized to continue their current CNI-based immunosuppression or convert to everolimus with predefined CNI exposure reduction. After a 12-month core trial, patients were followed up to month 24 after randomization.Of 245 patients who completed the month 12 visit, 235 patients (108 everolimus and 127 controls) entered the 12-month extension phase. At month 24, mean measured glomerular filtration rate had increased by 3.2±12.3 mL/min from the point of randomization in everolimus-treated patients and decreased by 2.4±9.0 mL/min in controls (P0.001), a difference that was significant within both the heart and lung transplant subpopulations. During months 12 to 24, 5.6% of everolimus patients and 3.1% of controls experienced biopsy-proven acute rejection (P=0.76). There were no significant differences in the rate of adverse events or serious adverse events (including pneumonia) between groups during months 12 to 24.Converting maintenance thoracic transplant recipients to everolimus with low-exposure CNI results in a renal benefit that is sustained to 2 years postconversion, with significantly improved measured glomerular filtration rate in both heart and lung transplant patients. Despite reductions of more than 50% in CNI exposure, there was no marked loss of efficacy. The safety profile of the everolimus-based regimen was acceptable.

BACKGROUND.: The proliferation signal inhibitor everolimus offers the potential to reduce calcineurin inhibitor (CNI) exposure and alleviate CNI-related nephrotoxicity. Randomized trials in maintenance thoracic transplant patients are lacking. METHODS.: In a 12-month, open-labeled, multicenter study, maintenance thoracic transplant patients (glomerular filtration rate >/=20 mL/min/1.73m and 1 year posttransplant were randomized to continue their current CNI-based immunosuppression or start everolimus with predefined CNI exposure reduction. RESULTS.: Two hundred eighty-two patients were randomized (140 everolimus, 142 controls; 190 heart, 92 lung transplants). From baseline to month 12, mean cyclosporine and tacrolimus trough levels in the everolimus cohort decreased by 57% and 56%, respectively. The primary endpoint, mean change in measured glomerular filtration rate from baseline to month 12, was 4.6 mL/min with everolimus and -0.5 mL/min in controls (P

Background: Cyclosporine (CsA) absorption varies early after transplantation and can be accurately assessed by the area under the absorption curve (AUC). The 2-hour post-dose (C2) level of CsA in whole blood is reported to be a useful surrogate marker of CsA AUC in kidney and liver transplant monitoring, but should be further explored in thoracic organ recipients. Methods: In a 12-month study we included de novo lung (n = 95) and heart (n = 96) recipients. All participants received cyclosporine (Sandimmun Neoral) monitored by CO and blood was collected for analysis of C2 retrospectively. Abbreviated AUC (AUC(0-4)) was measured at 7 days and 3 months. Primary outcome was C2 relation to the frequency of acute cellular rejection (ACR) needing treatment and possible decline in measured glomerular filtration rate (mGFR). Recipients were divided into lower, middle and upper third C2 groups based on 2-week post-operative values (tertiles T1 to T3). Results: C2 was the most robust substitute for AUC(0-4) in the group of patients studied. For lung, but not heart, recipients there were differences in mean number of ACRs (p = 0.05), incidence of any rejections (p = 0.04), mean number of any rejections (p = 0.001) and time to first rejection (p = 0.03) between T1 and T3. C2 did not predict reduction in mGFR. Conclusions: C2 is a sensitive predictor for ACR in lung, but not heart, recipients, C2 was not predictive of a decline in mGFR. This study suggests that management of lung recipients by C2 may diminish the number of ACRs. J Heart Lung Transplant 2009; 28:919-26. Copyright (C) 2009 by the International Society for Heart and Lung Transplantation. (Less)

The renal effects of the calcium-channel antagonist isradipine were evaluated in cyclosporin A (CsA)-treated renal allografted patients more than 5 months after transplantation. Twelve patients with stable renal function were given placebo for 2 weeks and then isradipine 1.25 mg x 2 for 1 week and 2.5 mg x 2 for the next 3 weeks in an open trial. The CsA dose was unchanged during the study. Isradipine did not interfere with the pharmacokinetics of CsA as both whole blood trough and peak levels were unchanged. Isradipine reduced mean arterial blood pressure (MAP) from 117.0 +/- 1.8 to 106.3 +/- 1.9 mmHg (P less than 0.01). The renal effects were studied during water diuresis 1-3 h after drug intake. Para-aminohippurate clearance (CPAH) increased from 256.4 +/- 21.5 to 291.5 +/- 26.3 ml/min (P less than 0.05), renal vascular resistance was reduced by 21.5% (P less than 0.01) and inulin clearance (CIn) was unchanged. Fractional proximal reabsorption, calculated from lithium clearance (CLi), was reduced by 11.9% (P less than 0.01) by isradipine. Isradipine also reduced proximal reabsorption of sodium (APRNa) and increased distal sodium delivery (DDNa). Distal sodium reabsorption (ADRNa) and free-water clearance (CH2O) were significantly increased. Urinary excretion of enzymes and proteins was unchanged by isradipine.

In a single-center study, 20 kidney transplant patients without prior rejection were abruptly converted from cyclosporine to everolimus at seven wk post-transplant. All patients received basiliximab induction with maintenance enteric-coated mycophenolate sodium and corticosteroids. Biopsy-proven acute rejection had occurred in three of 20 patients (15.0%) by the end of week seven post-conversion. All episodes were mild and reversible, with subsequent recovery of renal function. Calculated glomerular filtration rate (GFR) improved significantly (51 +/- 11 mL/min at time of conversion, 58 +/- 12 mL/min at week seven post-conversion, 57 +/- 17 mL/min at month six post-conversion; p = 0.001). No patient developed proteinuria in the nephrotic range. Twenty-two adverse events were reported in 10 patients, three of which had a suspected relationship to everolimus. Mean leukocyte and platelet count decreased significantly, and triglyceride level increased. This study suggests that kidney transplant patients without prior rejection can be converted abruptly from cyclosporine to everolimus at seven wk post-transplant, resulting in significantly improved renal function with no apparent increase, in risk of rejection and good tolerability.

Gastrointestinal (GI) symptoms are common in renal transplant recipients and are associated with impaired health-related quality of life (HRQoL). We investigated clinician attitudes to GI symptoms and HRQoL in these patients by surveying 145 nephrologists from Sweden, Denmark, Finland, and Norway. In total, 79 clinicians responded. They estimated that 20% of their patients experienced GI discomfort and that 36% had impaired HRQoL. We previously conducted a survey of the renal transplant recipients treated by these clinicians, in which 92% reported troublesome GI symptoms and 53% had impaired HRQoL compared with the general population. Nephrologists were more likely to manage GI symptoms by reducing immunosuppressant dose (87%) than by switching medication to one with fewer GI side effects (66%). We conclude that clinicians appear to underestimate the prevalence of GI symptoms and impaired HRQoL. Improving patient-clinician communication could lead to more informed management, resulting in better HRQoL and increased graft survival.

Increased urinary albumin-excretion (UAE) predicts cardiovascular events and clusters with the metabolic syndrome. The aim of this population-based, prospective study was to assess the relationship between baseline and longitudinal changes in cardiovascular risk-factors and 7 years' increase in UAE. Three thousand and four hundred non-diabetic participants (1838 men, 1562 women) of the Tromsø studies in 1994/1995 and 2001/2002 were included. In each survey, first-void spot-urine-samples were collected, and albumin-creatinine ratio (ACR) was calculated. Change in ACR (DeltaACR) was dichotomized into upper vs. the three lower quartiles. Median UAE in the population did not increase during follow-up. Baseline predictors for DeltaACR in the upper quartile were: age (OR 1.32 per 5 years, 95% CI 1.22-1.43), HbA1c (OR 1.43 per %, 95% CI 1.08-1.91) and waist circumference (OR 1.11 per 5 cm, 95% CI 1.04-1.19) in men, and age (OR 1.14 per 5 years, 95% CI 1.04-1.25) and current smoking (OR 1.71, 95% CI 1.27-2.30) in women. Systolic blood pressure and estimated glomerular filtration rate were predictors without gender-specificity. Clustering of three or more metabolic traits did not predict ACR increase independently. Protective factors against ACR increase were initiation of antihypertensive treatment in women (OR 0.59, 95% CI 0.39-0.87) and hard physical activity in men (OR 0.70, 95% CI 0.51-0.96). In summary, cardiovascular risk-factors at baseline predicted ACR increase, but initiation of antihypertensive therapy (women) and physical activity (men) seemed to protect from ACR increase during follow-up. Endpoint-data are needed to explore the clinical significance of low-grade UAE increase.

S. Arora ,1 K. Karason,2 H. Eisjaer,3 H. Botker,3 F. Gustafsson,4 K. Saunamaki,5 G. Radegran,6 E. Gude,1 L. Aaberge,1 T. Ueland,7 P. Aukrust,7 D. Solbu,8 L. Gullestad.1 1Cardiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway; 2Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden; 3Cardiology, Skeiby University Hospital, Aarhus, Denmark; 4Cardiology, Rigshospitalet, Copenhagen, Djibouti; 5Cardiology, Rigshospitalet, Copenhagen, Denmark; 6Cardiology, Lund Hospital, Lund, Sweden; 7Research Institute for Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway; 8Novartis Norge, Oslo, Norway.

Purpose Useful predictors of renal recovery following conversion from calcineurin inhibitor (CNI) to proliferation signal inhibitor based therapy are lacking. We hypothesized that plasma-neutrophil gelatinase-associated lipocalin (P-NGAL) - a new marker of kidney damage - in long term cardiac transplant recipients could predict improvement in glomerular filtration rate one year after conversion to an everolimus based regimen. Methods and Materials P-NGAL was measured at baseline in 88 cardiac transplant patients (median age 62 years, median 5 years post transplant) with mild to moderate renal dysfunction randomized to continuation of conventional immunosuppression (CNI, antiproliferative agent, steroid) or treatment with low dose everolimus, low dose CNI, an antiproliferative agent and steroid. Glomerular filtration rate was measured at baseline and after 1 year using crEDTA clearance (mGFR). Results Median P-NGAL was 109 (97-144) pg/L. Patients with NGAl above median were heavier and had higher white blood cell count and higher hsC-reactive protein levels at baseline. Median mGFR at baseline was 53 ml/min/1.73 m 2 . P-NGAL correlated with mGFR (R 2 =0.21, P 2 =0.32, P 2 ), P=0.006). Baseline P-NGAL predicted mGFR after one year (R 2 =0.18, P Conclusions P-NGAL and GFR correlate in long-term heart transplant recipients with renal dysfunction. P-NGAL did not predict improvement of renal function after conversion to everolimus based immunosuppression.

Summary Background Renal transplant recipients are at increased risk of premature cardiovascular disease. Although statins reduce cardiovascular risk in the general population, their efficacy and safety in renal transplant recipients have not been established. We investigated the effects of fluvastatin on cardiac and renal endpoints in this population. Methods We did a multicentre, randomised, double-blind, placebo-controlled trial in 2102 renal transplant recipients with total cholesterol 4·0–9·0 mmol/L. We randomly assigned patients fluvastatin (n=1050) or placebo (n=1052) and follow up was for 5–6 years. The primary endpoint was the occurrence of a major adverse cardiac event, defined as cardiac death, non-fatal myocardial infarction (MI), or coronary intervention procedure. Secondary endpoints were individual cardiac events, combined cardiac death or non-fatal MI, cerebrovascular events, non-cardiovascular death, all-cause mortality, and graft loss or doubling of serum creatinine. Analysis was by intention to treat. Findings After a mean follow-up of 5·1 years, fluvastatin lowered LDL cholesterol concentrations by 32%. Risk reduction with fluvastatin for the primary endpoint (risk ratio 0·83 [95% Cl 0·64-1·06], p=0·139) was not significant, although there were fewer cardiac deaths or non-fatal Ml (70 vs 104, 0·65 [0·48–0·88] p=0·005) in the fluvastatin group than in the placebo group. Coronary intervention procedures and other secondary endpoints did not differ significantly between groups. Interpretation Although cardiac deaths and non-fatal Ml seemed to be reduced, fluvastatin did not generally reduce rates of coronary intervention procedures or mortality. Overall effects of fluvastatin were similar to those of statins in other populations. Published online June 3, 2003 http://image.thelancet.com/extras/03art4377web.pdf

Purpose Immunosuppressant regimes centered on everolimus have been demonstrated to provide a quantitative reduction in cardiac allograft vasculopathy (CAV) amongst de-novo heart transplant (HTx) recipients. However, the effect of such therapy on CAV assessed by the qualitative method of Virtual Histology (VH) is unknown and was investigated in this prospective randomized-controlled trial. Methods and Materials In this 12-month multicenter Scandinavian study 190 maintenance HTx recipients were randomized to everolimus with reduced calcineurin inhibitor (CNI) exposure or continue standard CNI-therapy. Both groups continued their prior usage of azathioprine (AZA) or mycophenolate mofetil (MMF). 78 patients had evaluable VH examinations at baseline and 12 months and matched analysis was performed to measure change in fibrotic, fibrofatty, calcified and necrotic tissue component. Results When considering all 78 patients, mean age 57.4±10.3 years and mean time post-HTx 5.4±4.1 yrs, a similar rate of quantitative CAV progression was observed in the everolimus (n=30) versus standard CNI therapy group (n=48) (plaque index 1.9±3.9% and 1.6±3.7%, respectively; p=0.65). Virtual Histology analysis revealed a significant increase in calcified (2.4±4.0 versus 0.3±3.1%; p=0.02) and necrotic component (6.4±8.5 versus 1.0±8.6%; p 0.05). Conclusions Conversion to everolimus and reduced CNI does not significantly influence quantitative progression of CAV but is associated with a significant increase in calcified and necrotic tissue component. The prognostic implication of these qualitative changes in HTx recipients is unclear and warrants further investigation.