Proliferation Signal Inhibitors Research Articles

Latex-enhanced turbidimetric immunoassay for everolimus in whole blood using the Nanopia TDM everolimus assay with the JCA-BM6010 automatic analyzer.

Everolimus is a novel proliferation signal inhibitor used in immunosuppressive therapies for the prevention of acute and chronic rejection. It is an immunosuppressant requiring routine monitoring in whole blood. We evaluated analytical performance of the Nanopia TDM Everolimus assay kit for the measurement of everolimus in whole blood. Whole blood samples from patients receiving immunosuppressive therapy with everolimus after heart transplantation were used, and everolimus concentrations were measured by liquid chromatography combined with mass spectrometric detection and fluorescence polarization immunoassay and Nanopia TDM Everolimus assay. The within-assay coefficient of variation was 4.0%-6.8% (n = 20) at everolimus concentrations of 4.4-15.7 ng/mL, whereas the day-to-day coefficient of variation ranged from 3.6% to 5.4% at everolimus concentrations of 4.8-15.9 ng/mL. The limit of quantitation was 1.5 ng/mL. Calibration curves were stable for at least 14 days. The presence of conjugated bilirubin, unconjugated bilirubin, lipemic material, rheumatoid factor, and variation of the hematocrit did not affect this assay system. There was a strong positive correlation between values obtained with the Nanopia TDM Everolimus assay kit and the results of liquid chromatography combined with mass spectrometric detection (y = 0.960x + 0.312 ng/mL; r = 0.946; n = 91), as well as with data from the fluorescence polarization immunoassay (y = 0.966x - 0.440 ng/mL; r = 0.942; n = 91). The Nanopia TDM Everolimus assay showed good analytical performance. These results indicate that the Nanopia TDM Everolimus assay may be suitable for routine clinical use.

Chronic renal insufficiency in heart transplant recipients: risk factors and management options.

Renal dysfunction after heart transplantation is a frequently observed complication, in some cases resulting in significant limitation of quality of life and reduced survival. Since the pathophysiology of renal failure (RF) is multifactorial, the current etiologic paradigm for chronic kidney disease after heart transplantation relies on the concept of calcineurin inhibitor (CNI)-related nephrotoxicity acting on a predisposed recipient. Until recently, the management of RF has been restricted to the minimization of CNI dosage and general avoidance of classic nephrotoxic risk factors, with somewhat limited success. The recent introduction of proliferation signal inhibitors (PSIs) (sirolimus and everolimus), a new class of immunosuppressive drugs lacking intrinsic nephrotoxicity, has provided a completely new alternative in this clinical setting. As clinical experience with these new drugs increases, new renal-sparing strategies are becoming available. PSIs can be used in combination with reduced doses of CNIs and even in complete CNI-free protocols. Different strategies have been devised, including de novo use to avoid acute renal toxicity in high-risk patients immediately after transplantation, or more delayed introduction in those patients developing chronic RF after prolonged CNI exposure. In this review, the main information on the clinical relevance and pathophysiology of RF after heart transplantation, as well as the currently available experience with renal-sparing immunosuppressive regimens, particularly focused on the use of PSIs, is reviewed and summarized, including the key practical points for their appropriate clinical usage.

Is Late Conversion To Everolimus Beneficial in Kidney Transplant Patients With Interstitial Fibrosis Tubular Atrophy?

Introduction: Interstitial fibrosis & tubular atrophy is the leading cause of graft loss in kidney transplant patient. Proliferation signal inhibitors may help in reducing calcineurin inhibitor exposure without increasing acute rejection episodes. Current study evaluated efficacy of conversion from mycophenolate to everolimus with CNI minimization in patients with biopsy proven IFTA and deteriorating renal function. Methods: Prospective single center trial, study cohort selected from 200 live related renal transplant recipients in followup. All had received basiliximab induction and triple drug immunosupression (tacrolimus, MMF/EC-MFS, steroids). Inclusion criteria: biopsy proven IFTA, absence of significance proteinuria (<400 mg/24 hour), progressive graft dysfunction (decline of GFR > 15% over 1 month), eGFR>40ml/min/1.73m2. All underwent conversion from mycophenolate to everolimus with CNI minimization. Results: The study group composed of 22 patients (M:F=19:3), mean age 37 years (range 24-58). Conversion done at 24 months (range: 3-112 months) post-transplantation and median follow-up is 22 (IQR: 5-9) months. Of these 23 patients, only 2 had an early conversion and the rest 21 had a late conversion. The tacrolimus trough levels decreased from 5.1 ± 1.6 ng/ml to 3.6 ± 1.1 ng/ml (p=0.03). The everolimus levels achieved were 6.68 ± 2.4 ng/ml and 5.7±1.4 ng/ml at 1 and 3 months. The eGFR that had declined from best stable values of 59.3± 11.9ml/min to 48.2±9.5ml/min at conversion stabilized and improved to 50.7±11, 53.3±13.1, 54.9±13.9 and 57.1±10.1 ml/min at 1, 3, 6 and 12 months post conversion respectively (p=0.028 at 3 months). The eGFR showed futher improvement. After a total 471 patient treatment months, there were no episodes of rejection CMV or BK virus infection. Of 22 patients, certican was withdrawn in 2 patients at 12 months & 24 months due to appearance of proteinuria. Conclusion: Late conversion from mycophenolate to everolimus with CNI minimization resulted in stabilization of renal function with no evidnece of Rejection or infections.

(17) - De-Novo Low TAC/Low SIR Immunosuppression after HTx - 10 Year Results of a Prospective Trial

s S15 Conclusion: This was the first study to demonstrate a lower rate of CMV infection in patients treated with Tac vs. those treated with CsA after HTx.

(20) - Proliferation Signal Inhibitors for Cardiac Allograft Vasculopathy in Heart Transplant Recipients: A Systematic Review and Meta-Analysis of Randomized Clinical Trials

(20) - Proliferation Signal Inhibitors for Cardiac Allograft Vasculopathy in Heart Transplant Recipients: A Systematic Review and Meta-Analysis of Randomized Clinical Trials

Oedema, solid organ transplantation and mammalian target of rapamycin inhibitor/proliferation signal inhibitors (mTOR-I/PSIs).

Mammalian target of rapamycin inhibitor (mTOR-I)/proliferation signal inhibitors (PSI) including sirolimus and everolimus represent a new class of drugs increasingly used in solid-organ transplantation as alternatives to calcineurin inhibitors for patients with renal dysfunction, transplant coronary arterial vasculopathy or malignancy. The most frequently occurring mTOR-I/PSI-related adverse events are similar to those associated with other immunosuppressive therapies, but some side effects are more characteristic of proliferation signal inhibitors (e.g. lymphocele, arthralgia, oedema and hyperlipidaemia). The present paper review incidence, clinical presentation and mechanism of oedema within the clinical experience of mTOR-I/PSI in solid organ transplantation.

Immunosuppression Following Heart Transplantation: Prospects and Challenges

Immunosuppression after heart transplantation has significantly reduced the incidence of cellular rejection and improved patient outcomes with the routine use of calcineurin inhibitors. Antimetabolites and proliferation signal inhibitors add to the improvement in patient outcomes, particularly with respect to the reduced burden of cardiac allograft vasculopathy. Patients with antibody sensitization are potentially at higher risk of postoperative complications. Sensitized patients are undergoing heart transplantation with increased frequency, in part due to the emergence of ventricular assist device use as a bridge to heart transplantation. Despite improvements in immunosuppressive therapies, many challenges face physicians and patients, which will further refine and improve care of the post-heart transplant patient.

Influence of proliferation signal inhibitors on vascular endothelial growth factor production in heart transplant recipients - preliminary report.

Proliferation signal inhibitors (PSI) are especially beneficial for heart transplant recipients, but are rarely used due to frequent side effects. As they may be caused by vascular endothelial growth factor (VEGF), we performed a prospective cross-sectional pilot study to assess the influence of PSI and/or calcineurin inhibitors (CNI) presence in immunosuppressive protocols of heart transplant recipients on VEGF secretion. All electively screened heart transplant recipients willing to participate were enrolled in the study. The preliminary report was based on the results of the first 89 serum samples. The study group (n = 84) consisted of the PSI group (n = 14) further divided into the PSI + CNI subgroup (n = 10) and PSIw/oCNI subgroup (n = 4) based on concomitant CNI use, and the CNIw/oPSI group (n = 70) receiving CNI without PSI. The control group (n = 5) consisted of patients not requiring immunosuppression. VEGF was present in serum of 70 (83%) study group patients: median (range) 18 (0-316) pg/mL, mean 35 ± 57 pg/mL; in 13 (93%) PSI group patients: 22 (0-110) pg/mL, 28 ± 28 pg/mL, with 19 (8-20) pg/mL, 16 ± 6 pg/mL in the PSI + CNI subgroup, and 29 (0-110) pg/mL, 32 ± 32 pg/mL in the PSIw/oCNI subgroup. In the CNIw/oPSI group VEGF was present in 57 (81%) patients: 16 (0-316) pg/mL, 37 ± 62 pg/mL, and in the control group in 3 (60%) patients: 4 (0-110) pg/mL, 32 ± 48 pg/mL. None of the differences observed between any compared groups and/or subgroups was significant (χ2 and Mann-Whitney U test). In conclusion, differences of VEGF concentration observed among groups imply the influence of PSI and CNI on VEGF production, but further studies involving higher numbers of participants are needed to prove it.

Early introduction of everolimus immunosuppressive regimen in liver transplantation with extra-anatomic aortoiliac-hepatic arterial graft anastomosis.

Liver transplantation is the treatment of choice for patients with acute and chronic end-stage liver disease, when no other medical treatment is possible. Despite high rates of 1- to 5-year survival, long-term adverse effects of immunosuppressant agents remain of major concern. Current research and clinical efforts are made to develop immunosuppressant agents that minimize adverse effects along with a low rate of graft rejection. Tailoring immunosuppressive therapy to individual patients by the use of proliferation signal inhibitors seems to be the best way to minimize toxicity and increase efficacy. Recently everolimus has been introduced in clinical practice; among its adverse effects an increased incidence of arterial graft thrombosis in renal transplants, vascular anastomosis leakage, impaired wound healing, and thrombotic microangiopathy have been reported. We present the case of a 54-year-old patient submitted to liver transplantation for end-stage liver disease treated by an extra-anatomic aortoiliac-hepatic arterial graft anastomosis and early postoperative introduction of everolimus for acute renal failure. Postoperative period was characterized by two abdominal collections and reactivation of cytomegalovirus infection that were treated by percutaneous drainage and antiviral therapy, respectively; the patient is well after 8-month followup with patency of the arterial conduit and no leakage.

Evolving Concepts and Treatment Strategies for Cardiac Allograft Vasculopathy

The central event in the development of allograft vasculopathy is the inflammatory response to immune-mediated and nonimmune-mediated endothelial damage. This response is characterized by the release of inflammatory cytokines, upregulation of cell-surface adhesion molecules, and subsequent binding of leukocytes. Growth factors stimulate smooth muscle cell proliferation and circulating progenitor cells are recruited to sites of arterial injury leading to neointima formation. Because of its diffuse nature, intravascular ultrasound is more sensitive than angiography for early diagnosis. Proliferation signal inhibitors (PSIs) have the capacity to slow vasculopathy progression by inhibiting smooth muscle cell proliferation, but its side effects profile makes its use as a first line agent difficult. Retransplantation is still the only definitive therapy but is available only in selected cases. The current hope is that immunomodulation at the time of transplant could induce long-term tolerance and graft accommodation, leading to less vasculopathy.

Renal Recovery After Conversion to an Everolimus-Based Immunosuppression in Early and Late Heart Transplant Recipients: A 12-Month Analysis

Calcineurin inhibitor-induced nephrotoxicity reduces long-term patient survival after heart transplant. Proliferation signal inhibitors, in combination with or replacing calcineurin inhibitors, may preserve or improve renal function. We evaluated the effect of calcineurin inhibitor-reduction and withdrawal in everolimus-based immunosuppression on renal function after a heart transplant. Twenty-four patients with creatinine clearance < 1 mL/s (60 mL/min) were switched from tacrolimus and mycophenolate mofetil to low-dose tacrolimus/everolimus if their heart transplant was ≤ 1 year ago (group 1, n=13) and to everolimus/mycophenolate mofetil if their heart transplant was > 1 year ago (group 2, n=11). Serum creatinine levels and calculated creatinine clearance were analyzed up to 12 months after conversion. The switch in immunosuppression was associated with a significant decrease/increase of serum creatinine/creatinine clearance in both groups between baseline and month 12 (group 1, creatinine, 221.0 ± 70.7 to 159.1 ± 44.2 μmol/L (2.5 ± 0.8 to 1.8 ± 0.5 mg/dL); creatinine clearance, 0.75 ± 0.45 to 1.01 ± 0.50 mL/s (45.1 ± 26.7 to 60.5 ± 29.7 mL/min) (P < .01 each); group 2, creatinine, 247.5 ± 79.6 to 159.1 ± 44.2 μmol/L (2.8 ± 0.9 to 1.8 ± 0.5 mg/dL), creatinine clearance, 0.57 ± 0.23 to 0.93 ± 0.33 mL/s (34.1 ± 13.8 to 55.7 ± 19.6 mL/min) [P < .05 each]) with no significant group difference in the creatinine and the creatinine clearance levels after switching. No acute rejections or deaths occurred during the 12-month follow-up. Four patients (36.4%) from group 2 and 1 patient (7.7%) from group 1 discontinued everolimus because of adverse events. Everolimus allows calcineurin inhibitor-reduction and withdrawal after a heart transplant, resulting in improved renal function. However, adverse effects are common and lead to a high reconversion rate.

Safety of immunosuppressive drugs used as maintenance therapy in kidney transplantation: a systematic review and meta-analysis.

To evaluate the safety of regimens containing calcineurin inhibitors (CNI), proliferation signal inhibitors (TOR-I) and antimetabolites, we conducted a meta-analysis of randomized clinical trials (RCTs) and observational studies. A total of 4,960 citations were identified in our electronic search and 14 additional articles were identified through hand searching. Forty-eight articles (11,432 participants) from 42 studies (38 RCTs and four cohorts) met the inclusion criteria. Meta-analysis results revealed the following: (i) tacrolimus was associated with an increased risk for diabetes and lower risk of dyslipidemia, compared to cyclosporine; (ii) mycophenolate mofetil (MMF) was associated with increased risk for total infections, abdominal pain, diarrhea and vomiting, compared with azathioprine; (iii) sirolimus was associated with higher risk of anemia, diabetes, dyslipidemia, lymphoceles and withdrawal compared to tacrolimus or cyclosporine, and cyclosporine was associated with an increased risk of CMV infection; (iv) the combination of CNI with antimetabolites was associated with more adverse events than CNI alone; (v) TOR-I was related to more adverse events than MMF. The data observed in this meta-analysis are similar to those describe by others authors; thus, the choice of treatment must be made by the clinical staff based on specific patient characteristics.

Rejection after conversion to a proliferation signal inhibitor in chronic heart transplantation

We sought to determine the incidence, risk factors, and consequences of acute rejection (AR) after conversion from a calcineurin inhibitor (CNI) to a proliferation signal inhibitor (PSI) in maintenance heart transplantation. Relevant clinical data were retrospectively obtained for 284 long-term heart transplant recipients from nine centers in whom CNIs were replaced with a PSI (sirolimus or everolimus) between October 2001 and March 2009. The rejection rate at one yr was 8.3%, stabilizing to 2% per year thereafter. The incidence rate after conversion (4.9 per 100 patient-years) was significantly higher than that observed on CNI therapy in the pre-conversion period (2.2 per 100 patient-years). By multivariate analysis, rejection risk was associated with a history of late AR prior to PSI conversion, early conversion (<5 yr) after transplantation and age <50 yr at the time of conversion. Use of mycophenolate mofetil was a protective factor. Post-conversion rejection did not significantly influence the evolution of left ventricular ejection fraction, renal function, or mortality during further follow-up. Conversion to a CNI-free immunosuppression based on a PSI results in an increased risk of AR. Awareness of the clinical determinants of post-conversion rejection could help to refine the current PSI conversion strategies.

Virtual Histology and the Morphologic Assessment of Cardiac Allograft Vasculopathy

To the Editor: We read with great interest the paper by Arora et al. reporting the results of a12-month multicenter Scandinavian study on the qualitative evaluation of the influence of everolimus on cardiac allograft vasculopathy (CAV) morphology among heart transplant (HTx) recipients with a long follow up of >5 years post-HTx. (1Arora S Erikstad I Ueland T et al.Virtual histology assessment of cardiac allograft vasculopathy following introduction of everolimus—Results of a multicenter trial.Am J Transplant. 2012; 12: 2700-2709Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar). With the use of virtual histology (VH) (2Prasad A Cipher DJ Mohandas A Roesle M Brilakis ES Banerjee S Reproducibility of intravascular ultrasound virtual histology analysis.Cardiovasc Revasc Med. 2008; 9: 71-77Crossref PubMed Scopus (27) Google Scholar,3Hernandez JM de Prada JA Burgos V et al.Virtual histology intravascular ultrasound assessment of cardiac allograft vasculopathy from 1 to 20 years after heart transplantation.J Heart Lung Transplant. 2009; 28: 156-162Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar), the authors revealed a significant increase in calcified and necrotic tissue component in intimal lesions of the everolimus group of HTx patients compared to controls, while the overall plaque volume was not affected at all. Calcified and necrotic components of the plaques were considered by the authors as a result of the inflammatory tissue component of the plaque, and their findings on VH were indeed accompanied by a parallel rise in plasma levels of the markers for endothelial cell activation vWF and VCAM. Intriguing in this study is that the increase in calcified and necrotic components was more prominent in those patients who had a longer time since HTx (>5 years). As recognized also by the authors, CAV lesions are pathologically heterogeneous and can be characterized by a prevalence of fibrous/ fibrocellular pattern or a more atheroma-like pattern. Studies on native atherosclerotic plaques have shown that the cellular microenvironment differs significantly in these two type of lesions and that they can also be affected differently by everolimus (4Li X de Winter RJ van der Wal AC The iatrogenic pathology of percutaneous interventions in coronary arteries.Minerva Medica. 2012; 103: 487-502PubMed Google Scholar). Here, the question comes up whether the results of this study could have been influenced by the specific morphological types of CAV lesions. These were not classified by the authors, but proliferation signal inhibitors (PSIs) could influence one type of lesion more than the other. We have recently evaluated pathologically 70 coronary plaques from heart transplanted pts who died because of CAV (5Castellani C Angelini A de Boer O et al.Intraplaque haemorrhage as a trigger of lesion progression in cardiac allograft vasculopathy.J Heart Lung Transplant. 2012; 31: 5275Abstract Full Text Full Text PDF Google Scholar). With the use of conventional histology and immunohistochemistry, we could identify intraplaque hemorrhages in 60% of CAV lesions, which was even more than the 30.4% of plaque hemorrhages that we observed in the coronary plaques of the same patients in their explanted native heart (p = 0.01). Such intraplaque hemorrhages can be responsible for necrotic core enlargement as was detected in the everolimus treated patients, and this process favors deposition of calcification on the long term. We believe that the lack of reduction of plaque volume in everolimus patients represents not just the inability of the PSI to inhibit the myofibroproliferative response, but can be also attributed to another mechanism of CAV evolution, namely intraplaque hemorrages. Today, we still need pathological evaluation of plaque morphology in patients with CAV. It will be a challenge for in vivo imaging techniques including IVUS to visualize plaque components like inflammation, angiogenesis and hemorrhages, to further unravel the pathophysiological mechanism of PSI in CAV development. The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

Proliferation Signal Inhibitors Reduce Severity of Cardiac Allograft Vasculopathy after Heart Transplantation

Purpose The multicenter randomized trials of everolimus have demonstrated a significant reduction in 1st year maximal intimal thickness. It has been demonstrated from a validation study that 1st year intimal thickness >0.5 mm results in more angiographic abnormalities at 5 years after transplant. We sought to verify this finding by following our patients on everolimus at the time of heart transplant for 5 years and comparing them to age-match-sex controls. Methods and Materials Between 1994 and 2010, we evaluated 800 heart transplant patients and divided them into initial immunosuppression groups which included: Cyclosporine (CYA)/Mycophenolate (MMF), tacrolimus (TAC)/MMF and CYA/everolimus (EVR). Patients were followed for 5 years after heart transplantation for survival, freedom from cardiac allograft vasculopathy (CAV: any angiographic stenosis ≥30%) (including grades of CAV), freedom from non-fatal major adverse cardiac events (NF-MACE: MI, stroke, new-onset CHF, percutaneous cardiac intervention, need for defibrillator/pacemaker), and 1-year freedom from rejection. Results There was no significant difference in 5 year survival and freedom from CAV or NF-MACE among the 3 groups. However, review of CAV severity found no ISHLT grade 2-3 CAV in the CSA/EVR group compared to the CYA/MMF and TAC/MMF groups (0% vs 38% vs 31%) but numbers are small. Conclusions Patients treated with proliferation signal inhibitors at the time of heart transplantation appear to develop less severe CAV compared to patients not on proliferation signal inhibitors. A larger study is warranted to confirm these findings. Outcomes CYA/MMF (N=243) TAC/MMF (N=528) CYA/EVR (N=29) Log-Rank p-value 1-Year Freedom from Any-Treated Rejection 90% 87% 83% 0.417 5-Year Actuarial Survival 77% 83% 76% 0.106 5-Year Freedom from NF-MACE 84% 85% 83% 0.913 5-Year Freedom from CAV 83% 85% 93% 0.318 Total with CAV, n 42 79 2 CAV1, n (%) 26 (62%) 54 (69%) 2 (100%) CAV2, n (%) 8 (19%) 13 (16%) 0 (0%) CAV3, n (%) 8 (19%) 12 (15%) 0 (0%)

Incidence of Proteinuria after Initiation of Everolimus in Heart Transplantion. May It Have Repercussion on Renal Function?

Purpose Proliferation signal inhibitors(PSI) used after heart transplantation(HT) may reduce post-HT complications. The proteinuria associated with using PSI leads to deterioration of renal function(RF). Purpose To determine the incidence of proteinuria after beginning of Everolimus(EVE) and his influence on RF. Methods and Materials Retrospective study of 54HT patients receiving EVE in late phase. 4patients were excluded due to basal pathological proteinuria. Immunosuppression was Cyclosporine (CyA) vs Tacrolimus (FK), MMF vs Azathioprine and prednisone. Proterinuria was determined using urine dipstick method and value Results 50HT patients were analyzed (92% men, mean age:61±11 years), mean time between HT-EVE initiation 6±5 years. The mean proteinurina and creatinine(pre-EVE) was 12’5 mg/dl(12- 7’6) and 1’56 mg/dl (0’8-3’30). 86% had statins and 48% ACEi or ARBs. After EVE starting the incidence of proteinuria at 1, 3, 6 and 12 months was: 5(10%), 9(18%), 10(20%), 14(28%) respectively, with a median of 11(1’5-29), 17’3(4-93), 14(3’9-98) and 18(5-132). Median of RF evolution analyzed according to proteinuria (absence/presence) at pre was 53’7/53’8 (21-103/29-160); and for months 1,3,6,12 was: 54’6/54’7 (25-105/28-154); 50’4/66’3 (20-107/25-154); 57/53 ( 23-109/25/100); 47’7/54’4 ( 28-94/29-118) respectively,p=NS. No significant differences were found in the development of proteinuria and taking ACEi or ARBs. Conclusions The incidence of proteinuria to the year of the EVE initiation in long-term HT patients is 28%. EVE utilization in patients without proteinuria before beginning appears safe and is not associated with a significant increase in proteinuria or renal impairment. However, the number is small so that further studies with larger series are needed to confirm this hypothesis.

Can Plasma NGAL Predict Renal Response to Conversion from Calcineurin Inhbitor- to Everolimus Based Immunosuppression after Cardiac Transplantation?

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.

Are There Differences in the Development of Proteinuria after Everolimus Initiation and Calcineurin Withdrawal or Not in Heart Transplantation?

Purpose Proliferation signal inhibitors(PSI) used after heart transplantation(HT) are useful in long-term complications. Proteinuria associated with use of PSI and possible deterioration of renal function may be related to use of calcineurin inhibitors (CNI). Purpose To determine the incidence of proteinuria after 1year of initiation everolimus (EVE) and analyze its relationship with CNI withdrawal and type of CNI. Methods and Materials Retrospective study of 54HT patients receiving EVE in late phase. 4patients were excluded due to basal pathological proteinuria and 7patients for CNI reintroduction. Immunosuppression was Cyclosporine (CyA) vs Tacrolimus (FK), MMF vs Azathioprine and prednisone. Proterinuria was determined using urine dipstick method and value Results 43HT patients analyzed(91% men, mean age 61±11 years), mean time between HT-EVE starting 5,5±4,8 years, CNI was discontinued in 10patients. Mean time of CNI withdrawal 24.7±17,4 days. Mean initial proteinuria(pre-EVE): 13’1 mg/dl(1,5-29,8). Incidence of proteinuria after EVE starting in patients with CNI/non-CNI at 3, 6 and 12 months was: 6(18%)/2(20%); 7(21%)/2(22%); 10(31%)/5(56%),p=NS; and with a median of 15,5(4-93)/25’5 (4-61); 15(7-53)/14(4-98); 19(7,7-93)/27(5-132), p=NS. Regarding to the CNI type (n=33; CyA12 and FK21), the incidence of proteinuria at 3,6 and 12 months in patients with CyA/FK was: 3(25%)/3(14%); 3(25%)/4(19%); 4(33%)/6(30%); and with a median of 19(8-33)/15(4-93); 14(9-52)/18(7-48); 22(8-92)/16(8-64), p=NS. Conclusions Incidence of proteinuria after 1year of EVE initiation in long-term HT is 34,8%. Combination of CNI with EVE does not increase significantly the development of proteinuria, although an increasing trend in the CNI withdrawal is observed. Comparison between CyA/FK also showed no significant differences. Further studies are needed to corroborate this hypothesis.

The effectiveness of interventions to manage treatment adherence in adult heart transplant patients: a systematic review protocol

The effectiveness of interventions to manage treatment adherence in adult heart transplant patients: a systematic review protocol

Association of a Change in Immunosuppressive Regimen with Hemodynamic and Inflammatory Markers of Cardiovascular Disease After Kidney Transplantation

Although rejection rates and short-term graft survival have significantly improved in kidney transplantation with the introduction of calcineurin inhibitor (CNI), cardiovascular disease (CVD) and metabolic complications are being increasingly recognized as important causes of morbidity and mortality. We hypothesize that non-CNI proliferation signal inhibitor (PSI)-based immunosuppressive regimen is associated with improved arterial stiffness after kidney transplantation compared with CNI-based immunosuppressive regimens. This is a prospective, single-center study of renal transplant (RT) recipients comparing the metabolic, cardiovascular (pulse wave velocity and aortic augmentation index (AI) adjusted for heart rate (AI × 75)), inflammatory cytokines (interleukins (ILs) 6, 12, and 18) and graft-related outcomes at 3 and 15 months posttransplantation between RT recipients maintained on CNI- (CNI-CNI) or PSI-based (CNI-PSI) regimens including sirolimus and everolimus. Fifty and 17 RT recipients maintained on CNI-CNI and CNI-PSI, respectively, were included in this study. Median time to PSI conversion from CNI was 5 months. Compared with CNI-CNI recipients, CNI-PSI recipients had significantly lower fasting blood glucose in nondiabetics (coefficient = -16.2; 95% confidence interval (CI) = -14.4 to -18.0; P < 0.01), lower IL-18 levels (coefficient = -229.16; 95% CI = -343.94 to -114.38; P < 0.01), and lower AI × 75 (coefficient = -5.14; 95% CI = -9.99 to -0.28; P = 0.04) at 15 months posttransplant in the multivariable models. Our study suggests from the elimination of CNI for PSI may lower AIx75 and IL-18, both surrogate markers of CVD, but adequately powered, randomized, controlled studies are required to establish the causal relationship between immunosuppressive agents and CVD risk.