Cyclosporine lowering with everolimus versus mycophenolate mofetil in heart transplant recipients: Long-term follow-up of the SHIRAKISS randomized, prospective study

Potena, Luciano; Prestinenzi, P.; Bianchi, Isidoro Giorgio; Masetti, M.; Romani, Paolo; Magnani, Gaia; Fallani, Francesco; Coccolo, Fabio; Russo, Antonio; Ponticelli, Claudio; Rapezzi, Claudio; Grigioni, Francesco; Branzi, Angelo

doi:10.1016/j.healun.2012.01.002

Cited by 48 publications

(32 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…On the other hand, proteinuria, a frequently reported adverse event with mTOR inhibitors, was not routinely assessed in our first patients due to the ignorance about how clinically relevant proteinuria was in HT patients. Recently, a randomised study evaluating HT patients with Cyclosporine nephrotoxicity showed a better improvement in CrCL in patients without baseline proteinuria, whereas CrCl significantly worsened in patients with baseline proteinuria (-20%; P = 0.04) [38] . Since EVERODATA is an observational study, there is no control group to inform of safety and efficacy of EVL vs other treatments with CNI reduction/withdrawal.…”

Section: Discussionmentioning

confidence: 99%

Twelve-month efficacy and safety of the conversion to everolimus in maintenance heart transplant recipients

Manito

Delgado

Crespo‐Leiro

et al. 2015

WJT

View full text Add to dashboard Cite

AIM:To determine the clinical reasons for conversion to everolimus (EVL) and long-term outcomes in heart transplant (HT) recipients. METHODS:A retrospective 12-mo study has been carried out in 14 Spanish centres to assess the efficacy and safety of conversion to EVL in maintenance HT recipients. RESULTS:Two hundred and twenty-two patients were included (mean age: 53 ± 10.5 years; mean time from HT: 8.1 ± 4.5 years). The most common reasons for conversion were nephrotoxicity (30%), chronic allograft vasculopathy (20%) and neoplasms (17%). The doses and mean levels of EVL at baseline (conversion to EVL) and after one year were 1.3 ± 0.3 and 1.2 ± 0.6 mg/d and 6.4 ± 3.4 and 5.6 ± 2.5 ng/mL, respectively. The percentage of patients receiving calcineurin inhibitors (CNIs) at baseline and on the final visit was 95% and 65%, respectively. The doses and mean levels of CNIs decreased between baseline and month 12 from 142.2 ± 51.6 to 98.0 ± 39.4 mg/d (P < 0.001) and from 126.1 ± 50.9 to 89.2 ± 47.7 ng/mL (P < 0.001), respectively, for cyclosporine, and from 2.9 ± 1.8 to 2.6 ± 1.9 mg/d and from 8.3 ± 4.0 to 6.5 ± 2.7 ng/mL (P = 0.011) for tacrolimus. In the subgroup of patients converted because of nephrotoxicity, creatinine clearance increased from 34.9 ± 10.1 to 40.4 ± 14.4 mL/min (P < 0.001). There were 37 episodes of acute rejection in 24 patients (11%). The most frequent adverse events were oedemas (12%), infections (9%) and gastrointestinal problems (6%). EVL was suspended in 44 patients (20%). Since the database was closed at the end of the study, no further followup data is available. CONCLUSION:Conversion to EVL in maintenance HT recipients allowed minimisation or suspension of the CNIs, with improved kidney function in the patients with nephrotoxicity, after 12 mo.

show abstract

Section: Discussionmentioning

confidence: 99%

Twelve-month efficacy and safety of the conversion to everolimus in maintenance heart transplant recipients

Manito

Delgado

Crespo‐Leiro

et al. 2015

WJT

View full text Add to dashboard Cite

show abstract

“…Kidney function at the time of introduction of the drugs should be moderately decreased to see the most benefit and although patients with GFR below 30mL/ min can benefit many of the above studies showed that more patients with poor baseline GFR will progress despite PSI therapy due to advanced, irreversible CNI kidney toxicity [56]. The presence of baseline proteinuria is cause for concern as is the presence of diabetes and might negate any benefit of PSI use [34,37,46,47,54]. The use of ACE inhibitors and angiotensin receptor blockers might mitigate the adverse effect of PSI induced proteinuria on worsening renal function but this is not based on large number of patients [34,37,57].…”

Section: Discussionmentioning

confidence: 99%

“…EVRL was associated with twice as many pneumonias in the first year and 1.8 fold increases in risk of rejection after 2 years. Proteinuria was not reported.To complicate the picture, the small, randomized SHIRAKISS study, showed that late addition of MMF or EVRL while reducing CNI levels by 30% and 70% respectively, resulted in better renal function on MMF after 3 years [46,47]. This outcome was dependent on baseline proteinuria only with EVRL.…”

mentioning

confidence: 99%

Cardiac Troponin I Level in STEMI and Clinical Correlation with Left Ventricular Dysfunction in Indian Population

Sharma¹,

Sharma²

2013

J Cardiovasc Dis Diagn

View full text Add to dashboard Cite

Calcium Channel Blockers (CCBs): CNIs cause vasoconstriction as noted above. CCBs, specifically vasodilating dihydropyridines, have been shown to improve renal plasma flow and GFR [9,16]. A small prospective study comparing amlodipine to placebo showed a slower decline in GFR at one year [13]. There was no effect on LV mass and only a modest decrease in proteinuria. Diltiazem did not appear to offer the same protection [14]. RAAS Inhibitors:The use of RAAS inhibitors is beneficial in most patients with CKD; however, this has not been shown in OHT patients. A systematic review of randomized studies in CSA-treated kidney AbstractBackground: The use of calcineurin inhibitors revolutionized transplantation by prolonging patients' survival. However, their utility is limited by the development of significant chronic kidney disease. Methods:We reviewed the English literature looking for recent publications regarding the management of chronic kidney disease in cardiac transplant patients. We chose relevant papers based on design, number of patients and clinical utility.Results: Most publications on the subject involve small populations with few prospective, randomized studies. Early use of tacrolimus appears to be associated with better kidney function after one year compared to cyclosporine. Once chronic kidney disease is established, successful strategies include reduction or elimination of calcineurin inhibitors while relying on mycophenolate mofetil, proliferation signal inhibitors or anti-CD 25 antibodies to prevent rejection. There is no follow up longer than two years with these approaches. Kidney transplantation might offer improved long-term survival compared to dialysis in end-stage disease. Conclusions:Prospective studies with long-term follow-up are needed to decide about the timing and to confirm the utility of replacing calcineurin inhibitors with other agents in cardiac transplant patients with chronic kidney disease. transplant patients show, after a median of 27 months, a reduction in GFR (around 5.8 cc/min) with a reduction of proteinuria (decrease of 470 mg/day) [17]. It is uncertain if the reduction in proteinuria would translate into better outcomes in the long run. In fact, Opelz et al. showed, in a retrospective study of 1,744 OHT patients, that the use of RAAS inhibitors did not improve patient survival after 6 years [18]. The same study looked at 17,209 kidney transplant patients and showed no difference in graft or patient survival [18]. The use of spironolactone in rat models prevented the decline in GFR and the histologic changes seen with CSA [19]. There are no data in patients. Management of Calcineurin Modification of immunosuppressive drugsTransplant centers have tried multiple immunosuppressive strategies in OHT patient with CKD to prevent progression of renal dysfunction. Most of the data come from small studies, limiting the strength of recommendations that can be made. Larger studies come usually from kidney transplantation literature. Tacrolimus:In small studies, Tacrolimus (TAC) do...

show abstract

“…The SHIRAKISS study demonstrated that an EVLbased strategy with reduced CNI resulted in an improvement of renal function only in HTx recipients with baseline proteinuria < 150 mg/day. 13) Renal transplant recipients with ≥ 800 mg/day of baseline proteinuria experienced more chronic allograft dysfunction after conversion from CNI to sirolimus. 19) Proteinuria was not a significant predictor for the worsening of renal function in this study, probably because only one patient (3.7%) had significant proteinuria before EVL introduction.…”

Section: Previously Reported Predictors For Recovery Of Renal Functiomentioning

confidence: 99%

“…[11][12][13][14][15][16] According to these conflicting data, shortsighted administration of EVL would not be recommended because there may be a considerable number of non-responders to EVL-incorporated regimens from the viewpoint of renal function. Hence, it is very important to select responders to EVL for the preservation of renal function during immunosuppressive therapy.…”

mentioning

confidence: 99%

Plasma Neutrophil Gelatinase-Associated Lipocalin and Worsening Renal Function During Everolimus Therapy After Heart Transplantation

et al. 2015

View full text Add to dashboard Cite

SummaryRecently, the mammalian target of rapamycin inhibitor everolimus (EVL) has been introduced as a novel immunosuppressant for heart transplant (HTx) recipients, and is expected to preserve renal function compared to conventional calcineurin inhibitors (CNIs). However, a considerable number of recipients treated with EVL were not free from worsening renal function regardless of CNI reduction. Data were collected retrospectively from 27 HTx recipients who had received EVL (trough concentration, 3.1-9.2 ng/mL) along with reduced CNIs (%decreases in trough concentration, 27.3 ± 13.0%) because of switching from mycophenolate mophetil due to digestive symptoms or neutropenia, progressive coronary artery vasculopathy, or persistent renal dysfunction, and had been followed over 1 year between August 2008 and January 2013. Estimated glomerular filtration rate (eGFR) decreased in 5 recipients (18.5%) during the study period. Univariate logistic regression analysis demonstrated that a higher plasma neutrophil gelatinase-associated lipocalin (P-NGAL) level was the only significant predictor for a decrease in eGFR over a 1-year EVL treatment period among all baseline parameters (P = 0.008). eGFR and proteinuria worsened almost exclusively in patients with baseline P-NGAL ≥ 85 ng/mL, which was the cutoff value calculated by an ROC analysis (area under the curve, 0.955; sensitivity, 1.000; specificity, 0.955). In conclusion, higher P-NGAL may be a novel predictor for the worsening of renal function after EVL treatment that is resistant to CNI reduction in HTx recipients. (Int Heart J 2015; 56: 73-79)

show abstract

Cyclosporine lowering with everolimus versus mycophenolate mofetil in heart transplant recipients: Long-term follow-up of the SHIRAKISS randomized, prospective study

Cited by 48 publications

References 33 publications

Twelve-month efficacy and safety of the conversion to everolimus in maintenance heart transplant recipients

Twelve-month efficacy and safety of the conversion to everolimus in maintenance heart transplant recipients

Cardiac Troponin I Level in STEMI and Clinical Correlation with Left Ventricular Dysfunction in Indian Population

Plasma Neutrophil Gelatinase-Associated Lipocalin and Worsening Renal Function During Everolimus Therapy After Heart Transplantation

Contact Info

Product

Resources

About