Efficacy and Safety of an Everolimus- vs. a Mycophenolate Mofetil-Based Regimen in Pediatric Renal Transplant Recipients

<div><p>Introduction</p><p>Data on the efficacy and safety of everolimus in pediatric renal transplantation compared to other immunosuppressive regimens are scarce.</p><p>Patients/Methods</p><p>We therefore performed a multicenter, observational, matched cohort study over 4 years post-transplant in 35 patients on everolimus plus low-dose cyclosporine, who were matched (1:2) with a control group of 70 children receiving a standard-dose calcineurin-inhibitor- and mycophenolate mofetil-based regimen.</p><p>Results</p><p>Corticosteroids were withdrawn in 83% in the everolimus vs. 39% in the control group (p<0.001). Patient and graft survival were comparable. The rate of biopsy-proven acute rejection episodes Banff score ≥ IA during the first year post-transplant was 6% in the everolimus vs. 13% in the control group (p = 0.23). The rate of de novo donor-specific HLA antibodies (11% in everolimus, 18% in controls) was comparable (p = 0.55). At 4 years post-transplant, mean eGFR in the everolimus group was 56±33 ml/min per 1.73 m² vs. 63±22 ml/min per 1.73 m² in the control group (p = 0.14). Everolimus therapy was associated with less BK polyomavirus replication (3% vs. 17% in controls; p = 0.04), but with a higher percentage of arterial hypertension and more hyperlipidemia (p<0.001).</p><p>Conclusion</p><p>In pediatric renal transplantation, an everolimus-based regimen with low-dose cyclosporine yields comparable four year results as a standard regimen, but with a different side effect profile.</p></div

Patient characteristics at baseline.

<p>CMV, cytomegalovirus; HLA, human leukocyte antigen; RTx, renal transplantation: D, Donor; R, Recipient</p><p>(p calculated by t-test, Wilcoxon-test, chi-square-test or Fisher’s exact test).</p><p>*two sample t-test,</p><p>^#chi-square test,</p><p>^°Wilcoxon test,</p><p>^§Fisher’s exact test.</p><p>Patient characteristics at baseline.</p

Plasma triglyceride, cholesterol and low-density lipoprotein (LDL) cholesterol values and the urinary albumin/creatinine ratio in the everolimus (EVR) group (n = 35 until month 24 and n = 33 at month 36 and 48) and in the control group (n = 70).

<p>Month 1: Values determined before initiation of EVR therapy.</p><p>P values were calculated by the two-sample t-test.</p><p>Plasma triglyceride, cholesterol and low-density lipoprotein (LDL) cholesterol values and the urinary albumin/creatinine ratio in the everolimus (EVR) group (n = 35 until month 24 and n = 33 at month 36 and 48) and in the control group (n = 70).</p

Height standard deviation score (SDS) over the observation period of 4 years in the everolimus (EVR) group (n = 35 until year 2; n = 33 at year 3 and 4) and the control group (n = 70).

<p>Data are mean ± SD. P values (by unpaired t-test) were as follows: p = 0.01 at baseline, p = 0.10 at year 1, p = 0.05 at year 2, p = 0.03 at year 3 and p = 0.05 at year 4 post-transplant. Significant differences (p ≤ 0.05) between the two groups are marked by an asterisk (*).</p

Estimated glomerular filtration rate (eGFR) over the observation period of 4 years in the everolimus (EVR) group (n = 35 until year 2; n = 33 at year 3 and 4) and the control group (n = 70).

<p>Data are mean ± SD. BSA, body surface area.</p

Height and blood pressure standard deviation scores (SDS) and antihypertensive treatment in the everolimus (EVR) group (n = 35 until month 24, n = 33 at month 36 and 48) and the control group (n = 70).

<p>^aArterial hypertension was defined as systolic and/or diastolic blood pressure > 95^th percentile and/or antihypertensive medication administered. P values were calculated by the t-test for unpaired samples.</p><p>Height and blood pressure standard deviation scores (SDS) and antihypertensive treatment in the everolimus (EVR) group (n = 35 until month 24, n = 33 at month 36 and 48) and the control group (n = 70).</p

Hemoglobin concentration, treatment with erythropoiesis-stimulating agents (ESA) and leukocyte counts in the everolimus (EVR) group (n = 35 until month 24, n = 33 at months 36 and 48) and the control group (n = 70).

<p>Erythropoetin alpha, beta and zeta, Darbepoetin alpha and Methoxy-polyethylene-glycol-epoetin beta were summarized as erythropoiesis-stimulating agents (ESA). Month 1: values determined before initiation of EVR. P values were calculated by the two-sample t-test (hemoglobin, leukocyte count) and by the Fisher’s exact test for the ESA treatment.</p><p>Hemoglobin concentration, treatment with erythropoiesis-stimulating agents (ESA) and leukocyte counts in the everolimus (EVR) group (n = 35 until month 24, n = 33 at months 36 and 48) and the control group (n = 70).</p

Course of immunosuppressive therapy in the EVR group (a).

<p>CsA, cyclosporine; DSA, Donor Specific Antibodies; EVR, everolimus; BSA, body surface area;* Tx, transplantation; Pred, Prednisolone; TAC, tacrolimus; MMF, mycophenolate mofetil, PTLD, post transplant lymphoproliferative disease; CAMR, chronic antibody mediated rejection.</p

Results of indication biopsies during the first year post-transplant.

<p>CNI, calcineurin inhibitor; MPGN, membranoproliferative glomerulonephritis.</p><p>p values calculated by Fischer’s exact test. The respective numbers refer to number of patients. Acute Rejection Episodes (ARE) were defined as follows: (i) Biopsy-proven acute rejection episodes (BPAR) BANFF score ≥ IA on indication biopsy (11); (ii) BPAR including borderline findings on indication biopsy, which triggered anti-rejection therapy; (iii) over-all treated ARE (BPAR plus ARE, where a graft biopsy was either logistically not possible or medically contraindicated).</p><p>Results of indication biopsies during the first year post-transplant.</p

Infectious episodes and hospitalization rates in the everolimus (EVR) group (n = 35 until month 24, n = 33 at month 36 and 48) and the control group (n = 70).

<p>Data are given as median (range) or as percentage. P values were calculated by the ^$Wilcoxon test or by the ^§Fischer’s exact test. ARE, acute rejection episodes; EVR, everolimus; GI, Gastrointestinal</p><p>Infectious episodes and hospitalization rates in the everolimus (EVR) group (n = 35 until month 24, n = 33 at month 36 and 48) and the control group (n = 70).</p