Diego Bellino

Effect of everolimus on left ventricular hypertrophy of de novo kidney transplant recipients: a 1 year, randomized, controlled trial.

Background. Although conversion from calcineurin inhibitors to mammalian target of rapamycin inhibitors proved to be effective in regressing left ventricular hypertrophy (LVH) in renal transplant recipients (RTRs) with chronic allograft dysfunction, there are currently no reports of randomized trials on this issue involving de novo RTRs administered everolimus (EVL). Methods. This randomized, open-label, controlled trial evaluated the effect of EVL on the left ventricular mass index (LVMi) of 30 nondiabetic RTRs (21 men; age 28–65 years). Ten were allocated to EVL plus reduced-exposure cyclosporine A (CsA), and 20 to standard dose CsA. LVMi was assessed by echocardiography both at baseline and 1 year later. Blood pressure (BP), hemoglobin, serum creatinine, lipids, trough levels of immunosuppressive drugs, and daily proteinuria were also evaluated twice monthly. Antihypertensive therapy that did not include renin-angiotensin system blockers was administered to achieve BP less than or equal to 130/80 mm Hg. Results. Changes in BP were similar in the two groups (between group difference 1.2±5.7 mm Hg, P=0.84 for systolic, and −1.5±3.7, P=0.69, for diastolic BP), whereas LVMi significantly decreased in the EVL group alone (between group difference 9.2±3.1 g/m2.7, P=0.005), due to a reduction in both the interventricular septum and the left ventricular posterior wall thickness. EVL therapy together with baseline LVMi were the only significant predictors of LVH regression according to a multivariate model that explained 49% of the total LVMi variance (P=0.0015). Conclusions. An immunosuppressive regimen consisting of EVL plus reduced exposure CsA proved to be effective in regressing LVH in RTRs regardless of BP, mainly by reducing left ventricular wall thickness.

Is left ventricular hypertrophy a powerful predictor of progression to dialysis in chronic kidney disease

BACKGROUND The role of cardiovascular factors in predicting renal outcome has not been extensively elucidated. Herein, we report a prospective evaluation of the impact of left ventricular hypertrophy (LVH) on outcome in non-diabetic patients with chronic kidney disease (CKD). METHODS We studied 144 patients (99 men; age 62±14 years) with stage 3-4 CKD, with baseline assessment of left ventricular mass index (LVMi) by echocardiography, estimated glomerular filtration rate (eGFR) by MDRD equation, 24-h blood pressure profile and 24-h proteinuria. Combined end point was progression to ESRD requiring dialysis, or death within 5 years. RESULTS Forty-nine patients (34%) progressed to dialysis, 24 (17%) died, 57 (39%) were dialysis-free after 5 years and 14 were lost to follow-up. Multivariate Cox proportional hazards analysis showed that increased LVMi (HR 1.28, 95% CI 1.17-1.40 for each 10-g/m2 increase, P<0.0001) and reduced eGFR (5% risk increase for each 1-mL/min reduction, P=0.027) were the significant predictors of the combined end point in stage 3 CKD patients, whereas LVMi proved to be the only significant predictor of the combined end point in patients with stage 4 CKD (HR 1.19, 95% CI 1.09-1.31, P<0.0001). The same analysis showed that LVMi was the only significant predictor of progression to dialysis in stage 3 CKD patients (HR 1.42, 95% CI 1.23-1.64 for each 10-g/m2 increase, P<0.0001), while a 20% increase in the risk of progression to ESRD was observed for each 10-g/m2 increase in LVMi (P<0.0001), and a 10% increase for each 1-mL/min reduction in eGFR (P=0.046) in patients with stage 4 CKD. When evaluating the predictive role of LVMi on outcome using AUC-ROC curves, the overall performance of the model including LVMi (AUC 0.877, 95% CI 0.8-0.954) was superior to the model including eGFR (AUC 0.737, 95% CI 0.656-0.817) for the end point of progression to dialysis (P=0.026, Hanley test). CONCLUSIONS LVH proved to be the strongest predictor of the risk of progression to dialysis in non-diabetic CKD, especially among patients with less advanced renal dysfunction. Regardless of whether it is a simple marker or a pathogenetic factor, LVH encompasses all factors possibly affecting renal and general outcome in CKD patients.

Effects of ACE inhibitors on long-term outcome of renal transplant recipients: a randomized controlled trial.

Background Available data on the role of renin-angiotensin system blockade in renal transplantation are inconclusive. Herein, we report the long-term results of a randomized controlled trial planned to evaluate the impact of angiotensin-converting enzyme inhibitors (ACE-i) on the cardiovascular outcome of renal transplant recipients (RTRs) receiving calcineurin inhibitors, steroids, and mycophenolate mofetil. Methods Thirty-six RTRs were allocated to receive ACE-i and 34 served as controls. Survival free of a composite endpoint consisting of death, major cardiovascular events, renal graft loss or creatinine doubling, and survival free of each single endpoint were analyzed in both groups according to a modified intention-to-treat analysis. Results During a 10-year follow-up, three patients died (one in the ACE-i group and two controls) and three lost their graft (two receiving ACE-i and one control). Three major cardiovascular events were observed in the ACE-i group and 12 among controls (P=0.008). At the end of observation, a significant increase in urinary protein excretion rate was only observed in controls (P=0.017). Compared with controls, RTRs administered ACE-i had significantly better survival free of the combined endpoint (P=0.0102, log-rank test) and free of major cardiovascular events (P=0.0027) without significant differences in renal outcome. By Cox regression analysis, ACE-i therapy resulted in the most powerful predictor of survival free of composite endpoint (hazard ratio, 0.165; 95% confidence interval, 0.053–0.512; P=0.0018) and survival free of major cardiovascular events (hazard ratio, 0.209; 95% confidence interval, 0.068–0.636; P=0.0059). Conclusions Prolonged therapy with ACE-i was associated with better general and cardiovascular outcome of RTRs without detrimental effects on renal graft function.

Effect of early conversion from CNI to sirolimus on outcomes in kidney transplant recipients with allograft dysfunction.

BACKGROUND Studies evaluating the effect of conversion from calcineurin inhibitor (CNI) to sirolimus (SRL) in renal transplant recipients (RTRs) have shown conflicting results, and only few short-term uncontrolled studies are available in patients with chronic allograft dysfunction. This is the first controlled study to evaluate long-term survival and both renal and cardiac outcomes in nondiabetic RTRs with allograft dysfunction who were converted from CNI to SRL. METHODS We evaluated 13 RTRs with biopsy-proven allograft dysfunction who underwent early conversion from CNI to SRL, and 26 controls with normal graft function taking CNI. All continued both steroids and mycophenolate mofetil. SRL was titrated to trough levels of 4-8 ng/mL. Outcome measures included 3-year event-free survival, acute rejection rate and 3-year changes in Modification of Diet in Renal Disease (MDRD) Study equation estimated glomerular filtration rate (eGFR) and left ventricular mass index (LVMi) as assessed by echocardiography. RESULTS Compared with controls, patients on SRL showed better 3-year event-free survival (p=0.024; log-rank test), significant eGFR increase (+5.5 ± 8.9 vs, -6.4 ± 14.7 ml/min per 1.73 m2, p=0.011), LVMi regression (-9.0 ± 7.6 g/m(2.7) vs. 1.0 ± 10.1 g/m(2.7), p=0.0038) and similar acute rejection rate. Three-year change in eGFR was the only significant predictor of event-free survival by Cox regression analysis (hazard ratio = 0.96; 95% confidence interval, 0.93-0.99; p=0.017), whereas SRL was the strongest predictor of both eGFR increase (beta coefficient, 0.342; p=0.01) and LVM reduction (beta coefficient, -0.609; p=0.0001) by multivariate regression analysis. CONCLUSIONS Conversion from CNI to SRL in RTRs with allograft dysfunction proved to be associated with better survival, improved renal graft function and regression of cardiac hypertrophy.

De novo post-transplant thrombotic microangiopathy localized only to the graft in autosomal dominant polycystic kidney disease with thrombophilia

Introduction: Thrombotic microangiopathy (TMA) is a serious complication of renal transplantation and is mostly related to the prothrombotic effect of calcineurin inhibitors (CNIs). A subset of TMA (29%-38%) is localized only to the graft. Case 1: A young woman suffering from autosomal dominant polycystic kidney disease (ADPKD) underwent kidney transplant. After 2 months, she showed slow renal deterioration (serum creatinine from 1.9 to 3.1 mg/dl), without hematological signs of hemolytic-uremic syndrome (HUS); only LDH enzyme transient increase was detected. Renal biopsy showed TMA: temporary withdraw of tacrolimus and plasmapheresis was performed. The renal function recovered (serum creatinine 1.9 mg/dl). From screening for thrombophilia, we found a mutation of the Leiden factor V gene. Case 2: A man affected by ADPKD underwent kidney transplantation, with delay graft function; first biopsy showed acute tubular necrosis, but a second biopsy revealed TMA, while no altered hematological parameters of HUS was detected. We observed only a slight increase of lactate dehydrogenase (LDH) levels. The tacrolimus was halved and plasmapheresis was performed: LDH levels normalized within 10 days and renal function improved (serum creatinine from 9 to 2.9 mg/dl). We found a mutation of the prothrombin gene. Only a renal biopsy clarifies the diagnosis of TMA, but it is necessary to pay attention to light increasing level of LDH. Conclusion: Prothrombotic effect of CNIs and mTOR inhibitor, mutation of genes encoding factor H or I, anticardiolipin antibodies, vascular rejection, cytomegalovirus infection are proposed to trigger TMA; we detected mutations of factor II and Leiden factor V, as facilitating conditions for TMA in patients affected by ADPKD.