Evaldo Favi

Long-Term Clinical Impact of Vesicoureteral Reflux in Kidney Transplantation

INTRODUCTION It is unclear whether the presence of vesicoureteral reflux (VUR) after renal transplantation compromises long-term graft function. The aim of this study in renal allograft recipients with a history of late recurrent urinary tract infections (UTI) was to determine whether the presence of VUR conferred an increased risk of long-term graft dysfunction. METHODS We included 37 renal allograft recipients, who were at least 2 years after transplantation and had a history of at least 1 recurrent UTI per year underwent voiding cystourethrograms (VCUG). The presence and severity of VUR were graded with severity scores ranging from G1 to G5. RESULTS Of the 37 patients, 15 (41%) showed low grades of reflux (G1-3) on VCUG. Patient and graft survivals were not significantly different in the VUR group (n = 15) compared with the no VUR group (n = 22) at 1, 3, or 5 years. Renal function assessment by means of serum creatinine (Cr) concentration also demonstrated similar results in both groups at 1, 3, and 5 years: 5 y mean Cr: VUR 1.5 +/- 0.6 mg/dL versus no VUR 1.8 +/- 1.1 mg/dL (P = NS). No difference was also observed in the 2 groups in the number of UTI episodes for each patient per year. CONCLUSIONS In patients with late UTIs, the presence of low-grade VUR did not affect long-term graft function. There was no indication for a operative repair of low-grade VUR.

Metabolic Syndrome and Cardiovascular Disease in Kidney Transplantation

INTRODUCTION Metabolic syndrome (MS) is an important cardiovascular risk factor. The aim of this study was to evaluate the incidence of MS in an Italian kidney transplant recipient population and its relationship to the incidence of major adverse cardiovascular events (MACE) after renal transplantation. METHODS The prevalence of MS was evaluated according to the National Cholesterol Education Program Adult Treatment Panel III criteria among adult recipients who underwent a renal transplant between January 1997 and December 2007. In this period, we prospectively recorded the incidence of MACE to be related to the presence of MS. RESULTS We included 425 kidney transplant recipients in the study including 62% males and an overall median age 46 years (interquartile range=36-54). The prevalence of MS was 41.2% at 6 months after transplantation and 46.6% at 5 years. During the follow-up (median=5.1 years), 32 patients (7.5%) experienced at least one MACE. The detection of MS at 6 months after transplantation was significantly associated with an increased risk of MACE occurrence (MS IRR=2.2 P=.05). CONCLUSIONS Our findings indicated that MS was largely present in the transplant population confirming that as in the general population, it was a significant risk factor for the occurrence of severe cardiovascular disease. Early identification and treatment of patients with MS may improve long-term patient survival.

Cardiovascular Risk Profile in Kidney Transplant Recipients Treated With Two Immunosuppressive Regimens: Tacrolimus and Mycophenolate Mofetil Versus Everolimus and Low-Dose Cyclosporine

OBJECTIVE The aim of this prospective study was to compare the cardiovascular risk (CVR) profile in patients treated with 2 different immunosuppressive regimens: tacrolimus and mycophenolate mofetil (TAC) compared with everolimus and low-dose cyclosporine (EVL). PATIENTS AND METHODS Sixty consecutive renal transplant recipients prospectively assigned to TAC (n = 30) or to EVL (n = 30) were followed for 6 months. TAC group immunosuppression consisted of basiliximab, tacrolimus, mycophenolate mofetil (MMF), and steroid. EVL group immunosuppression consisted of basiliximab, everolimus, and low doses of cyclosporine and steroid. Main CVR factors analyzed were: hypertension, dyslipidemia, posttransplant diabetes mellitus, and weight gain. RESULTS Six months posttransplantation, patients in the EVL group showed significantly higher mean serum cholesterol (P < .003) and serum triglyceride levels (P < .027), as well as a greater number of patients were receiving statin treatment (P < .05). Mean systolic blood pressure, mean diastolic blood pressure, number of patients treated for hypertension, number of antihypertensive medications prescribed per patient, posttransplant weight gain, and posttransplant diabetes mellitus were not significantly different among the EVL and TAC groups after 1, 3, and 6 months posttransplantation. CONCLUSIONS This study showed that at 6 months posttransplantation, patients on EVL displayed significantly greater dyslipidemia with respect to the TAC group. A longer follow-up will be necessary to discover whether the presence of everolimus in the immunosuppressive regimen provides significant benefits for the CVR of renal transplant recipients.

Induction With Basiliximab Plus Thymoglobulin Is Effective and Safe in Old-for-Old Renal Transplantation: Six-Month Results of a Prospective Clinical Study

Old-for-old renal transplantation is becoming more frequent, but the optimal immunosuppressive regimens for this transplant population are still unclear. The aim of this pilot prospective study was to evaluate the efficacy and safety of the combination of basiliximab with a short course of low-dose thymoglobulin induction therapy among a group of patients receiving kidneys from donors >60 years (OLD), compared with those receiving organs from donors <60 years (YNG). Forty-six consecutive deceased donor kidney transplant patients received induction therapy with a combination of basiliximab (20 mg IV on days 0 and 4) and thymoglobulin (200 mg total dose IV on days 0-3). As maintenance immunosuppression starting on day 4, patients received a low dose of calcineurin inhibitor and steroids. Demographic characteristics at baseline were not significantly different between the 2 groups. At 6 months, patient survival, graft survival, and acute rejection rates were similar between the YNG and OLD groups: 100% and 95%, 96% and 95%, and 8% and 0%, respectively. Patients in the OLD group showed higher serum creatinine concentrations (YNG 1.5 +/- 0.3 vs OLD 1.9 +/- 0.3 mg/dL; P = .0002) but not proteinuria (YNG 0.11 +/- 0.11 vs OLD 0.15 +/- 0.14 g/24 h; P = ns). No significant difference was evident between the 2 groups regarding infectious, hematologic, or posttransplantation lymphoproliferative disorder complications. This study showed that a combination of basiliximab and a short course of low-dose thymoglobulin provided effective and safe immunosuppression, in old-for-old renal transplantation, with good renal function without an increased risk of posttransplantation infectious or hematologic complications.

Evolution of Causes of Mortality in Renal Transplantation in the Last 10 Years

INTRODUCTION Improvements in immunosuppressive therapy have significantly changed results of organ transplantation. The aim of this study was to review the causes of mortality among our renal transplant population. METHODS This study population included 750 patients who underwent kidney transplantation between 1970 and 2007. During the follow-up, we recorded all causes of death and major cardiovascular events: stroke, myocardial infarction, angina pectoris, and cardiac death were considered major adverse cardiovascular events (MACE) The occurrence of MACE was related to wellestablished cardiovascular risk factors-age, sex, arterial blood pressure, diabetes, renal function, cardiovascular body mass index, history, or dyslipidemia measured at 6 months, as well as 5 and 10 years after transplantation. At these times we also calculated the INDANA, Framingham, and ltalian Heart Project scores. RESULTS The median follow-up was 63 months and mean age was 45 +/- 11 years. The median waiting time for transplant was 34 months. During follow up, 22 patients (6.1%) developed MACE, with 2 (0.55%) events within 6 months 10 (3.1%) between 6 months and 5 years, and 10 (6.5%) between 5 and 10 years. The INDANA score at all the time periods was significantly different among patients with vs without MACE (P < .0001), whereas no significant difference was observed using the Framinghan or the Italian Heart Project scores (P < .11). CONCLUSION Our study indicated that the INDANA scoring system better predicted the risk of MACE as approved to the Framinghan or Italian Heart Project systems. The INDANA score might be used to plan selective cardiovascular screening among recipients.

Significant improvement in patient survival after renal transplantation in the last decade.

INTRODUCTION The extremely good results of renal transplantation have favored the use of pre-emptive procedures for treatment of patients with end-stage renal disease before entering dialysis, but still some concerns exist about patient survival. The aim of this study was to analyze the evolution of death rates and the causes of mortality among recipients of procedures performed between 1970 and 2007. METHODS We examined the outcomes at 1, 5, 10, and 15 years follow-up of 793 adults who underwent primary or repeat renal transplantation from living or deceased donors between January 1, 1970 and December 31, 2007. To evaluate the impact of immunosuppressive regimens on patient survivals, we considered 3 time intervals: the precyclosporine era, the cyclosporine era, and the postcyclosporine era. RESULTS During follow-up 115/793 (14.5%) renal transplant recipients died. There was a significant decrease in the overall mortality rate over the years. Patients who underwent transplantation more recently in the postcyclosporine era (1997-2007) showed a mortality rate of 1.8% (7/394) at 1 year and 3.3% (13/394) at 5 years, significantly lower than in previous periods. There was no significant change in the most frequent causes of death: cardiovascular diseases and sepsis. CONCLUSION Our data indicated a significant improvement in patient survival after renal transplantation over the last decade. These data are significantly better than those reported for dialysis treatment thus supporting the strategy of pre-emptive transplantation for end-stage renal disease.

Once-a-Day Administration of Everolimus Is Safe in De Novo Renal Transplant Recipients: 1-Year Results of a Pilot Study

INTRODUCTION The half-life of everolimus is approximately 28 hours, but everolimus is generally administered twice a day. The aim of this prospective, single-center, exploratory study was to compare the efficacy and safety of a once a day everolimus (OD) with the standard twice a day administration regimen (BID) as immunosuppressive therapy in renal transplantation. METHODS Forty-one de novo renal transplant recipients prospectively assigned to OD (n=21) or BID (n=20) treatment were followed for 1 year. In the OD group, everolimus was orally administered targeting a trough blood level of 2 to 5 ng/mL. In the BID group, everolimus was given twice a day targeting a trough blood level of 3 to 12 ng/mL. All patients also received induction with basiliximab and low-dose calcineurin inhibitor immunosuppression. RESULTS At 1 year follow-up patient and graft survivals were 100%. The intention-to-treat analysis showed similar renal function between the two regimens: serum creatinine values for OD 1.54 ± 0.6 versus BID 1.48 ± 0.53 mg/dL (P=NS). Also the occurrence of acute rejection episodes was not significantly different: 4.8% in the OD versus 15% in the BID group, (P=NS). The median trough blood levels were significantly lower among the OD group: OD 4.5 versus BID 7.2 ng/mL (P<.001). DISCUSSION This study demonstrated that once a day administration of everolimus achieved excellent patient and graft survival and good renal function without an increased incidence of acute rejection episodes.

Tacrolimus plus mycophenolate mofetil vs. cyclosporine plus everolimus in deceased donor kidney transplant recipients: three-yr results of a single-center prospective clinical trial.

We compared in kidney transplantation two immunosuppressive regimens: tacrolimus plus mycophenolate mofetil (MMF) (TAC) and everolimus plus low‐dose cyclosporine (EVE). Sixty consecutive patients received TAC (30 patients) or EVE (30 patients) as immunosuppressive regimen; all subjects also received induction with basiliximab and corticosteroids. After three‐yr follow‐up, no difference was found in patient and graft survival (PTS: TAC: 97% vs. EVE: 100%; GS: TAC: 93% vs. EVE: 93%). The incidence of acute rejection was higher in the EVE group but the difference was not statistically significant (17% vs. 23%, p = ns). Patients in EVE showed higher serum cholesterol (205 ± 41 vs. 235 ± 41 mg/dL, p = 0.0012) and lower hemoglobin concentration (13.6 ± 1.4 vs. 12.4 ± 1.9, p = 0.01). Renal function was not significantly different in the two groups (3 Y creatinine: TAC 1.4 ± 0.8 vs. EVE 1.6 ± 0.8 mg/dL, p = ns). Treatment discontinuation was higher in the EVE group (TAC 17 vs. EVE 36%, p = ns). Our data show that in the middle‐term follow‐up, an immunosuppressive regimen with tacrolimus plus MMF has a similar efficacy and safety profile in comparison with the combination of low‐exposure cyclosporine plus everolimus. Further follow up could evidence the benefits related to the anti‐proliferative effects of everolimus.

Once Daily Everolimus Is Safe and Effective in De Novo Renal Transplant Recipients: Six-Month Results of a Pilot Study

INTRODUCTION The half-life of everolimus is approximately 28 hours, but everolimus is normally administered twice a day. The aim of this prospective, single-center, exploratory study was to compare the efficacy and safety of a once a day (OD) everolimus regimen versus the standard twice a day regimen (BID) for immunosuppressive therapy in renal transplantation. METHODS Forty de novo renal transplant recipients prospectively assigned to OD (n = 21) or BID (n = 19) were followed for 6 months. In the OD group, everolimus was given orally once a day to target a trough blood level of 2-6 ng/mL. In the BID, group everolimus was given twice a day to target a trough blood level of 3-12 ng/mL. All patients also received induction treatment with basiliximab and low-dose calcineurin inhibitors. RESULTS At 6 months follow-up, patient and graft survivals were 100%; renal function and acute rejection rates were similar between the 2 regimens. Patients in the OD group showed significantly lower cholesterol and triglyceride levels compared with those in the BID group, namely, total cholesterol level, OD 212 +/- 54 versus BID 249 +/- 59 mg/dL (P < .05), and serum triglycerides, OD 162 +/- 72 versus BID 245 +/- 133 mg/dL (P < .02). DISCUSSION This study showed that OD administration of everolimus provided excellent patient and graft survivals and good renal function without an increased incidence of acute rejection episodes. The lipid profile was significantly better among patients receiving everolimus OD. These findings suggested that everolimus can be safely administered once a day.

Prospective Clinical Trial Comparing Two Immunosuppressive Regimens, Tacrolimus and Mycophenolate Mofetil Versus Everolimus and Low-Dose Cyclosporine, in De Novo Renal Transplant Recipients: Results at 6 Months Follow-up

OBJECTIVE The aim of this study in renal transplant recipients was to compare a tacrolimus plus mycophenolate mofetil (MMF) immunosuppressive regimen with a combination of low dose of cyclosporine and everolimus. PATIENTS AND METHODS Sixty consecutive patients were prospectively assigned to receive tacrolimus and MMF (TAC; n = 30) or everolimus and low-dose cyclosporine (EVL; n = 30). Tacrolimus was dosed seeking a trough blood level of 8 to 10 ng/mL by month 3 and 5 to 8 ng/mL thereafter. Everolimus was dosed seeking a trough blood level of 3 to 8 ng/mL by day 7. Cyclosporine was dosed aiming at a C2 blood level of 350 to 700 ng/mL in the first week and 150 to 400 ng/mL thereafter. All patients received induction with basiliximab and maintenance treatment with corticosteroids. RESULTS At 6-months follow-up, patient survival rates (TAC 100% vs EVL 100%) and graft survival rates (TAC 96.7% vs EVL 93.3%) were not significantly different between the groups. Patients in the EVL group showed more acute rejection episodes, but serum creatinine concentrations and creatinine clearances were not significantly different from the TAC group. Among the observed side effects, hypercholesterolemia was significantly higher in the EVL group (total cholesterol: TAC 206 +/- 38 vs EVL 250 +/- 55 mg/dL; P < .003). CONCLUSIONS This study showed that the immunosuppressive association of tacrolimus and MMF produced similar acute rejection episodes, graft survivals, and renal function at 6 months after renal transplantation compared with an immunosuppressive combination of everolimus and low-dose cyclosporine. Dyslipidemia was significantly greater among patients who received everolimus.