Thymoglobulin induction and sirolimus versus tacrolimus in kidney transplant recipients receiving mycophenolate mofetil and steroids.

BACKGROUND: To define the role of mammalian target of rapamycin inhibitors in kidney transplantation, we compared efficacy and safety of two immunosuppressive regimens-a calcineurin inhibitor-free regimen with depletive induction versus a calcineurin inhibitor-based regimen. METHODS: De novo renal allograft recipients were randomized before transplantation to receive sirolimus (SRL; n=71, group A) or tacrolimus (n=70, group B). All patients received mycophenolate mofetil and corticosteroids. In group A, patients received rabbit antithymocyte globulin induction. In group B, antithymocyte globulin therapy could be given in case of delayed graft function. The estimated glomerular filtration rate (GFR) (Nankivell's formula) at month 12 was the primary endpoint. RESULTS: GFR showed no significant difference at month 12, with 56.1 in group A versus 58.4 mL/min/1.73 m in group B. In functioning grafts, renal function was significantly better in the SRL group, with higher GFR values at months 1, 2, 3, 6, and 9 (P<0.05). At month 12, patient survival and incidence of biopsy-proven rejection were not different between groups (95.8% vs. 97.1%, and 16.9% vs. 12.9%, respectively). However, proportion of graft loss was higher with SRL at months 6 and 12 (11.3% vs. 0.0%, P=0.004; 14.1% vs. 4.3%, P=0.044, respectively). Adverse events and premature withdrawals were more frequent with SRL (P<0.001 and P<0.05, respectively), whereas cytomegalovirus infections were more frequent with tacrolimus (P<0.001). CONCLUSION: Patients treated with induction plus SRL, mycophenolate mofetil, and corticosteroids may obtain good renal function but have a higher risk of adverse events, drug withdrawal, and graft loss.

[Incidence and management of anemia in renal transplantation: an observational-French study]. / Incidence et prise en charge de l'anémie en transplantation rénale: une étude observationnelle française.

The management of anemia after kidney transplantation remains poorly explored. The Management of Anemia in French Kidney Transplant Patients (MATRIX) study is an observational study conducted in 10 academic hospitals among kidney-transplant patients designed to evaluate the prevalence, associated factors and management of post-transplant anemia. Over two consecutive weeks, 418 recipients (males: 248; age: 50.8+/-12.7 years) were included, all were transplanted for more than six months. Mean serum creatinine (Scr) was 152+/-67 micromol/l and mean hemoglobin (Hb) was 12.4+/-1.8 g/dl (males: 12.8+/-1.9 g/dl; females 11.9+/-1.6 g/dl). Irrespective of the delay following transplantation, 23% of patients (n=95) were severely anemic (Hb < or = 11 g/dl). Eighteen percent of the patients received an antianemic treatment (10% oral iron, 7% erythropoiesis stimulating agents (ESA), 4% folic acid) and only 35% of the severely anemic patients were actually treated (n=33). A significantly-negative correlation was observed between eGFR and Hb levels (R= -0.347, p<0.02). Ninety-six percent of the 193 patients transplanted for more than six months and a Scr greater than 150 micromol/l (n=185) suffered at least one comorbidity (89% hypertension, 32% hypercholesterolemia, 13% diabetes); this group represent the second cohort. Seventy-four percent of them were treated with mycophenolate mofetil, 16% with azathioprine, and 62% with an ACEI or angiotensin II receptor antagonists. Since the transplantation, 127 patients (66%) have been anemic (Hb < or = 11 g/dl) and 58% (n=112) were treated (iron and/or ESA, respectively 81 and 55%). Among the patients not treated for anemia, 74% had an Hb level below 12g/dl. ESA-treated patients received a mean dose of 8500 UI+/-2800 per week. Anemia is under-diagnosed and under-treated in renal-transplant recipients, despite its high prevalence. As expected, a correlation between renal function and Hb levels was observed, as in CKD patients. Prospective studies are underway to assess the consequences of postkidney transplant anemia on quality of life, cardiovascular morbidity and chronic allograft nephropathy and to define the benefit of the treatment.

[First acute rejection episode after renal transplantation: study of the histopathological characteristics according to the immunological risk]. / Premier épisode de rejet aigu après transplantation rénale: étude des caractéristiques histopathologiques en fonction du risque immunologique du patient.

Renal allograft biopsies (n=34) of two different populations of patients according to the immunological risk (high versus low-risk) have been compared retrospectively. The presence of polymorphonuclear leukocytes in peritubular capillaries was more frequent in the high-risk group. The C4d staining was positive in 10% of the low-risk patients and in 50% of the high-risk patients (P=0.03). There were more early graft loss, renal infarctions, interstitial hemorrhage, severe glomerulitis, neutrophilic glomerulitis and Banff III grade rejection in the positive C4d group. In conclusion, half of the immunized patients had a humoral rejection, patients with a C4d positive rejection had more early graft loss and more severe histological lesions.

Renal function with delayed or immediate cyclosporine microemulsion in combination with enteric-coated mycophenolate sodium and steroids: results of follow up to 30 months post-transplant.

BACKGROUND: In the multicenter, open-label Myriade study, renal transplant patients were randomized to early cyclosporine microemulsion (CsA-ME, day 0) or delayed CsA-ME (day 6) with enteric-coated mycophenolate sodium (EC-MPS), steroids and interleukin-2 receptor induction. One-yr results have been published previously. We now report the results of an extension study in which patients were followed up for a period of three yr post-transplant. METHODS: All patients completing the one-yr core study on-treatment were eligible to enter the extension study. RESULTS: Of the 203 patients, 153 completed the core trial on-treatment; 144 (94%) entered the extension study with a minimum follow-up of one yr (73 early CsA-ME, 71 delayed CsA-ME). In 75% of patients receiving EC-MPS during the extension, the recommended dose was administered (1440 mg/d). Median creatinine clearance remained constant (57 mL/min) at 12, 24 and 30 months post-transplant and was similar in the early and delayed CsA-ME groups as well as in subpopulations with or without delayed graft function. One patient in the early CsA-ME group died. No grafts were lost. The incidence of BPAR from time of transplant to the end of the extension study was 17% (24/139). Seven patients (5%) discontinued the extension study prematurely because of adverse events. CONCLUSION: These results suggest that a regimen of CsA-ME, EC-MPS and steroids results in excellent survival rates with stable renal function over a mean follow-up of 30 months. Immediate introduction of CsA-ME has no deleterious effect on long-term renal function, even among patients with delayed graft function.

Efficacy and safety of enteric-coated mycophenolate sodium in renal transplant patients with diabetes mellitus: post hoc analyses from three clinical trials.

To examine the efficacy and safety of enteric-coated mycophenolate sodium (EC-MPS, myfortic) in renal transplant patients with diabetes mellitus, six- and 12-month data from three clinical trials with EC-MPS (Studies B301, B302, and myPROMS) were analyzed post hoc. Studies B301 (de novo patients) and B302 (maintenance patients) followed a randomized double-blind design whereas myPROMS was an open-label study in de novo and maintenance renal transplant patients in which all patients received EC-MPS as part of their immunosuppressive regimen. In studies B301 and B302, diabetic patients were compared against mycophenolate mofetil (MMF, CellCept), the reference drug. For myPROMS, data from diabetic and non-diabetic patients were compared. In total, 246 diabetic patients receiving EC-MPS were analyzed. In study B301, the efficacy failure rate [biopsy-proven acute rejection (BPAR), graft loss, death or loss to follow-up] in diabetics at 12 months was 17.6% (EC-MPS) vs. 26.2% (MMF), and of BPAR alone 14.7% vs. 19.0% (both n.s.). In de novo patients from myPROMS, the treatment failure rate was similar in diabetic (20.3%) and non-diabetic patients (27.1%), as was the incidence of BPAR (17.7% vs. 23.1%, both n.s.). The overall incidence, severity and pattern of AEs were comparable between EC-MPS and MMF in de novo patients. This was supported by the safety results assessed in maintenance patients (B302) indicating no increased safety risk with the use of EC-MPS in the diabetic patient population, if compared with MMF. Likewise, apart from a higher incidence of severe/serious infections in diabetics, the safety profile of EC-MPS was not different to non-diabetics in myPROMS. In conclusion, preliminary data suggest that EC-MPS in combination with cyclosporine (+/- steroids) can be used efficiently and safely for the prophylaxis of organ rejection in diabetic renal transplant patients. Moreover, diabetic patients can apparently be safely converted from MMF to EC-MPS. More data from prospective studies are needed to fully judge the efficacy and safety profile of EC-MPS in the diabetic transplant population.

12-month safety and efficacy of everolimus with reduced exposure cyclosporine in de novo renal transplant recipients.

The proliferation signal inhibitor everolimus (Certican), has demonstrated efficacy with full-dose cyclosporine (CsA) (Neoral). Two multicenter randomized controlled studies were performed to compare 12-month efficacy and safety of everolimus 1.5 and 3.0 mg/day with reduced-dose CsA. Study 1 enrolled 237 de novo renal allograft recipients, randomizing 222 nonblack patients to either everolimus 1.5 or 3.0 mg/day, with the Neoral) dose guided by C(2) (monitoring of CsA concentration 2 h after dosing). Study 2 had a similar protocol, with basiliximab included, enrolling 256 recipients and randomizing 243 nonblack patients. In Study 1, there was a lower incidence of acute rejection in nonblack patients on 3 mg/day (16.4%) compared with 1.5 mg/day (25.9%), P = 0.08. In Study 2, the inclusion of basiliximab lowered the overall incidence of acute rejection; 14.3% of nonblack patients (3 mg/day) and 13.6% of nonblack patients (1.5 mg/day) had acute rejection by 12 months (P =0.891). Renal function was preserved throughout the study, with no differences observed between groups within studies. Everolimus was well tolerated with no significant differences between doses. Everolimus, in combination with reduced-dose Neoral), demonstrated efficacy and was well tolerated. Basiliximab allows for utilization of lower doses of everolimus with reduced dosing of Neoral).

Toxoplasmosis-associated hemophagocytic syndrome in renal transplantation.

Toxoplasmosis is an infrequent, often difficult to diagnose and potentially lethal disease in kidney transplant recipients. Among reported cases, a few were associated with hemophagocytic syndrome (HPS), a rare condition characterized by widespread proliferation of macrophages phagocytizing blood elements, accompanied by fever and pancytopenia. We report here the case of a patient who received a Toxoplasma gondii positive kidney allograft and developed invasive toxoplasmosis 10 days after surgery, with high fever, skin rash, arthralgias, and renal failure, followed by pneumonia, anemia, thrombocytopenia, liver dysfunction, and encephalitis. Mislead by the absence of Toxoplasma on blood smears, alveolar fluid, renal graft biopsy, and negative brain computed tomography, confusion with serum sickness, and simultaneous herpetic infection, we failed to make the right diagnosis and the patient died with septic shock 11 days later. An HPS was revealed by a late bone marrow analysis. This may well be the fourth case ever reported of toxoplasmosis-associated HPS in renal transplant recipients.

Everolimus with optimized cyclosporine dosing in renal transplant recipients: 6-month safety and efficacy results of two randomized studies.

Two prospective, randomized studies evaluated everolimus 1.5 vs. 3 mg/day with steroids and low-exposure cyclosporine (CsA) (C2 monitoring) in de novo renal transplant patients. Everolimus dosing was adjusted to maintain a minimum trough level of 3 ng/mL. Study 1 (A2306; n=237) had no induction therapy; in Study 2 (A2307; n=256) basiliximab was administered (Days 0 and 4). The primary endpoint was renal function at 6 months. CsA C2 target levels, initially 1200 ng/mL in Study 1 and 600 ng/mL in Study 2, were tapered over time post-transplant. Median creatinine levels in Study 1 were 133 and 132 micromol/L at 6 months in the 1.5 and 3 mg/day groups, respectively, and 130 micromol/L in both groups in Study 2. Biopsy-proven acute rejection (BPAR) occurred in 25.0% and 15.2% of patients in the 1.5 and 3 mg/day groups in Study 1, and 13.7% and 15.1% in Study 2. Incidence of BPAR was significantly higher in patients with an everolimus trough <3 ng/mL. There were no significant between-group differences in the composite endpoint of BPAR, graft loss or death, nor any significant between-group differences in adverse events in either study. Concentration-controlled everolimus with low-exposure CsA provided effective protection against rejection with good renal function.

A three-arm study comparing immediate tacrolimus therapy with antithymocyte globulin induction therapy followed by tacrolimus or cyclosporine A in adult renal transplant recipients.

BACKGROUND: Induction therapy with antithymocyte globulin (ATG) reduces the incidence of acute rejection after transplantation. A study was undertaken to assess the efficacy and safety of ATG induction on tacrolimus-based and cyclosporine A (CsA)-based therapies compared with immediate tacrolimus triple therapy in kidney transplant recipients. METHODS: In a 6-month, open-label, randomized, prospective study conducted in 30 European centers, 555 renal transplant patients were randomly assigned to tacrolimus triple therapy (Tac triple, n=185), ATG induction with tacrolimus (ATG-Tac, n=186), or ATG induction with CsA microemulsion (ATG-CsA, n=184); all were combined with azathioprine and corticosteroids. The primary endpoint was incidence and time to first acute rejection episode confirmed by biopsy. RESULTS: Patient demographics and clinical parameters at baseline were similar. Patient and graft survival rates were similar in all groups. The incidence of clinically apparent acute rejection was significantly higher (P=0.003) for Tac triple (33.0%) compared with ATG-Tac (22.6%) and the incidence for ATG-Tac was significantly lower (P=0.004) than for ATG-CsA (37.0%). The incidences of acute rejection confirmed by biopsy (primary endpoint) were 25.4%, 15.1%, and 21.2% for Tac triple, ATG-Tac, and ATG-CsA, respectively (Tac triple vs. ATG-Tac, P=0.004). The incidences of corticosteroid-resistant acute rejection were 7.0% (Tac triple), 4.8% (ATG-Tac), and 10.9% (ATG-CsA) (ATG-Tac vs. ATG-CsA, P=0.038). In the ATG groups, the incidences of leukopenia, thrombocytopenia, serum sickness, fever, and cytomegalovirus infection were significantly higher (P<0.05). CONCLUSIONS: Acute rejection was significantly lower in the ATG-Tac group compared with the ATG-CsA and Tac triple groups. Significantly more hematologic and infectious adverse events were observed in both ATG induction groups.

Randomized double-blind study of immunoprophylaxis with basiliximab, a chimeric anti-interleukin-2 receptor monoclonal antibody, in combination with mycophenolate mofetil-containing triple therapy in renal transplantation.

BACKGROUND: Acute rejection remains a major problem in renal transplantation. Immunoprophylaxis with basiliximab (Simulect) has achieved significant reductions in acute rejection episodes in renal allograft recipients receiving dual immunosuppression. This study explored the tolerability and cumulative benefit of combining basiliximab with triple-drug therapy-cyclosporine (USP Modified, Neoral), mycophenolate mofetil, and steroids. METHODS: In a randomized, double-blind, placebo-controlled, multicenter study, 123 kidney transplant recipients received either basiliximab at 20 mg before transplantation (day 0) and 20 mg on day 4 (n=59), or placebo (n=64). All received triple-drug immunosuppression and were followed for 6 months. RESULTS: Tolerability of basiliximab was equivalent to placebo, with no increase in serious adverse events, infection, malignancy, or posttransplant lymphoproliferative disorder. At 6 months, there were trends in favor of basiliximab over placebo in the incidences of first biopsy-confirmed acute rejection (15.3% vs. 26.6%, P=NS) and of acute rejection treated with antibody (5.1% vs. 15.6%, P=NS). Kaplan-Meier estimates at 4 weeks and 6 months were significantly in favor of basiliximab treatment for first acute rejection, biopsy-confirmed rejection, rejection episodes treated with antibody therapy, and treatment failure. Renal function improved more rapidly in the basiliximab group, with mean creatinine clearance at week 2 being 54.7 mL/min versus 43.2 mL/min for placebo (P=0.034). At 12 months, patient survival was 100% in both groups; graft survival was 94.9% with basiliximab and 92.2% with placebo. CONCLUSIONS: Basiliximab immunoprophylaxis is safe, well tolerated, and shows a trend toward reduction in number of acute rejection episodes in renal transplant patients receiving cyclosporine, mycophenolate mofetil, and steroids.