Immunological Risk Kidney Transplant Recipients Research Articles

Combining cytochrome P-450 3A4 modulators and cyclosporine or everolimus in transplantation is successful.

To describe the long term follow-up of kidney allograft recipients receiving ketoconazole with calcineurin inhibitors (CNI) alone or combined with everolimus. This is an open-label, prospective observational clinical trial in low immunologic risk patients who, after signing an Institutional Review Board approved consent form, were included in one of two groups. The first one (n = 59) received everolimus (target blood level, 3-8 ng/mL) and the other (n = 114) azathioprine 2 mg/kg per day or mycophenolate mofetyl (MMF) 2 g/d. Both groups also received tapering steroids, the cytochrome P-450 3A4 (CYP3A4) modulator, ketoconazole 50-100 mg/d, and cyclosporine with C0 targets in the everolimus group of 200-250 ng/mL in 1 mo, 100-125 ng/mL in 2 mo, and 50-65 ng/mL thereafter, and in the azathioprine or MMF group of 250-300 ng/mL in 1 mo, 200-250 ng/mL in 2 mo, 180-200 ng/mL until 3-6 mo, and 100-125 ng/mL thereafter. Clinical visits were performed monthly the first year and quarterly thereafter by treating physicians and all data was extracted by the investigators. The clinical characteristics of these two cohorts were similar. During the follow up (66 + 31 mo), both groups showed comparable clinical courses, but the biopsy proven acute rejection rate during the full follow-up period seemed to be lower in the everolimus group (20% vs 36%; P = 0.04). The everolimus group did not show a higher surgical complication rate than the other group. By the end of the follow-up period, the everolimus group tended to show a higher glomerular filtration rate. Nevertheless, we found no evidence of a consistent negative slope of the temporal allograft function estimated by the modification of the diet in renal disease formula in any of both groups. At 6 years of follow-up, the uncensored and death-censored graft survivals were 91% and 93%, and 91% and 83% in the everolimus plus cyclosporine, and cyclosporine alone groups, respectively. The addition of ketoconazole saved 80% of cyclosporine and 56% of everolimus doses. Combining CYP3A4 modulators with CNI or mammalian target of rapamycin inhibitor, in low immunological risk kidney transplant recipients is feasible, effective, safe and affordable even in the long term.

A Prospective Randomized Trial Aimed to Reduce the Incidence of Cytomegalovirus (CMV) Infection in Kidney Transplant Recipients.

Introduction: CMV infection is associated with inferior long-term patient and graft survival. This single center prospective randomized study compares the influence of 3 immunosuppressive regimens on the incidence of CMV infection in kidney transplant recipients. Methods: This is a single center prospective randomized study included 288 low immunological risk kidney transplant recipients to receive: (G1, N=85) single 3 mg/kg dose of antithymocyte globulin, reduced exposure tacrolimus (TAC<5 ng/ml), everolimus (EVR: 4-8 ng/mL) and prednisone; (G2, N=102) basiliximab, reduced exposure TAC (6 ng/ml for 3 months then <5 ng/mL thereafter), EVR (4-8 ng/mL) and prednisone; (G3, N=101) basiliximab, TAC (6-8 ng/ml), mycophenolate (MPA) and prednisone. None of the patients received any CMV prophylaxis. CMV viral replication was monitored weekly using pp65 antigenemia and PCR. The primary outcome is the incidence of CMV infection (viremia or disease) during the first year of transplantation. This report includes data of all patients up to 6 month after transplantation. Results: There were no differences in demographic characteristics including pre-transplant CMV donor/recipient serostatus. The incidence of first CMV infection episode was lower in EVR groups (4.7 vs. 7.8 vs. 35.6%, p<0.0001). There was no difference comparing mean time to first CMV infection episode or mean time of ganciclovir treatment. The total number of CMV infection episodes was also lower in EVR groups (4 vs. 14 vs. 55) because there were no recurrent episodes in G1 but 6 in G2 and 19 in G3. Twelve patients were converted from MPA to EVR due to CMV infection. There were no differences in incidence of biopsy proven acute rejection (8 vs. 20 vs. 14%, p=0.085), wound-healing adverse events (28 vs. 35 vs. 25%, p=0.2), delayed graft function (48 vs. 53 vs. 45%, p=0.4), mean estimated GFR (64±24 vs. 58±23 vs. 66±29 ml/min, p=0.06) and mean protein/creatinine ratio (0.5±1.0 vs. 0.4±0.7 vs. 0.3±0.9, p=0.5). There were 8 deaths (G1=2; G2=3; G3=3) and 6 graft losses (G1=0; G2=3; G3=3). Conclusions: This 6 month analysis indicates that patients receiving EVR are at lower risk of developing CMV infection compared to patients receiving MPA. Patients receiving EVR showed efficacy and safety profiles comparable to those receiving MPA. DISCLOSURES:Tedesco, H.: Grant/Research Support, Novartis.

Improvement in Renal Function in High Immunologic Risk Kidney Transplant Recipients Switched From Tacrolimus to Belatacept.

Improvement in Renal Function in High Immunologic Risk Kidney Transplant Recipients Switched From Tacrolimus to Belatacept.

Association Between Immunosuppressive Drug Concentration and the Incidence of CMV Infection or Biopsy Proven Acute Rejection (BPAR) in Kidney Transplant Recipients.

Introduction: The purpose of this analysis was to evaluate the effects of 3 immunosuppressive regimens on the incidence of CMV infection and BPAR in kidney transplant recipients. Methods: This is a single center prospective randomized study including 288 low immunological risk kidney transplant recipients randomized to: (G1, N=85) single 3 mg/kg dose of antithymocyte globulin, reduced exposure tacrolimus (TAC<5 ng/ml), everolimus (EVR: 4-8 ng/mL) and prednisone; (G2, N=102) basiliximab, reduced exposure TAC (6 ng/ml for 3 months then <5 ng/mL thereafter), EVR (4-8 ng/mL) and prednisone; (G3, N=101) basiliximab, TAC (6-8 ng/ml), mycophenolate (MPA) and prednisone. None of the patients received any CMV prophylaxis. All patients were followed for 6 months after transplant. Time-average drug concentrations from day 7 to day 180 were use for this analysis. Results: There were no differences in main demographic characteristics between groups. The mean age was 45 years, 66% male, 52% caucasian and 69% recipients of grafts from deceased donors. In G1 the incidence of CMV infection was 5%. Patients with CMV infection showed higher TAC concentrations compared to those without CMV infection (6.2±0.6 vs. 5.1±1.0 ng/ml, p=0.026) with no differences in EVR concentrations (5.3±1.6 vs. 5.6±1.2 ng/ml, p=ns), respectively. In G2 the incidence of CMV infection was 8%. Patients with CMV infection showed similar TAC concentrations compared to those without CMV infection (7.7 ± 1.7 vs. 6.6 ± 1.8 ng/ml, ns) but lower EVR concentrations (4.3±1.0 vs. 5.4±1.2 ng/ml, p=0.009), respectively. In G3 the incidence of CMV infection was 36%. Patients with CMV infection showed similar TAC concentrations compared to those without CMV infection (7.7±1.6 vs. 7.5±1.1 ng/ml, ns) but higher MPA concentrations (7.2±7.7 vs. 2.3±1.6 ng/ml, p=0.037), respectively. The incidence of BPAR was 8%, 20% and 14% in G1, G2 and G3, respectively (p=0.085). There were no significant differences in TAC, EVR or MPA concentrations comparing patients with or without BPAR in each group. Conclusion: In this population receiving no CMV prophylaxis, lower incidence of CMV infection was observed among patients receiving EVR containing regimens. Higher TAC or MPA and lower EVR concentrations were associated with higher incidence of CMV infection.

Wound Healing Complications in Kidney Transplant Recipients Receiving Everolimus (EVR).

Introduction: De novo use of EVR has been associated with lower incidence of CMV infection but is associated with a concentration dependent increase in wound healing adverse events (WHAE). This study specifically evaluated WHAE within a prospective randomized trial comparing EVR and mycophenolate (MPA) in kidney transplant recipients receiving tacrolimus (TAC). Methodology: In this single center prospective randomized study 288 low immunological risk kidney transplant recipients were randomized to: (G1, N=85) single 3 mg/kg dose of antithymocyte globulin, reduced exposure (TAC<5 ng/ml), EVR (4-8 ng/mL) and prednisone; (G2, N=102) basiliximab, reduced exposure TAC (6 ng/ml for 3 months then <5 ng/mL thereafter), EVR (4-8 ng/mL) and prednisone; (G3, N=101) basiliximab, TAC (6-8 ng/ml), MPA(1440 mg/day) and prednisone. All drugs were started within 24 hours of graft revascularization. None of the patients received any CMV prophylaxis. All 12 surgeons involved were not aware of the trial and therefore no specific surgical procedures were implemented. A specific case report form was developed to capture all WHAE. An ultrasound evaluation was also scheduled for all patients reaching 30 days to capture subclinical abnormalities. Results: No differences in main demographic characteristics were observed. Mean EVR concentrations at day 7 were 4.1±1.3 in G1 and 4.0±1.4 ng/ml in G2. There was no difference in the incidence of patients with at least one WHAE (28 vs. 35 vs. 25%, p=0.246) or those requiring surgical reintervention (13 vs. 13 vs. 12%, p=0,972). Total number of events was higher in G2 (35 vs. 61 vs. 42). The most frequent events observed were lymphocele (16 vs. 25 vs. 12), incisional hernia (6 vs. 11 vs. 2), urinary fistula (6 vs. 7 vs. 7) and surgical site infection (1 vs. 10 vs. 8). Ultrasound was performed in 96% of patients reaching 30 days. Among patients without previous WHAE, specific findings were observed in 13%, 11% and 4% of patients in G1, G2 and G3, respectively, mostly small fluid collections. The incidence of CMV infection was lower among patients receiving EVR (4.7 vs. 7.8 vs. 35.6, p < 0.0001), respectively. Conclusion: In this rigorous analysis involving 12 blinded surgeons the proportion of patients with any WHAE were comparable in patients receiving EVR compared to MPA, although the total number of events appears to be higher in patients receiving basiliximab induction and EVR.

De Novo Everolimus (EVR) Versus Mycophenolate (MPA) in Kidney Transplant Recipients Receiving Tacrolimus (TAC).

Introduction: Head-to-head comparison of the efficacy of de novo use of EVR or MPA has not been investigated in kidney transplant recipients receiving TAC. Methods:This is a single center prospective randomized study including 288 low immunological risk kidney transplant recipients receiving: (G1, N=85) single 3 mg/kg dose of antithymocyte globulin, reduced exposure TAC (<5 ng/ml), EVR (4-8 ng/mL) and prednisone; (G2, N=102) basiliximab, reduced exposure TAC (6 ng/ml for 3 months then <5 ng/mL thereafter), EVR (4-8 ng/mL) and prednisone; (G3, N=101) basiliximab, TAC (6-8 ng/ml), MPA(1440 mg/day) and prednisone. None of the patients received any CMV prophylaxis. All patients were followed for 6 months after transplant and 28%, 29% and 27% reached one year of follow up, respectively. This report includes detailed analysis of the incidence and characteristics of acute rejection (AR) up to one year after transplantation (mean follow up of 297±98 days). Results: There were no differences in demography including recipient age, gender, race, PRA, CMV recipient status, donor age and donor source. The incidence of delayed graft function was high but comparable among the groups (48 vs. 53 vs. 45%, p=0.391), respectively. The incidence of biopsy proven acute rejection (BPAR) was not different among the groups (8.2 vs. 19.6 vs 13.9%, p=0.085). There was no significant difference in mean time to first treated AR (64±55 vs 34±53 vs 60±113 days, p=0.419) or in the total number of BPAR episodes (10 vs. 24 vs. 17 p=0.112). Vascular involvement (grade IIA or IIB, Banff 97) was less frequent in G1 (0 vs. 29 vs. 52%, p=0.01) while the incidence of AR episodes requiring antithymocyte globulin treatment was not different (10 vs. 29 vs. 47%, p=0.07). There was no difference in the number of patients with recurrent AR episodes (3 vs. 4 vs. 3). Also, there were no differences in the number of graft losses (1 vs. 3 vs. 6) and patient death (3 vs. 3 vs. 4). The incidence of CMV infection was lower in EVR groups (4.7 vs. 7.8 vs. 35.6%, p<0.0001) with no differences in mean estimated GFR (64±24 vs. 58±23 vs. 66±29 ml/min, p=0.08 ml/min). Conclusions: In this cohort of patients receiving TAC, a single dose 3mg/kg antithymocyte globulin induction combined with reduced exposure TAC and EVR is associated with less severe AR and lower incidence of CMV infection compared to MPA.

Effects of Three Immunosuppressive Regimens On Renal Function in Kidney Transplant Recipients.

Introduction: Renal function is associated with long-term renal allograft survival. Everolimus (EVR) have been combined with reduced exposure of calcineurin inhibitors (CNi) and therefore may determine superior renal function compared to those patients receiving standard exposure CNi and mycophenolate (MPA). Methods: In this single center prospective randomized study 288 low immunological risk kidney transplant recipients were randomized to: (G1, N=85) single 3 mg/kg dose of antithymocyte globulin, reduced exposure (TAC<5 ng/ml), EVR (4-8 ng/mL) and prednisone; (G2, N=102) basiliximab, reduced exposure TAC (6 ng/ml for 3 months then <5 ng/mL thereafter), EVR (4-8 ng/mL) and prednisone; (G3, N=101) basiliximab, TAC (6-8 ng/ml), MPA(1440 mg/day) and prednisone. All drugs were started within 24 h of revascularization. No patient received CMV prophylaxis. This analysis evaluated renal function at 6 months using estimated glomerular filtration rate (eGFR) by MDRD. A last observation carried forward was used for patients who died with functioning graft. An eGFR=0 was attributed to patients with graft loss. Results: The mean age was 44.6±13.3 years, 66% male, 52% Caucasian, 69% recipients of deceased donors. There was no difference in the incidence of delayed graft function (DGF, 48 vs. 53 vs. 45%, p=0.3) or in the incidence of biopsy proven acute rejection (8 vs. 20 vs. 14%, p=0.08). At month 6 there were no differences in mean creatinine (1.5±1.0 vs. 1.4±0.6 vs. 1.4±1.0 mg/dl, p=0.54), mean eGFR (64±24 vs. 58±23 vs. 66±29ml/min, p=0.06) and mean urinary protein concentration (0.5±1.0 vs. 0.4±0.7 vs. 0.3±0.9 g/l, p=0.5), respectively. Among patients with DGF, lower eGFR was observed in G2 (67±28 vs. 48±24 vs. 63±35 ml/min, p=0.03). There were no differences in eGFR among patients with biopsy proven acute rejection (56±26 vs. 46±22 vs. 71±45 ml/min, p= 0.11) and CMV infection (78±22 vs. 55±29 vs. 68±30 ml/min, p=0.38), respectively. The proportion of patients with eGFR<50ml/min was higher in G2 (24% vs. 38% vs. 24%, p=0.033). Protocol biopsies performed at month 12 in 86/181 patients (G1=31, G2=32 G3=23) showed chronic allograft nephropathy in 7(22%), 5(15%) and 4(17%) patients (p= 0.76). Conclusion: This preliminary analysis suggests that EVR with antithymocyte globulin induction is associated with similar renal function compared to patients receiving MPA. DISCLOSURES:Tedesco, H.: Grant/Research Support, Novartis.

Efficacy and Safety of Combination Therapy With Tacrolimus and Sirolimus in Immunological High Risk Kidney Transplant Recipients.

Objective: The aim of this study was to evaluate the efficacy and safety of combination therapy with tacrolimus and sirolimus in immunological high risk recipients. Methods: From January 2010 to December 2011, 28 immunological high risk patients were enrolled according to the following criteria: 1) retransplantation, 2) Class I or II PRA >50%, 3) 5 or 6 HLA mismatches The efficacy endpoints were incidence of biopsy-proven acute rejection reaction, graft loss, patient death and renal function. The safety was evaluated by analyzing the adverse effects. Results: Among 28 total patients, 8 (28.6%) were dropped due to acute rejection, infection, pneumonitis, or postoperative hemorrhage. One patient death occurred due to fungal infection. Acute rejection developed in 6 (21.4%) patients. The mean eGFR (MDRD) for the 1st year after transplantation was 52.0 ± 4.0 mL/min/1.73m2. Fifteen (53.6%) patients had infections and 3 (10.7%) patients experienced pneumonitis. Lymphocele developed in 4 (14.3%) patients. Conclusion: The combination therapy with tacrolimus and sirolimus must be considered with caution for immunological high risk recipients due to high incidence of adverse events. Special attention should be given to the target blood concentration levels of the two drugs in order to minimize adverse events.

MP72-03 SERUM BAFF LEVELS AND B CELL SUBSETS IN DIFFERENT LYMPHOID ORGANS AFTER RITUXIMAB ADMINISTRATION: ITS ASSOCIATION WITH CLINICAL OUTCOMES

You have accessJournal of UrologyTransplantation & Vascular Surgery II1 Apr 2014MP72-03 SERUM BAFF LEVELS AND B CELL SUBSETS IN DIFFERENT LYMPHOID ORGANS AFTER RITUXIMAB ADMINISTRATION: ITS ASSOCIATION WITH CLINICAL OUTCOMES Mitsuru Saito, Shigeru Satoh, Kazuyuki Numakura, Mingguo Huang, Hiroshi Tsuruta, Susumu Akihama, Takamitsu Inoue, Shintaro Narita, Norihiko Tsuchiya, and Tomonori Habuchi Mitsuru SaitoMitsuru Saito More articles by this author , Shigeru SatohShigeru Satoh More articles by this author , Kazuyuki NumakuraKazuyuki Numakura More articles by this author , Mingguo HuangMingguo Huang More articles by this author , Hiroshi TsurutaHiroshi Tsuruta More articles by this author , Susumu AkihamaSusumu Akihama More articles by this author , Takamitsu InoueTakamitsu Inoue More articles by this author , Shintaro NaritaShintaro Narita More articles by this author , Norihiko TsuchiyaNorihiko Tsuchiya More articles by this author , and Tomonori HabuchiTomonori Habuchi More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.2242AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Rituximab (RIT), anti-CD20 antibody, has been applied to kidney transplantation because of its potent B-cell depleting effect. Although CD20+ cells in peripheral blood (PB) and spleen are consistently depleted in patients receiving RIT, the clinical effects are heterogeneous, probably related to differences in the depleting effects of secondary lymphoid organs (SLOs), such as peripheral lymph nodes (LNs). Meanwhile, B cell activation factor of the TNF family (BAFF) promotes B cell development and antibody secretion, and also serum BAFF levels increase after RIT administration. The aim of this study was to investigate the relationship between serum BAFF levels and B cell subsets in different lymphoid organs after RIT administration and its association with clinical outcomes. METHODS Since April 2005, 50 patients with immunological high risks [ABO-incompatible (ABOI) or donor specific anti-HLA antibody (DSA) positive or both] received a single dose of RIT with 200 mg/body at 3 weeks before kidney transplantation. They received 3 to 4 sessions of apheresis prior to transplantation. The induction immunosuppressive therapy was consisted of tacrolimus, MMF, steroid, and basiliximab. In all patients, the several pelvic LNs were dissected at the time of transplantation. Of those, 2 ABOI (induction period of RIT) and 6 DSA positive patients received splenectomy concurrently with transplantation. Immunohistochemical intensity of B cell subsets (CD20, CD27, CD79a, and CD138) in both LN and spleen was scored. Serum BAFF levels at day -7, 7, and 28 post-transplant were measured by ELISA. RESULTS Acute antibody-mediated rejection (AAMR) developed in 9 patients (19%) in this series. The intensity score of CD138 in LNs was significantly higher in AMR patients (p<0.01) than those in non-AMR patients. No significant difference was found in the intensity scores of all B cell subsets in spleen among the patients with or without AMR. The serum BAFF levels at day -7 (p<0.01), 7 (p<0.05), and 28 (p<0.01) post-transplantation were significantly lower in AMR patients than in non-AMR patients. The existence of DSA before transplant, the intensity score of CD138 in LNs, and low serum BAFF level at 7 days before transplant were significantly associated with the occurrence of AAMR. CONCLUSIONS In immunological high risk kidney transplant recipients receiving RIT before transplant, the plasma cell intensity in LNs and low serum BAFF level were risk factors of AAMR. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e824 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Mitsuru Saito More articles by this author Shigeru Satoh More articles by this author Kazuyuki Numakura More articles by this author Mingguo Huang More articles by this author Hiroshi Tsuruta More articles by this author Susumu Akihama More articles by this author Takamitsu Inoue More articles by this author Shintaro Narita More articles by this author Norihiko Tsuchiya More articles by this author Tomonori Habuchi More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Solid phase detection of C4d-fixing HLA antibodies to predict rejection in high immunological risk kidney transplant recipients

Protocols for recipient desensitization may allow for successful kidney transplantation across major immunological barriers. Desensitized recipients, however, still face a considerable risk of antibody-mediated rejection (AMR), which underscores the need for risk stratification tools to individually tailor treatment. Here, we investigated whether solid phase detection of complement-fixing donor-specific antibodies (DSA) has the potential to improve AMR prediction in high-risk transplants. The study included 68 sensitized recipients of deceased donor kidney allografts who underwent peritransplant immunoadsorption for alloantibody depletion (median cytotoxic panel reactivity: 73%; crossmatch conversion: n=21). Pre and post-transplant sera were subjected to detection of DSA-triggered C4d deposition ([C4d]DSA) applying single-antigen bead (SAB) technology. While standard crossmatch and [IgG]SAB testing failed to predict outcomes in our desensitized patients, detection of preformed [C4d]DSA (n=44) was tightly associated with C4d-positive AMR [36% vs. 8%, P=0.01; binary logistic regression: odds ratio: 10.1 (95% confidence interval: 1.6-64.2), P=0.01]. Moreover, long-term death-censored graft survival tended to be worse among [C4d]DSA-positive recipients (P=0.07). There were no associations with C4d-negative AMR or cellular rejection. [C4d]DSA detected 6months post-transplantation were not related to clinical outcomes. Our data suggest that pretransplant SAB-based detection of complement-fixing DSA may be a valuable tool for risk stratification.

Basiliximab induction in patients receiving tacrolimus-based immunosuppressive regimens

The use of basiliximab induction increased significantly in recent years based on its superior efficacy and excellent safety profile demonstrated in studies with cyclosporine-based immunosuppression. However, its clinical utility in patients receiving tacrolimus-based immunosuppressive regimens is still uncertain. We retrospectively reviewed data of 366 low immunological risk recipients of deceased donor kidney transplants. Of them, 134 received basiliximab and tacrolimus (TAC-IL2-RA), 100 received basiliximab and delayed tacrolimus(dTAC-IL2-RA), and 132 patients received tacrolimus without basiliximab(TAC-No). The endpoints were the incidence of acute rejection, graft function, and patient and graft survivals at 1 year. The incidence of acute rejection was higher in dTAC-IL2-RA compared to TAC-IL-2RA and TAC-No Groups (33 vs.14.9 vs. 14.3 %, p < 0.001). Inferior creatinine clearance was observed in dTAC-IL2-RA Group compared to TAC-IL2-RA and TAC-No Groups at months 1 (41.6 vs. 49.9 vs. 44.8 mL/min, p = 0.004), 3 (49.8 vs. 57.2 vs. 53.5 mL/min, p = 0.017), and 6 (53.1 vs. 61.8 vs. 57.0 mL/min, p = 0.001). Patients who received basiliximab (TAC-IL2-RA and dTAC-IL2-RA Groups) had lower incidence of posttransplant diabetes (24 vs.18 vs. 39.3 %, p = 0.009). Patient and graft survivals were similar among the groups. In low immunological risk kidney transplant recipients receiving tacrolimus, the use of basiliximab induction was not associated with lower rejection rates and did not allow delayed tacrolimus introduction.

MTOR inhibitor monotherapy. A good treatment choice in renal transplantation?

Calcineurin inhibitors have reduced acute rejection rates and improved short-term graft survival, but without any improvement in long-term outcomes, since calcineurin inhibitors cause nephrotoxicity and death with a functioning graft. mTOR inhibitors have antiproliferative and anti-angiogenic effects with no nephrotoxicity. These properties could improve patient and graft long-term survival rates in select transplant recipients. In addition, monotherapy always diminishes the rate of non-compliance in chronic patients. We examined the evolution of 47 low immunological risk kidney transplant recipients with mTOR inhibitor monotherapy. The mean age was 45 ± 10 years (range: 18-69 years), with 25 males y 22 females. We performed an immunological evaluation before and at 3 and 12 months after starting monotherapy by detection of donor-specific antibodies by microsphere cytometry and the determination of lymphocyte activity with production of ATP by CD4+ T-lymphocytes activated by PHA mitogen. We considered patients to be of low immunological risk when the patient had an ATP production less than 520 ng/dl and no history of acute rejection episode or donor-specific antibodies. Initially, 5 patients received immunosuppression induction without calcineurin inhibitors (mycophenolate, prednisone, mTOR inhibitors and anti-CD25), and 42 were converted to mTOR inhibitors due to secondary effects of calcineurin inhibitors or malignancies. A total of 34 recipients had received sirolimus and 13 everolimus. Eighteen out 47 patients (38.2%) received prednisone and 29 (61.7%) mycophenolate with mTor before starting monotherapy. The mean follow-up period after starting monotherapy was 46.9 months (95% CI: 38.8-55.0 months). At the end of the follow-up, 7 out of 47 recipients (11.5%) had to change immunosuppression without losing their grafts after 1 year, due to heavy proteinuria in 2 cases, pulmonary infection in 1, acute rejection in 1, hepatotoxicity in 1, vasculitis in 1 and a temporary inclusion on dialysis after acute pyelonephritis in 1. Four out of 47 patients (8.5%) lost their grafts, as a result of chronic rejection in 3 cases, and as a result of death with a functioning graft in 1. The rate of acute rejection was 2.1%, one episode, which was solved with steroid pulses and switching from mTOR inhibitors to tacrolimus and mycophenolate. No patients developed donor-specific antibodies, and all of them maintained an ATP production less than 520 ng/dl. The rates of graft and recipient survival were both 100% at 1 year, and 88.7% and 95.7% at 5 years. The percentages of patients on monotherapy were 97.9% and 70.5 % at 1 and 5 years, respectively. At the end of the follow-up, 36 out of 47 recipients remained on mTOR inhibitor monotherapy. Serum creatinine and glomerular filtration rates improved significantly, from 2.16 ± 1.05 mg/dl to 1.49 ± 0.56 mg/dl (P=.001) and from 39.23 ± 25.23 ml/min to 52.23 ± 23.20 ml/min (P=.001), respectively. Proteinuria increased but not significantly, from 306.6 ± 400 mg/24h to 418.1 ± 514.1mg/24h (P=.17). The patients treated with mTOR inhibitors received significantly more erythropoietin and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers than before starting mTOR, but there was no change in the treatment with statins or hypotensive agents. Body weight and the percentage of diabetic recipients were similar during the study. No cases of non-compliance were observed during the follow-up. The present study supports the safety and efficacy of monotherapy with mTOR inhibitors in select kidney transplant recipients.

Steroid avoidance or withdrawal in kidney transplantation

Steroid avoidance or early withdrawal in kidney transplantation is supported by recent guidelines, but late steroid withdrawal after the first posttransplant months has been recently discouraged in those guidelines. We have assessed the recent data trying to confirm whether or not these different steroid-sparing strategies are well tolerated. Reversible, mild acute rejection rates are increased after steroid avoidance or withdrawal. However, steroid avoidance or early withdrawal is well tolerated in low immunological risk kidney transplant recipients receiving induction with anti-IL2 receptor antibodies or thymoglobulin and a drug regimen based on calcineurin inhibitor and mycophenolate mofetil, at least during 5 years, the longest follow-up reported. In addition, steroid withdrawal after 3-6 months is associated with stable graft function and survival stable up to 3 years after transplantation, the longest follow-up reported. Although clear benefits (cardiovascular and others) are obvious in some observational studies, true benefits in randomized controlled trials remain unclear. Both early and late steroid withdrawals are well tolerated in selected low-risk renal allograft recipients treated with modern potent immunosuppression. More trials with carefully designed outcome measures are needed, especially with other modern combinations, including mTOR inhibitors and/or belatacept.

Rabbit Anti-Thymocyte Globulin: Evidence for Clinical Benefit in High Immunological Risk Kidney Transplantation

Rabbit anti-thymocyte globulin is used worldwide to treat and prevent rejection in kidney transplantation. Multiple mechanisms of action of this polyclonal preparation are responsible for its success. Studies have supported clinical benefits of rabbit anti-thymocyte globulin in high immunological risk kidney transplant recipients when used as an induction agent at the time of transplant and for treatment of rejection when compared to other antibody therapy. The evidence of this clinical benefit will be reviewed in addition to examining the dosing and safety profile of rabbit anti-thymocyte globulin.

Thymoglobulin Dose Optimization for Induction Therapy in High Risk Kidney Transplant Recipients

Thymoglobulin (rATG) has become the agent of choice for induction therapy in high immunological risk kidney transplant recipients. However, its optimal dosing in this subgroup has not been studied. To evaluate the effect of total rATG dosing on graft outcomes in such patients, we conducted a retrospective cohort study of 96 adult patients who received repeat transplants (85%) or had panel reactive antibody more than 40% (19%) and were maintained on tacrolimus, mycophenolate mofetil, and steroid. Group 1 (n=33) received less than or equal to 7.5 and group 2 (n=63) received more than 7.5 mg/kg rATG. Graft and patient survival, incidence of acute rejection (AR), and 12-month serum creatinine (SCr) were examined. The groups were comparable regarding demographics, donor source, retransplantation, panel reactive antibody, and human leukocyte antigen mismatch. Group 2 had more African Americans (44.4% vs. 21.2%, P=0.03). During the 25.4+/-18.0 months follow-up graft survival was 82.5% and 79.4%, respectively (P=0.54). Three in group 1 and four in group 2 died (P=0.65). The incidence of biopsy proven AR during the first 12-months did not differ between the groups (9.5% vs. 8.8%, respectively, P=0.9). SCr at 12 months was 1.6+/-0.7 in group 1 and 1.8+/-1.0 in group 2 (P=0.3). There was no independent association between rATG dose and graft survival (hazard ratio: 0.85, P=0.79, 95% CI: 0.26-2.7 for group 2 vs. 1) or 1-year SCr (regression coefficient=0.02 for ln(SCr), P=0.3; 95%CI: -0.01 to 0.6). Our results suggest that in high risk kidney transplant recipients total rATG doses less than or equal to 7.5 mg/kg are safe and effective in achieving a low rate of AR and graft outcomes comparable to higher doses.