Low-dose rabbit antithymocyte globulin versus basiliximab induction therapy in low-risk renal transplant recipients: 8-year follow-up.

Antibody induction is effective in preventing acute rejection, but its effects on long-term renal allograft function and survival remain controversial. Moreover, given the risks of antibody induction, full-dose lymphocyte-depleting therapy for low-risk patients is usually avoided. However, the benefit and risks associated with low-dose (Lo) rabbit antithymocyte globulin (rATG; 3-5 mg/kg total) induction in a low-risk population have not been explored. We now report the long-term outcomes in this patient population. We defined low risk as white, panel-reactive antibody<30%, and non-Donor with Cardiac Death (DCD) recipients. We compared the risk of acute rejection and graft survival for both living donor (LD) and deceased donor (DD) recipients. The average dose of rATG was 3.1±1.2 mg/kg. Forty DD recipients received basiliximab (BSX) and 145 patients were induced with Lo rATG. Twenty LD recipients received BSX and 64 received Lo rATG. The groups did not differ in demographics, donor characteristics, and maintenance immunosuppression. At 8 years, patient survival was higher for LD patients compared to DD recipients (91% vs 45%, P=.004). In recipients of LD kidneys, 8-year patient survivals were not different comparing Lo rATG and BSX groups (92% vs 91%, respectively, P=.55). In LD, 8-year graft survival was excellent irrespective of induction (Lo rATG 100% vs BSX 98%); however, Lo rATG was associated with a lower rate of acute rejection (7.8% vs 35% BSX, P<.01) and better mean serum creatinine at 3 and 5 years (1.2 vs 1.5, P=.02 and 1.18 vs 1.54, P=.04, respectively). For DD, Lo rATG was associated with a better long-term graft survival (86% vs 76% BSX, P=.02). Viral infections and cancer rates were similar for Lo rATG and BSX. Thus, we conclude that Lo rATG induction may add long-term benefit in low-risk patients compared to anti-interleukin-2 receptor therapy without incurring additional risks of infectious or malignant diseases.

Low-dose rabbit antithymocyte globulin induction therapy results in prolonged selective lymphocyte depletion irrespective of maintenance immunosuppression.

Rabbit antithymocyte globulin therapy (rATG) is a potent lymphocyte-depleting agent commonly used following renal transplantation to reduce the risk of acute rejection. Standard doses (7-10 mg/kg) of rATG result in profound lymphopenia and predispose patients to infection and malignancy. The effects of lower doses of rATG (LoD-rATG, 3-5 mg/kg) on peripheral blood lymphocytes (PBL) are as yet unknown. In this prospective clinical trial, PBL subsets were characterized by flow cytometry over 12 months following LoD-rATG therapy. All patients were initially treated with standard doses of tacrolimus, mycophenolic acid, and prednisone. At 3 months, patients were randomized to either lower doses of tacrolimus or sirolimus to examine the effects of maintenance immunosuppression on PBL reemergence. LoD-rATG therapy resulted in prolonged suppression of CD19+ B cells, total CD3+ T cells, as well as naïve and memory CD4+ T cell and CD4/CD25/Foxp3+ T-regulatory subsets irrespective of chronic immunosuppressive therapy. Selective depletion was only noted in the CD4CD45RA+ naïve T-cell subset resulting in an altered memory/naïve CD4+ ratio. LoD-rATG failed to deplete CD8+ T cells, which increased their relative contribution to the total CD3+ pool. All other lymphocyte subsets maintained near normal proportions. Thus, LoD-rATG therapy may lessen the adverse effects of full dose rATG while maintaining overall efficacy.

Low-dose thymoglobulin use in elderly renal transplant recipients is safe and effective induction therapy.

Current immunosuppressive therapies and protocols have led to significant improvements in early patient and graft survival rates following kidney transplantation. Whether induction therapies such as rabbit anti-thymocyte globulin (rATG) contribute to these improved results remains controversial. Full-dose rATG induction therapy (7-10 mg/kg) has been associated with increased morbidity, which may be especially true in a high-risk population such as the elderly. Therefore, we studied the efficacy and tolerability of a low-dose rATG induction strategy in 45 older recipients (>65 years) compared to 45 concurrently transplanted younger patients (<65 years). Both groups received a similar low-dose of rATG induction therapy (older: 2.96±1.29 vs younger: 3.2±2.11 mg/kg). All patients were maintained on a calcineurin inhibitor, mycophenolic acid, and low-dose prednisone (5 mg/d). To date, none of the older patients experienced acute rejection, whereas one younger patient had an acute rejection episode. Initial hospital stays were equal (older: 7.8±3.2 vs younger: 7.5±4.4 days, P=.35). Within the first 6 months, nine older patients required rehospitalization compared to 15 younger patients (P=.15). Bacterial infections in older and younger recipients were equal including wound (4 vs 0), urine (20 vs 15), lung (1 vs 1), and skin (0 vs 2), respectively. There were two BK viral infections in older patients, whereas there were three viral infections, two cytomegalovirus cases, and one Herpes zoster case in younger patients. Calculated 6-month glomerular filtration rate was equal in both groups (older: 55.7±18.5 vs younger: 52.7±18.5 mL/min). Three-year patient and graft survival rates were equivalent for older and younger patients (86.6% vs 97.6%, respectively). In conclusion, low-dose rATG induction therapy is safe and effective in patients older than 65. When compared to younger patients, low-dose rATG leads to equivalent graft survival and function without incurring excess morbidity in the older population.

Obesity in renal transplantation: the role of induction therapy on long-term outcomes.

Obesity is a burgeoning problem among renal transplant recipients given its association with increased morbidity, graft loss, and mortality. The long-term influence of different induction therapies in obese compared to nonobese patients is uncertain. We examined the long-term effect of low-dose rabbit antithymocyte globulin (rATG; 3-5 mg/kg) induction therapy compared to two doses of 20 mg basiliximab (BSX) in nonobese and obese renal transplant patients. The medical records of all adult (>18 years) recipients of kidney transplants between June 2001 and June 2009 in our center were reviewed. Patients whose body mass index (BMI) was greater than 30 were considered to be obese. The average dose of rATG was 3.2±1.6 mg/kg. A total of 475 patients were included. In the nonobese group with a BMI less than 30, 68 received BSX and 247, rATG. In the obese group, 27 patients were given BSX and 133 were given rATG. Mean follow-up was 1523 days. These four groups were similar in baseline characteristics including: donor and recipient age, percent diabetes, living donors, panel-reactive antibodies>35, HLA mismatch, race, gender, and maintenance immunosuppression. Serum creatinine levels at 3 months and 1, 5, and 7 years were not statistically different between groups. Compared to BSX induction therapy, rATG was associated with better graft survival at 47.4±10 months in obese (63.6% vs 90.3%, P<.05, respectively) as well as nonobese patients (68.2% vs 88.7%, P<.05, respectively). Rejections were numerically lower in rATG-treated obese patients, which reached statistical significance in nonobese patients. Wound and viral infections were not statistically different between rATG and BSX groups. Therefore, low-dose rATG is associated with a better long-term graft survival rate in obese patients without incurring an increased risk of infectious complications. When rATG was used in obese and nonobese patients, there was no difference in graft and patient survival.

Mycophenolic acid dose reductions result in poor long-term renal allograft survival: comparison between mycophenolate sodium and mycophenolate mofetil.

Mycophenolate acid (MPA) therapy is associated with a decrease in acute rejection rates and excellent renal allograft survival. Unfortunately, mycophenolate mofetil (MMF) is associated with significant adverse effects (AE), which, in many cases, preclude full-dose therapy. Previously, lower MMF drug exposure was significantly associated with a greater risk of rejection. Patients who had a ≥50% dose reduction of MMF experienced a lower graft survival compared to those who tolerated full-dose MMF. Mycophenolate sodium (MPS) was designed to lessen MPA-associated AE. In this retrospective study, we studied the tolerability and long-term outcomes in renal transplant recipients (RTR) treated with MPS versus MMF. Four hundred forty-nine RTRs who received MPS or MMF for more than 3 months were classified into three groups: group 1: MMF-treated; group 2: MPS-treated; and group 3; patients who converted from MMF to MPS due to AE. Donor and recipient demographics as well as induction and maintenance immunosuppressive therapies were similar in all groups. Patient survival was not different in all groups. However, long-term graft survival was lower in patients whose dose of either MPS or MMF was reduced by ≥50%. Moreover, a ≥50% MPA dose reduction was associated with a higher rate of rejection compared to full dose (38% vs 21%, respectively, P<.01). Compared to patients treated initially with MMF, fewer MPS-treated recipients required dose reductions (65% vs 42%, respectively, P<.001). Furthermore, 38% of patients in group 3 tolerated full-dose MPS despite previous intolerance to MMF. Finally, the long-term graft survival was best in MPS-treated RTR and worst in those who converted from MMF to MPS due to AE. We conclude that MPS is better tolerated than MMF, which may explain the superior graft outcome in RTR who were treated with MPS from the onset.

African-American women and older patients are at risk for a greater decline in renal function following living kidney donation.

Living donor kidney transplantation offers many advantages to the recipients. Longer allograft survival, fewer postoperative complications, and better renal function are some of the benefits of receiving living donor kidneys compared to deceased donor organs. However, the consequences to the donor in terms of renal function are not as well defined. Moreover, it is not clear whether all donors share an equal risk to their renal function following donation regardless to ethnicity, sex, and age. In this retrospective study, we identify and compare the reduction in estimated glomerular filtration rate (eGFR) among ethnic groups, women, and older donors prior to, immediately after, and 1 year postdonation. We compared the percentage decline in renal function among various ages and other demographic groups using individual patients as their own controls. Medical records of 103 consecutive living donors (mean age 40.3±9.6 years) were reviewed. On average, donors experienced a 34.7% fall in eGFR at 273 days posttransplant. A greater decline was noticed in the African-American (AA) group (41% compared to 34% in white patients, P=.03). The majority of the decline in the AA eGFR was among women, in whom the fall was 46% compared to AA men at 31%. White women had a 34% fall in eGFR (P=.02). The percentage decline in eGFR was not different among the different age groups; however, donors older than 50 years had a postdonation eGFR of 55.1 mL/min versus 60.9 mL/min in those less than 50 years old (P=.03), reflecting lower eGFR predonation (older 84.7 mL/min vs younger 95.2 mL/min, P=.02). The percent decline in eGFR did not change with time after donation (0-1 month 37%, 1-12 months 34%, >1 year 30%). eGFR declines abruptly post-kidney donation in all patients but remains stable and improves afterwards. AA women and older donors are more prone to reduction in eGFR post-kidney donations.

Conversion to low-dose tacrolimus or rapamycin 3 months after kidney transplantation: a prospective, protocol biopsy-guided study.

Long-term survival of kidney allografts is primarily limited by a progressive decline in function characterized by the presence of interstitial fibrosis (IF) and tubular atrophy (TA) on biopsy. Since chronic calcineurin-inhibitor (CNI) drug toxicity has been implicated as a significant cause of IF/TA, a major effort in transplantation has been to decrease or eliminate CNI therapy. We now report the clinical and histological consequences of converting renal transplant recipients at 3 months to either very low levels of tacrolimus (TAC; 4-6 ng/mL) or sirolimus (SRL; 6-10 ng/mL) therapy. Fifty-eight enrollees in this prospective randomized trial received low-dose (2.9±0.6 mg/kg) rabbit antithymocyte globulin induction followed by standard doses of TAC (10-15 ng/mL), mycophenolic acid, and low-dose steroids for 3 months. Protocol biopsies were performed at implantation and 3 and 12 months. Six patients had evidence of either borderline changes (n=5) or grade 1A rejection (n=1) on the 3-month protocol biopsy and were not randomized. Only one patient had clinically evident rejection that occurred after randomization to SRL. One patient in each group had borderline changes at 12 months. Renal function (estimated glomerular filtration rate) was equivalent in both groups at 12 months (TAC 74±15 vs SRL 66±18 mL/min, P=.22). Chronic allograft damage index scores at 1 year were similar in both groups (TAC 2.8±2.4 vs SRL 2.0±2.7, P=.71). The percentage of patients with IF/TA scores greater than 2 at 1 year was low in both groups (TAC 12% vs SRL 9%, P=.78). Therefore, in a low-risk population defined as having a normal 3-month protocol biopsy, TAC levels can be successfully decreased to very low concentrations. One-year graft function and histology were equally well maintained with either low-dose TAC or SRL immunosuppression.