A multicenter prospective study to define the natural history of BK viral infections in kidney transplantation.

BACKGROUND: BK polyomavirus (BKV) can cause permanent loss of allograft function due to BKV-associated nephropathy (BKVN) in kidney transplant recipients. Besides immunosuppression reduction, there are no consistently effective interventions for BKV infection. Study purpose was to define natural history of BKV infection, identify risk factors for BKV reactivation and BKVN in kidney transplant recipients, and inform the design/conduct of future clinical trials of BKV-targeted therapeutics. METHODS: We conducted a multicenter prospective observational study of incident kidney transplant recipients at six U.S. transplant centers. Participants were monitored every 4 weeks for BKV reactivation and followed for up to 24 months post-transplant. We used regression models (logistic, survival, mixed models) to study relationships between BK viremia/BKVN, clinical characteristics, and allograft function. RESULTS: We enrolled 335 participants. Fifty-eight (17%) developed BK viremia, 6 (2%) developed biopsy-proven BKVN, and 29 (9%) developed suspected/presumed BKVN (defined as BKV viral load > 10,000 copies/mL without biopsy). Male donor sex was associated with lower odds for BK viremia, whereas recipient Black race was associated with two-fold increased odds for BK viremia. Recipient female sex was associated with more rapid clearance of BK viremia. Persistent BK viremia/BKVN was associated with poorer allograft function by 24 months post-transplant. CONCLUSIONS: We identified multiple donor and recipient demographic factors associated with risk for BKV infection and poorer allograft function by 24 months post-transplant. This may help design future clinical trials of therapies to prevent or mitigate the deleterious impact of BKV reactivation on kidney transplant outcomes.

Treatment of De Novo Renal Transplant Recipients With Calcineurin Inhibitor-free, Belatacept Plus Everolimus-based Immunosuppression.

Compared with calcineurin inhibitor-based immunosuppression, belatacept (BELA)-based treatment has been associated with better renal function but higher acute rejection rates. This phase 2 study (NCT02137239) compared the antirejection efficacy of BELA plus everolimus (EVL) with tacrolimus (TAC) plus mycophenolate mofetil (MMF), each following lymphocyte-depleting induction and rapid corticosteroid withdrawal. Methods: Patients who were de novo renal transplant recipients seropositive for Epstein-Barr virus were randomized to receive BELA+EVL or TAC+MMF maintenance therapy after rabbit antithymocyte globulin induction and up to 7 d of corticosteroids. The primary endpoint was the rate of biopsy-proven acute rejection at month 6. Results: Because of an unanticipated BELA supply constraint, enrollment was prematurely terminated at 68 patients, of whom 58 were randomized and transplanted (intention-to-treat [ITT] population: n = 26, BELA+EVL; n = 32, TAC+MMF). However, 25 patients received BELA+EVL' and 33 received TAC+MMF (modified ITT population). In the ITT population, the 6-mo biopsy-proven acute rejection rates were 7.7% versus 9.4% in the BELA+EVL versus TAC+MMF group. The corresponding 24-mo biopsy-proven acute rejection rates were 19.2% versus 12.5% in the ITT population and 16.0% versus 15.2% in the mITT population; all events were Banff severity grade ≤IIA and similar between groups. One patient in each group experienced graft loss unrelated to acute rejection. The 24-mo mean unadjusted estimated glomerular filtration rates were 71.8 versus 68.7 mL/min/1.73 m2 in the BELA+EVL versus TAC+MMF groups. Posttransplant lymphoproliferative disorder was reported for 1 patient in each group. No deaths or unexpected adverse events were observed. Conclusions: A steroid-free maintenance regimen of BELA+EVL may be associated with biopsy-proven acute rejection rates comparable to TAC+MMF.

Serial Peripheral Blood Gene Expression Profiling to Assess Immune Quiescence in Kidney Transplant Recipients with Stable Renal Function.

BACKGROUND TruGraf is a blood-based biomarker test that measures differential expression of a collection of genes that have been shown to correlate with surveillance biopsy results. However, in the majority of U.S. transplant centers, surveillance biopsies are not performed. The objectives of this study were to evaluate the clinical validity of TruGraf in stable kidney transplant recipients and to demonstrate the potential clinical utility of serial TruGraf testing in a center not utilizing surveillance biopsies. MATERIAL AND METHODS Serum creatinine levels, TruGraf testing at multiple time points, and subsequent clinical follow-up were obtained for 28 patients. RESULTS Overall concordance of TruGraf results, when compared with independent clinical assessment of testing, was 77% (54/70) for all tests; 79% (22/28) for test 1, 75% (21/28) for test 2, and 79% (11/14) for test 3. The negative predictive value (NPV) was 98.0%. Analysis of clinical utility indicated that 77% of TruGraf results would have been useful in patient management. CONCLUSIONS Our results indicate the value of serial TruGraf testing in those transplant centers that do not perform surveillance biopsies as part of their standard of care. The high negative predictive value indicates the ability of TruGraf to confirm immune quiescence with a high degree of probability in patients with a Transplant eXcellence (TX) result, without the need to perform a surveillance biopsy.

Long-term Follow-up of Kidney Transplant Recipients in the Spare-the-Nephron-Trial.

In the Spare-the-Nephron (STN) Study, kidney transplant recipients randomized about 115 days posttransplant to convert from CNI (calcineurin inhibitor)/MMF to sirolimus (SRL)/MMF had a significantly greater improvement in measured GFR (mGFR) at 12 months compared with those kept on CNI/MMF. The difference at 24 months was not statistically significant. From 14 top enrolling centers, 128 of 175 patients identified with a functioning graft at 2 years consented to enroll in an observational, noninterventional extension study to collect retrospectively and prospectively annual follow-up data for the interval since baseline (completion of the parent STN study at 24 months posttransplant). Overall, 11 patients died, including 5 (7.6%) in the SRL/MMF group and 6 (9.7%) in the CNI/MMF group. Twenty-two grafts have been lost including 10 (15.2%) in the SRL/MMF arm and 12 (19.4%) in the CNI/MMF arm. Death and chronic rejection were the most common causes of graft loss in both arms. There were modestly more cardiovascular events in the MMF/SRL group. Estimated creatinine clearance (Cockcroft-Gault) from baseline out to 6 additional years (8 years posttransplant, ITT analysis, SRL/MMF, n = 34; CNI/MMF, n = 26) was 63.2 ± 28.5 mL/min/1.73 m in the SRL/MMF group and 59.2 ± 27.2 mL/min/1.73 m in the CNI/MMF group and was not statistically significant, but there is a clinically meaningful trend for improved long-term renal function in the SRL/MMF group compared with the CNI/MMF group. The long-term decision for immunosuppression needs to be carefully individualized.

Open-Label, Randomized Study of Transition From Tacrolimus to Sirolimus Immunosuppression in Renal Allograft Recipients.

UNLABELLED: Calcineurin inhibitor-associated nephrotoxicity and other adverse events have prompted efforts to minimize/eliminate calcineurin inhibitor use in kidney transplant recipients. METHODS: This open-label, randomized, multinational study evaluated the effect of planned transition from tacrolimus to sirolimus on kidney function in renal allograft recipients. Patients received tacrolimus-based immunosuppression and then were randomized 3 to 5 months posttransplantation to transition to sirolimus or continue tacrolimus. The primary end point was percentage of patients with 5 mL/min per 1.73 m(2) or greater improvement in estimated glomerular filtration rate from randomization to month 24. RESULTS: The on-therapy population included 195 patients (sirolimus, 86; tacrolimus, 109). No between-group difference was noted in percentage of patients with 5 mL/min per 1.73 m(2) or greater estimated glomerular filtration rate improvement (sirolimus, 34%; tacrolimus, 42%; P = 0.239) at month 24. Sirolimus patients had higher rates of biopsy-confirmed acute rejection (8% vs 2%; P = 0.02), treatment discontinuation attributed to adverse events (21% vs 3%; P < 0.001), and lower rates of squamous cell carcinoma of the skin (0% vs 5%; P = 0.012). CONCLUSIONS: Our findings suggest that renal function improvement at 24 months is similar for patients with early conversion to sirolimus after kidney transplantation versus those remaining on tacrolimus.

Early corticosteroid withdrawal in the real world: a long-term analysis of kidney transplant recipients from the Mycophenolic Acid Observational Renal Transplant Registry.

BACKGROUND: Prospective, long-term data on corticosteroid withdrawal (CSW) versus corticosteroid continuation (CSC) following kidney transplantation are scarce. MATERIAL/METHODS: The Mycophenolic Renal Transplant (MORE) Registry was a prospective, observational study of de novo kidney transplant patients receiving mycophenolic acid (MPA) and standard of care. Adult patients receiving tacrolimus and enteric-coated mycophenolate sodium (EC-MPS) or mycophenolate mofetil (MMF) at time of transplant were analyzed to 4 years according to CSW by month 3 (n=363) or CSC (n=509). RESULTS: In the CSW and CSC groups, 3.3% and 13.0% had undergone retransplantation (p<0.001), 89.9% and 77.0% had panel reactive antibodies <30% (p<0.001), and 72.5% and 87.2% received pretransplant dialysis (p<0.001), respectively. Rabbit antithymocyte induction was used in 62.3% of CSW patients and 58.6% of CSC patients (p=0.015), and alemtuzumab in 23.7% and 4.7%, respectively (p=0.002). At all time points to 3 years post-transplant, significantly fewer CSW patients were maintained on the full recommended dose of MPA versus CSC patients. Biopsy-proven acute rejection occurred in 10.1% and 14.3% of CSW and CSC patients (p=0.12), graft survival was 96.9% versus 93.7% (p=0.030), and patient survival was 95.6% versus 95.0% (p=0.65), respectively. Adverse events were similar except for leukopenia (CSW 60.6%, CSC 29.9%; p<0.001) and neutropenia (CSW 17.4%, CSC 11.4%; p=0.013), with infections in 24.8% and 30.8% of CSW and CSC patients, respectively (p=0.057). CONCLUSIONS: CSW patients were less likely to receive the full dose of MPA than CSC patients, possibly due to induction-related hematological toxicity. Graft survival to 4 years post-transplant was superior in CSW patients.

Review of combination therapy with mTOR inhibitors and tacrolimus minimization after transplantation.

We evaluated the efficacy and safety of immunosuppressive regimens containing a mammalian target of rapamycin (mTOR) inhibitor with tacrolimus (TAC) minimization therapy in solid organ transplant recipients. A PubMed search was conducted using the terms (mTOR OR sirolimus OR everolimus) AND tacrolimus AND renal AND (low OR reduced OR reduction OR minimization) AND transplant*; limited to title/abstract and English-language articles published from January 1, 2003, through January 28, 2013. Twenty-one relevant studies of TAC minimization therapy were identified and evaluated in the context of known concerns associated with immunosuppressive therapy. Review of these studies suggests that immunosuppressive regimens including an mTOR inhibitor and TAC minimization therapy better preserve renal function versus standard-dose TAC, without significant changes in patient survival or graft rejection rates. Among patients treated with an mTOR inhibitor plus TAC minimization therapy in 12 randomized controlled trials (n=856 kidney, n=190 heart, n=108 lung, n=719 liver patients), reported rates of infection (BK, cytomegalovirus, or Epstein-Barr virus) and malignancy were low (0% to 7%). Other adverse events were more commonly reported including dyslipidemia/hyperlipidemia in up to two thirds of patients, new-onset diabetes mellitus in up to 38%, wound complications in up to 22%, and hypertension in up to 17%.

Renal Function and NODM in De Novo Renal Transplant Recipients Treated with Standard and Reduced Levels of Tacrolimus in Combination with EC-MPS.

Information is lacking concerning concomitant administration of enteric-coated mycophenolate sodium with tacrolimus (EC-MPS+Tac) in renal transplant recipients (RTxR). In this 6-month, prospective, open-label, multicenter study, de novo RTxR were randomized (1 : 1) to low-dose (LD) or standard-dose (SD) Tac with basiliximab, EC-MPS 720 mg bid, and steroids. Primary objective was to compare renal function at 6-month posttransplantation. Secondary objectives were to compare the incidences of biopsy-proven acute rejection (BPAR), graft loss and death, and new-onset diabetes mellitus (NODM). 292 patients (LD n = 151, SD n = 141) were included. Mean Tac levels were at the low end of the target range in standard-exposure patients (SD, n = 141) and exceeded target range in low-exposure patients (LD = 151) throughout the study. There was no significant difference in mean glomerular filtration rate (GFR) between treatments (ITT-population: 63.6 versus 61.0 mL/min). Incidence of BPAR was similar (10.6% versus 9.9%). NODM was significantly less frequent in LD Tac (17% versus 31%; P = 0.02); other adverse effects (AEs) were comparable. EC-MPS+Tac (LD/SD) was efficacious and well tolerated with well-preserved renal function. No renal function benefits were demonstrated, possibly related to poor adherence to reduced Tac exposure.

Altered balance between effector T cells and FOXP3+ HELIOS+ regulatory T cells after thymoglobulin induction in kidney transplant recipients.

This study examined the effect of thymoglobulin induction therapy on leukocyte population dynamics in kidney transplant patients. Patients receiving standard immunosuppression were compared with those who received additional thymoglobulin at the time of kidney transplantation. Thymoglobulin induction led to an immediate and significant decrease of all T cells and NK cells, but not B cells or monocytes. CD8(+) T cells recovered to near pretransplant level by 4 weeks post-transplant. CD4(+) T cells remained at less than 30% of pretransplant level for the entire study period of 78 weeks. Both CD4(+) and CD8(+) T cells showed reduced cytokine production after recovery. Deletion of CD4(+) FOXP3(+) HELIOS(+) regulatory T cells (Tregs) was less profound than that of CD4(+) FOXP3(-) cells, thus the relative percentage of Tregs elevated significantly when compared with pretransplant levels in thymoglobulin-treated patients. In contrast, the percentages of Tregs and their expression of FOXP3 in the standard immunosuppression group decreased steadily and by 12 weeks after transplant the average percentage of Tregs was 56% of the pretransplant level. Thus, thymoglobulin-induced deletion of T cells led to significant and long-lasting alterations of the T-cell compartment characterized by a preservation of Tregs and long-lasting reduction in CD4(+) , and potentially pathogenic, T cells.

Alemtuzumab induction in renal transplantation.

BACKGROUND: There are few comparisons of antibody induction therapy allowing early glucocorticoid withdrawal in renal-transplant recipients. The purpose of the present study was to compare induction therapy involving alemtuzumab with the most commonly used induction regimens in patient populations at either high immunologic risk or low immunologic risk. METHODS: In this prospective study, we randomly assigned patients to receive alemtuzumab or conventional induction therapy (basiliximab or rabbit antithymocyte globulin). Patients were stratified according to acute rejection risk, with a high risk defined by a repeat transplant, a peak or current value of panel-reactive antibodies of 20% or more, or black race. The 139 high-risk patients received alemtuzumab (one dose of 30 mg, in 70 patients) or rabbit antithymocyte globulin (a total of 6 mg per kilogram of body weight given over 4 days, in 69 patients). The 335 low-risk patients received alemtuzumab (one dose of 30 mg, in 164 patients) or basiliximab (a total of 40 mg over 4 days, in 171 patients). All patients received tacrolimus and mycophenolate mofetil and underwent a 5-day glucocorticoid taper in a regimen of early steroid withdrawal. The primary end point was biopsy-confirmed acute rejection at 6 months and 12 months. Patients were followed for 3 years for safety and efficacy end points. RESULTS: The rate of biopsy-confirmed acute rejection was significantly lower in the alemtuzumab group than in the conventional-therapy group at both 6 months (3% vs. 15%, P<0.001) and 12 months (5% vs. 17%, P<0.001). At 3 years, the rate of biopsy-confirmed acute rejection in low-risk patients was lower with alemtuzumab than with basiliximab (10% vs. 22%, P=0.003), but among high-risk patients, no significant difference was seen between alemtuzumab and rabbit antithymocyte globulin (18% vs. 15%, P=0.63). Adverse-event rates were similar among all four treatment groups. CONCLUSIONS: By the first year after transplantation, biopsy-confirmed acute rejection was less frequent with alemtuzumab than with conventional therapy. The apparent superiority of alemtuzumab with respect to early biopsy-confirmed acute rejection was restricted to patients at low risk for transplant rejection; among high-risk patients, alemtuzumab and rabbit antithymocyte globulin had similar efficacy. (Funded by Astellas Pharma Global Development; INTAC ClinicalTrials.gov number, NCT00113269.).

A prospective, randomized, multicenter study evaluating early corticosteroid withdrawal with Thymoglobulin in living-donor kidney transplantation.

BACKGROUND: This study compared the safety and efficacy of early corticosteroid withdrawal (ECSWD) with rabbit anti-thymocyte globulin (rATG) induction to chronic corticosteroid therapy (CCST) without antibody induction in primary, living-donor renal transplant recipients. METHODS: Eligible subjects were randomized 2:1 to receive either an ECSWD (n = 103) or CCST (n = 48) regimen, with all subjects receiving tacrolimus and mycophenolate mofetil (MMF). RESULTS: Results are reported as ECSWD vs. CCST. No significant differences were observed in the primary composite endpoint of freedom from biopsy-proven acute rejection (BPAR), graft loss, and death at six months (85.4% vs. 85.4%) or 12 months (84.4% vs. 74.4%). At 12 months, no difference was observed in BPAR (13.9% vs. 19.4%); however, ECSWD was associated with lower total cholesterol (159.7 +/- 39.2 vs. 196.5 +/- 56.7 mg/dL, p = 0.012), and trends toward significance were noted in serum triglycerides (151.9 +/- 92.0 vs. 181.4 +/- 78.8 mg/dL, p = 0.073) and weight gain (+3.6 +/- 9.4 vs. +6.4 +/- 9.3 kg, p = 0.069). No differences were observed in serious adverse events or infectious complications, with the exception of a higher incidence of leukopenia with ECSWD. CONCLUSIONS: rATG with tacrolimus and MMF therapy may allow early elimination of corticosteroids, is associated with trends toward lower lipid levels, less weight gain, and a safety profile comparable to CCST therapy.

Laparoscopic donor nephrectomy vs. open live donor nephrectomy: a quality of life and functional study.

BACKGROUND: Few studies have compared the quality of life (QoL) and functional recuperation of laproscopic donor nephrectomy (LDN) vs. open donor nephrectomy (ODN) donors. This study utilized the SF-36 health survey, single-item health-related quality of life (HRQOL) score, and a functional assessment questionnaire ('Donor Survey'). METHODS: Questionnaires were sent to 100 LDN and 50 ODN donors. These donors were patients whose procedures were performed at The University Hospital and The Christ Hospital in Cincinnati, Ohio. RESULTS: A total of 46 (46%) LDN and 21 (42%) ODN donors returned the completed surveys. The demographics of the two groups were similar. LDN patients reported a more rapid return to 100% normal health (69 vs. 116 d; p = 0.24), part-time work (21.9 vs. 23.2 d; p = 0.09), and necessitated fewer physician office visits post-operative (2.8 vs. 4.4; p = 0.01). ODN patients reported shorter duration of oral pain medication use (13.4 vs. 7.2 d; p = 0.02). However, a greater number of ODN patients reported post-surgical chronic pain (3 vs. 6; p < 0.05) and hernia (0 vs. 2; p = 0.19). The overall QoL for both groups was comparable with the general USA population. CONCLUSIONS: The results of this study support the decisions of many kidney transplant centers to adopt LDN programs as standard of care.

An open-label, pilot study evaluating the safety and efficacy of converting from calcineurin inhibitors to sirolimus in established renal allograft recipients with moderate renal insufficiency.

This pilot study was designed to evaluate the safety and efficacy of converting from a calcineurin inhibitor (CI) to a sirolimus (SRL)-based regimen in established renal transplant recipients with moderate renal insufficiency. Sixty renal transplant recipients on CI-based immuno-suppression with a serum creatinine (SCr) between 159 and 265 microM (1.8 and 3.0 mg/dL) and a glomerular filtration rate (GFR) between 30 and 70 mL/min were enrolled. SRL dosing was dependent upon concomitant immunosuppressive therapy. The mean patient age was 45 yr and the mean time from transplant to study enrollment was 60.8 months (range: 7-198). The median SCr was 168 microM (1.9 mg/dL) and the median GFR was 51 mL/min. Twelve months after conversion the patient and graft survival rates were 96.7% and 95%, respectively. The incidence of biopsy-proven acute rejection was 3.3% (two cases reported, Banff grades IA and IB). The median SCr and median creatinine clearance were 168 microM (1.9 mg/dL) and 53 mL/min, respectively. Hyperlipidemia, diarrhea, peripheral edema, rash, and anemia were the most commonly reported adverse events. Patients with moderate renal insufficiency can be converted from CI to SRL-based therapy and maintain renal function over a 1-yr period.

Incidental diagnosis of gastric cancer in transplant recipients improves patient survival.

BACKGROUND: Gastric cancer in the United States is often diagnosed at advanced stages, resulting in dismal outcomes. In the immunosuppressed transplant recipient population, little is known about the clinical staging and outcome of these compromised patients. METHODS: All US cases reported to the Israel Penn International Transplant Tumor Registry were retrospectively examined for patient demographics, immunosuppressive therapy, tumor characteristics, therapeutic modalities, and mortality. Statistical analysis was performed with Students t test, chi-square analysis, and log-rank analysis by the method of Kaplan-Meier. RESULTS: Gastric cancer was identified in 34 recipients: 28 (82%) were male; 24 (71%) were white. Mean age at diagnosis was 58 +/- 11 years. Twenty-four (71%) patients received kidney transplants, 7 (21%) received heart transplants, and 3 (9%) received liver transplants. Fifty percent received induction therapy, whereas 94% were maintained on calcineurin inhibitors and corticosteroids. Thirty-five percent of patients were diagnosed during evaluation for gastrointestinal symptoms, with the remaining cases discovered incidentally during endoscopy (53%) or during computed tomography (12%) performed for other reasons. Stage varied at presentation as follows: stage I (n = 6), stage II (n = 11), stage III (n = 13), and stage IV (n = 4). Incidental diagnoses resulted in a lower stage malignancy (P <.001) and greater 1-year and 5-year survivals (P <.05) compared with those patients whose were diagnosed after being evaluated of gastrointestinal symptoms. CONCLUSION: In the United States, because gastric cancer in the transplant recipient is frequently identified at an earlier stage (50% were stages I and II) than in the general population, survivals are equivalent despite continued administration of immunosuppression. This early identification may be attributed to more frequent presymptom diagnosis and staging, resulting from incidental detection of these malignancies during posttransplant upper endoscopy or computed tomography. Early detection has resulted in a 29% 5-year survival for the entire transplant recipient group compared with a 5% to 15% 5-year survival in the general population.

Safety, efficacy, and cost analysis of thymoglobulin induction therapy with intermittent dosing based on CD3+ lymphocyte counts in kidney and kidney-pancreas transplant recipients.

BACKGROUND: In view of the superior T-cell depletion and prolonged half-life of thymoglobulin, we initiated a protocol to administer thymoglobulin intermittently based on peripheral blood CD3+ lymphocyte counts. METHODS: In this prospective study, 41 consecutive high-risk cadaver transplant recipients (panel reactive antibody level >30%, repeat transplant recipients, simultaneous pancreas and kidney or pancreas after kidney recipients, prolonged cold-ischemia time, prolonged donor hypotension, non-heart-beating donors) who received thymoglobulin induction therapy were included. The first dose (1.5 mg/kg) of thymoglobulin was administered intraoperatively. CD3+ lymphocyte count in the peripheral blood was determined daily and repeat doses were administered when the CD3+ count was >20 cells/mm3. Calcineurin inhibitors (CI) in low doses were introduced when the allograft function recovered and the serum creatinine level dropped by at least 25% from the pretransplant level. Thymoglobulin treatment was discontinued once therapeutic CI drug levels were achieved. Concomitant immunosuppression consisted of mycophenolate mofetil and prednisone. RESULTS: The mean individual thymoglobulin dose was 104 mg (1.4 mg/kg), and the total cumulative dose per patient was 318 mg (4.2 mg/kg). Patients received an average of three doses and a mean of six CD3 counts were obtained per patient. Introduction of CI was delayed for an average of 6 days posttransplantation. At a mean follow-up of 340 days, two (4.9%) patients died; three (7.3%) renal allografts and two (18.2%) pancreas allografts were lost. Five (12.2%) patients developed a total of six acute rejection episodes. The mean serum creatinine in the 38 patients with a functioning kidney was 1.47 mg/dl, and the mean blood glucose in the 9 pancreas allograft recipients was 89 mg/dl. Cytomegalovirus (CMV) infection occurred in one (2.4%) patient. No posttransplant lymphoproliferative disorders were seen in this patient cohort. The hospital pharmacy charge for a 100-mg dose of thymoglobulin at this center was $2,165, and the laboratory charge for a single CD3 determination was $70. In this study, the average charges per patient for the total dose of thymoglobulin and six CD3 determinations were $7305. In comparison, the charge for daily administration of 104 mg of thymoglobulin (which was the mean dose) for 6 days (mean time to CI therapy initiation) would be $13,510 and for 10 days (mean time to therapeutic CI levels) would be $22,516. This represents a savings of 46% and 68%, respectively. CONCLUSIONS: Intermittent thymoglobulin therapy, based on peripheral blood CD3+ lymphocyte counts, is safe and associated with low acute rejection rate in high-risk kidney and kidney-pancreas transplant recipients. A mean of three doses resulted in adequate suppression of CD3+ lymphocytes permitting delayed introduction of CI in low doses until recovery of renal function occurred. When compared to traditional daily administration, intermittent therapy results in significant cost savings and reduces the total cumulative dose of this potent immunosuppressive agent.