Cyclocreatine Phosphate: A Novel Bioenergetic/Anti-Inflammatory Drug That Resuscitates Poorly Functioning Hearts and Protects against Development of Heart Failure.

Irreversible myocardial injury causes the exhaustion of cellular adenosine triphosphate (ATP) contributing to heart failure (HF). Cyclocreatine phosphate (CCrP) was shown to preserve myocardial ATP during ischemia and maintain cardiac function in various animal models of ischemia/reperfusion. We tested whether CCrP administered prophylactically/therapeutically prevents HF secondary to ischemic injury in an isoproterenol (ISO) rat model. Thirty-nine rats were allocated into five groups: control/saline, control/CCrP, ISO/saline (85 and 170 mg/kg/day s.c. for 2 consecutive days), and ISO/CCrP (0.8 g/kg/day i.p.) either administrated 24 h or 1 h before ISO administration (prophylactic regimen) or 1 h after the last ISO injection (therapeutic regimen) and then daily for 2 weeks. CCrP protected against ISO-induced CK-MB elevation and ECG/ST changes when administered prophylactically or therapeutically. CCrP administered prophylactically decreased heart weight, hs-TnI, TNF-α, TGF-ß, and caspase-3, as well as increased EF%, eNOS, and connexin-43, and maintained physical activity. Histology indicated a marked decrease in cardiac remodeling (fibrin and collagen deposition) in the ISO/CCrP rats. Similarly, therapeutically administered CCrP showed normal EF% and physical activity, as well as normal serum levels of hs-TnI and BNP. In conclusion, the bioenergetic/anti-inflammatory CCrP is a promising safe drug against myocardial ischemic sequelae, including HF, promoting its clinical application to salvage poorly functioning hearts.

Rapid estimation of whole blood everolimus concentrations using architect sirolimus immunoassay and mathematical equations: comparison with everolimus values determined by liquid chromatography/mass spectrometry.

United States Food and Drug Administration (FDA) in 2010 approved the use of immunosuppressant drug everolimus, which requires therapeutic drug monitoring in whole blood. Taking advantage of structural similarity between sirolimus and everolimus we attempted to rapidly estimate everolimus concentration from apparent sirolimus concentration obtained by using Architect sirolimus immunoassay and mathematical equations (both polynomial and linear). Mathematical equations were derived by curve-fitting methods based on observed apparent sirolimus concentration and true everolimus concentration determined by a liquid chromatography combined with mass spectrometry (LC/MS) method using eight everolimus standards (concentration range 1-30 ng/mL) prepared in whole blood. In order to determine the validity of our approach, we analyzed 12 specimens from patients receiving everolimus using both Architect sirolimus assay and LC/MS method. We observed good correlation between calculated everolimus values and true everolimus values as determined by LC/MS. However, if a patient is switched from sirolimus to everolimus, then sirolimus immunoassay can roughly estimate everolimus concentration plus any residual sirolimus present in whole blood and it is not possible to calculate everolimus concentration.

Pancreas transplantation utilizing thymoglobulin, sirolimus, and cyclosporine.

BACKGROUND: This study aims to determine the impact of thymoglobulin-sirolimus-cyclosporine immunosuppression on the alloimune response of pancreas-kidney transplant recipients. METHODS: Thirty-six pancreas transplant recipients received an induction protocol of thymoglobulin, sirolimus, reduced-dose cyclosporine, and corticosteroids. Ten recipients were also enrolled in a study to measure immune responsiveness. Flow PRA determined HLA antibody, donor-specific flow cytometry crossmatching (FCXM), T-cell subset, and suppressor cell assays were performed during the first posttransplant year. RESULTS: One-year patient, kidney, and pancreas graft survivals were 97%, 94%, and 92%, respectively. There was one death and three graft losses. There were no acute rejection episodes. Recipients in the immune-monitoring study (n=10) displayed>80% depression of CD3, CD4, and CD8 (+) cell counts up to 3 months posttransplant. At transplantation 9/10 patients displayed<10% class I and no class II HLA antibody. By 3 months, 7/10 monitored recipients showed a transient elevation in class I HLA antibodies, including 2 patients who expressed>80% Flow PRA. One patient was pretransplant FCXM positive, whereas by 3 months posttransplant 2/10 patients demonstrated a positive FCXM. There were no clinical consequences of the presence of HLA antibody or the positive FCXMs. By 6 months, 7/9 patients demonstrated immunoregulatory suppressor cells. CONCLUSIONS: The absence of acute rejection events was likely due to inhibition of donor-specific immunity by the immunosuppressive regimen. Seventy percent of patients demonstrated an early, non-donor-directed HLA antibody response that had no adverse effect on graft function and 78% of the monitored patients displayed immunoregulatory cells probably contributing to the successful outcomes.

A comparative study of sirolimus tablet versus oral solution for prophylaxis of acute renal allograft rejection.

This multicenter, open-label study compared the efficacy, safety, and pharmacokinetic parameters of sirolimus (rapamycin) tablet and liquid formulations for prevention of efficacy failure. A total of 477 renal allograft recipients were randomly assigned (1:1) to receive either tablet or solution formulations of sirolimus for 12 months, plus cyclosporine (CsA) and steroids. Pharmacokinetic parameters were analyzed based on trough concentrations and 24-hour pharmacokinetic profiles. There were no significant differences in efficacy failure at 3 or 12 months between tablet and solution groups. Graft survival, patient survival, rate of first biopsy-confirmed acute rejection, time to and severity of acute rejection, and laboratory parameters were not significantly different between groups. Mean steady-state sirolimus and CsA pharmacokinetic parameters on days 30 and 90 were not significantly different by formulation, except for longer sirolimus t(max) after tablet administration. Multivariate logistic regression analysis indicated that low sirolimus C(min,TN) and more human leukocyte antigen mismatches were predictors of acute rejection. The tablet and solution formulations of sirolimus demonstrated therapeutic equivalence.

Low incidence of malignancy among sirolimus/cyclosporine-treated renal transplant recipients.

BACKGROUND: Malignancies, a well-known complication of immunosuppressive therapy in renal transplant recipients, represent an important cause of long-term morbidity and mortality. One approach to addressing this problem is identifying agents that display antineoplastic properties concomitant with their immunosuppressive effects. METHODS: We examined the neoplasms among 1008 renal transplant recipients treated at a single center with sirolimus-cyclosporine +/- prednisone. RESULTS: Clinical and laboratory data, including 62.3+/-26.1 months follow-up (range 27.1-131), revealed 36 tumors in 35 patients (3.6%) presenting at 32.5+/-29.8 months. The 2.4% incidence of skin tumors, the most common neoplasms, was 1.58-fold greater than the general U.S. population. In addition to a 0.4% incidence of posttransplant lymphoproliferative disorders (PTLD) and a 0.2% incidence of renal cell carcinomas, we observed single cases of breast, bladder, endometrial, lung, and brain neoplasms as well as leukemia. The mean trough drug concentrations at the time of diagnosis in affected recipients were within our putative target ranges. In addition to eleven graft losses due to death with a functioning kidney, two were related to chronic rejection following reduced immunosuppression, and one, therapeutic nephrectomy for PTLD. Five of twelve deaths were caused by malignancies; four others among 1008 patients over the entire follow-up were attributed to cardiovascular events; one, to respiratory failure; and two, at distant locations to unknown causes. CONCLUSIONS: The sirolimus-cyclosporine +/- prednisone combination appears likely to be associated with a reduced incidence of tumors.

De novo hemolytic uremic syndrome after kidney transplantation in patients treated with cyclosporine-sirolimus combination.

OBJECTIVE: We sought to examine factors that predisposed 1.5% (10/672) of renal transplant recipients treated with a cyclosporine (CsA)/sirolimus (SRL)/steroid immunosuppressive regimen to develop hemolytic uremic syndrome (HUS). METHODS: Two cohorts of recipients were treated for 1-212 months (mean: 25.0+/-26.4, median: 18.1) with concentration-control CsA regimens based upon either area under the concentration-time curve (AUC; n=412 patients) or trough measurements (C0; n=260 patients). RESULTS: The only demographic feature more common to affected patients was an original glomerulopathic disease in 7 patients, 4 of whom had displayed IgA glomerulonephritis. All 10 affected patients showed a clinical picture of hemolysis with schistocytes, thrombocytopenia (nadir: 35,000+/-19,600 platelets/mm3), as well as elevated serum levels of lactate dehydrogenase (1697+/-1427 IU) and creatinine (Scr; 2.05+/-1.52 mg/dL prediagnosis to 5.13+/-2.43 mg/dL at diagnosis). Seven patients experienced adverse events concomitant with the bout of HUS, namely, acute rejection episodes prior to (n=2) or during (n=3), and 2 patients, infections (Herpes simplex and pancolitis). The mean values of daily steroid dose and the immunosuppressive drug C0 values were above the putative therapeutic targets: namely, CsA C0=294.9+/-153.2 ng/ml versus 150+/-50 ng/ml and SRL C0=20.1+/-14.0 ng/ml versus 10+/-5 ng/ml, respectively. The therapeutic approach included discontinuation of CsA in 9/10, which was transient in 6/9; discontinuation of SRL in all 10, which was transient in 3, OKT3 for concurrent rejection in 3, and plasmapheresis in 5 patients. At 24 weeks postdiagnosis 9/10 patients have well-functioning kidneys with a mean Scr value of 1.6+/-0.59 mg/dL. One patient who underwent transplant nephrectomy subsequently succumbed due to a cluster of refractory thrombocytopenia, Aspergillus infection, and multiorgan failure. CONCLUSION: This initial experience suggests that a time-limited and reversible de novo HUS syndrome may be less frequent and milder among renal transplant recipients treated with SRL-based immunosuppression.

Phase I and phase II safety and efficacy trial of intercellular adhesion molecule-1 antisense oligodeoxynucleotide (ISIS 2302) for the prevention of acute allograft rejection.

BACKGROUND: ISIS 2302, an antisense oligonucleotide that inhibits the expression of human intercellular adhesion molecule (ICAM)-1, was evaluated in combination with a cyclosporine (CsA)-prednisone (Pred) regimen first in a phase I safety and pharmacokinetic study and then in a phase II assessment of prophylaxis of acute rejection episodes in deceased donor renal allografts. METHODS: Both phase I and phase II trials were double-blinded and placebo-controlled, including 17 stable and 39 de novo patients, respectively, in time-lagged, ascending-dose regimens. Each study compared the outcomes of 8 alternate-day intravenous infusions of four ISIS 2302 dose levels (0.05, 0.5, 1.0, or 2.0 mg/kg) versus placebo (3:1 ratio). Patients were followed for 34 days (phase I) or 6 months (phase II). All transplant patients were followed for 3 years. RESULTS: ISIS 2302 produced no evident toxicity; a significant, dose-related increase in activated partial thromboplastin time was accompanied by a trend toward a decreased platelet count. ISIS 2302 did not alter the pharmacokinetic behavior of CsA. At 6 months, the rates of acute rejection episodes were 38.1% in the ISIS 2302 group versus 20.0% in the placebo group. Three-year graft survivals were similar. The mean creatinine values at 1, 2, and 3 years for all ISIS dose groups combined versus placebo over 3 years showed no significant differences. CONCLUSIONS: ISIS 2302 did not evoke side-effects and produced slightly improved renal function. However, in this pilot study, it did not further reduce the rate of acute rejection episodes or increase graft survival compared to a concentration-controlled CsA-Pred regimen.

The selective use of basiliximab versus thymoglobulin in combination with sirolimus for cadaveric renal transplant recipients at low risk versus high risk for delayed graft function.

BACKGROUND: We previously reported that the use of basiliximab together with sirolimus permits a window of recovery from delayed graft function before the introduction of reduced-dose cyclosporine. The present study reviews our experience with the substitution of thymoglobulin for basiliximab as induction therapy for recipients at increased risk for early acute rejection episodes. METHODS: We retrospectively reviewed 145 cadaveric renal allograft recipients who received either basiliximab (n=115) or thymoglobulin (n=30) in combination with sirolimus and prednisone, followed by delayed introduction of reduced doses of cyclosporine. Recipients were stratified as high immune responders if they were African American, a retransplant recipient, or a recipient with a panel-reactive antibody greater than 50%. All other recipients were considered low immune responders. RESULTS: Basiliximab-treated high immune responders exhibited a higher incidence of acute rejection episodes (26%) than either basiliximab-treated low immune responders (10%, P=0.04) or thymoglobulin-treated high immune responders (3%, P=0.01). The median time to initiation of cyclosporine was 12 days; cyclosporine was initiated when the serum creatinine level was 2.5 mg/dL or less. Patients with early return of renal function displayed a lower incidence of acute rejection episodes than those with later recovery of function (P=0.003). High immune responders treated with basiliximab expressed a higher mean serum creatinine level at 3 months (P<0.01), 6 months (P=0.02) and 12 months (P=0.01) than either low immune responders treated with basiliximab or high immune responders treated with thymoglobulin. CONCLUSION: A strategy combining sirolimus with basiliximab for low-immunologic risk recipients and thymoglobulin for high-risk recipients leads to prompt recovery of renal function with a low risk of acute rejection episodes.

Thymoglobulin, sirolimus, and reduced-dose cyclosporine provides excellent rejection prophylaxis for pancreas transplantation.

BACKGROUND: We investigated a novel immunosuppressive protocol including thymoglobulin induction in combination with sirolimus and corticosteroids, followed by introduction of markedly reduced exposures to cyclosporine to prevent pancreas-transplant rejection. METHODS: A 7-day course of thymoglobulin (1.5 mg/kg per day) was begun on postoperative day (POD) 0, together with 15 mg of sirolimus on POD 1, and followed by 5 mg per day, targeting these doses to achieve a trough of 10 to 20 ng/mL. When the serum creatinine was below 2.5 mg/dL, cyclosporine was introduced at 50 mg twice daily with dose adjustment to maintain a trough concentration of 100 to 125 ng/mL. RESULTS: The 18 patients included 14 simultaneous pancreas-kidney and 4 pancreas-after-kidney transplant recipients. Two patients were African-American, three patients had a pretransplant panel reactive antibody greater than 20%, and the human leukocyte antigen (HLA) mismatch was 4.5+/-1 (mean+/-standard deviation). With a mean follow-up of 13.6+/-4.7 months, patient, kidney, and pancreas graft survivals are 100%, 100%, and 94%, respectively. A single pancreas graft was lost to thrombosis. There were no acute rejection episodes and no opportunistic infections. Mean hospital stay was 9+/-3 days. At 3 months posttransplantation, the mean value of serum creatinine was 1.2+/-0.3 mg/dL, fasting glucose was 88+/-15 mg/dL, and sirolimus dose at month 3 was 6.3+/-3 mg per day and at month 12 2.7+/-1 mg per day. The average total daily cyclosporine A dose at month 3 was 208+/-62 mg per day and 133+/-13 mg per day at 1 year. CONCLUSIONS: This immunosuppressive regimen provided excellent prophylaxis against acute rejection with no opportunistic infections. We believe that careful monitoring of sirolimus and cyclosporine levels was critical to success of this protocol.

Location of in-house organ procurement organization staff in level I trauma centers increases conversion of potential donors to actual donors.

BACKGROUND: Of 5810 acute care hospitals in the United States, only 3.9% (231) are Level 1 Trauma Centers (L1TCs). L1TCs have a significant number of potential organ donors (PODs). Placement of Organ Procurement Organization (OPO) staff, In House Coordinators (IHCs), directly within the L1TC to increase the number of families who consent to donate and to provide system management for the trauma center's donation program, was evaluated. METHODS: Four OPO staff, IHCs, were placed in offices inside two L1TCs in Houston, Texas. The IHCs were responsible for development of a donation system, donor surveillance, management, and most importantly, family support. RESULTS: Calendar year 2000 data on conversion of PODs to actual donors were compared between the L1TCs with IHCs (IHC-L1TC) (n=2) and trauma centers without IHCs (n=4) within the OPO's service area. IHC-L1TCs converted 44% more of the PODs to actual donors. Furthermore, the IHC-L1TCs were compared with 85 L1TCs (37% of U.S. L1TCs) without IHCs. IHC-L1TCs had a 28% greater donor consent rate and a 48% greater conversion rate of PODs to actual donors than the national L1TCs. CONCLUSIONS: L1TC status is the America College of Surgeons' highest level of verification for trauma care. To be certified as a L1TC, hospitals must meet strict criteria in both services and patient care. The donation process is often profoundly affected by the burden of demands made on the resources of these institutions and from divergent responsibilities between specialty services within the facility. Dedicated IHCs (OPO staff) are needed to provide early family intervention and to orchestrate the donation process to maximize organ recovery.

Increasing organ recovery from level I trauma centers: the in-house coordinator intervention.

PURPOSE: Daily presence of organ procurement organization staff in level I trauma centers combined with early family contact and interaction can increase donation rates. METHODS: A successful in-house coordinator program already in place at 2 level I trauma centers in Houston was replicated in 6 other level I trauma centers in New York City, Los Angeles, and Seattle. Organ procurement organization staff were placed inside the 8 trauma centers to provide early family support in potential donor situations and day-to-day donation system management. Comparison data were obtained on 83 level I trauma centers nationally. Data from 1999 to 2000 were compared with data from 2001 to 2002. RESULTS: Despite demographic differences, the 8 centers with in-house coordinators had higher consent rates (60% vs 53%) and conversion rates (55% vs 45%) than centers without them. Conversion of potential to actual donors was 22% higher in centers with in-house coordinators than in centers without them. Donation rates were affected by donor age, ethnicity, previous family discussion of donation, the family's initial reaction to the request (favorable, unfavorable, undecided), amount of time family spent with the in-house coordinator, presence of the in-house coordinator during explanation of brain death, whether the request was made at the same time as the brain-death explanation, and, in cases where donation was mentioned to the family before the formal request, who first mentioned donation to the family. CONCLUSIONS: In-house coordinators improve the donation process by interacting with families and staff earlier and more often during potential organ donations and improving donation systems through closer relationships with hospital staff.

Can we use dilution-titration studies to identify clinically relevant HLA antibody specificities?

These data suggest the presence of virtual crossmatch positive, low titer donor specific anti-human leukocyte antigen antibody (DSA) positive sera does not guarantee that real-time crossmatches will be positive. DSA that are present at an undiluted concentration but absent at a 1:8 or 1:16 dilution may not have to be considered unacceptable. This would allow potential recipients wider access to donor organs by reducing the number of listed unacceptable antigens. It also calls into question the use of virtual crossmatching, which may be disenfranchising minorities. Finally, evaluation of antibody concentration by dilution or titer may be clinically more useful than mean fluorescence intensity.

Comparing an early corticosteroid/late calcineurin-free immunosuppression protocol to a sirolimus-, cyclosporine A-, and prednisone-based regimen for pancreas-kidney transplantation.

AIM: A prednisone and calcineurin inhibitor (CNI)-free protocol was compared with a sirolimus, cyclosporine A (CsA), and prednisone-based immunosuppressive regimen for simultaneous pancreas-kidney transplantation (SPK). METHODS: A nonrandomized, single-center, sequential study enrolled low-immune responder SPK transplant recipients. The prednisone/CNI-free (minimization) group of 22 patients received thymoglobulin followed by sirolimus and reduced-dose CsA. Prednisone was withdrawn on day 5, and recipients were converted from CsA to mycophenolic acid at 6 months posttransplantation. The sirolimus/CsA group of 20 consecutive recipients transplanted immediately before this series received thymoglobulin followed by sirolimus, reduced-dose CsA, and prednisone. RESULTS: Donor and recipient demographic variables were equivalent between groups. The 24-month actual patient, kidney, and pancreas survivals for the minimization group were 100%, 100%, and 91% vs. 100%, 95%, and 95% for the sirolimus/CsA group (P=not significant [NS] for patient, kidney, and pancreas survivals). One acute rejection occurred in the minimization group and none in the sirolimus/CsA group. After withdrawal of CsA at 6 months, the minimization group showed an increase in mean estimated glomerular filtration rate, resulting in a significant improvement in renal function compared with the sirolimus/CsA group. At 24 months, the mean glomerular filtration rate of the minimization and sirolimus/CsA groups was 71.6+/-11.2 mL/min/1.73 m and 60.1+/-13.4 mL/min/1.73 m, respectively (P<0.05). Mean fasting blood glucose levels were equivalent between groups at all time points studied. CONCLUSION: Low-immune responder SPK recipients receiving a prednisone/CNI-free protocol achieved similar 2-year graft survivals and improved renal function compared with those treated with a sirolimus, CsA, and prednisone regimen.

Comparison of sirolimus plus tacrolimus versus sirolimus plus cyclosporine in high-risk renal allograft recipients: results from an open-label, randomized trial.

BACKGROUND: The efficacy and safety of sirolimus (SRL) plus tacrolimus (TAC) versus SRL plus cyclosporine (CsA) were compared in high-risk renal allograft recipients. METHODS: Evaluable patients (448) were randomly assigned (1:1) before transplant to receive SRL+TAC or SRL+CsA with corticosteroids. Eligible patients were black and/or repeat transplant recipients, and/or those with high titer of panel-reactive antibodies. RESULTS: Demographics were similar between groups. Both treatments demonstrated equivalent efficacy of the composite endpoint at 12 months with efficacy failure rates of 21.9% vs. 23.2% (SRL+TAC vs. SRL+CsA, respectively, 95% CI -10.0 to 7.1, P=0.737). Biopsy-confirmed acute rejection rate (13.8% vs. 17.4%) and graft survival rate (89.7% vs. 90.2%) were similar (SRL+TAC vs. SRL+CsA, respectively). In evaluable patients (received at least 1 dose of study drug), renal function (calculated Nankivell glomerular filtration rate) was not superior in SRL+TAC versus SRL+CsA (54.5 vs. 52.6 mL/min, P=0.466); however, in on-therapy patients, glomerular filtration rate was significantly higher in SRL+TAC at most time points. At 12 months, there were no significant differences in rates of death, discontinuation because of adverse events, hypercholesterolemia, hyperlipemia, or proteinuria. Diarrhea and herpes simplex infections occurred significantly more often in SRL+TAC patients. Hypertension, cardiomegaly, increased creatinine, overdose (primarily calcineurin inhibitor toxicity), acne, urinary tract disorders, lymphocele, and ovarian cysts occurred significantly more often in SRL+CsA patients. CONCLUSIONS: This study demonstrated that SRL-based therapy was efficacious in high-risk renal allograft recipients in the first year after transplant, providing equivalent efficacy with CsA or TAC, similar graft survival, low biopsy-confirmed acute rejection rates, excellent renal function, and an acceptable safety profile.

Risk factors for impaired wound healing in sirolimus-treated renal transplant recipients.

AIM: As sirolimus has been implicated in impaired wound healing, the aim of this study was to evaluate risk factors for wound complications after renal transplantation in patients treated with this drug de novo. METHODS: This single center retrospective review of wound complications included 194 renal transplant recipients, all of whom received sirolimus immunosuppression in combination with reduced doses of cyclosporine (CsA) and corticosteroids de novo. A wound complication was defined as an infection, incisional hernia, or lymphocele. RESULTS: The overall incidence of wound complications within the first year post-transplantation was 36% (n = 70) including infection in 12% (n = 23), lymphocele formation in 18% (n = 34), and incisional hernia in 18% (n = 34) of patients. Seventeen patients suffered more than one wound complication. A multivariate analysis showed that independent risk factors for the development of wound complications were recipients over the age of 40 yr (odds ratio 2.536, p = 0.011), subjects with body mass index (BMI) >26 (odds ratio 2.498, p = 0.027) and especially BMI >30 (odds ratio 3.738, p = 0.007), the use of thymoglobulin for induction immunosuppression (odds ratio 3.627, p = 0.002), and a cumulative dose of sirolimus of at least 35 mg by post-transplant day 4 (odds ratio 2.694, p = 0.023). African-American (odds ratio 0.139, p < 0.001) or Hispanic recipients (odds ratio 0.337, p = 0.014) were less likely to experience a wound problem than Caucasian recipients. CONCLUSION: A number of potentially modifiable risk factors independently increase the incidence of wound complications among renal transplant recipients receiving sirolimus-based immunosuppression de novo.

The crossmatch may still be the most clinically relevant histocompatibility test performed.

We evaluated patient sera for flow PRA, FCXM, and end-point donor-antigen titer, and we correlated the results with graft survival. You cannot accurately predict a positive or negative FCXM result-not even when the sera have donor-specific antigens-unless you actually perform a crossmatch. Using fluorescence intensity as a surrogate for antibody concentration does not correlate quantitatively with the occurrence of a positive or negative crossmatch. Therefore, it is imperative to give each recipient a chance at being offered a donor organ by performance of a real-time crossmatch and not rely on a virtual evaluation.

Long-term outcomes of single paediatric vs. ideal adult renal allograft transplants in adult recipients.

AIM: To compare the outcomes of single paediatric vs. adult kidneys transplanted into adult recipients. METHODS: A retrospective single-centre review of 38 single cadaver kidney transplants from donors less than five yr of age to wait-listed patients of low body mass index (BMI). Survival of grafts and quality of renal function were compared with 121 similarly low BMI recipients of grafts from donors 18-45 yr of age that were transplanted during the same period. Immunosuppression consisted of sirolimus, minimal-dose cyclosporine and prednisone. The mean age of the paediatric vs. adult donors was 2.8+/-1.0 and 31.1+/-9.2 yr, respectively (p<0.01) and of the recipients, 42.0+/-12.4 and 45.7+/-14.8 yr, respectively (p=NS). The mean BMI of paediatric vs. adult donor kidney recipients was 21.8+/-2.9 and 22.4+/-2.0 kg/m2 (p=NS). Sixty-six per cent of paediatric donor recipients were women compared with 44% of adult donor recipients (p=0.03). RESULTS: Death censored actuarial graft survivals at one and five yr for recipients of paediatric vs. adult donor grafts were 93 and 84% compared with 93 and 85% (p=NS). There were no graft losses because of technical complications in the paediatric kidney donor group. At one and five yr post-transplantation, the mean estimated creatinine clearances of the paediatric donor graft recipients were 52.9+/-19.6 and 54.0+/-17.8 mL/min, respectively, compared with 56.4+/-19.8 and 49.1+/-21.7 mL/min for recipients of adult donor grafts at the same times (p=NS). CONCLUSION: Transplantation of single paediatric donor kidneys into low BMI adult recipients provided equivalent outcomes to those of grafts from adult donors between the ages of 18 and 45 yr.