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Background. Short-term outcomes using steroid-free immunosuppression after renal transplantation have been promising. No studies have examined the incidence of and reasons for steroid-avoidance protocol failures. Methods. We present a single-center analysis of steroid-free immunosuppression failures among 129 pediatric renal transplant recipients with mean follow-up of 5 years. We analyzed causes for failure and examined reasons for conversion to steroid-based therapy. We compared actual patient and allograft survival and allograft function in the cohort of patients who required conversion to steroid-based immunosuppression with that of the cohort maintaining steroid-free immunosuppression. Results. A total of 13.2% (17/129) of patients failed steroid-free immunosuppression. Actual patient survival was equivalent in the two cohorts, 96.4% for the cohort maintaining steroid-free immunosuppression and 94.1% for those requiring conversion. Actual allograft survival was lower in patients requiring conversion to a steroid-based protocol, 76.5% vs. 95.5% (P=0.004). Estimated glomerular filtration rates 12-months and 24-months posttransplant were greater in patients maintaining steroid-free immunosuppression (P=0.003). Most patients (52.9%, 9/17) who broke the steroid-free protocol did so because of refractory acute rejection. The second most common reason was recurrence of glomerulonephritis (GN; 35.3%, 6/17). Conclusion. The failure rate of steroid-free immunosuppression among selective pediatric patients undergoing renal transplantation is low. Patients maintaining steroid-free immunosuppression have better allograft survival and function than those requiring conversion to steroid-based therapy. The most common reasons for failure of steroid-free immunosuppression are recalcitrant or recurrent allograft rejection and recurrent GN; the role of conversion to steroid-based immunosuppression after episodes of acute rejection and recurrent GN requires additional analysis.

Background. In contrast to adult kidney recipients, in whom the long-term evolution and clinical determinants of tacrolimus pharmacokinetics are well studied, less is known about the long-term evolution of tacrolimus pharmacokinetics in pediatric kidney transplant recipients. Methods. One-hundred and five pediatric recipients of a kidney allograft, all treated with a corticosteroid-free immunosuppressive protocol, were included. The evolution of tacrolimus doses and predose trough (C 0 ) levels was recorded at 3, 6, 9, 12, 18, and 24 months after transplantation, as well as all C 0 levels obtained in the first 2 years after transplantation. The evolution and clinical determinants of tacrolimus exposure parameters were analyzed. Results. Dose-corrected tacrolimus C 0 levels (C 0 /dose/kg) increased in the first 2 years after kidney transplantation in pediatric recipients (P=0.001). This decrease in dose requirement by time was only significant in children older than 5 years at the time of transplantation (P=0.38,0.03, and 0.001 for age groups 12 years, respectively). In addition, the younger patients had significantly higher dose requirements (dose/kg) compared with older recipients (P=0.0002). Conclusion. Pediatric kidney transplant recipients exhibit maturation of dose-corrected tacrolimus predose trough levels with time after transplantation. This cannot be explained by differences in corticosteroid use, because all patients were treated with a corticosteroid-free protocol. The higher dose requirements for younger recipients and the absence of tacrolimus maturation in the youngest recipients suggest that age-dependent changes in tacrolimus intestinal first-pass effect, metabolism, or distribution play a role. Whether age-specific tacrolimus dosing algorithms will improve outcome needs further study. 1 Department of Pediatrics, Stanford University School of Medicine, Stanford, California. 2 Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium. 3 Department of Surgery, Stanford University School of Medicine, Stanford, California. 4 Department of Pathology, Stanford University School of Medicine, Stanford, California.

Background Combined liver-kidney transplantation is the definitive treatment for end-stage renal disease caused by primary hyperoxaluria type I (PH1). The infantile form is characterized by renal failure early in life, advanced systemic oxalosis, and a formidable mortality rate. Although others have reported on overall results of transplantation for PH1 covering a wide age spectrum, none has specifically addressed the high-risk infantile form of the disease. Methods Six infants with PH1 underwent simultaneous liver-kidney transplantation at our center between May 1994 and August 1998. Diagnosis was made at 5.2+/-3.3 months of age, they were on dialysis for 11.8+/-2.3 months, and they underwent transplantation at 14.8+/-3.0 months of age when they weighed 10.6+/-1.7 kg. Results At a mean follow-up of 6.4+/-1.7 years (range, 3.9-8.1 years), we report 100% patient and kidney allograft survival. There were no cases of acute tubular necrosis. Long-term kidney allograft function remained stable in all patients, with serum creatinine values of less than 1.1 mg/dL and a mean creatinine clearance of 99 mL/min/1.73 m2 at follow-up. Those who received combined hemodialysis and peritoneal dialysis pretransplant had lower posttransplant urinary oxalate values than those receiving peritoneal dialysis alone. There was improvement in growth and psychomotor and mental developmental scores after transplantation. Conclusions Combined liver-kidney transplantation for the infantile presentation of PH1 is associated with excellent outcome when the approach includes early diagnosis and early combined transplantation, aggressive pretransplant dialysis, and avoidance of posttransplant renal dysfunction.

BACKGROUND Corticosteroids have been invariant transplant immunosuppressives with numerous adverse effects. We previously reported 6-month results in 10 patients using extended daclizumab induction to safely eliminate steroid use in pediatric renal transplantation. This expanded pilot series discusses immunosuppression dosing modification to further minimize drug toxicity without sacrificing regimen efficacy. METHODS Fifty-seven pediatric renal transplant recipients were enrolled in the pilot steroid-free protocol. Extended daclizumab induction, tacrolimus, and mycophenolate mofetil (MMF) were intended maintenance drugs. Fourteen patients were equal to or younger than 5 years, and 43 patients were older than 5 years of age at transplantation. There were seven protocol breaks. Study patients underwent serial protocol transplant biopsies (n=246), and serum daclizumab and mycophenolic acid (MPA) trough levels were evaluated. In this efficacy study, controls were 50 historical-matched steroid-based children receiving tacrolimus with 100% 2-year graft survival and without delayed graft function. RESULTS Mean follow-up was 20 (range, 4.5-41) months with 98% overall graft and patient survival. At 1 year of analysis, steroid-free recipients showed significant improvements for clinical acute rejection (8%), graft function, hypertension, and growth, without increased infectious complications. Leukopenia, anemia, and allograft nephrotoxicity were addressed by solely decreasing MMF and tacrolimus dosing and/or by replacing MMF with sirolimus, without increasing acute rejection. Early daclizumab levels of more than 5 microg/mL were observed for the first time in children of all ages. CONCLUSIONS Pediatric renal transplantation is safe without steroids. Daclizumab first-dose doubling and extended use for 6 months replaces steroids effectively without evidence of overimmunosuppression and may be the pivotal cause for the reduced acute rejection seen in this trial. This pilot study provides preliminary data to test this protocol in a prospective, multicenter randomized study.

Background. Pediatric transplant recipients are at increased risk for Epstein Barr virus (EBV)-related B cell lymphomas. In healthy individuals, the expansion of EBV-infected B cells is controlled by CD8 + cytotoxic T cells. However, immunosuppressive therapy may compromise antiviral immunity. We identified and determined the frequency of EBV-specific T cells in the peripheral blood of pediatric transplant recipients. Methods. HLA-B*0801 and HLA-A*0201 tetramers folded with immunodominant EBV peptides were used to detect EBV-specific CD8 + T cells by flow cytometry in peripheral blood mononuclear cells from 24 pediatric liver and kidney transplant recipients. The expression of CD38 and CD45RO on EBV-specific, tetramer-binding cells was also examined in a subset of patients by immunofluorescent staining and flow cytometry. Results. Tetramer-binding CD8 + T cells were identified in 21 of 24 transplant recipients. EBV-specific CD8 + T cells were detected as early as 4 weeks after transplant in EBV seronegative patients receiving an organ from an EBV seropositive donor. The frequencies (expressed as a percentage of the CD8 + T cells) of the tetramer-binding cells were HLA-B8-RAKFKQLL (BZLF1 lytic antigen peptide) tetramer, range=0.96 to 3.94%; HLA-B8-FLRGRAYGL (EBNA3A latent antigen peptide) tetramer, range=0.03 to 0.59%; and HLA-A2-GLCTLVAML (BMLF1 lytic antigen peptide) tetramer, range=0.06 to 0.76%. The majority of tetramer reactive cells displayed an activated/memory phenotype. Conclusions. Pediatric transplant recipients receiving immunosuppression can generate EBV-specific CD8 + T cells. Phenotypic and functional analysis of tetramer + cells may prove useful in defining and monitoring EBV infection in the posttransplant patient.

Background. Rodents and dogs conditioned with total-lymphoid irradiation (TLI), with or without anti-thymocyte globulin (ATG), have been shown to develop mixed chimerism and immune tolerance without graft-versus-host disease (GVHD) after the infusion of major histocompatability complex (MHC)-mismatched donor bone marrow cells given alone or in combination with an organ allograft. Methods. Four human leukocyte antigen (HLA)-mismatched recipients of living donor kidney transplants were conditioned with TLI and ATG posttransplantation and infused with cyropreserved donor granulocyte colony-stimulating factor (G-CSF) mobilized hematopoietic progenitor (CD34 + ) cells (3-5 ×10 6 cells/kg) thereafter. Maintenance prednisone and cyclosporine dosages were tapered, and recipients were monitored for chimerism, GVHD, graft function, T-cell subsets in the blood, and antidonor reactivity in the mixed leukocyte reaction (MLR). Results. Three of the four patients achieved multilineage macrochimerism, with up to 16% of donor-type cells among blood mononuclear cells without evidence of GVHD. Prolonged depletion of CD4 + T cells was observed in all four patients. Rejection episodes were not observed in the three macrochimeric recipients, and immunosuppressive drugs were withdrawn in the first patient by 12 months. Prednisone was withdrawn from a second patient at 9 months, and cyclosporine was tapered thereafter. Conclusions. Multilineage macrochimerism can be achieved without GVHD in HLA-mismatched recipients of combined kidney and hematopoietic progenitor transplants. Conditioning of the host with posttransplant TLI and ATG was nonmyeloablative and was not associated with severe infections. Recipients continue to be studied for the development of immune tolerance.

Background Corticosteroids have been a cornerstone of immunosuppression for four decades despite their adverse side effects. Past attempts at steroid withdrawal in pediatric renal transplantation have had little success. This study tests the hypothesis that a complete steroid-free immunosuppressive protocol avoids steroid dependency for suppression of the immune response with its accompanying risk of acute rejection on steroid withdrawal. Methods An open labeled prospective study of complete steroid avoidance immunosuppressive protocol was undertaken in 10 unsensitized pediatric recipients (ages 5-21 years; mean 14.4 years) of first renal allografts. Steroids were substituted with extended daclizumab use, in combination with tacrolimus and mycophenolate mofetil. Protocol biopsies were performed in the steroid-free group at 0, 1, 3, 6, and 12 months posttransplantation. Clinical outcomes were compared to a steroid-based group of 37 matched historical controls. Results Graft and patient survival was 100% in both groups. Clinical acute rejection was absent in the steroid-free group at a mean follow-up time of 9 months (range 3-13.7 months). Protocol biopsies in the steroid-free group (includes 10 patients at 3 months, 7 at 6 months, and 4 at 12 months) revealed only two instances of mild (Banff 1A) subclinical rejection (reversed by only a nominal increase in immunosuppression) and no chronic rejection. At 6 months the steroid-free group had no hypertension requiring treatment (P=0.003), no hypercholesterolemia (P=0.007), and essentially no body disfigurement (P=0.0001). Serum creatinines, Schwartz GFR, and mean delta height Z scores trended better in the steroid-free group. In the steroid-free group, one patient had cytomegalovirus disease at 1 month and three had easily treated herpes simplex stomatitis, but with no significant increase in bacterial infections or rehospitalizations over the steroid-based group. The steroid-free group was more anemic early posttransplantation (P=0.004), suggesting an early role of steroids in erythrogenesis; erythropoietin use normalized hematocrits by 6 months. Conclusions Complete steroid-free immunosuppression is efficacious and safe in this selected group of children with no early clinical acute rejection episodes. This protocol avoids the morbid side effects of steroids without increasing infection, and may play a future critical role in avoiding noncompliance, although optimizing renal function and growth.

BACKGROUND Infants with end-stage renal disease are at highest risk for early graft loss and mortality of any subgroup undergoing renal transplantation. This study evaluates the influence of donor tissue mass and acute tubular necrosis (ATN) on graft survival and incidence of acute rejection episodes in infant and small child recipients of living donor (LD) and cadaver (CAD) adult-size kidneys (ASKs), pediatric CAD kidneys and combined kidney-liver transplants. Methods. Kidney transplants in infants and small children at a single center and those reported to the UNOS Scientific Renal Transplant Registry were analyzed. At Stanford, multi-variate analysis was conducted on 45 consecutive renal allograft recipients weighing < or = 15 kg, mean weight 11.2 +/- 2.6 kg. The UNOS Registry results in age groups 0-2.5 (n=548) and 2.5-5 years (n=743) were compared with age groups 6-12, 13-18, and the lowest risk adult group of 19-45 years. STANFORD RESULTS. Graft survival was 97.8 +/- 0.0 at 2 years and 84.6 +/- 0.1% at 8 years. The incidence of biopsy proven rejection was 8.8% in the first 3 months and 15.5% over the 8-year follow-up. None of the pediatric CAD kidneys had ATN. Rejection episodes were restricted to the pediatric CAD kidneys alone (3/3), with no kidney rejections in the combined pediatric CAD kidney-liver transplants (0/6; P=0.003). Four ASK transplants had ATN (1 postoperative and 3 late), and all predisposed to subsequent acute rejection episodes (4/4), whereas there were no rejection episodes in ASK transplants without ATN (0/32; P

BACKGROUND Major, almost insurmountable, deterrents exist to the use of the small capacity, defunctionalized, nonneurogenic urinary bladder in renal transplantation, namely, the technical difficulty in performing a satisfactory ureteral implantation with conventional methods and the potential secondary problems with high grade ureteral reflux and obstruction. Alternatives are less than ideal and include transplantation into a bowel-augmented urinary bladder with intermittent self-catheterization, ileal conduit urinary diversion, or avoidance of transplantation and relegating the patient to life-long dialysis. METHODS Eight consecutive patients (ages 13 months to 29 years) with small, defunctionalized urinary bladders underwent a new method of intravesical implantation of the transplant ureter. The mean capacity of these bladders was 18.5+/-13.1 ml (range 6 to 45 ml), with the bladders defunctionalized for a mean 81.6+/-24.3% of the patients' total lifetime. The technique involved placement of the transplant ureter into a shallow, mucosa-denuded, rectangular trough extending from a superiorly placed ureteral hiatus distally to the trigone. We hypothesized that the mucosal margins on the two lateral aspects of the rectangular trough would grow over the anterior surface of the ureter until they met the advancing mucosal edges from the contralateral side to form a natural neosubmucosal tunnel. RESULTS Posttransplantation cystoscopic examination demonstrated bladder mucosal regeneration and growth over the ureter, confirming the spontaneous development of a good length neosubmucosal tunnel. All patients demonstrated no evidence of ureteral reflux or ureteral obstruction, whereas an immediate prior cohort of four consecutive patients with bladder capacities < or =30 ml showed that three of four had ureteral reflux (P=0.02) and four of four developed hydronephrosis (P=0.002). All urinary bladders in the present cohort enlarged to expected normal or nearnormal capacities. Serum creatinines were stable throughout the entire follow-up period, with the exception of one patient who had rejection episodes. Two patients had urinary tract infections posttransplantation, but there were no episodes of acute pyelonephritis. CONCLUSIONS This novel technique for ureteral implantation successfully capitalizes on the regenerative potential of the bladder mucosa, resulting in a physiological, anatomically natural, and very effective neosubmucosal tunnel. It appears to guarantee success against both ureteral reflux and obstruction, no matter how small the urinary bladder, and offers no hindrance to enlarging the bladder to near normal capacity posttransplantation. The implantation technique is simple and safe, and its use should eliminate the reluctance to use these bladders. Moreover, this procedure offers a major incentive for the successful rehabilitation of small, defunctionalized, nonneurogenic bladders after kidney transplantation.

Background. Nationally, results of renal transplantation in infants are inferior to those in older children and adults. Within the infant group, best results are obtained with adult-sized kidneys (ASKs) rather than size-compatible pediatric kidneys. However, transplantation of ASKs into infants has an increased risk of acute tubular necrosis and graft loss from vascular thrombosis and primary nonfunction. The aim of this study was to define and understand the hemodynamic changes induced by ASK transplantation, so that outcomes of transplantation in infants can be improved. Methods. Nine hemodynamically stable and optimally hydrated infants were studied under a controlled sedation with cine phase-contrast magnetic resonance at three time periods: before transplantation, 8-12 days after transplantation, and 4-6 months after transplantation. Cross-sectional images of both the infant aorta and the adult transplant renal artery were obtained and blood flow was quantitated. Renal volumes were also obtained, and expected renal artery blood flow based on early posttransplant volume was calculated. In addition, renal artery blood flow was determined in 10 in situ native adult kidneys prior to donor nephrectomy. Supplemental nasogastric or gastrostomy tube feeding was carried out during the blood flow study period to optimize intravascular volume. Results. Mean infant aortic blood flows were 331±148 ml/min before transplantation, 761±272 ml/ min at 8-12 days after transplantation (P=0.0006 with pretransplant flow), and 665±138 ml/min at 4-6 months after transplantation (P=0.0001 with pretransplant flow). Mean transplanted renal artery flows were 385±158 ml/min at 8-12 days and 296±113 ml/min at 4-6 months after transplantation. Transplanted renal artery flows were less than prenephrectomy in situ donor renal artery blood flow (618±130 ml/min; P=0.02 and P=0.0003) and expected normal renal artery blood flow (666±87 ml/min; P=0.003 and P=0.001) at both 8-12 days and 4-6 months after transplantation. A 26% reduction in renal volume (P=0.003) occurred between the two postoperative time periods, and this paralleled the decrease in posttransplant renal artery flow. One-year graft and patient survival in the nine infants was 100%. The mean serum creatinine levels at 3, 6, and 12 months were 0.43±0.10, 0.48±0.15, and 0.49±0.16 mg/dl. Conclusions. This study is the first to quantitatively document the blood flow changes occurring after ASK transplantation in infants. There was a greater than two-fold increase in aortic blood flow after ASK transplantation, and this increase was sustained for at least 4 months and appeared to be driven by the blood flow demand of the ASK. However, actual posttransplant renal artery blood flow was significantly less than normal renal artery flow. Our study suggests that aggressive intravascular volume maintenance may be necessary to achieve and maintain optimum aortic blood flow, so as not to further compromise posttransplant renal artery flow and to avoid low-flow states that could induce acute tubular necrosis, vascular thrombosis, or primary nonfunction.

The continuing shortage of cadaveric donors necessitates constant reappraisal of donor refusal criteria. From 1/1/95 to 3/20/96, 180 renal transplants were performed at our center. Of these, 26 were kidney/pancreas, 30 pediatric, 37 live donor adult, and 87 adult cadaveric renal transplants (CRT). In the CRT group there were 31 recipients of kidneys that all other local transplant centers declined. We retrospectively compared this group of kidneys that nobody wanted (KNW) to the remaining 56 CRTs (controls) performed at our center during the same period. Of the 31 recipients of KNW, 18 received kidneys declined for reasons of advanced age, defined as > or =60 years (including 8 who also had a history of hypertension, 4 who also had >10% sclerosed glomeruli on biopsy, and 3 also declined based upon donor quality because of acute injury), 8 for donor quality alone (e.g., prolonged hypotension), 3 on the basis of biopsy results alone, and 2 for anatomic abnormalities. Twelve recipients of KNW were "dual transplanted" with both donor kidneys. Of 27 donor variables compared between the KNW and control groups, only donor age (52+/-17 versus 40+/-17 years, respectively) and lowest total 4-hr urine output (327+/-208 versus 507+/-437 cc, respectively) proved to be significantly different (p or =60 years. Similar outcome was achieved by transplanting both kidneys from a KNW donor into a single recipient as compared with single-kidney transplantation from control donors. Careful donor-recipient pairing using kidneys from advanced-age donors for smaller, advanced-age recipients provided good short-term outcome. In conclusion, there was no significant difference in short-term outcome in recipients of KNW versus controls despite differences in donor age and lowest total 4-hr urine output. We believe that, with careful consideration, existing donor selection criteria can be expanded to include certain donors previously considered unusable.

During the two-year period May 1991 to April 1993, 36 kidney transplants were performed in children less than 18 years of age at California Pacific Medical Center using an aggressive quadruple-therapy regimen of immunosuppression. The regimen consisted of induction with an antilymphocyte preparation (MALG in 21, OKT3 in 2, ATGAM in 12, none in 1), initial moderate-dose steroid therapy, early intravenous cyclosporine therapy, and azathioprine. Twenty living-related graft recipients were pretreated with donor-specific transfusions. Long-term cyclosporine was dosed by levels to keep through whole-blood levels (RIA) at 200-300 ng/ml. Twenty-five grafts were from living-related donors, two from living unrelated donors, and nine from cadaveric donors. Eleven (30%) recipients were five years old or under at the time of transplantation. Of these recipients 44% had complex congenital urologic disease and required urologic surgery prior to or at the time of transplantation. Patients have been followed for a mean of one year, with actual patient and graft survivals of 100% and 97%, respectively. Only one graft has been lost, to severe, early recurrent focal segmental glomerulosclerosis. Four of the 36 patients have had one rejection episode each, all reversed completely. Graft function is stable, with serum creatinine proportionate to age--mean serum creatinine in the children under two years old being 0.4 mg/dl, and in the adolescents 1.3 mg/dl, with two adolescent boys having the highest creatinine levels at 1.8 mg/dl. We conclude that an aggressive approach to immunosuppressive therapy in the early posttransplant period with MALG/OKT3/ATGAM induction and rapid achievement of therapeutic cyclosporine levels prevents rejection and results in excellent patient and graft survival with subsequent stable good graft function.

Background. Children with small capacity, defunctionalized urinary bladders present unique operative challenges Thus, traditional practice has included pretransplant bladder augmentation, but this has several adverse consequences Methods. A single-institutional, retrospective review from January 1, 2004 to December 31, 2008 was conducted Twelve pediatric patients, whom had not undergone pretransplant bladder augmentation, did not have neurogeni, bladders or require preoperative catheterization, and a small capacity defunctionalized bladders were included. All were managed by the same surgeon with a previously described ureteral implantation, and a 7F ureteral stent attached to ; large diameter suprapubic catheter was removed in a joint manner without cystoscopy at 2 weeks. Data were collected on patient and graft survival, rejection episodes, urinary tract infection (UTI) requiring antibiotics, grade of vesi coureteral reflux, and posttransplant bladder capacity. Results. One-year patient and graft survival rates were 100%. One patient experienced a clinical rejection episode which was successfully treated. Five patients (41.7%) had a UTI requiring abx treatment within the first postoperative year, but at 1 year, all patients had sterile urinary tracts. After removal of suprapubic catheters and ureteral stents, all patients were able to void spontaneously. Seven patients had no posttransplant ureteral reflux, three had grade 1 reflux, and two had grade 3 reflux (both successfully treated). The average age estimated pretransplant bladder and 1 yea posttransplant bladder capacity was 14.5% and 84% of expected, respectively. Conclusions. In pediatric end-stage renal disease patients with a small capacity defunctionalized bladder, it is reason able to proceed with kidney transplantation without pretransplant bladder augmentation, thus avoiding an unneces sary surgery.

Background. Given the recent withdrawal of daclizumab (DAC), the safety and efficacy of thymoglobulin (TMG) was tested as an alternative induction agent for steroid-free (SF) immunosuppression in pediatric kidney transplant recipients. Methods. Thirteen pediatric renal transplant recipients meeting defined high-risk criteria at transplantation were offered TMG induction and SF immunosuppression with maintenance mycophenolate mofetil and tacrolimus between October 2008 and January 2010. Patients were closely monitored at baseline, 3, 6, 9, and 12 months posttransplant for protocol biopsy and clinical outcomes. Outcomes were compared with 13 consecutively transplanted low-risk patients receiving an established DAC-based SF protocol (Sarwal et al., WA, American Transplant Congress 2003). Results. There was a significant trend for overall decrease in the absolute lymphocyte counts in TMG group (F=5.86, mixed model group effect P=0.02), predominately at 3 months compared with DAC group (0.7±0.6 vs. 2.1±1.0, P=0.0004); however, lymphocyte count was recovered and was back to reference range by 6 months in TMG. There was trend toward more subclinical cytomegalovirus (15% vs. 0%) and BK viremia (17% vs. 0%) in the TMG group, with no differences in the incidence of subclinical Epstein Barr virus viremia (23% vs. 31%) or clinical viral disease. Mean graft function was excellent, and with a minimum follow-up of 6 months, there were no episodes of acute rejection. Conclusion. TMG seems to be a safe alternative induction strategy in patients for SF immunosuppression in pediatric renal transplantation. Extended follow-up and greater enrollment are necessary to fully explore the impact of TMG dosing on viral replication posttransplantation.

Short-term outcomes using steroid-free immunosuppression after renal transplantation have been promising. No studies have examined the incidence of and reasons for steroid-avoidance protocol failures.We present a single-center analysis of steroid-free immunosuppression failures among 129 pediatric renal transplant recipients with mean follow-up of 5 years. We analyzed causes for failure and examined reasons for conversion to steroid-based therapy. We compared actual patient and allograft survival and allograft function in the cohort of patients who required conversion to steroid-based immunosuppression with that of the cohort maintaining steroid-free immunosuppression.A total of 13.2% (17/129) of patients failed steroid-free immunosuppression. Actual patient survival was equivalent in the two cohorts, 96.4% for the cohort maintaining steroid-free immunosuppression and 94.1% for those requiring conversion. Actual allograft survival was lower in patients requiring conversion to a steroid-based protocol, 76.5% vs. 95.5% (P=0.004). Estimated glomerular filtration rates 12-months and 24-months posttransplant were greater in patients maintaining steroid-free immunosuppression (P=0.003). Most patients (52.9%, 9/17) who broke the steroid-free protocol did so because of refractory acute rejection. The second most common reason was recurrence of glomerulonephritis (GN; 35.3%, 6/17).The failure rate of steroid-free immunosuppression among selective pediatric patients undergoing renal transplantation is low. Patients maintaining steroid-free immunosuppression have better allograft survival and function than those requiring conversion to steroid-based therapy. The most common reasons for failure of steroid-free immunosuppression are recalcitrant or recurrent allograft rejection and recurrent GN; the role of conversion to steroid-based immunosuppression after episodes of acute rejection and recurrent GN requires additional analysis.

Background. Inferior vena cava (IVC) thrombosis is generally a contraindication to renal transplantation in small children because of the technical difficulty and limitations in allograft venous outflow drainage that risk graft thrombosis. Methods. The records of six consecutive children (9.9-27.4 kg) with end-stage renal disease and thrombosed IVCs were reviewed. Small deceased donor renal allografts were utilized in all cases where immediate posttransplant venous renal outflow would theoretically not exceed the drainage capacity of the iliac or adjacent pelvic collateral veins. Results. There is 100% patient survival with two patients returning to dialysis at seven and three years posttransplantation. There were no surgical complications or delayed graft function. Postoperatively, progressive renal vein and simultaneous iliac venous enlargement was observed in five of six recipients concomitant with renal allograft enlargement. In these patients, maximum renal volume achieved was between 152 and 275 ml and last recorded Schwartz glomerular filtration rates ranged from 67 to 118 ml/min. The sixth allograft had an early, severe rejection episode that limited renal growth and attainment of good renal function. All patients demonstrated resumption of growth rates commensurate with age but without significant catch-up growth. Conclusion. A small deceased donor kidney can provide freedom from dialysis and better quality of life for small children with IVC thrombosis during an age when dialysis treatment is difficult and the complications of the thrombosed IVC may compromise life. Good renal function was attained in patients without rejection episodes. In those with rejection, our approach allowed for patient growth during allograft function, providing a bridge for a repeat transplant.

Combined liver-kidney transplantation is the definitive treatment for end-stage renal disease caused by primary hyperoxaluria type I (PH1). The infantile form is characterized by renal failure early in life, advanced systemic oxalosis, and a formidable mortality rate. Although others have reported on overall results of transplantation for PH1 covering a wide age spectrum, none has specifically addressed the high-risk infantile form of the disease.Six infants with PH1 underwent simultaneous liver-kidney transplantation at our center between May 1994 and August 1998. Diagnosis was made at 5.2+/-3.3 months of age, they were on dialysis for 11.8+/-2.3 months, and they underwent transplantation at 14.8+/-3.0 months of age when they weighed 10.6+/-1.7 kg.At a mean follow-up of 6.4+/-1.7 years (range, 3.9-8.1 years), we report 100% patient and kidney allograft survival. There were no cases of acute tubular necrosis. Long-term kidney allograft function remained stable in all patients, with serum creatinine values of less than 1.1 mg/dL and a mean creatinine clearance of 99 mL/min/1.73 m2 at follow-up. Those who received combined hemodialysis and peritoneal dialysis pretransplant had lower posttransplant urinary oxalate values than those receiving peritoneal dialysis alone. There was improvement in growth and psychomotor and mental developmental scores after transplantation.Combined liver-kidney transplantation for the infantile presentation of PH1 is associated with excellent outcome when the approach includes early diagnosis and early combined transplantation, aggressive pretransplant dialysis, and avoidance of posttransplant renal dysfunction.

Pediatric transplant recipients are at increased risk for Epstein Barr virus (EBV)-related B cell lymphomas. In healthy individuals, the expansion of EBV-infected B cells is controlled by CD8+ cytotoxic T cells. However, immunosuppressive therapy may compromise antiviral immunity. We identified and determined the frequency of EBV-specific T cells in the peripheral blood of pediatric transplant recipients.HLA-B*0801 and HLA-A*0201 tetramers folded with immunodominant EBV peptides were used to detect EBV-specific CD8+ T cells by flow cytometry in peripheral blood mononuclear cells from 24 pediatric liver and kidney transplant recipients. The expression of CD38 and CD45RO on EBV-specific, tetramer-binding cells was also examined in a subset of patients by immunofluorescent staining and flow cytometry.Tetramer-binding CD8+ T cells were identified in 21 of 24 transplant recipients. EBV-specific CD8+ T cells were detected as early as 4 weeks after transplant in EBV seronegative patients receiving an organ from an EBV seropositive donor. The frequencies (expressed as a percentage of the CD8+ T cells) of the tetramer-binding cells were HLA-B8-RAKFKQLL (BZLF1 lytic antigen peptide) tetramer, range=0.96 to 3.94%; HLA-B8-FLRGRAYGL (EBNA3A latent antigen peptide) tetramer, range=0.03 to 0.59%; and HLA-A2-GLCTLVAML (BMLF1 lytic antigen peptide) tetramer, range=0.06 to 0.76%. The majority of tetramer reactive cells displayed an activated/memory phenotype.Pediatric transplant recipients receiving immunosuppression can generate EBV-specific CD8+ T cells. Phenotypic and functional analysis of tetramer cells may prove useful in defining and monitoring EBV infection in the posttransplant patient.

Rodents and dogs conditioned with total-lymphoid irradiation (TLI), with or without antithymocyte globulin (ATG), have been shown to develop mixed chimerism and immune tolerance without graft-versus-host disease (GVHD) after the infusion of major histocompatability complex (MHC)-mismatched donor bone marrow cells given alone or in combination with an organ allograft.Four human leukocyte antigen (HLA)-mismatched recipients of living donor kidney transplants were conditioned with TLI and ATG posttransplantation and infused with cyropreserved donor granulocyte colony-stimulating factor (G-CSF) "mobilized" hematopoietic progenitor (CD34+) cells (3-5x10(6) cells/kg) thereafter. Maintenance prednisone and cyclosporine dosages were tapered, and recipients were monitored for chimerism, GVHD, graft function, T-cell subsets in the blood, and antidonor reactivity in the mixed leukocyte reaction (MLR).Three of the four patients achieved multilineage macrochimerism, with up to 16% of donor-type cells among blood mononuclear cells without evidence of GVHD. Prolonged depletion of CD4+ T cells was observed in all four patients. Rejection episodes were not observed in the three macrochimeric recipients, and immunosuppressive drugs were withdrawn in the first patient by 12 months. Prednisone was withdrawn from a second patient at 9 months, and cyclosporine was tapered thereafter.Multilineage macrochimerism can be achieved without GVHD in HLA-mismatched recipients of combined kidney and hematopoietic progenitor transplants. Conditioning of the host with posttransplant TLI and ATG was nonmyeloablative and was not associated with severe infections. Recipients continue to be studied for the development of immune tolerance.

Corticosteroids have been a cornerstone of immunosuppression for four decades despite their adverse side effects. Past attempts at steroid withdrawal in pediatric renal transplantation have had little success. This study tests the hypothesis that a complete steroid-free immunosuppressive protocol avoids steroid dependency for suppression of the immune response with its accompanying risk of acute rejection on steroid withdrawal.An open labeled prospective study of complete steroid avoidance immunosuppressive protocol was undertaken in 10 unsensitized pediatric recipients (ages 5-21 years; mean 14.4 years) of first renal allografts. Steroids were substituted with extended daclizumab use, in combination with tacrolimus and mycophenolate mofetil. Protocol biopsies were performed in the steroid-free group at 0, 1, 3, 6, and 12 months posttransplantation. Clinical outcomes were compared to a steroid-based group of 37 matched historical controls.Graft and patient survival was 100% in both groups. Clinical acute rejection was absent in the steroid-free group at a mean follow-up time of 9 months (range 3-13.7 months). Protocol biopsies in the steroid-free group (includes 10 patients at 3 months, 7 at 6 months, and 4 at 12 months) revealed only two instances of mild (Banff 1A) subclinical rejection (reversed by only a nominal increase in immunosuppression) and no chronic rejection. At 6 months the steroid-free group had no hypertension requiring treatment (P=0.003), no hypercholesterolemia (P=0.007), and essentially no body disfigurement (P=0.0001). Serum creatinines, Schwartz GFR, and mean delta height Z scores trended better in the steroid-free group. In the steroid-free group, one patient had cytomegalovirus disease at 1 month and three had easily treated herpes simplex stomatitis, but with no significant increase in bacterial infections or rehospitalizations over the steroid-based group. The steroid-free group was more anemic early posttransplantation (P=0.004), suggesting an early role of steroids in erythrogenesis; erythropoietin use normalized hematocrits by 6 months.Complete steroid-free immunosuppression is efficacious and safe in this selected group of children with no early clinical acute rejection episodes. This protocol avoids the morbid side effects of steroids without increasing infection, and may play a future critical role in avoiding noncompliance, although optimizing renal function and growth.

Infants with end-stage renal disease are at highest risk for early graft loss and mortality of any subgroup undergoing renal transplantation. This study evaluates the influence of donor tissue mass and acute tubular necrosis (ATN) on graft survival and incidence of acute rejection episodes in infant and small child recipients of living donor (LD) and cadaver (CAD) adult-size kidneys (ASKs), pediatric CAD kidneys and combined kidney-liver transplants. Methods. Kidney transplants in infants and small children at a single center and those reported to the UNOS Scientific Renal Transplant Registry were analyzed. At Stanford, multi-variate analysis was conducted on 45 consecutive renal allograft recipients weighingor = 15 kg, mean weight 11.2 +/- 2.6 kg. The UNOS Registry results in age groups 0-2.5 (n=548) and 2.5-5 years (n=743) were compared with age groups 6-12, 13-18, and the lowest risk adult group of 19-45 years. STANFORD RESULTS. Graft survival was 97.8 +/- 0.0 at 2 years and 84.6 +/- 0.1% at 8 years. The incidence of biopsy proven rejection was 8.8% in the first 3 months and 15.5% over the 8-year follow-up. None of the pediatric CAD kidneys had ATN. Rejection episodes were restricted to the pediatric CAD kidneys alone (3/3), with no kidney rejections in the combined pediatric CAD kidney-liver transplants (0/6; P=0.003). Four ASK transplants had ATN (1 postoperative and 3 late), and all predisposed to subsequent acute rejection episodes (4/4), whereas there were no rejection episodes in ASK transplants without ATN (0/32; P0.001). At 3 years posttransplantation, mean serum creatinines were worse in ASKs with ATN (1.5 vs. 0.9 mg/dL; P0.001) and in all grafts with rejection episodes (1.2 vs. 0.9 mg/dL; P0.05). UNOS RESULTS: Among the 5 age groups studied, significantly better (P0.001) long-term graft survival rates were observed in allograft recipients in the 2 youngest age groups with ASKs without ATN: 82 +/- 3% and 81 +/- 3% for LD and 70 +/- 7% and 78 +/- 4% for CAD recipients in the 0-2.5 and 2.5- to 5-year age groups, respectively, at 6 years after transplantation. Moreover, the projected graft half-lives after the 1st year in the LD groups without ATN were at least equivalent to those of HLA-identical sibling recipients ages 19-45 years: 26.3 +/- 5 and 29.3 +/- 6 years for the 0- to 2.5- and 2.5- to 5-year age groups, respectively, and 23.3 +/- 1 years for HLA-identical transplants. The graft half-lives for CAD recipients without ATN ages 0-2.5 and 2.5-5 yearswere equivalent or better than those for LD transplants without ATN in recipients aged 19-45 years: 15.4+/- 7 and 23.7 +/- 8 years versus 15.0 +/- 0.3 years. Mean serum creatinines were superior in the 2 younger recipient age groups compared with older age groups.Increased donor tissue mass of the ASK or kidney-liver transplants, in the absence of ATN, seems to confer a protective effect to infant and small child recipients of these allografts. This is manifested by a prolonged rejection-free state in the single center experience and enhanced graft survival and function in the UNOS analysis, comparable to HLA identical sibling transplants for LD infant and small child recipients and to LD adult results for CAD infant and small child recipients. To optimize this protective effect by whatever mechanism, absolute avoidance of ATN is essential in infant recipients of ASK or combined kidney-liver transplants.

Major, almost insurmountable, deterrents exist to the use of the small capacity, defunctionalized, nonneurogenic urinary bladder in renal transplantation, namely, the technical difficulty in performing a satisfactory ureteral implantation with conventional methods and the potential secondary problems with high grade ureteral reflux and obstruction. Alternatives are less than ideal and include transplantation into a bowel-augmented urinary bladder with intermittent self-catheterization, ileal conduit urinary diversion, or avoidance of transplantation and relegating the patient to life-long dialysis.Eight consecutive patients (ages 13 months to 29 years) with small, defunctionalized urinary bladders underwent a new method of intravesical implantation of the transplant ureter. The mean capacity of these bladders was 18.5+/-13.1 ml (range 6 to 45 ml), with the bladders defunctionalized for a mean 81.6+/-24.3% of the patients' total lifetime. The technique involved placement of the transplant ureter into a shallow, mucosa-denuded, rectangular trough extending from a superiorly placed ureteral hiatus distally to the trigone. We hypothesized that the mucosal margins on the two lateral aspects of the rectangular trough would grow over the anterior surface of the ureter until they met the advancing mucosal edges from the contralateral side to form a natural neosubmucosal tunnel.Posttransplantation cystoscopic examination demonstrated bladder mucosal regeneration and growth over the ureter, confirming the spontaneous development of a good length neosubmucosal tunnel. All patients demonstrated no evidence of ureteral reflux or ureteral obstruction, whereas an immediate prior cohort of four consecutive patients with bladder capacitiesor =30 ml showed that three of four had ureteral reflux (P=0.02) and four of four developed hydronephrosis (P=0.002). All urinary bladders in the present cohort enlarged to expected normal or nearnormal capacities. Serum creatinines were stable throughout the entire follow-up period, with the exception of one patient who had rejection episodes. Two patients had urinary tract infections posttransplantation, but there were no episodes of acute pyelonephritis.This novel technique for ureteral implantation successfully capitalizes on the regenerative potential of the bladder mucosa, resulting in a physiological, anatomically natural, and very effective neosubmucosal tunnel. It appears to guarantee success against both ureteral reflux and obstruction, no matter how small the urinary bladder, and offers no hindrance to enlarging the bladder to near normal capacity posttransplantation. The implantation technique is simple and safe, and its use should eliminate the reluctance to use these bladders. Moreover, this procedure offers a major incentive for the successful rehabilitation of small, defunctionalized, nonneurogenic bladders after kidney transplantation.

Nationally, results of renal transplantation in infants are inferior to those in older children and adults. Within the infant group, best results are obtained with adult-sized kidneys (ASKs) rather than size-compatible pediatric kidneys. However, transplantation of ASKs into infants has an increased risk of acute tubular necrosis and graft loss from vascular thrombosis and primary nonfunction. The aim of this study was to define and understand the hemodynamic changes induced by ASK transplantation, so that outcomes of transplantation in infants can be improved.Nine hemodynamically stable and optimally hydrated infants were studied under a controlled sedation with cine phase-contrast magnetic resonance at three time periods: before transplantation, 8-12 days after transplantation, and 4-6 months after transplantation. Cross-sectional images of both the infant aorta and the adult transplant renal artery were obtained and blood flow was quantitated. Renal volumes were also obtained, and expected renal artery blood flow based on early posttransplant volume was calculated. In addition, renal artery blood flow was determined in 10 in situ native adult kidneys prior to donor nephrectomy. Supplemental nasogastric or gastrostomy tube feeding was carried out during the blood flow study period to optimize intravascular volume.Mean infant aortic blood flows were 331+/-148 ml/min before transplantation, 761+/-272 ml/ min at 8-12 days after transplantation (P=0.0006 with pretransplant flow), and 665+/-138 ml/min at 4-6 months after transplantation (P=0.0001 with pretransplant flow). Mean transplanted renal artery flows were 385+/-158 ml/min at 8-12 days and 296+/-113 ml/min at 4-6 months after transplantation. Transplanted renal artery flows were less than prenephrectomy in situ donor renal artery blood flow (618+/-130 ml/min; P=0.02 and P=0.0003) and expected normal renal artery blood flow (666+/-87 ml/min; P=0.003 and P=0.001) at both 8-12 days and 4-6 months after transplantation. A 26% reduction in renal volume (P=0.003) occurred between the two postoperative time periods, and this paralleled the decrease in posttransplant renal artery flow. One-year graft and patient survival in the nine infants was 100%. The mean serum creatinine levels at 3, 6, and 12 months were 0.43+/-0.10, 0.48+/-0.15, and 0.49+/-0.16 mg/dl.This study is the first to quantitatively document the blood flow changes occurring after ASK transplantation in infants. There was a greater than two-fold increase in aortic blood flow after ASK transplantation, and this increase was sustained for at least 4 months and appeared to be driven by the blood flow demand of the ASK. However, actual posttransplant renal artery blood flow was significantly less than normal renal artery flow. Our study suggests that aggressive intravascular volume maintenance may be necessary to achieve and maintain optimum aortic blood flow, so as not to further compromise posttransplant renal artery flow and to avoid low-flow states that could induce acute tubular necrosis, vascular thrombosis, or primary nonfunction.

The continuing shortage of cadaveric donors necessitates constant reappraisal of donor refusal criteria. From 1/1/95 to 3/20/96, 180 renal transplants were performed at our center. Of these, 26 were kidney/pancreas, 30 pediatric, 37 live donor adult, and 87 adult cadaveric renal transplants (CRT). In the CRT group there were 31 recipients of kidneys that all other local transplant centers declined. We retrospectively compared this group of kidneys that nobody wanted (KNW) to the remaining 56 CRTs (controls) performed at our center during the same period. Of the 31 recipients of KNW, 18 received kidneys declined for reasons of advanced age, defined asor =60 years (including 8 who also had a history of hypertension, 4 who also had10% sclerosed glomeruli on biopsy, and 3 also declined based upon donor quality because of acute injury), 8 for donor quality alone (e.g., prolonged hypotension), 3 on the basis of biopsy results alone, and 2 for anatomic abnormalities. Twelve recipients of KNW were "dual transplanted" with both donor kidneys. Of 27 donor variables compared between the KNW and control groups, only donor age (52+/-17 versus 40+/-17 years, respectively) and lowest total 4-hr urine output (327+/-208 versus 507+/-437 cc, respectively) proved to be significantly different (por =0.05). Of the 25 recipient variables examined, a significant difference was found only in serum creatinine at one month posttransplant (2.6+/-1.8 versus 1.8+/-1.0 mg/dl, respectively), although there was no difference in serum creatinine at three and six months. Actuarial one year patient (100 vs. 95%) and graft (97 vs. 91%) survival, KNW vs. controls respectively, are excellent to date. Further analyses showed no differences in outcome variables between recipients of KNW versus controls when the donor age wasor =60 years. Similar outcome was achieved by transplanting both kidneys from a KNW donor into a single recipient as compared with single-kidney transplantation from control donors. Careful donor-recipient pairing using kidneys from advanced-age donors for smaller, advanced-age recipients provided good short-term outcome. In conclusion, there was no significant difference in short-term outcome in recipients of KNW versus controls despite differences in donor age and lowest total 4-hr urine output. We believe that, with careful consideration, existing donor selection criteria can be expanded to include certain donors previously considered unusable.

Alternatives to traditional organ donor usage has allowed expansion of the organ donor pool to help compensate for the increasing disparity between recipients and donors. The use of bilateral adult renal transplants is a novel idea to salvage older donor kidneys with suboptimal nephron mass that would otherwise be destined for discard. Ten renal transplants were performed utilizing both kidneys from adult cadaver donors with diminished nephron mass determined by calculated glomerular filtration rate or biopsy evidence of significant glomerulosclerosis (>10%). Nine of ten (90%) recipients have satisfactory renal function at a mean follow-up of 7 months. The single case of graft failure was due to documented medical non-compliance. Mean serum creatinine at 6 months was 1.5 mg/dl. Mean measured creatinine clearance was 43.2+/-3.4. These preliminary findings suggest that the use of bilateral renal transplants provide satisfactory early function and allows salvage of older donor kidneys with suboptimal nephron mass.