Longitudinal evaluation of the pharmacokinetics of cyclosporin microemulsion (Neoral) in pediatric renal transplant recipients and assessment of C2 level as a marker for absorption

BACKGROUND: There are important differences in CsA pharmacokinetics between adult and pediatric patients, such that pharmacokinetic data can not necessarily be extrapolated from the adult to the pediatric setting. Research in adult renal transplant patients has shown that adequate cyclosporin exposure (AUC0-4) in the first week post-transplant is important for successful clinical outcome, and that cyclosporin concentration at 2 h post-dose (C2) provides the optimal single-time point marker for AUC0-4. Clinically, dose management based on C2 level results in a low incidence of acute rejection in the adult renal transplant population. The study reported here undertook pharmacokinetic profiling in de novo renal transplant patients over a period of 6 months and retrospectively assessed alternative monitoring strategies based on pharmacokinetic findings and clinical outcomes. METHODS: This open-label, observational, prospective study was carried out at four UK transplant centers over a period of 6 months in pediatric de novo renal transplant recipients receiving the microemulsion formulation of cyclosporin (Neoral) according to local protocol. Twelve-hour pharmacokinetic profiles (8-16 blood samples each) were performed on days 5 and 14 and at weeks 4, 13 and 26 post-transplant. RESULTS: Thirty-two patients were recruited (median age 10 yr, range 3-18 yr). At 6 months, patient survival was 100% and graft survival was 91%. The incidence of clinically determined acute rejection was 41% (13 of 32). Six patients discontinued Neoral before 6 months: three due to graft loss, one due to rejection, one due to renal toxicity and one due to hypertrichosis. At all time points studied, C2 correlated more closely with AUC0-4 and with AUC0-12 than did the pre-dose cyclosporin concentration (C0, or trough). Patients achieving C2 > 1.5 microg/mL by the fifth postoperative day experienced no acute rejection in the first 6 months, compared with a 50% rejection rate among patients with C2 < 1.5 microg/mL (P < 0.05). Binary logistic regression analysis showed that C2 level >1.7 microg/mL was associated with approximately 90% probability of freedom from acute rejection. Analysis of renal function across patients grouped according to cyclosporine exposure (AUC0-4, C2) showed no adverse effects of higher/increased exposure on creatinine or GFR. CONCLUSIONS: C2 level provides a more reliable marker for CsA exposure than C0 in pediatric renal transplant recipients, and is more closely predictive of acute rejection risk. A C2 target of 1.7 microg/mL appears appropriate in this population during the immediate post-transplant period in order to maximize clinical benefit.     

Use of anti-hypertensive medications and post-transplant renal allograft function in children

Post-transplant hypertension is a common occurrence in children. The relative effect of this hypertension on renal allograft function is uncertain. Examining the accumulated data for pediatric renal transplant recipients at our institution from monthly visits for up to three years, we determined whether the use of anti-hypertensive medications (anti-HTN medications) was associated with allograft dysfunction. Monthly clinical data included height, weight, serum creatinine, cyclosporin A (CsA) trough levels, number of acute rejection episodes, and number of anti-HTN medications. Estimated glomerular filtration rate (eGFR) was calculated monthly for each patient using the Schwartz formula. Time post-transplant was grouped into 6-month intervals. One thousand three hundred and sixty-three monthly data sets from 6 months (n = 76 patients) to 3 yr post-transplant (n = 47 patients) were analyzed. Overall mean eGFR was 75 mL/min/1.73 m2 at 6 months and 54 mL/min/1.73 m2 at 3 yr. A lower eGFR was found at all post-transplant time intervals for patients receiving anti-HTN medications compared with those who were not (p < 0.01). This lower eGFR was found at some but not all times post-transplant when patients were grouped by donor type or history of acute rejection episodes and analyzed separately. Mean CsA trough levels were higher at all post-transplant time intervals in patients receiving anti-HTN medications (p < 0.05). While a causal relationship between post-transplant hypertension and graft dysfunction cannot be established from this study, we conclude that the need for anti-HTN medications is associated with worse allograft function.     

Tacrolimus withdrawal and conversion to sirolimus at three months post-pediatric renal transplantation

Nephrotoxicity caused by CNI may adversely affect long-term graft outcomes. For this reason, we have adopted a protocol for withdrawing TAC and converting to SRL at three months post-renal transplantation. All recipients received basiliximab induction and TAC, MMF, and prednisone. Patients without acute rejection by surveillance biopsy at three months were eligible for SRL conversion. Results: From August 2004 to September 2006, TAC was withdrawn and replaced by SRL in 30 first transplant recipients, who were followed for six to 39 months (mean 18 +/- 8). Renal function did not improve significantly after SRL conversion (p = 0.25). Acute rejection occurred in three patients (10%) at five to 12 months after CNI withdrawal. There were no occurrences of wound healing problems, pneumonitis or post-transplant lymphoproliferative disease. Thrombocytopenia and diabetes each occurred in one patient. Four patients received treatment for hypercholesterolemia. CNI withdrawal and replacement with SRL was an effective regimen in children who did not display biopsy evidence of acute rejection at three months post-transplant. While these early results are promising, the ultimate benefit of this protocol to enhance the long-term renal function and graft survival requires ongoing follow-up.     

Estimated one-yr glomerular filtration rate is an excellent predictor of long-term graft survival in pediatric first kidney transplants

Acute rejection episodes following pediatric renal transplantation have been progressively reduced by recent immunosuppressive regimens. Nevertheless, grafts continue to fail over time and surrogate parameters for long-term RGS are lacking. We investigated post-transplant renal function within the first yr as an independent predictor of long-term RGS in 104 pediatric first kidney transplant recipients (mean age 11.1 +/- 3.9 yr; mean follow-up 8.3 +/- 3.5 yr) transplanted between January 1989 and December 2000. GFR was assessed by use of the Schwartz formula at 30 days and six and 12 months after transplantation, respectively. Patients were further stratified at all times according to GFR: (i) GFR<45 mL/min/1.73 m(2), (ii) GFR 45-80 mL/min/1.73 m(2), and (iii) GFR>80 mL/min/1.73 m(2). Cox regression analysis including factors potentially influencing long-term RGS, e.g., age, gender, transplant yr, HLA-mismatch, underlying renal disease, clinical acute rejection, absolute GFR as well as the change in GFR within the first yr was performed. Graft failure occurred in 24 out of 104 patients (23%) 6.2 yr (mean) after transplantation corresponding to a cumulative five-yr graft survival of 87.5%. GFRs at 30 days and six and 12 months were significantly associated with long-term RGS in the univariate cox regression analysis (GFR at 30 days, p = 0.045; GFR at six months, p = 0.004; GFR at 12 months, p < 0.001). None of the other variables were significant parameters of correlation. Multivariate cox analysis revealed a GFR below 45 mL/min/1.73 m(2) at 12 months after transplantation as the only independent predictor of long-term RGS (hazard ratio 55.9, 95% CI 5.29-591, p = 0.001). GFR at 12 months post-transplant is an excellent surrogate parameter for long-term RGS in children. This parameter might be useful as a primary end-point in short-term pediatric clinical trials.     

Dense B cell infiltrates in paediatric renal transplant biopsies are predictive of allograft loss

Abstract:  Recent studies have suggested adverse outcome for renal allograft rejection associated with dense CD20 lymphocytic infiltrates in transplant renal biopsies. We investigated further the relationship between renal allograft survival and CD20+ lymphocytic infiltrates in renal transplant biopsies from children with graft dysfunction. Fifty consecutive unselected renal transplant biopsies were performed for investigation of acute, chronic or acute on chronic renal allograft dysfunction in 48 children aged 1–17 (median 13.1) years, at 0–155 (median 22) months post-transplantation with median follow up of 24 months post-biopsy. Seventeen (35%) graft losses occurred at 1–163 (median 49) months post-transplantation. There was increased graft loss in those with dense (>300 cells/hpf) CD20+ lymphocytic infiltrates present on biopsy (p = 0.043). Dense B-cell infiltrates were also associated with increased glucocorticoid requirement in those with acute cellular rejection (p = 0.0015). There were no significant differences in age, sex, HLA-mismatch, type of transplantation, EBV or CMV serology or baseline immunosuppressive regimens between those with or without dense CD20+ infiltrates. Dense CD20+ lymphocytic infiltrates in renal transplant biopsies are associated with adverse clinical outcome, including increased graft loss. This observation raises the possibility of future studies examining the efficacy of B cell depletion therapy in this clinical context.     

Rapid discontinuation of corticosteroids in pediatric renal transplantation

Abstract:  Corticosteroid immunosuppression has permitted the development of successful allotransplantation; however, corticosteroids are associated significant post-transplant complications. To circumvent these problems, we implemented a protocol of rapid discontinuation of corticosteroids in 19 consecutive pediatric primary kidney transplant recipients. Mean age at time of transplant was 13.4 (±4.5) yr, 52.6% were male, 63.2% underwent living donor transplantation. All patients were administered Thymoglobulin^® [anti-thymocyte globulin (rabbit)] as induction immunosuppression with a rapid tapering dose of corticosteroids (total of five daily doses), and maintained on mycophenolate mofetil and tacrolimus. Two patients had immediate recurrence of primary disease (FSGS), requiring further corticosteroid therapy. Otherwise, remaining 17 patients were maintained off corticosteroids, with excellent graft function; mean baseline eGFR of 112 mL/min/1.73 m² (±19) at 28 months (±14) post-transplantation. There was 100% patient and rejection-free graft survival at 27 months (range 5–58 months) post-transplantation; 47% underwent renal transplant biopsy secondary to acute rise in serum creatinine with or without worsening hypertension. All biopsies had no evidence of acute rejection; 62.5% had findings consistent with tacrolimus toxicity. Renal transplantation utilizing a rapid discontinuation of corticosteroid protocol in pediatric patients appears to be safe and effective, without increasing the risk of acute rejection or graft loss.     

Determinants of graft survival in pediatric and adolescent live donor kidney transplant recipients: a single center experience

To study the independent determinants of graft survival among pediatric and adolescent live donor kidney transplant recipients. Between March 1976 and March 2004, 1600 live donor kidney transplants were carried out in our center. Of them 284 were 20 yr old or younger (mean age 13.1 yr, ranging from 5 to 20 yr). Evaluation of the possible variables that may affect graft survival were carried out using univariate and multivariate analyses. Studied factors included age, gender, relation between donor and recipient, original kidney disease, ABO blood group, pretransplant blood transfusion, human leukocyte antigen (HLA) matching, pretransplant dialysis, height standard deviation score (SDS), pretransplant hypertension, cold ischemia time, number of renal arteries, ureteral anastomosis, time to diuresis, time of transplantation, occurrence of acute tubular necrosis (ATN), primary and secondary immunosuppression, total dose of steroids in the first 3 months, development of acute rejection and post-transplant hypertension. Using univariate analysis, the significant predictors for graft survival were HLA matching, type of primary urinary recontinuity, time to diuresis, ATN, acute rejection and post-transplant hypertension. The multivariate analysis restricted the significance to acute rejection and post-transplant hypertension. The independent determinants of graft survival in live-donor pediatric and adolescent renal transplant recipients are acute rejection and post-transplant hypertension.     

Varicella in the first year after renal transplantation: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS)

Prior reports document that children with renal transplants are at risk of severe varicella, with a 5-25% mortality rate. We have examined the current incidence and mortality of varicella requiring hospitalization in pediatric patients in the first year after kidney transplantation through a multi-center retrospective cohort study. Data from the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) for 2320 pediatric patients who received renal transplants between 1987 and 1993 and were followed until 1995 were examined. Varicella requiring hospitalization in the first post-transplant year occurred in 44 children. Characteristics of the patients who developed varicella were compared to the rest of the NAPRTCS cohort using chi-square analysis. Kaplan-Meier estimates of graft survival were used to compare graft survival in varicella patients and other NAPRTCS patients. Varicella patients tended to be younger (p=0.09) and more often male (p=0.07, chi-square) than other NAPRTCS patients. None of the 44 patients with varicella in their first post-transplant year died from this infection. The number of episodes of acute rejection per transplant and the time to first rejection was not different in patients with varicella compared to the other NAPRTCS patients. Five-year graft survival was not different for varicella cases when compared to other NAPRTCS patients with grafts surviving at least 6 months post-transplant. We conclude that the mortality rate of patients hospitalized with varicella in the first post-transplant year and the risk of subsequent graft dysfunction may be significantly lower than previously described. However, varicella remains a significant cause of potentially avoidable hospitalization in the first post-transplant year. Further study of the safety and efficacy of varicella vaccination in children with renal insufficiency and those post-transplant is warranted.     

The impact of recombinant human growth hormone treatment during chronic renal insufficiency on renal transplant recipients

OBJECTIVE: To evaluate post-transplant outcomes for patients treated with human growth hormone (rhGH) during the course of chronic renal insufficiency (CRI). STUDY DESIGN: Patients (the "cohort" group) were identified who had been enrolled in 2 controlled studies to determine the efficacy and safety of rhGH in growth-retarded children with CRI and were subsequently enrolled in the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) and received a renal transplant. Patient survival, graft survival, time to first acute rejection episode, causes of graft failure, adverse events, and serial growth data from transplant to 60 months were evaluated. Data from the cohort group of 102 patients were compared with data from 4913 primary transplants from "other NAPRTCS" recipients (the "control" group). RESULTS: No significant difference was seen in patient survival or graft survival, incidence of acute rejection episode, or time to first rejection episode between the cohort and control groups. No specific adverse events were attributable to previous rhGH treatment. Only 2 patients had post-transplant lymphoproliferative disease in the cohort group, with no other malignancies reported. The mean height z scores in the cohort group at baseline and 60 months after transplant were -1.92 and -1.90, and the Deltaz score at 60 months was +0.20 compared with the control group (-1.88 and -2.10). CONCLUSIONS: Treatment of growth-retarded patients with CRI does not adversely affect graft function after renal transplantation. "Catch-down" growth does not occur after renal transplantation.     

Tacrolimus vs. cyclosporine A as primary immunosuppression in pediatric renal transplantation: a NAPRTCS study

Using the North American Renal Transplant Cooperative Study (NAPRTCS) database, we performed a retrospective cohort study of 986 pediatric renal transplant recipients (index transplant 1997-2000) who were treated either with Cyclosporine A (CSA), Mycophenolate Mofetil (MMF) and steroids (n = 766) or tacrolimus (TAC), MMF and steroids (n = 220) to examine potential difference in clinical outcomes between these two groups. In the first year post-transplant, time to first rejection (29.1% vs. 29%, p = 0.840), risk for rejection [Adjusted Relative Risk (aRR) 1.01, 95% Confidence Interval (CI) 0.77, 1.323], graft survival (96.8% vs. 97.9%, p = 0.607) and risk for graft failure (aRR 0.988, 95% CI 0.64, 1.928) were not significantly different in TAC and CSA-treated patients. At 2 yr post-transplant, there was also no difference in risk for rejection (aRR 0.918, 95% CI 0.669, 1.259), graft survival (91.4% vs. 95.1%, p = 0.152) and risk for graft failure (aRR 0.702, 95% CI 0.461, 1.762) in the subset of 391 CSA-treated patients and 77 TAC-treated patients on whom 2 yr follow data were available in the database. TAC-treated patients were significantly less likely to require antihypertensive medication at 1 yr [aRR 0.74 (95% CI 0.454, 0.637)] and 2 yr post-transplant [aRR 0.67 (95% CI 0.56, 0.793)]. At 1 yr post-transplant, TAC-treated patients enjoyed a higher mean GFR as estimated by the Schwartz formula [89.1 mL/min/1.73 m(2) (SE 2.64) vs. 78.6 mL/min/1.73 m(2) (SE 1.07), p = 0.0003]. In addition, in the subset of patients with 2 yr of follow-up, TAC patients had a higher mean GFR at both 1 yr [98.6 mL/min/1.73 m(2) (SE 3.83) vs. 78.0 mL/min/1.73 m(2) (SE 1.44), p = 0.0003] and 2 yr post-transplant [96.7 mL/min/1.73 m(2) (SE 3.33) vs. 73.2 mL/min/1.73 m(2) (SE 1.48), p < 0.0001]. In summary, TAC and CSA, in combination with MMF and steroids, produce similar rejection rates and graft survival in pediatric renal transplant recipients. However, TAC is associated with improved graft function at 1 and 2 yr post-transplant. Further analysis as more patient data are obtained will be necessary to determine if this difference in graft function persists and translates into improved graft survival.     

Neoral dose monitoring using 2-hour cyclosporine post-dose levels in stable children with liver transplants: improvement in renal function

In adult liver transplant recipiens, 2-h post-Neoral (C2) dose monitoring is associated with a lower incidence and severity of acute cellular rejection and improved renal function than C0 (trough level) monitoring. This study examined whether switching from C0 to C2 monitoring during maintenance also improves renal function in pediatric liver transplant recipients. Three boys aged 11-16 yr with stable graft function at 6-50 months after liver transplantation were switched from C0 to C2 monitoring. Median C0 was 148 ng/mL (range 100-186), and median C2 was 767 ng/mL (range 702-1187). At the time of conversion, C2 levels exceeded the recommended targets (0-6 months 1000 ng/mL; > 12 months 600 ng/mL in all children). Within 3 months, serum creatinine level decreased by a median of 42.8%, and glomerular filtration rate increased by a median of 86%. No clinical or biochemical evidence of rejection was noted during the 6-month follow-up. Our results suggest that in pediatric liver transplant recipients, C2 monitoring is associated with greater improvement in renal function than C0 monitoring; switching to C2 monitoring can correct cyclosporine-associated toxicity.     

Short-term pediatric renal transplant survival: Blood pressure and allograft function

Hypertension is prevalent after renal transplantation (Tx) and associated with graft failure in children and adults. However, the effect of blood pressure (BP) on short-term renal allograft function is uncertain. We assessed the associations among BP pretransplant, and 3 months and 1 yr post-transplant, and 1-yr post-transplant measured glomerular filtration rate (mGFR) in 61 children with a functioning graft. The GFR was determined using a single intravenous (i.v.) injection of Optiray 350(R). Data were collected between January 1994 and January 2000. The mean mGFR 1 yr after renal transplant was 63.6 +/- 19.9 mL/min/1.73 m2 in 26 live donor recipients and 50.8 +/- 23.3 mL/min/1.73 m2 in 35 cadaveric donors (p = 0.029). Correlation analysis showed significant negative associations of 1-yr mGFR with systolic blood pressure (SBP) and diastolic blood pressure (DBP) 3 months after renal Tx (r = - 0.58, p < 0.0001 and r = - 0.50, p < 0.0001, respectively), and with SBP (r = - 0.37, p = 0.003) and DBP (r = - 0.32, p = 0.01) 1 yr after renal Tx. Multi-variate regression analysis showed that the SBP 3 months after Tx (p < 0.001), number of acute rejections (p = 0.002), donor age (p = 0.02), and cold ischemia time (p = 0.03) were independent predictors for the 1-yr mGFR. These results indicate that a higher SBP in the first few months post-renal Tx is associated with decreased renal allograft function in children 1 yr post-Tx.     

Endomyocardial biopsy in pediatric heart transplant recipients: A useful exercise? (Analysis of 1169 biopsies)

The objective of this study was to define the diagnostic yield for endomyocardial biopsy (EMB) procedures performed for various indications in a large pediatric heart transplant population. Endomyocardial biopsy procedure has been employed as the 'gold standard' for rejection surveillance. Previous studies have questioned the value of surveillance EMB beyond the early post-transplant period. We retrospectively reviewed data on 82 pediatric heart transplant recipients with serial EMB. A total of 1,169 EMB were performed during a follow-up period of 2-149 months (median 41 months). EMB were classified by age at transplantation, time from transplant, immunosuppressive regimen used [tacrolimus vs. cyclosporin A (CsA)] and indication, i.e. surveillance, follow-up after rejection or lowering of immunosuppression, non-specific clinical symptoms and graft dysfunction. During the first year after heart transplantation, surveillance EMB demonstrated significant rejection [International Society for Heart and Lung Transplantation (ISHLT) grade > or = 3A] in 18% of biopsies with the yield being 14-43% for all other indications. Surveillance EMB 1-5 yr post-transplantation were found to have a lower diagnostic yield in infants (4%, vs. 13% in children) and in patients with favorable first-year rejection history (9% vs. 17% in 'frequent rejectors'). Tacrolimus-based immunosuppression was associated with significantly less rejection, but only in the first year post-transplantation (14% in tacrolimus vs. 24% in CsA surveillance EMB, p = 0.035). Surveillance EMB remains an important diagnostic tool for rejection surveillance during the first 5 years after pediatric heart transplantation. Endomyocardial biopsy is particularly warranted after reduction of immunosuppression and for monitoring for ongoing rejection after treatment of acute rejection episodes.     

Variability in tacrolimus blood levels increases the risk of late rejection and graft loss after solid organ transplantation in older children

Late graft rejection impairs the long-term function of organ transplants in children. Previous studies suggest patients with wide variation in tacrolimus levels may have higher rates of late kidney and liver graft rejection. The reproducibility of this finding and impact on graft and recipient survival have not been reported. We investigated factors associated with late rejection > 6 months post-transplant in 144 heart, kidney, liver, and lung transplant recipients (ages 8-18, ≥ 1-yr survivors, receiving tacrolimus-based immunosuppression), comparing late rejectors (n = 61, 42%) to non-rejectors (no rejection > 6 months); groups had similar mean tacrolimus concentrations ≤ 6 months post-transplant. For all organ types, increased standard deviation in intrapatient tacrolimus blood levels was an independent risk factor for late rejection (OR 1.6 [CI 1.1-2.1]; p = 0.02). Each 1-point increase in s.d. > 2 of tacrolimus level > 6 months post-transplant associated with 1.58 increase in hazard of graft loss (p = 0.003). Graft survival (conditional on one-yr survival) was significantly better for those with s.d. < 2 at > 6 months post-transplant: 98% at three and five yr, versus 88%, 70%, at three and five yr, in patients with s.d. > 2 (p = 0.003). In conclusion, high s.d. in serial tacrolimus concentrations associated with increased risk of late rejection and graft loss in pediatric organ transplant recipients, providing opportunities for screening and interventions.     

Sirolimus in pediatric gastrointestinal transplantation: the use of sirolimus for pediatric transplant patients with tacrolimus-related cardiomyopathy

Hypertrophic obstructive cardiomyopathy (HOCM) associated with the use of tacrolimus is a rare complication of liver and intestinal transplantation seen almost exclusively among pediatric patients. Reduction of tacrolimus dosage or conversion to cyclosporin A (CsA) has been used as an effective treatment in reviewed cases. We present three pediatric transplant recipients who developed hypertrophic obstructive cardiomyopathy while under tacrolimus immunosuppression and were treated with conversion to sirolimus (Rapamycin). The patients (ages 6 yr, 12 yr and 11 months) were transplant recipients (liver, n = 2; liver and intestine, n = 1) who developed significant cardiomyopathy 15 and 96 months post-transplant. One patient died of post-transplant lymphoproliferative disorder 21 days after starting sirolimus. One patient had received two liver transplants and had been on CsA for 12 yr before conversion to tacrolimus at 60 months post-transplant for acute and chronic rejection. The surviving patients were receiving mycophenolate mofetil, tacrolimus and steroids at the time of diagnosis. Dose reduction of tacrolimus and treatment with beta blockers failed to alleviate the hemodynamic changes. The patients were converted to sirolimus 1.6, 37 and 148 months post-transplant and maintained a whole-blood trough level of 15-20 ng/mL 21 days after starting sirolimus. Repeat echocardiograms in the surviving patients showed improvement in cardiomyopathy. One patient had one rejection episode (intestinal biopsy, mild acute cellular rejection) after starting sirolimus that responded to a transient increase in steroids. The early demise of the third patient after sirolimus conversion prevented an adequate assessment of cardiomyopathy. Conversion to sirolimus was associated with a reduction in the cardiomyopathy of the two surviving patients while still providing effective immunosuppression. To our knowledge this observation has not been previously reported.     

Polyomavirus (BK) in pediatric renal transplants: evaluation of viremic patients with and without BK associated nephritis

Polyoma BK virus (BKV) is emerging as a significant complication in renal transplantation, which may lead to renal dysfunction and graft loss caused by BK nephritis (BKN). We report the management and outcome of 20 children who developed BK viremia. Serum polymerase chain reaction (PCR) for BKV DNA was measured monthly for the first year in transplant recipients and every six months thereafter, or for unexplained creatinine elevation. With seroconversion to +PCR, patients were managed with reduction of immunosuppression. Renal biopsy was performed if PCR or creatinine did not improve. From June 2003 to January 2006, 20 children seroconverted for BKV at 23 to 1410 days post-transplant (mean 467 days). Sixteen underwent renal biopsy. Eight displayed BKN, three acute rejection and five were normal. Patients with BKN displayed higher PCR and serum creatinine and presented later than children with viremia without BKN. There were no differences between the two groups for age, gender, donor source or immunosuppression. Seven children with BKN received treatment with cidofovir. Thirteen patients (65%) remained PCR+ after reduction of immunosuppression or treatment with cidofovir. Renal function was stable in 16 children (80%) at 13 +/- 6 months after seroconversion. Four patients with BKN demonstrated progressive loss of renal function. BKV infection in children can occur as an early complication or may develop years after transplantation. Patients with BKN presented later and displayed higher viral loads and serum creatinine than viremic patients without BKN. Children with BKN remained PCR+ despite reduction of immunosuppression or treatment with cidofovir and were at greater risk for loss of renal function.     

Mycophenolate mofetil suspension in pediatric renal transplantation: three-year data from the tricontinental trial

Mycophenolate mofetil (MMF) is widely used to prevent acute rejection in adult solid organ transplant recipients, but data in children and adolescents are scarce. This prospective, multicenter, open-labeled, single-arm study investigated the efficacy and safety of an MMF-based immunosuppressive regimen in 100 pediatric renal transplant recipients over a 3-yr period of time. Three age groups were formed (<6 yr, n = 33; 6 to <12 yr, n = 34; 12-18 yr, n = 33). Basic immunosuppression consisted of MMF (600 mg/m(2) b.i.d), cyclosporin A microemulsion and corticosteroids. Seventy-three percent of patients were given anti-lymphocyte antibody induction therapy, of whom 74% received anti-thymocyte globulin. Patient and graft survival 3 yr after transplantation amounted to 98 and 95%, respectively. Twenty-five percent of all patients suffered a biopsy-proven acute rejection episode in the first 6 month post-transplant. Children undergoing induction therapy exhibited a numerically lower rejection rate (21 vs. 37%, p = 0.11). Three years after transplantation, the acute rejection rate added up to 30% (26% with induction therapy vs. 41% without induction therapy, p = 0.21). The number of patients with acute rejection was lowest in the youngest age group (18%), in comparison with 39% in the 6 to <12 yr and 33% in the 12-18 yr age group, respectively. For the entire patient population, the rate of patients who withdrew prematurely because of adverse events was low (12%). The present study shows that MMF therapy in pediatric renal transplant recipients leads to an excellent patient and graft survival 3 yr post-transplant with an acceptable safety profile.     

Fibroblast growth factor‐23 and chronic allograft injury in pediatric renal transplant recipients: a Midwest Pediatric Nephrology Consortium study

The chronic kidney disease‐mineral bone disorder (CKD‐MBD) produces fibroblast growth factor‐23 (FGF‐23) and related circulating pathogenic factors that are strongly associated with vascular injury and declining kidney function in native CKD. Similarly, chronic renal allograft injury (CRAI) is characterized by vascular injury and declining allograft function in transplant CKD. We hypothesized that circulating CKD‐MBD factors could serve as non‐invasive biomarkers of CRAI. We conducted a cross‐sectional, multicenter case–control study. Cases (n = 31) had transplant function >20 mL/min/1.73 m² and biopsy‐proven CRAI. Controls (n = 31) had transplant function >90 mL/min/1.73 m² and/or a biopsy with no detectable abnormality in the previous six months. We measured plasma CKD‐MBD factors at a single time point using ELISA. Median (range) FGF23 levels were over twofold higher in CRAI vs. controls [106 (10–475) pg/mL vs. 45 (8–91) pg/mL; p < 0.001]. FGF23 levels were inversely correlated with transplant function (r² = ?0.617, p < 0.001). Higher FGF23 levels were associated with increased odds of biopsy‐proven CRAI after adjusting for transplant function, clinical, and demographic factors [OR (95% CI) 1.43 (1.23, 1.67)]. Relationships between additional CKD‐MBD factors and CRAI were attenuated in multivariable models. Higher FGF23 levels were independently associated with biopsy‐proven CRAI in children.     

First experience with basiliximab in pediatric liver graft recipients

Several studies have shown a significant reduction of acute cellular graft rejection in adult liver and kidney graft recipients treated with monoclonal anti-interleukin-2 (IL-2)-receptor antibodies. The mechanism was inhibition of activated T-helper cells by blocking the alpha-chain (CD25) of the IL-2 receptor. The pilot study described here evaluated the use of basiliximab in pediatric liver transplantation (LTx), which is the first report on its use in children. Fifty-two liver-transplanted children were analyzed in this study. A matched-pair historical control group (n = 26) received cyclosporin A (CsA) and prednisolone, and patients in the basiliximab group (n = 26) were treated with low-dose CsA and basiliximab (after reperfusion and on day 4 post-transplant). The incidences were compared of acute graft rejections, infectious complications, and the adverse effects of immunosuppressive medication within the first 6 months post-transplant. The incidence of acute rejection was significantly higher in the control group (61.5% vs. 11.5%, p = 0.0004). The frequency of infectious complications was similar (46.1% vs. 53.8%). Patients in the basiliximab group showed less arterial hypertension; however, the differences were not statistically significant (30.7% vs. 7.7%, p = 0.07). Nephrotoxicity, hepatotoxicity or neurotoxicity were only seen in the control group (7.7%; 3.8%; 3.8%, respectively). Hence, the use of basiliximab in combination with CsA and steroids in pediatric liver transplant recipients is safe and reduces the incidence of acute graft rejection. Further studies are needed to confirm our preliminary results and to analyze long-term effects on post-transplant lymphoproliferative disease, chronic rejection, and patient survival.     

Failure of isolated kidney transplantation in a pediatric patient with primary hyperoxaluria type 2

PH type 2 is caused by decreased activity of GRHPR enzyme that eventually leads to ESRD and systemic oxalosis. Here, we describe an Iranian pediatric patient with PH2 and early ESRD development who received recommended treatment by undergoing isolated kidney transplantation. Diagnosis criteria included a history of reoccurring calcium oxalate renal stones and elevated oxalate levels combined with liver biopsy and decreased enzymatic activity at age five. ESRD prompted transplantation and was performed at age nine. On Day 12 post‐op, his serum creatinine level increased. A graft biopsy showed calcium oxalate crystal deposits in renal tubes with no evidence of acute rejection, which resolved with intensive hydration and administration of a potassium citrate solution. Subsequent biopsies confirmed results found in first biopsy. Despite the immunosuppressive therapy, his serum creatinine level increased again after 11 months. Renal tubular obstruction then led to graft nephrectomy. Pathological analysis of tissue confirmed findings of past biopsies. This was a very rare case of early ESRD in PH2 resulting in a failed isolated kidney transplant. As the GRHPR enzyme is predominantly expressed in liver, we suggest a combined liver‐kidney transplant may be beneficial in patients with PH2.