Phase I study of single-dose pharmacokinetics and pharmacodynamics of belatacept in adolescent kidney transplant recipients.

Belatacept is an intravenously infused selective T cell costimulation blocker approved for preventing organ rejection in renal transplant recipients aged ≥18 years. This phase I trial examined the pharmacokinetics and pharmacodynamics (percentage CD86 receptor occupancy [%CD86RO]) of a single dose of belatacept (7.5 mg/kg) administered to kidney transplant recipients aged 12-17 years receiving a stable calcineurin inhibitor-based immunosuppressive regimen. Nine adolescents (mean age 15.1 years) who were seropositive for Epstein-Barr virus were enrolled; all completed the 6-month study. Pharmacokinetics suggested relatively low variability of exposure (coefficients of variation for maximum observed serum concentration [Cmax ] and area under the serum concentration-time curve from time zero extrapolated to infinity [AUC0-INF ] were 20% and 25%, respectively). Mean half-life (T1/2 ) occurred 7.2 days postinfusion. Belatacept total body clearance was 0.48 mL/h/kg, and volume of distribution at steady-state (Vss ) was low at 0.09 L/kg. Compared with historical data from healthy adult volunteers administered a single dose of belatacept 10 mg/kg and adult kidney transplant recipients administered multiple doses of belatacept 5 mg/kg, pharmacokinetic values for adolescents were similar, indicating consistency across adolescent and adult populations. Mean %CD86RO increased with increasing belatacept concentration, indicating a direct relationship between pharmacokinetics and pharmacodynamics. Four patients reported 7 serious adverse events; none was considered related to belatacept. These data will inform belatacept dose selection in future studies of adolescent kidney transplant recipients.

Mycophenolate mofetil-related leukopenia in children and young adults following kidney transplantation: Influence of genes and drugs.

MMF is commonly prescribed following kidney transplantation, yet its use is complicated by leukopenia. Understanding the genetics mediating this risk will help clinicians administer MMF safely. We evaluated 284 patients under 21 years of age for incidence and time course of MMF-related leukopenia and performed a candidate gene association study comparing the frequency of 26 SNPs between cases with MMF-related leukopenia and controls. We matched cases by induction, steroid duration, race, center, and age. We also evaluated the impact of induction and SNPs on time to leukopenia in all cases. Sixty-eight (24%) patients had MMF-related leukopenia, of which 59 consented for genotyping and 38 were matched with controls. Among matched pairs, no SNPs were associated with leukopenia. With non-depleting induction, UGT2B7-900A>G (rs7438135) was associated with increased risk of MMF-related leukopenia (P = .038). Time to leukopenia did not differ between patients by induction agent, but 2 SNPs (rs2228075, rs2278294) in IMPDH1 were associated with increased time to leukopenia. MMF-related leukopenia is common after transplantation. UGT2B7 may influence leukopenia risk especially in patients without lymphocyte-depleting induction. IMPDH1 may influence time course of leukopenia after transplant.

Linear growth in pediatric renal transplant recipients receiving sirolimus.

SRL is a potent macrolide immunosuppressive agent that can be used as maintenance therapy for prevention of rejection and avoidance of CNI nephrotoxicity. However, animal studies indicate that SRL may inhibit skeletal and muscle growth. We analyzed linear growth in 25 children, age 1-15 yr old, maintained on SRL to determine whether SRL is detrimental to linear growth. Height z-scores at baseline were compared with those at 24 months. We also compared linear growth in children receiving SRL to patients maintained on TAC. Height z-scores over 24 months did not significantly change in the SRL group as a whole. Z-scores improved in 13 of 25 patients (52%). Children with improved z-scores were significantly younger than patents who did not display improved growth: 6 ± 5 yr vs. 11 ± 4 yr (p < 0.05). Height z-scores in SRL and TAC-based patients were no different initially and at 24 months, and a similar number of patients in each group displayed improved height scores. Height z-scores improved in 52% of patients on SRL and occurred predominantly in younger patients for the initial 24 months of treatment. Linear growth in SRL patients was also similar to the results in TAC-based patients. Therefore, our data did not identify a significant adverse effect of SRL on growth.

Five-year experience using sirolimus-based, calcineurin inhibitor-free immunosuppression in pediatric renal transplantation.

From December 2003 to December 2008, we employed a protocol for withdrawing TAC and converting to SRL in a cohort of low-risk renal pediatric transplant recipients. We report our experience in these children with respect to graft survival, AR episodes, renal function, and adverse events. All patients received basiliximab induction and TAC, MMF, and prednisone. Criteria for conversion to SRL included first transplants without histologic evidence for AR on three-month surveillance biopsies. Patient exclusion criteria included AR prior to or before surveillance biopsies, polyoma (BK) virus nephropathy, a history of nephrotic syndrome, or multiple organ transplants. Fifty-one of 137 patients who received transplants from December 2003 to December 2008 met criteria for withdrawal of TAC and were converted to SRL. SRL was discontinued in 11 children because of adverse events within 12 months after conversion. Among the remaining 40 patients, actuarial graft survival was 91% at five yr. AR occurred in 13% of patients within one yr after conversion. Complications from SRL included aphthous ulcers (30%); viremia with BK virus (20%), EBV (13%), and CMV (3%); proteinuria (7%); elevated cholesterol (7%); diabetes mellitus (2%); thrombocytopenia (2%); erectile dysfunction (2%); and lymph edema (2%). SRL was discontinued in 20%, predominantly for aphthous ulcers. Our experience with SRL-based immunosuppression demonstrates that a CNI-free regimen can be successful in lower-risk patients meeting our selection criteria. Aphthous ulcers and BK virus viremia were the most prevalent adverse events.

Recovery of renal function and survival after continuous renal replacement therapy during extracorporeal membrane oxygenation.

OBJECTIVE: To assess the outcome of pediatric patients supported by concomitant extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT). DESIGN, SETTING, AND PATIENTS: Acute kidney injury is associated with mortality in ECMO patients. CRRT in patients on ECMO provides an efficient and potentially beneficial method of acute kidney injury management. Concern that concomitant CRRT use increases the risk of developing anuria and chronic renal failure limits its use in some centers. We hypothesized that development of chronic renal failure is rare with concurrent ECMO and CRRT. We evaluated the outcomes of 154 ECMO/CRRT patients cared for over 10 yrs at a referral pediatric medical center. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 68 (44%) ECMO/CRRT survivors, 45 were assigned a pediatric risk, injury, failure, loss and end-stage (referred to as "pRIFLE") score at CRRT initiation. Seventeen (38%) patients met the criteria for Risk, 15 (33%) for Injury, and 10 (22%) for Failure. Two Failure patients later met End stage criteria. Of all survivors, 18 (26%) required ongoing renal replacement therapy (15 required continuous veno-venous hemofiltration, two required peritoneal dialysis, and one patient required intermittent hemodialysis) post ECMO discontinuation. Renal recovery occurred in 65 (96%) of 68 patients before discharge. One neonatal patient had sepsis-induced renal injury on transfer, but had normal creatinine 1 month later. Two pediatric patients with vasculitis and primary renal disease at presentation (both meeting Failure criteria) developed end-stage renal disease. One received peritoneal dialysis and subsequent renal transplant. The other has diminished function without need for renal replacement therapy. CONCLUSION: In the absence of primary renal disease, chronic renal failure did not occur after concurrent use of CRRT with ECMO. Concern for precipitating chronic renal failure by using CRRT during ECMO is not substantiated by this large single-center experience. Consistent with previous reports, mortality is higher in patients receiving concomitant CRRT and ECMO compared with those receiving ECMO alone. Mortality is similar to patients requiring CRRT who are not on ECMO. Additional studies are warranted to determine the optimal role of CRRT use in ECMO patients.

Prevalence of clinical rejection after surveillance biopsies in pediatric renal transplants: does early subclinical rejection predispose to subsequent rejection episodes?

We analyzed rates of both SCR and CR in children receiving SB at three months post-transplant to determine if SCR predisposed patients to acute CR. Acute rejection was defined according to Banff criteria to include borderline classification or higher. All cases of SCR and CR were treated with anti-rejection protocols. Between October 2004 and July 2008, 89 SB were performed at three months post-transplant. Twenty-six cases of SCR were detected (29%). Sixteen patients experienced 22 episodes of biopsy-proven CR occurring after SB, including seven episodes following SCR and 15 after normal SB. The onset of CR varied from one to 27 months after SB and occurred at similar intervals for cases with SCR and normal SB. The percentage of patients remaining free of CR at 30 months post-transplant was similar in patients with SCR and normal SB. Renal function and graft survival at 30 months also were no different between patients with SCR and those with normal SB. Early-SCR, when treated with rejection protocols, is not a prognostic indicator for subsequent CR episodes.

Understanding the pathway between the transplant experience and health-related quality of life outcomes in adolescents.

Developments in solid organ transplantation have resulted in improved survival for children with advanced kidney, liver, and heart disease; however, concerns have been raised regarding the quality of life of survivors. This study examined HRQOL in adolescent transplant recipients. We examined the influence of demographic, treatment regimen, and family factors on physical and mental health domains of HRQOL. The current single-center investigation involved 68 solid organ transplant recipients and their parents. All families participated in a structured interview to collect information on demographics, characteristics of the adolescents' disease and treatment regimen, family functioning, and HRQOL for parents and adolescents. Using hierarchical regression analyses, predictive models of physical functioning and mental health outcomes for adolescent transplant recipients were developed for parent-proxy and adolescent self-report. Perceived frequency of medication side-effects and family conflict significantly contributed to adolescent physical functioning and mental health outcomes. Taken together, transplant consequences and family environment significantly impact physical and mental health outcomes in adolescent transplant recipients. Our findings demonstrate the need for pharmacological considerations and psychological interventions to address these areas.

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

UNLABELLED: 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.

Surveillance renal transplant biopsies and subclinical rejection at three months post-transplant in pediatric recipients.

UNLABELLED: Subclinical acute rejection (SCR) has been increasingly recognized in adult renal transplant recipients with the advent of surveillance biopsies. However, in children, surveillance biopsies are not routinely performed at most centers. Therefore, the incidence, predisposing factors, treatment, and clinical outcomes of SCR remain unclear in children. From August 2004 to December 2005, we performed 36 protocol biopsies at three months post-transplantation. All patients had received induction therapy with basiliximab and were maintained on prednisone, MMF, and tacrolimus. Sixteen cases of SCR were detected by biopsy (44%). Age, gender, race, donor source, or serum creatinine did not discriminate between children with SCR and those with normal biopsies. All cases of SCR were treated with high doses of methylprednisolone. At one yr post-transplant, renal function was similar in children with SCR to those with normal surveillance biopsies (p = 0.62). Because of the high incidence of SCR, the maintenance dose of MMF was increased by 50% in 20 children transplanted after December 2005. This resulted in a significant decline in the incidence of SCR from 44 to 15% (p < 0.05). However, the incidence of polyomavirus (BK) viremia also increased significantly in these children (p < 0.005). CONCLUSION: A high incidence of SCR was found on surveillance biopsies at three months post-transplant and could not be predicted by age, gender, race, donor source, or serum creatinine. The occurrence of SCR declined significantly by increasing the dose of MMF, but resulted in an increase in BK viremia. We conclude that surveillance biopsies provide valuable information in the management of pediatric renal transplant recipients. Increasing immunosuppression to avoid SCR should be weighed against the risk for infection.

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.

Sirolimus in pediatric patients: results in the first 6 months post-renal transplant.

We report our experience with sirolimus in children during the first 6 months after renal transplantation. From July 2000 to January 2004, 66 children received 33 deceased donor and 33 living donor transplants. Maintenance immunosuppression included sirolimus 3 mg/m(2) in addition to prednisone and tacrolimus or cyclosporine. Patient survival was 100% and graft survival was 65 of 66. Seven children experienced acute rejection episodes. All were reversible with increased doses of corticosteroid. One case of graft failure was caused by ischemic renal injury. Adverse events included Epstein-Barr viremia (8 patients) with three cases of post-transplant lymphoproliferative disease (PTLD), cytomegalovirus viremia (4 patients), poor wound healing (4 patients), pneumonitis (3 patients), nephrotic syndrome (3 patients), perinephric abscess (1 patient) and insulin-dependant diabetes (2 patients). Sirolimus was discontinued in 13 children for adverse events predominantly for wound dehiscence and pneumonitis. Cholesterol levels >200 mg/dL were observed in 33 children. Thrombocytopenia (platelet count <140 000) was not observed. We concluded that early outcomes with sirolimus were acceptable with 98% graft survival and 11% incidence of acute rejection. Medication was discontinued in 20% for adverse events which included poor wound healing and non-infectious pneumonitis. Infections with cytomegalovirus and Epstein-Barr virus, and PTLD were also significant early complications. Therefore, a sirolimus-based regimen that is combined with both an interleukin-2 receptor antibody and a calcineurin inhibitor may be excessive immunosuppression for pediatric renal transplant recipients.

Fluid overload before continuous hemofiltration and survival in critically ill children: a retrospective analysis.

OBJECTIVE: Continuous venovenous hemofiltration (CVVH) is used for renal replacement and fluid management in critically ill children. A previous small study suggested that survival was associated with less percent fluid overload (%FO) in the intensive care unit (ICU) before hemofiltration. We reviewed our experience with a large series of pediatric CVVH patients to evaluate factors associated with outcome. DESIGN: Retrospective chart review. SETTING: Tertiary children's hospital. PATIENTS: CVVH pediatric ICU patients from November 1997 to January 2003. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: %FO was defined as total fluid input minus output (up to 7 days before CVVH for both hospital stay and ICU stay) divided by body weight. One hundred thirteen patients received CVVH; 69 survived (61%). Multiple organ dysfunction syndrome (MODS) was present in 103 patients; 59 survived (57%). Median patient age was 9.6 yrs (25th, 75th percentile: 2.5, 14.3). Median %FO was significantly lower in survivors vs. nonsurvivors for all patients (7.8% [2.0, 16.7] vs. 15.1% [4.9, 25.9]; p =.02] and in patients with > or =3-organ MODS (9.2% [5.1,16.7] vs. 15.5% [8.3, 28.6]; p =.01). The Pediatric Risk of Mortality Score III at CVVH initiation also was associated with survival in these groups, but by multivariate analysis, %FO was independently associated with survival in patients with > or =3-organ MODS (p =.01). CONCLUSIONS: Survival in critically ill children receiving CVVH in this large series was higher than in previous reports. CVVH survival may be associated with less %FO in patients with > or =3-organ MODS. Prospective studies are necessary to determine whether earlier use of CVVH to control fluid overload in critically ill children can improve survival.

Efficacy of nephrectomy for the treatment of nephrogenic hypertension in a pediatric population.

PURPOSE: We evaluated the efficacy of nephrectomy for the management of nephrogenic hypertension in children. MATERIALS AND METHODS: We retrospectively reviewed the records of 320 children who underwent nephrectomy between 1991 and 2001, and 22 underwent nephrectomy for the management of hypertension. Of the 22 patients 16 (73%) had long-term followup, including 8 with end stage renal disease who were dialysis dependent, and 8 with normal renal function and unilateral parenchymal renal disease (UPRD). Within the UPRD group 3 patients had renovascular hypertension, 3 had reflux nephropathy, 1 had renal artery thrombosis and 1 had Page kidney. Age at hypertension onset, age at nephrectomy and elapsed time between diagnosis and intervention were studied. Antihypertensive medication requirements before surgery and after postoperative followup were evaluated to assess treatment efficacy. Complete success was defined as blood pressure normalization without antihypertensive requirements. Partial success was defined as decrease in medication requirements and/or discontinuation of minoxidil. Failure of treatment was defined as persistent hypertension, increased medication requirements or minoxidil dependence. RESULTS: In the end stage renal disease group mean age at diagnosis was 5.9 years (range 15 months to 10 years) and bilateral nephrectomy was performed at a mean age of 8.9 years (19 months to 15 years) with average elapsed time between diagnosis of hypertension and nephrectomy of 3 years. After a mean followup of 4.4 years (range 6 months to 8 years) 7 patients (88%) experienced complete or partial success and nephrectomy management failed in 1. In the UPRD group average elapsed time was 2.2 years (range 1 month to 10 years) between a mean age at diagnosis of 6.7 years (birth to 16 years) and a mean age at nephrectomy of 8.9 years (1 month to 17 years). After a mean followup of 1.6 years (range 1 month to 5 years) complete or partial success was experienced by all 8 patients (100%). All 8 UPRD group patients experienced adequate residual renal function. CONCLUSIONS: The vast majority of patients in both categories experienced complete or partial success from nephrectomy for the management of medication refractory hypertension. Nephrectomy for hypertension control is safe and effective, and obviates the need for morbid medications. We continue to accrue patients in a prospective manner.