Pediatric Renal Transplant Research Articles

Whole-Exome Sequencing Enables a Precision Medicine Approach for Kidney Transplant Recipients

Whole-exome sequencing (WES) finds a CKD-related mutation in approximately 20% of patients presenting with CKD before 25 years of age. Although provision of a molecular diagnosis could have important implications for clinical management, evidence is lacking on the diagnostic yield and clinical utility of WES for pediatric renal transplant recipients. To determine the diagnostic yield of WES in pediatric kidney transplant recipients, we recruited 104 patients who had received a transplant at Boston Children's Hospital from 2007 through 2017, performed WES, and analyzed results for likely deleterious variants in approximately 400 genes known to cause CKD. By WES, we identified a genetic cause of CKD in 34 out of 104 (32.7%) transplant recipients. The likelihood of detecting a molecular genetic diagnosis was highest for patients with urinary stone disease (three out of three individuals), followed by renal cystic ciliopathies (seven out of nine individuals), steroid-resistant nephrotic syndrome (nine out of 21 individuals), congenital anomalies of the kidney and urinary tract (ten out of 55 individuals), and chronic glomerulonephritis (one out of seven individuals). WES also yielded a molecular diagnosis for four out of nine individuals with ESRD of unknown etiology. The WES-related molecular genetic diagnosis had implications for clinical care for five patients. Nearly one third of pediatric renal transplant recipients had a genetic cause of their kidney disease identified by WES. Knowledge of this genetic information can help guide management of both transplant patients and potential living related donors.

Clinical characteristics of Campylobacter enteritis after pediatric renal transplantation: A retrospective analysis from single center.

There are few reports of patients with Campylobacter enteritis after renal transplantation, and only a few case reports of bacteremia have been published. Although antibiotic therapy for 3-5days has been recommended for immunocompromised patients, the optimal treatment for Campylobacter enteritis after renal transplantation has not been established. This study aimed to clarify the clinical characteristics and treatment outcomes of Campylobacter enteritis after pediatric renal transplantation. This retrospective study included patients who underwent pediatric renal transplantation and were found to have Campylobacter species in stool cultures between January 2014 and May 2017. This study included eight patients who underwent pediatric renal transplantation. The median age at the time of renal transplantation was 14years, and the median period between transplantation and disease occurrence was 4.6years. Clinical symptoms were abdominal pain for eight patients, diarrhea for eight patients, fever for seven patients, vomiting for three patients, and headache for three patients. Campylobacter jejuni was isolated from the stool cultures of all patients. The median administration period of antibiotics as initial therapy was 7days (range, 4-11days). However, clinical relapse was observed in four patients after completing antibiotic therapy. Patients who experienced clinical relapse required a second course of antibiotic therapy for a median duration of 7days (range, 5-10days). Patients with Campylobacter enteritis after pediatric renal transplantation are at high risk for clinical relapse and may require a longer duration of antibiotic therapy than that generally described.

Successful Treatment of Recurrent Focal Segmental Glomerulosclerosis After Transplantation in Children: A Single-Center Experience

ObjectiveWe aim to report our experience managing cases of recurrent focal segmental glomerulosclerosis (FSGS) in a group of pediatric renal transplant recipients. MethodsThis study was a retrospective chart review of pediatric patients who had their first kidney transplant at King Faisal Specialist Hospital & Research Center between 2014 and 2016. ResultsWe reviewed the files of 6 patients, 3 of whom were male. The median age of the children was 2.75 years (range, 2–4 years) at disease onset, with an average time of progression to end-stage renal disease of 19 months (range, 8–30 months). Five of the patients received a living related donor transplant, and 1 received a living nonrelated donor transplant. Patients had FSGS recurrence at varying intervals (1 to 3 days) post transplant. All cases had plasmapheresis prior to receiving abatacept or rituximab. The therapeutic strategy in 4 patients involved switching tacrolimus to cyclosporine. A complete response was observed in 5 of the 6 patients (83.3%), and treatment was well tolerated in 5 patients. Patient 1 had severe oliguria and required intermittent hemodialysis during the first 3 weeks post transplant. He showed minimal response to the therapeutic plasma exchange and rituximab and was subsequently treated with abatacept. However, he died 8 months post transplant of pneumonia and sepsis. ConclusionRituximab and switching tacrolimus to cyclosporine, in conjunction with plasmapheresis, appeared to be effective and safe in children with recurrent FSGS. Conversely, abatacept did not appear to provide clinical benefit.

Evaluation of growth in children and adolescents after renal transplantation.

Büyükkaragöz B, Bakkaloğlu SA, Tuncel AF, Kadıoğlu-Yılmaz B, Karcaaltıncaba D, Paşaoğlu H. Evaluation of growth in children and adolescents after renal transplantation. Turk J Pediatr 2019; 61: 217-227. Despite the advances in the last decades, it is well-known that optimal growth is usually not achieved in children with chronic kidney disease (CKD) even after successful renal transplantation (RTx). In this study, our aim was to evaluate growth patterns and factors affecting growth in pediatric and adolescent renal transplant recipients (RTR). Thirty-seven prevalent RTR with mean age of 17.0±2.9 years and mean post-RTx duration of 4.2±2.0 years were evaluated. Growth parameters, height velocities and factors affecting growth at the time of RTx (baseline) and in the post-RTx follow-up were also retrospectively assessed. Cumulative corticosteroid (CS) doses were calculated. Mean height and weight standard deviation score (SDS) values were negative (-1.4±1.1 and -1.2±1.5, respectively), whereas height SDS was positive in 16% of the patients. Mean weight, height, and BMI (body mass index) SDS of the RTR were significantly higher than the values at transplantation (p < 0.001 for weight and height SDS; p < 0.05 for BMI SDS). Height SDS was < -2.0 in 19% of the patients while 60% at the baseline. Main factors associated with post-RTx height SDS were pre-RTx height SDS (B: 0.448, p < 0.01) and CKD duration (B: -0.01, p < 0.05). Although it was much better than the pre-RTx period, the present study reveals that post- RTx growth was less than anticipated. As well as minimizing post-RTx CS doses and preserving graft function in the post-RTx follow-up, performing early transplantation and all efforts for minimizing pre-RTx growth deficit are crucial for an optimal post-RTx growth.

Immunosuppressants in Organ Transplantation.

The goal of immunosuppressive therapy post-transplantation in pediatric renal transplant recipients is to prevent acute and chronic rejection while minimizing drug side effects. Most therapies alter immune response mechanisms but are not immunologically specific, and a careful balance is required to find the dose that prevents rejection of the graft while minimizing the risks of overimmunosuppression leading to infection and cancer. While this chapter because of space constraints focuses on immunosuppressive therapy in pediatric renal transplant recipients, many aspects can be applied on pediatric recipients of other solid organ transplants such as the liver and heart. The major maintenance immunosuppressive agents currently used in various combination regimens are tacrolimus, cyclosporine, mycophenolate mofetil, azathioprine, everolimus, sirolimus, and glucocorticoids (steroids). Although data from adult renal transplantation trials are used to help guide management decisions in pediatric patients, immunosuppressive therapy in pediatric renal transplant recipients often must be modified because of the unique dosage requirements and clinical effects of these agents in children, including their impact on growth and development. The optimal immunosuppressive therapy post-transplant is not established. The goal remains to find the best combination of immunosuppressive agents that optimizes allograft survival by preventing acute rejection while limiting drug toxicities.

Ureteric Stricture following Pediatric Dual En-Bloc Renal Transplantation

Ureteric Stricture following Pediatric Dual En-Bloc Renal Transplantation

Cytokine Profiles Associated With Angiotensin II Type 1 Receptor Antibodies

IntroductionAngiotensin II type 1 receptor antibody (AT1R-Ab), is a non–human leukocyte antigen (HLA) antibody implicated in poor renal allograft outcomes, although its actions may be mediated through a different pathway than HLA donor-specific antibodies (DSAs). Our aim was to examine serum cytokine profiles associated with AT1R-Ab and distinguish them from those associated with HLA DSA in serially collected blood samples from a cohort of pediatric renal transplant recipients.MethodsBlood samples from 65 pediatric renal transplant recipients drawn during the first 3 months posttransplant, at 6, 12, and 24 months posttransplant, and during suspected episodes of kidney transplant rejection were tested for AT1R-Ab, HLA DSA, and a panel of 6 cytokines (tumor necrosis factor [TNF]-α, interferon [IFN]-γ, interleukin [IL]-8, IL-1β, IL-6, and IL-17). Associations between antibodies and cytokines were evaluated.ResultsAT1R-Ab, but not HLA DSA, was associated with elevations in TNF-α, IFN-γ, IL-8, IL-1β, IL-6, and IL-17. This relationship remained significant even after controlling for relevant clinical factors and was consistent across all time points. In contrast to HLA DSA, AT1R-Ab was associated with elevations in vascular inflammatory cytokines in the first 2 years posttransplant.ConclusionsThis profile of vascular cytokines may be informative for clinical monitoring and designing future studies to delineate the distinct pathophysiology of AT1R-Ab–mediated allograft injury in kidney transplantation.

Effects of the strict control of blood pressure in pediatric renal transplant recipients-ESCORT trial.

Strict BP control can retard progression of CKD in children. This prospective 3-year randomized controlled trial is aimed to investigate whether strict BP control can retard progression of chronic allograft dysfunction. Twenty-three pediatric patients were randomly selected to the standard BP group (STAND, target 24-hour MAP 50-95th percentile, n=11) or the intensified BP group (INTENS, target 24-hour MAP <50th percentile, n=12). The primary endpoint was an annual reduction in eGFR (Schwartz formula, mL/min/1.73m2 /y), secondary graft survival, BP, proteinuria, and safety. A total of 21 children (age at entry 11.2 (range 6.2-16.8) years) completed the study, with 73% of children in INTENS and 70% of children in STAND group reached their goal BP. Ambulatory indexed 24-hour MAP decreased significantly in INTENS group (from 0.94 (range 0.86-1.17) to 0.85 (range 0.79-1.01, P<0.01)) but not in STAND group (from 0.93 (range 0.85-1.07) to 0.90 (range 0.84-1.01)). Proteinuria did not change significantly in either group (22.1mg/mmol creatinine to 15.3 in STAND group vs 25.7 to 11.8 in INTENS group). The annual reduction in eGFR did not differ between the INTENS and STAND groups (-1.9mL/min/1.73m2 /y (range +6.4 to -14.3) vs -0.9 (range +4.0 to -8.5)). This first randomized controlled trial on strict BP control has demonstrated that strict BP control is feasible in 73% of children but the strict BP control does not lead to retardation of graft function decline in comparison with standard BP control. However, the results need to be interpreted with caution keeping the major limitation of the study, that is, small sample size in mind.

1564. Lower Rates of Epstein–Barr Virus (EBV) Viremia in Pediatric Solid Organ Transplant (SOT) Recipients Who Received Valganciclovir Prophylaxis

BackgroundAntiviral prophylaxis to prevent PTLD remains controversial, but some data suggest that valganciclovir or ganciclovir ([val]ganciclovir) use in EBV high-risk pediatric renal transplants reduces EBV viremia. We evaluated the impact of [val]ganciclovir on EBV viremia and post-transplant lymphoproliferative disease (PTLD) in pediatric nonrenal SOT recipients.MethodsRetrospective study of 100 patients who underwent a first heart, liver, lung, intestine, or multivisceral SOT between November 2013 and November 2016 at Boston Children’s Hospital who survived without re-transplantation for at least 30 days. Data collected included EBV donor/recipient serostatus, donor’s age >2 years-old (to avoid misclassification of EBV risk due to maternal antibody), antiviral use ([val]ganciclovir or acyclovir), time to EBV viremia (>1,000 copies/mL by whole blood PCR), and time to development of PTLD. EBV high-risk patients were those with donor EBV positive [D+]/recipient EBV negative [R–] serologies; intermediate-risk were EBV R+; low risk were EBV D–/R–. Time-to-event analysis using the Kaplan–Meier method was performed and significance (P = 0.05) was evaluated using the log-rank test.ResultsHigh (n = 45) or intermediate (n = 27) EBV risk was associated with increased EBV viremia (P = 0.007, table). EBV viremia was significantly decreased in the subgroup of high-risk patients with donors >2 years old who received [val]ganciclovir vs. those who received no antiviral (n = 23, n = 4, P = 0.03, Figure 1). Most PTLD cases (8/9) occurred in the high-risk group (P = 0.03, Figure 2). Overall, patients who received [val]ganciclovir had less PTLD than those who did not (P = 0.03), but this was not significant in the high-risk subgroup (P = 0.14, Figure 3).ConclusionLower rates of EBV viremia occurred in high EBV risk transplant recipients who received [val]ganciclovir, possibly by preventing primary EBV infection. Recipients with high EBV risk have the highest rate of PTLD.cases=100EBV RiskOutcomeOrganUnknownLowIntermediateHighViremiaPTLDHeart581320185Liver11101862Lung114462Intestine10Multivisceral11Dual organ31Total7212745439AntiviralNo Antiviral6652Acyclovir213873[Val]ganciclovir5132431314OutcomeViremia2214259PTLD189 Disclosures F. M. Marty, Merck: Consultant and Investigator, Consulting fee, Research support and Speaker honorarium; Astellas: Consultant and Investigator, Consulting fee and Research support; Chimerix: Consultant and Investigator, Consulting fee and Research support; Fate Therapeutics: Consultant, Consulting fee; GlaxoSmithKline: Consultant, Consulting fee; LFB: Consultant, Consulting fee; Roche Molecular Diagnostics: Consultant, Consulting fee; Shire: Consultant and Investigator, Consulting fee and Research support.

Urinary proteomics to diagnose chronic active antibody-mediated rejection in pediatric kidney transplantation - a pilot study.

Chronic antibody-mediated rejection (cABMR) is the main cause of long-term renal graft loss. Late-stage diagnosis is made by detecting donor-specific antibodies (DSA) in blood combined with typical histomorphological lesions in renal allografts. There is a need for noninvasive biomarkers for cABMR that might permit screening and earlier diagnosis. In a case control study of 24 pediatric renal transplant recipients, urine samples were analyzed using capillary electrophoresis and mass spectrometry. Patients were matched with 36 pediatric renal transplant patients without cABMR. Statistical analysis used the nonparametric Wilcoxon test to identify 79 significant biomarkers, which were combined to a support vector machine-based classifier. After validation in an independent test cohort of eight pediatric patients with and 12 without cABMR, the area under the receiver operating characteristic (ROC) curve (AUC) for detection of cABMR was 0.92 (95% CI 0.71-0.99) with a sensitivity of 100% (95% CI 63-100%) and a specificity of 75% (95% CI 43-95%). Combining this classifier with the urinary proteomic marker CKD273 improved the detection of patients with cABMR with misclassification in only 2/20 of the patients. These data indicate that a biomarker pattern derived from urinary proteomics allows the detection of cABMR in pediatric renal transplant recipients with high sensitivity and moderate specificity.

Vitamin B6 in Pediatric Renal Transplant Recipients

Our aim was to assess the vitamin B6 intake and biochemical status in a sample of children who have undergone renal transplantation. A prospective observational study was performed in 10 pediatric renal transplant recipients to determine their vitamin B6 status through dietary assessment and serum Pyridoxal 5'-phosphate (PLP) measurement. Ten children (mean age of 11.9years) had median serum PLP concentrations of 62.45nmol/L (interquartile range ±83.40). Two children (20%) had values above the reference range, and none below. Mean vitamin B6 intake was 138.7% of reference nutrient intake (standard deviation ±35.2%). No children were in receipt of vitamin B6 supplementation. There is no previous literature on vitamin B6 status in children who have undergone renal transplantation. In adult transplant recipients, elevated serum PLP concentrations have been described and ascribed to possible excessive intakes. In this sample, no children appeared biochemically deficient, but 20% had elevated concentrations. Dietary intakes were not excessive, and no children reported oral Vitamin B6 supplementation. Exploration of vitamin B6 metabolism in this population is required.

Utility of thrombophilia screening in pediatric renal transplant recipients.

Thrombosis after kidney transplantation may result in catastrophic outcomes, including graft loss. Thrombophilia has been implicated in post-transplant thrombosis; data, however, are inconclusive on the impact of acquired and inherited thrombophilia and resultant thrombosis in renal graft recipients. We aimed to evaluate whether identifying children with thrombophilia during the pretransplant evaluation predicted post-transplant outcomes. We reviewed 100 kidney transplants performed in 100 children, aged 1-18years, in a single-center retrospective study. Routine pretransplant comprehensive thrombophilia evaluation was completed. Thrombophilia was demonstrated in 36% patients (N=36). TEs occurred in 11 patients before kidney transplant. Low PS and antithrombin were found in 9/86 (10.5%) and 2/89 (2.2%) children, respectively. Heterozygosity for FLV and PGM were found in 5/81 (6.2%) and 1/93(1.1%) children, respectively. A post-transplant thrombotic event occurred in 10 children (10%); six involved the renal transplant. The association between a history of a pretransplant thrombotic event and post-operative renal graft thrombosis approached, but did not reach significance (P=0.071). There was no association between preoperative screening abnormalities and post-operative TEs. Graft loss due to a thrombotic event occurred in two patients; none had underlying thrombophilia. Our data suggest that the utility of universal, comprehensive preoperative thrombophilia testing is not beneficial in determining risk of post-operative graft thrombosis. Thrombophilia testing may be considered in a select population with a history of pretransplant thrombotic event.

49] Surgical complications in live-donor paediatric and adolescent renal transplantation: Study of risk factors – Mansoura experience 1976–2017

ObjectiveTo report the surgical complications amongst our paediatric and adolescent renal transplant patients and to analyse the different factors that may influence the occurrence of complications.

Population Pharmacokinetics of Tacrolimus in Transplant Recipients: What Did We Learn About Sources of Interindividual Variabilities?

Tacrolimus, a calcineurin inhibitor, is a common immunosuppressant prescribed after organ transplantation and has notable inter- and intrapatient pharmacokinetic variability. The sources of variability have been investigated using population pharmacokinetic modeling over the last 2 decades. This article provides an updated synopsis on published nonlinear mixed-effects analyses developed for tacrolimus in transplant recipients. The objectives were to establish a detailed overview of the current data and to investigate covariate relationships determined by the models. Sixty-three published analyses were reviewed, and data regarding the study design, modeling approach, and resulting findings were extracted and summarized. Most of the studies investigated tacrolimus pharmacokinetics in adult and pediatric renal and liver transplants after administration of the immediate-release formulation. Model structures largely depended on the study sampling strategy, with ∼50% of studies developing a 1-compartment model using trough concentrations and a 2-compartment model with delayed absorption from intensive sampling. The CYP3A5 genotype, as a covariate, consistently impacted tacrolimus clearance, and dosing adjustments were required to achieve similar drug exposure among patients. Numerous covariates were identified as sources of interindividual variability on tacrolimus pharmacokinetics with limited consistency across these studies, which may be the result of the study designs. Additional analyses are required to further evaluate the potential impact of these covariates and the clinical implementation of these models to guide tacrolimus dosing recommendations. This article may be useful for guiding the design of future population pharmacokinetic studies and provides recommendations for the selection of an existing optimal model to individualize tacrolimus therapy.

Epstein-Barr virus infection in children with renal transplantation: A single-centre experience.

This study aimed to investigate the incidence, timing, manifestations, managements, and outcomes of Epstein-Barr virus (EBV) infection in paediatric renal transplant recipients in Korea. We retrospectively evaluated 70 patients aged <18 years who had undergone renal transplantation between January 1990 and November 2014 at a single centre in Korea. EBV infection was diagnosed via serological test or real-time quantitative polymerase chain reaction (PCR). The diagnosis of post-transplant lymphoproliferative disorder (PTLD) was based on biopsy findings. In total, 21 patients (30.0% of renal transplant recipients) had EBV infection. EBV infection occurred at an average age of 12.6 ± 4.5 (median, 12.0; range, 7.0-24.0 years, with a mean period of 28.3 ± 27.2 (median, 14.0; range, 2.0-75.0) months for developing EBV infection after transplantation. EBV infection developed 12 times more frequently in pre-transplant EBV-seronegative recipients. Eight patients (38% of EBV-infected patients) had EBV disease, and six patients (75% of patients with EBV disease) had PTLD. The maximum EBV PCR titer was greater in patients with EBV disease than in the asymptomatic EBV infection group. The main treatment for EBV infection was the reduction in immunosuppressants. Asymptomatic EBV infection resolved in approximately 80% of the patients. One patient (17% of the patients with PTLD) expired. The glomerular filtration rate did not deteriorate during the treatment of EBV infection. Regular EBV monitoring in renal transplant recipients is mandatory for early diagnosis and treatment of EBV infections and prevention of PTLD, especially in pre-transplant EBV IgG-negative patients.

Early conversion of pediatric kidney transplant patients to everolimus with reduced tacrolimus and steroid elimination: Results of a randomized trial.

In a 12-month, multicenter, open-label study, 106 children were randomized at 4 to 6 weeks after kidney transplantation to switch to everolimus with reduced TAC (EVR/rTAC) and steroid elimination from month 5 posttransplant or to continue standard tacrolimus with mycophenolate mofetil (sTAC/MMF) and steroids. The cumulative incidence of a co-primary efficacy end point (biopsy-proven acute rejection [BPAR], graft loss, or death from randomization to month 12) was 10.3% with EVR/rTAC and 5.8% with sTAC/MMF (difference 4.4%; P = .417). BPAR occurred in 9.6% and 5.6% of patients, respectively. Patient and renal allograft survival were 100%. The co-primary end point of mean estimated glomerular filtration rate at month 12 was 76.2 mL/min/1.73 m2 with EVR/rTAC and 72.5 mL/min/1.73 m2 for sTAC/MMF (difference 3.8 mL/min/1.73m2 ; P = .49). One EVR/rTAC patient developed posttransplant lymphoproliferative disease. Longitudinal growth and sexual maturation were equivalent between groups. The randomized drug regimen was discontinued in 34.6% and 13% of patients in the EVR/rTAC and sTAC/MMF groups, respectively (P = .024), and discontinued due to adverse events/infections in 25.0% and 11.1% of patients (P = .062). In conclusion, early conversion of pediatric kidney transplant patients from TAC, MMF, and steroids to EVR/rTAC and steroid withdrawal maintains immunosuppressive efficacy and preserves renal function.

Clinical implication of renal allograft volume to recipient body surface area ratio in pediatric renal transplant.

Our study aims to assess the clinical implication of RAV/rBSA ratio in PRT as a predictor for attained renal function at 1year post-transplantation and its association with surgical complications. A retrospective cohort was performed for PRT cases from January 2000 to December 2015 in our institution. Extracted clinical information includes the recipient's demographics, donor type, renal allograft characteristics, arterial, venous and ureteral anastomoses, vascular anastomosis time while kidney off ice, overall operative time, and estimated blood loss. The RAV/rBSA was extrapolated and assessed for its association with renal graft function attained in 1year post-transplantation and surgical complications within 30-day post-transplantation. A total of 324 PRTs cases were analyzed. The cohort consisted of 187 (52.4%) male and 137 (42.3%) female recipients, with 152 (46.9%) living donor and 172 (53.1%) deceased donor renal transplants, and an overall median age of 155.26months (IQR 76.70-186.98) at time of renal transplantation. The receiver operating characteristic identified that a RAV/rBSA ratio of 135 was the optimal cutoff in determining the renal graft function outcome. Univariate and multivariate analyses revealed the relative OR for RAV/rBSA≥135 ratio in predicting an eGFR≥90 attained within 1year post-transplant was highest among younger pediatric recipients (<142.5months) of deceased kidney donors (OR=11.143, 95% CI=3.156-39.34). Conversely, Kaplan-Meier analysis revealed that RAV/rBSA ratio≥135 is associated with lower odds of having eGFR <60 (OR=0.417, 95% CI=0.203-0.856). The RAV/rBSA ratio was not associated nor predictive of transplant-related surgical complications. Our study determined that the RAV/rBSA ratio is predictive of renal graft function at 1-year PRT, but not associated with any increased surgical complications.

A16787 ACE activity and its expression as a hypertension biomarker in the urine of pediatric renal transplant recipients

Objectives: Analyze ACE isoform in urine of pediatric renal transplant recipients before and after transplantation and urine of donor, to verify the 90 kDa isoform transmission and correlating with hypertension Methods: 30 pediatric recipients with living donors; ACE activity was performed before, 1, 3 and 6 months post transplantation using ZPhe and HHL as substrates and its ratio Results: 69% had pre-transplant hypertension and 85.7% family history. After 6 months 25% remained. From the pre-transplant until the sixth month after, ACE activity was reduced. In the model of linear regression between ACE activity and variables, including pre-transplantation for the substrates ZPhe-HL remained significant, time and uropathy (0.023 more); with HHL, time and uropathy with higher activity of ACE (0.019 more) and for weight, reduction of ACE activity (0.00038 at 1 kg increase in weight). At post-transplant only time and weight remained significant with ZPhe-HL, and for HHL uropathy, proteinuria (0.010 more ACE activity) and weight. Recipients before transplantation had higher urinary ACE activity when compared to controls. Western blotting data showed that all recipients without ACE 90KDa when received a kidney from the donor that had this isoform, started to express it Conclusion: Increased ACE activity in uropathies may be associated with renal injury or intra-renal production. Proteinuria, a marker of renal injury, can be associated with increase on ACE activity. With nutritional recovery and a healthy kidney after transplantation, patients can reverse the degree of renal damage and decrease the production of ACE

Pharmacokinetics of Enoxaparin After Renal Transplantation in Pediatric Patients.

Enoxaparin is commonly used in the prevention of renal allograft vascular thrombosis but off-label in children, and no consensus exists regarding the optimal dosing and dose adjustment. In this retrospective study, 444 anti-Xa levels were obtained from 30 pediatric renal transplant recipients in order to investigate enoxaparin population pharmacokinetics. The main results were (1) 25% of children achieved the target anti-Xa activity 36hours after initiation of treatment, (2) anti-Xa time courses were best described by a 1-compartment open model with first-order absorption, (3) body weight but not renal function was the sole covariate influencing clearance and volume of distribution, and (4) large between-subject and between-occasion variabilities in anti-Xa activity were observed. However, creatinine-based estimated glomerular filtration rate in the first post-renal transplantation hours may not reliably reflect the actual renal function of the children. Based on the final population model, a Bayesian-based program was developed in order to estimate the individual pharmacokinetic parameters on a single anti-Xa measurement, allowing determination of the next enoxaparin dose that will quickly achieve an appropriate anti-Xa activity (targeting 0.3-0.5IU/mL) and anticoagulation. Finally, these results should help standardize practices that remain to date largely heterogeneous in pediatric intensive care units.

The Regulatory/Cytotoxic T Cell Profiles in Blood of Pediatric Kidney-Transplant Recipients with Acute Rejection

Background: The equilibrium between regulatory cells and cytotoxic cells may define graft consequence. We investigated the relationship between the expression of main regulatory and cytotoxic markers (i.e., FOXP3 and granzyme B (GZM-B), respectively) and acute rejection (AR) in the peripheral blood of pediatric renal transplant recipients. Methods: In this retrospective study, FOXP3 mRNA expression and serum GZM-B levels in peripheral blood samples from 47 first-time pediatric kidney-transplant recipients were measured, with 17 children classified as possessing AR; whereas the remaining 30 children had functionally stabilized allografts. Results: Levels of the FOXP3 mRNA vs. the expression levels GADPH mRNA (FOXP3 mRNA/GADPH mRNA) were significantly elevated in children with AR than those with stabilized renal allograft (0.48 ± 0.26 vs.0.23 ± 0.18, respectively, P=0.002) Also, serum GZM-B levels in the AR group were elevated than those in the functionally stabilized children (120.07 ± 91.42p g/ml and, 60.16 ± 46.29 pg/ml respectively, P=0.01). ROC curve evidenced that measuring FOXP3 mRNA may have a scope as a decision-taking agent in clinical proceedings to diagnose AR. Measuring peripheral blood FOXP3 mRNA elucidated scope to help in the noninvasive diagnosis of AR. Conclusions: Our results emphasize FOXP3 mRNA as a biomarker for AR in pediatrics. Assessment of regulatory/cytotoxic profiles in the peripheral blood of pediatric renal transplant recipients is a potentially useful tool for patient selection and early detection of rejection. Depending on many variables, such as the method of sample normalization, the technique used, the extent of graft inflammation, the immunosuppression regimen, depletion/ repletion of T-lymphocyte component, the importance of FOXP3 may differ.