Pediatric Kidney Transplant Recipients Research Articles

Assessment of Serum Soluble CD30 Levels in Pediatric Kidney Transplant Recipients

BACKGROUND: CD30 is considered to be a marker for the activated immune system; however, its association with acute rejection and kidney graft function showed severe heterogeneity. AIM: The aim of this study is to examine the predictive value of soluble CD30 (sCD30) levels for kidney transplantation (KT) outcomes in children. MATERIALS AND METHODS: CD30 in serum was measured by ELISA technique in 50 pediatric kidney transplant recipients (KTRs) within 13.4 ± 4.5 days before and within 19.5 ± 9.2 days after KT. sCD30 values were correlated with clinical, laboratory, and immunosuppressive (IS) therapy data and graft function of included patients. Twenty age/gender-matched healthy controls participated as reference values for sCD30 levels. RESULTS: Our study revealed that serum levels of CD30 showed a significant relation between serum sCD30 levels: Pre/post-transplantation (p = 0.02) with increasing sCD30 levels after transplantation (71.60 pg/mL vs. 90.20 pg/mL). In the time, there were no relations between sCD30 with other parameters. CONCLUSIONS: Our results suggest that the measurement of serums CD30 levels may be used as a valuable biomarker in renal transplantation when it is measured pre/post-transplantation.

Time-Varying Determinants of Graft Failure in Pediatric Kidney Transplantation in Europe.

Little is known about the time-varying determinants of kidney graft failure in children. We performed a retrospective study of primary pediatric kidney transplant recipients (younger than 18 years) from the Eurotransplant registry (1990-2020). Piece-wise exponential additive mixed models were applied to analyze time-varying recipient, donor, and transplant risk factors. Primary outcome was death-censored graft failure. We report on 4528 kidney transplantations, of which 68% with deceased and 32% with living donor. One thousand six hundred and thirty-eight recipients experienced graft failure, and 168 died with a functioning graft. Between 2011 and 2020, the 5-year graft failure risk was 10% for deceased donor and 4% for living donor kidney transplant recipients. Risk of graft failure decreased five-fold from 1990 to 2020. The association between living donor transplantation and the lower risk of graft failure was strongest in the first month post-transplant (adjusted hazard ratio, 0.58; 95% confidence interval, 0.46 to 0.73) and remained statistically significant until 12 years post-transplant. Risk factors for graft failure in the first 2 years were deceased donor younger than 12 years or older than 46 years, potentially recurrent kidney disease, and panel-reactive antibody >0%. Other determinants of graft failure included dialysis before transplantation (until 5 years post-transplant), human leukocyte antigen mismatch 2-4 (0-15 years post-transplant), human leukocyte antigen mismatch 5-6 (2-12 years post-transplant), and hemodialysis (8-14 years post-transplant). Recipients older than 11 years at transplantation had a higher risk of graft failure 1-8 years post-transplant compared with other age groups, whereas young recipients had a lower risk throughout follow-up. Analysis of the combined effect of post-transplant time and recipient age showed a higher rate of graft failure during the first 5 years post-transplant in adolescents compared with young transplant recipients. In contrast to deceased donor younger than 12 years, deceased donor older than 46 years was consistently associated with a higher graft failure risk. We report a long-term inverse association between living donor kidney transplantation and the risk of graft failure. The determinants of graft failure varied with time. There was a significant cumulative effect of adolescence and time post-transplant. The ideal donor age window was dependent on time post-transplant.

Longitudinal analysis of the impact of rituximab on circulating EBV miRNAs in three paediatric kidney transplant recipients

BackgroundEBV DNA monitoring is currently the main strategy to identify renal transplant recipients potentially at risk of EBV complications. EBV miRNA expression is markedly altered in different disease presentations associated with EBV. We performed a longitudinal assessment of the impact of rituximab on circulating EBV miRNA in 3 paediatric kidney transplant recipients. MethodsForty-two miRNAs encoded within 2 EBV open reading frames (BART and BHRF) were examined over a 28-month period using miRNA qPCR custom panels. EBV DNA was measured using qPCR and lymphocyte subsets were measured by flow cytometry. ResultsPatients were 3 years post kidney transplant and received cycles of rituximab infusions. Treatment with rituximab caused an immediate depletion of the circulating B cells and reduced the expression of the miRNAs and EBV DNA levels. About 4 months post treatment, as the circulating B cells repopulated, EBV miRNAs levels increased. A total of 29 plasma samples were studied and between 4 and 34 EBV miRNAs were detected. A significant correlation was observed between the numbers of EBV miRNAs expressed and the EBV DNA level (r = 0.63, p = 0.001). ConclusionWe provide an in-depth longitudinal assessment of the impact of rituximab on specific circulating EBV miRNA expression in three paediatric kidney transplant recipients. Rituximab treatment resulted in the reduction of EBV miRNA expression and EBV DNA viral loads. Larger studies are required to determine whether EBV miRNA levels could be useful biomarkers to predict transplant recipients at risk of developing post-transplant lymphoproliferative disease.

Neighborhood Socioeconomic Deprivation Among Pediatric Kidney Transplant Recipients

Neighborhood Socioeconomic Deprivation Among Pediatric Kidney Transplant Recipients

Ultrasound Evaluation of Fibrosis in Pediatric Kidney Transplant Recipients

Ultrasound Evaluation of Fibrosis in Pediatric Kidney Transplant Recipients

A pragmatic, open-label, randomized controlled trial of Plasma-Lyte-148 versus standard intravenous fluids in children receiving kidney transplants (PLUTO)

Acute electrolyte and acid-base imbalance is experienced by many children following kidney transplant. This is partly because doctors give very large volumes of artificial fluids to keep the new kidney working. When severe, fluid imbalance can lead to seizures, cerebral edema and death. In this pragmatic, open-label, randomized controlled trial, we randomly assigned (1:1) pediatric kidney transplant recipients to Plasma-Lyte-148 or standard of care perioperative intravenous fluids (predominantly 0.45% sodium chloride and 0.9% sodium chloride solutions). We then compared clinically significant electrolyte and acid-base abnormalities in the first 72 hours post-transplant. The primary outcome, acute hyponatremia, was experienced by 53% of 68 participants in the Plasma-Lyte-148 group and 58% of 69 participants in the standard fluids group (odds ratio 0·77 (0·34 - 1·75)). Five of 16 secondary outcomes differed with Plasma-Lyte-148: hypernatremia was significantly more frequent (odds ratio 3·5 (1·1 – 10·8)), significantly fewer changes to fluid prescriptions were made (rate ratio 0·52 (0·40-0·67)), and significantly fewer participants experienced hyperchloremia (odds ratio 0·17 (0·07 – 0·40)), acidosis (odds ratio 0·09 (0·04 - 0·22)) and hypomagnesemia (odds ratio 0·21 (0·08 – 0·50)). No other secondary outcomes differed between groups. Serious adverse events were reported in 9% of participants randomized to Plasma-Lyte-148 and 7% of participants randomized to standard fluids. Thus, perioperative Plasma-Lyte-148 did not change the proportion of children who experienced acute hyponatremia compared to standard fluids. However fewer fluid prescription changes were made with Plasma-Lyte-148, while hyperchloremia and acidosis were less common.

Prevalence of mycophenolate mofetil discontinuation and subsequent outcomes in pediatric kidney transplant recipients: A PNRC study.

Mycophenolate Mofetil (MMF) is an effective immunosuppressant used in kidney transplant recipients to prevent acute rejection. Complications such as diarrhea, leukopenia, and infections may necessitate the reduction or discontinuation of MMF. The objective of the study was to investigate the prevalence, timing, and reasons for MMF discontinuation and its association with outcomes in pediatric kidney transplant recipients. Seven Pediatric Nephrology Research Consortium (PNRC) centers participated in a retrospective analysis of kidney transplant recipients <21 years of age. Characteristics and outcomes of patients in whom MMF was discontinued were compared to those who continued taking MMF throughout the first 2 years post-transplant. The study population included 288 participants (mean age 11.2 years) from 7 North American transplant centers. MMF was discontinued in 93/288 (32%) of participants. Common reasons for discontinuation included infections (35%), diarrhea (32%), leukopenia (15%), and others (18%). Increased cumulative alloimmunity (55% vs. 42%, p = .02), increased number of hospitalizations (82% vs. 67%, p = .01), and viral replications (79% vs. 47%, p < .0001) were observed in the MMF discontinuation group compared to the continuation group. Greater eGFR decline also occurred in the MMF discontinuation group over 2 years of follow-up (-7 vs. -1 mL/min/1.73 m2 , p = .05). Almost a third of pediatric kidney transplant recipients who begin MMF for maintenance immunosuppression have it discontinued within the first 2 years post-transplant, and this subset of patients is more likely to experience adverse outcomes. New strategies are needed to manage MMF therapy and improve post-transplant outcomes.

Holistic care and symptom management for pediatric kidney transplant recipients.

While many aspects of life may improve substantially for children and young people undergoing kidney transplant, there may be new challenges including symptoms that can be detrimental to health-related quality of life. Addressing symptoms requires attention to patient and family perspectives and a holistic approach grounded in symptom management. The interdisciplinary pediatric nephrology transplant team should be attuned to the prevalence of common symptoms including fatigue, anxiety, depression, post-traumatic stress, pain, and sleep disturbances, as well as poor body image and sexual health. These common symptoms require regular assessment with a focus on appropriate interventions and how care may be impacted by transplant status.

Safety and Immunogenicity of Live Viral Vaccines in a Multicenter Cohort of Pediatric Transplant Recipients

Live vaccines (measles-mumps-rubella [MMR] and varicella-zoster virus [VZV]) have not been recommended after solid organ transplant due to concern for inciting vaccine strain infection in an immunocompromised host. However, the rates of measles, mumps, and varicella are rising nationally and internationally, leaving susceptible immunocompromised children at risk for life-threating conditions. To determine the safety and immunogenicity of live vaccines in pediatric liver and kidney transplant recipients. This cohort study included select pediatric liver and kidney transplant recipients who had not completed their primary MMR and VZV vaccine series and/or who displayed nonprotective serum antibody levels at enrollment between January 1, 2002, and February 28, 2023. Eligibility for live vaccine was determined by individual US pediatric solid organ transplant center protocols. Exposure was defined as receipt of a posttransplant live vaccine. Transplant recipients received 1 to 3 doses of MMR vaccine and/or 1 to 3 doses of VZV vaccine. Safety data were collected following each vaccination, and antibody levels were obtained at 0 to 3 months and 1 year following vaccination. Comparisons were performed using Mann-Whitney U test, and factors associated with development of postvaccination protective antibodies were explored using univariate analysis. The cohort included 281 children (270 [96%] liver, 9 [3%] kidney, 2 [1%] liver-kidney recipients) from 18 centers. The median time from transplant to enrollment was 6.3 years (IQR, 3.4-11.1 years). The median age at first posttransplant vaccine was 8.9 years (IQR, 4.7-13.8 years). A total of 202 of 275 (73%) children were receiving low-level monotherapy immunosuppression at the time of vaccination. The majority of children developed protective antibodies following vaccination (107 of 149 [72%] varicella, 130 of 152 [86%] measles, 100 of 120 [83%] mumps, and 124 of 125 [99%] rubella). One year post vaccination, the majority of children who initially mounted protective antibodies maintained this protection (34 of 44 [77%] varicella, 45 of 49 [92%] measles, 35 of 42 [83%] mumps, 51 of 54 [94%] rubella). Five children developed clinical varicella, all of which resolved within 1 week. There were no cases of measles or rubella and no episodes of graft rejection within 1 month of vaccination. There was no association between antibody response and immunosuppression level at the time of vaccination. The findings suggest that live vaccinations may be safe and immunogenic after solid organ transplant in select pediatric recipients and can offer protection against circulating measles, mumps, and varicella.

BK Virus Infections in Pediatric Kidney Transplant Recipients: A Single-Center Experience

BK Virus Infections in Pediatric Kidney Transplant Recipients: A Single-Center Experience

Programmed cell death ligand 1 expression associated with subtypes of post-transplant lymphoproliferative disorder among pediatric kidney transplant recipients.

Programmed cell death ligand 1 (PD-L1) expression on tumor cells engages the PD-1 receptor on T cells, inhibiting anti-tumor responses. PD-L1 has been detected in cases of post-transplant lymphoproliferative disorder (PTLD) but reports are limited. Here we examine PD-L1 expression and evaluate for clinical correlations. Twenty-one cases of PTLD were identified among pediatric kidney transplant recipients at our institution from February 1996 to April 2017. Using paraffin-embedded tissue biopsies, we examined 21 primary tumors for expression using PD-L1 monoclonal antibody performed with PAX5 as a double stain. We scored expression of PD-L1 on lesional B-cells as a percentage of positive cells. Clinical course and outcome were obtained from retrospective chart review. Applying revised 2017 WHO PTLD classification showed five non-destructive, nine polymorphic, and seven monomorphic cases. Average PD-L1 expression based upon PTLD subtype was: non-destructive 11%, polymorphic 43%, and monomorphic 73% (p=.01). Two patients transferred shortly after diagnosis, five received chemotherapy, and three died from PTLD. Among the fatalities, all showed monomorphic PTLD and 90% of lesional B-cells expressed PD-L1. In this case series, significant differences in PD-L1 expression were seen among different subtypes, and monomorphic PTLD demonstrated the highest expression. Study of a larger cohort is needed, and if the correlation of PD-L1 expression and PTLD subtype is confirmed, this may highlight the potential utility of checkpoint inhibitor therapy in cases of severe or refractory disease among kidney transplant recipient in whom the risk of allograft loss is acceptable given the option of chronic dialysis.

More than four decades of graft survival in pediatric kidney transplant recipients.

Early in the history of kidney transplantation, short-term graft survival was low. Yet some have had excellent long-term survival. Herein, we describe characteristics of pediatric recipients with > 40years of graft survival currently alive with a functioning first graft. We reviewed all pediatric (age < 18years) kidney transplants performed at the University of Minnesota between January 1, 1970, and December 31, 1979 (n = 148), to identify all recipients currently alive with a functioning first graft. Data are presented as medians with interquartile ranges (IQR) and proportions. We identified 10 recipients with > 40-year graft survival (median follow-up: 45.0years (IQR: 43.1, 48.1)). The median age at transplant was 13.8years (IQR: 5.1, 16.3). All recipients were white; half were male. Of the 10, 4 had glomerulonephritis, 2 had congenital anomalies of the kidney and the urinary tract, 2 had congenital nephrotic syndrome, 1 had Alport syndrome, and 1 had cystic kidney disease as kidney failure cause. Nine patients received a living-related donor transplant, and 1 patient received a deceased-donor transplant. The median estimated glomerular filtration rate at 20years post-transplant was 79.9 (IQR: 72.3, 98.4); at 30years, 67.7 (IQR: 63.2, 91.8); and at 40years, 80.3ml/min/1.73 m2 (IQR: 73.7, 86.0). None developed rejection, 5 developed hypertension, 2 developed dyslipidemia, 1 developed diabetes, and 7 patients developed malignancy (4 skin cancer, 2 breast cancer, and 1 post-transplant lymphoproliferative disease). Pediatric kidney transplant recipients may achieve > 4 decades of graft survival. Cancer is a common complication warranting vigilant screening.

Incidence, risk factors, and outcomes of recurrent focal segmental glomerulosclerosis in pediatric kidney transplant recipients: A systematic review and meta-analysis.

Focal segmental glomerulosclerosis is the most prevalent acquired kidney disease leading to end-stage renal disease in children and has a propensity for recurring in the transplanted kidney. The recurrence of FSGS after kidney transplantation in children varies greatly. In addition, the risk factors and outcomes of recurrence of FSGS remain controversial. This study evaluated the recurrence rate, risk factors, and prognosis of FSGS after kidney transplantation in order to provide advice and assistance in clinical decision-making for pediatric kidney transplantation. PubMed, Embase, Web of Science, CNKI, and other databases were searched from the establishment of the repository to March 2022. We extracted data on incidence, risk factors, and outcomes. The results showed that the recurrence rate of primary FSGS in children after renal transplantation was 48% (95% CI 36%-59%) and the recurrence rate of FSGS (all forms) was 35% (95% CI 17%-52%). The graft loss rate of primary FSGS in children after kidney transplantation was 29% (95% CI 17%-42%) and the graft loss rate of FSGS (all forms) was 29% (95% CI 4%-62%). 57% (95% CI 42%-73%) of pediatric patients with recurrent primary FSGS showed complete remission. Risk factor analyses showed that age of onset (SMD .69, 95% CI .20-1.19, p=.006) was related to the recurrence of primary FSGS, whereas the living related donor was not a risk factor for recurrent primary FSGS in pediatrics after kidney transplantation (OR 1.22, 95% CI .48-3.10, p=.674). The recurrence rate and graft loss rate of FSGS in children after kidney transplantation were relatively high. Age at onset was associated with a risk for recurrent primary FSGS, whereas the living related donor was not a risk factor for recurrent FSGS in pediatric kidney recipients.

Continuous allocation: The problem with EPTS and pediatric kidney candidates.

The 2014 Kidney Allocation System (KAS) introduced longevity matching for adult candidates using the Estimated Post-Transplant Survival (EPTS) score, which includes candidate age, time on dialysis, diabetes status, and number of previous solid organ transplants. The proposed continuous distribution framework may expand the use of this attribute to pediatric candidates, but there is no data on its performance among pediatric kidney transplant recipients. We performed a retrospective cohort study of 6800 pediatric kidney transplant recipients from 2001 to 2011 using Organ Procurement and Transplantation Network (OPTN) data. EPTS score was calculated for each patient and compared to reported patient survival to estimate the validity of the score in children. The median age of patients was 14.01 years (IQR 9.29-16.37 years), and dialysis vintage was 0.67 years (IQR 0-1.82 years). 18.2% of the cohort had a prior transplant and 1% had diabetes. Median EPTS score was 2 (IQR 1-2). Seven percent of patients died during the study period and 54.7% of the cohort was censored prior to 10 years. The c-statistic was 0.505 (95% CI: 0.49-0.53). Overall, EPTS is not a valid predictor of patient survival among pediatric kidney transplant recipients.

Understanding the impact of pediatric kidney transplantation on cognition: A review of the literature.

Chronic kidney disease (CKD) is a relatively rare childhood disease that is associated with a wide array of medical comorbidities. Roughly half of all pediatric patients acquire CKD due to congenital anomalies of the kidneys and urinary tract, and of those with congenital disease, 50% will progress to end-stage kidney disease (ESKD) necessitating a kidney transplantation. The medical sequelae of advanced CKD/ESKD improve dramatically following successful kidney transplantation; however, the impact of kidney transplantation on neurocognition in children is less clear. It is generally thought that cognition improves following kidney transplantation; however, our knowledge on this topic is limited by the sparsity of high-quality data in the context of the relative rarity of pediatric CKD/ESKD. We conducted a narrative review to gauge the scope of the literature, using the PubMed database and the following keywords: cognition, kidney, brain, pediatric, neurocognition, intelligence, executive function, transplant, immunosuppression, and neuroimaging. There are few published longitudinal studies, and existing work often includes wide heterogeneity in age at transplant, variable dialysis exposure/duration prior to transplant, and unaccounted cofounders which persist following transplantation, including socio-economic status. Furthermore, the impact of long-term maintenance immunosuppression on the brain and cognitive function of pediatric kidney transplant (KT) recipients remains unknown. In this educational review, we highlight what is known on the topic of neurocognition and neuroimaging in the pediatric KT population.

Demographic Factors, Medication Adherence, and Post-transplant Health Outcomes: A Longitudinal Multilevel Modeling Approach.

Few studies in pediatric solid organ transplantation have examined non-adherence to immunosuppressive medication over time and its associations with demographic factors and post-transplant outcomes including late acute rejection and hospitalizations. We examined longitudinal variation in patient Medication Level Variability Index (MLVI) adherence data from pediatric kidney, liver, and heart transplant recipients. Patient and administrative data from the United Network for Organ Sharing were linked with electronic health records and MLVI values for 332 patients. Multilevel mediation modeling indicated comparatively more variation in MLVI values between patients than within patients, longitudinally, over 10years post transplant. MLVI values significantly predicted late acute rejection and hospitalization. MLVI partially mediated patient factors and post-transplant outcomes for patient age indicating adolescents may benefit most from intervention efforts. Results demonstrate the importance of longitudinal assessment of adherence and differences among patients. Efforts to promote medication adherence should be adapted to high-risk patients to increase likelihood of adherence.

Risk for graft loss in pediatric and young adult kidney transplant recipients due to recurrent IgA nephropathy

IgA nephropathy (IgAN) is associated with a risk for posttransplant recurrence. Data are limited regarding graft loss attributable to recurrence of IgAN among pediatric and young adult kidney transplant (KT) recipients. This was a retrospective cohort study of patients aged 0 to 25 years from the Scientific Registry of Transplant Recipients who received a primary KT for IgAN. Patients with history of KT attributable to renal dysplasia were comparators. Outcomes included the incidence of graft loss attributable to IgAN recurrence, association with donor type, and posttransplant corticosteroid use. In total, 5475 transplant recipients were included, with 1915 patients with IgAN and 3560 patients with renal dysplasia. In a multivariable Cox proportional hazards model, IgAN was associated with higher risk of graft loss (adjusted hazard ratio [aHR], 1.35; 95% CI, 1.21-1.50; P < .001) compared with dysplasia. Graft loss was attributed to recurrent disease in 5.4% of patients with IgAN. In a multivariable competing risks analysis, patients with IgAN receiving a parental living-donor kidney were more likely to report graft loss from recurrent disease compared with patients with a nonparental living donor (aHR, 0.52; 95% CI, 0.31-0.91; P = .02). Posttransplant prednisone use was not associated with improved graft survival (P = .2). These data challenge existing paradigms in posttransplant management of patients with IgAN.

Utilization of donor-derived Cell-Free DNA in pediatric kidney transplant recipients: A single center study.

Forty-two pediatric kidney transplant patients were enrolled between February 2020 and August 2021. Dd-cfDNA was tested before and after biopsy/rejection treatment. There was a total of 61 allograft biopsies (44 for-cause, 17 surveillance). Graft rejection was found in 35/61 biopsies. Rejection was more common in basiliximab induction compared to rATG (77.1% vs. 22.9%, p = .0121). Median dd-cfDNA was higher in those with rejection (1.2% [0.34-3.12] vs. 0.24% [0.08-0.78], p < .0001). Dd-cfDNA was highest in biopsies with AMR and mixed AMR/TCMR. In addition, dd-cfDNA in basiliximab induction was higher compared to rATG (0.92% [0.27-1.8] vs. 0.26% [0.08-2], p = .0437). Median change in dd-cfDNA after rejection treatment was -0.57% (-1.67 to 0.05). Median time to dd-cfDNA <1% post-rejection treatment was 8.5 days (3.0-19.5). Dd-cfDNA in AMR was higher compared to TCMR or mixed rejection, and levels remained higher in AMR after treatment. In surveillance biopsies, 4/17 had rejection. Median dd-cfDNA was not different in those with versus without rejection (0.48% vs. 0.28%, p = .2342). Those without rejection all had dd-cfDNA <1%. In those with rejection, only one patient had dd-cfDNA >1%, and all had TCMR. Our findings support dd-cfDNA as a useful indicator of graft rejection and response to treatment. Additional studies are needed to determine the role of dd-cfDNA in graft health surveillance.

Lipid abnormalities in pediatric kidney transplant recipients on steroid withdrawal maintenance immunosuppression.

Dyslipidemia is a modifiable risk factor for cardiovascular disease. The prevalence of dyslipidemia in pKTR (pediatric kidney transplant recipients) under modern immunosuppression remains unknown. We determined the prevalence, risk factors, co-morbidities, and treatment patterns of lipid abnormalities in pediatric kidney transplant recipients on steroid withdrawal immunosuppression. pKTR (age ≤ 21years) at a single center on steroid withdrawal immunosuppression underwent lipid screening between January 1, 2020, and September 30, 2022. Continuous and categorical variables were compared using the Wilcoxon rank-sum and chi-square or Fisher's exact tests, respectively. The correlation between total cholesterol and BMI (body mass index) was assessed using Pearson's product-moment correlation, and predictors of lipid abnormalities were evaluated using the multivariable logistic regression. A total of 96 patients were included, with a median post-transplant time of 2.5years (IQR: 1.3-5.4). Of the total, 64.6% (n = 62) of patients had a fasting lipid abnormality. We found a significant linear correlation between total cholesterol and BMI (r = 0.38, p = 0.0022). After multivariable adjustment, every 1ml/min/1.73 m2 increase in eGFR was associated with a 2% lower odds of a lipid abnormality (OR 0.979, p = 0.026). Obesity, hypertension, and left ventricular hypertrophy were similar between those with and without lipid abnormalities, while insulin-treated diabetes was more prevalent in recipients with lipid abnormalities (12.9% vs. 0%, p = 0.047). Only 36.5% of patients (n = 19) were referred to a dietician and/or lipid specialist; one received statin therapy. Lipid abnormalities are highly prevalent in pKTR, but therapeutic intervention is infrequent. Calcineurin inhibition without corticosteroids may not be protective; however, higher eGFR is associated with a lower prevalence of lipid abnormalities. A higher resolution version of the Graphical abstract is available as Supplementary information.

Significant Effects of Renal Function on Mycophenolic Acid Total Clearance in Pediatric Kidney Transplant Recipients with Population Pharmacokinetic Modeling.

Mycophenolic acid (MPA) is an immunosuppressant commonly prescribed in pediatric kidney transplantation to prevent graft rejection. Large variabilities in MPA plasma exposures have been observed in this population, which could result in severe adverse effects. The majority of the MPA pharmacokinetic data have been reported in adult populations, whereas information in pediatric patients is still very limited. The objective of this study was to establish a novel, nonlinear mixed-effects model for MPA and investigate the clinical variables affecting MPA population pharmacokinetics in pediatric kidney transplant recipients. Data were collected retrospectively from pediatric kidney transplant patients (≤ 18 years when MPA concentrations were initially collected; on oral administration of mycophenolate mofetil) in Calgary, Alberta, Canada. Nonlinear mixed-effect modeling was conducted using stochastic approximation expectation-maximization in Monolix 2021R2 (Lixoft SAS, France) to determine population pharmacokinetic estimates, interindividual variabilities, and interoccasional variabilities. Covariate models were constructed using the Model Proposal function in Monolix in conjunction with a systematic stepwise inclusion/elimination protocol. The best model was selected based on objective function values, relative standard errors, goodness-of-fit plots, prediction-corrected visual predictive checks, and numerical predictive checks. A total of 50 pediatric kidney transplant patients (25 female) with 219 MPA plasma concentration-time profiles were included. The average age (± standard deviation) and posttransplant time for the sample population were 12.8 ± 4.8 years and 762 ± 1160 days, respectively. The majority of study subjects (i.e., > 85% based on all occasions) were co-administered tacrolimus. A two-compartment, first-order absorption with lag time and linear elimination structural model with lognormal distributed proportional residual errors best described the MPA concentration-time data. The absorption rate constant (2.52 h-1 or 0.042 min-1), lag time (0.166 h or 9.96 min), volumes of distributions of the central (22.8 L) and peripheral (216 L) compartments, and intercompartment clearance (17.6 Lh-1 or 0.293 Lmin-1) were consistent with literature values; whereas total MPA clearance (0.72 Lh-1 or 0.012 Lmin-1) was relatively reduced, likely due to the general lack of cyclosporine interactions and the stabilized graft functions from significantly longer posttransplant time in our sample population. Of the clinical variables tested, only estimated glomerular filtration rate (eGFR) was identified a significant covariate affecting total MPA clearance with a positive, exponential relationship. The final population pharmacokinetic model was successfully evaluated/validated using a variety of complementary methods. We have successfully constructed and validated a novel population pharmacokinetic model of MPA in pediatric kidney transplant patients. A positive, nonlinear relationship between eGFR and total MPA clearance identified in our model is likely attributed to multiple concurrent mechanisms, which warrant further systematic investigations.