Impact of center volume and the adoption of laparoscopic donor nephrectomy on outcomes in pediatric kidney transplantation

Reports for pediatric kidney transplant recipients suggested better outcomes for ODN compared to LDN. Contemporary outcomes stratified by donor type and center volume have not been evaluated in a national dataset. UNOS data (2000‐2014) were analyzed for pediatric living donor kidney transplant recipients. The primary outcome was GF; secondary outcomes were DGF, rejection, and patient survival. Live donor nephrectomies for pediatric recipients decreased 30% and transitioned from ODN to LDN. GF rates did not differ for ODN vs LDN (P = .24). GF was lowest at high volume centers (P < .01). Donor operative approach did not contribute to GF. LDN was associated with less rejection than ODN (OR 0.66, CI 0.5‐0.87, P < .01). Analysis of the 0‐ to 5‐yr recipient group showed no effect of ODN vs LDN on GF or rejection. For the contemporary era, there was no association between DGF and LDN in the 0‐ to 5‐yr group (OR 1.12, CI 0.67‐1.89, P = .67). Outcomes of kidney transplants in pediatric recipients following LDN have improved since its introduction and LDN should be the approach for live donor nephrectomy regardless of recipient age. The association between case volume and improved outcomes highlights future challenges in organ transplantation.     

Effects of the influenza vaccine on pediatric kidney transplant outcomes

The influenza vaccine is critical for preventing influenza‐related complications in transplant patients. Previous studies demonstrated de novo donor‐specific antibody formation and rejection following the influenza vaccination. This risk has not been adequately assessed in the pediatric population. We performed a single‐center retrospective analysis of 187 unique pediatric kidney transplant recipients, transplanted from January 1, 2006, to December 31, 2015, assessing for an association of the influenza vaccination with various transplant outcomes. The influenza vaccine was received by 125 of 187 patients within the first year post‐transplant. Using log‐rank tests and Kaplan‐Meier curves, vaccinated patients had a significantly lower risk of mortality (P = 0.048). There were no differences in death‐censored graft survival (P = 0.253), graft survival (P = 0.098), or rejection (P = 0.195) between vaccinated and unvaccinated groups. To address the problem of multiple exposures for a yearly vaccine, Cox proportional hazards regression was utilized with post‐transplant vaccination status considered as a time‐dependent covariate; analyses were performed using both a 360‐ and 180‐day vaccination period following any post‐transplant influenza vaccination. In this model, being vaccinated did not result in a significant difference in mortality (HR 0.90 [0.16, 5.15], P = 0.91), death‐censored graft survival (HR 0.70 [0.31, 1.58], P = 0.39), graft survival (HR 0.69 [0.32, 1.49], P = 0.34), or rejection (HR 0.67 [0.37, 1.19], P = 0.17). Eight patients developed de novo donor‐specific antibodies following the first post‐transplant influenza vaccination; three then developed biopsy‐proven rejection. These results suggest influenza vaccination is safe in pediatric kidney transplant recipients, and larger prospective studies are required to conclusively confirm our findings.     

Donor‐specific antibodies in a pediatric kidney transplant population—Prevalence and association with antiproliferative drug dosing

Prevalence and implications of anti‐HLA class I and class II antibodies are beginning to be better characterized in pediatric kidney transplant recipients. dnDSA formation is predictive of AMR and downstream diminished graft function and survival. However, risk factors for the development of dnDSA are not well defined in this patient population. After introducing DSA surveillance into our pediatric kidney transplant program, we are reporting the prevalence of class I and class II DSA in 67 otherwise stable recipients. Secondary end‐points included risk factors for DSA development and assessment of graft function. Significantly, lower median daily MMF doses were observed in patients with DSAs compared to patients without DSAs (371 vs 617 mg/m²/d, respectively; P = 0.035). Class II DSA formation was more common, with a prevalence of 17.9%, as compared to 10.4% for class I DSA. Estimated glomerular filtration rate was also decreased in patients with positive DSA vs those with negative titers (71, SD 25 vs 78, SD 29 mL/min/1.73 m², respectively; P = 0.034). We conclude that reduced‐dose MMF is associated with dnDSA and DSA is associated with diminished graft function in stable pediatric kidney transplant recipients.     

Use of oral immunoglobulins to treat diarrhea in pediatric kidney transplant recipients—Single‐center experience and review of the literature

Effective treatment modalities for diarrhea in solid organ transplant recipients are lacking. We evaluated the effect of oral IgG on clinical course of diarrhea in pediatric kidney transplant recipients. We retrospectively studied all pediatric kidney transplant recipients who required hospitalization for diarrhea between January 1, 2015, and December 31, 2017. We divided the recipients into two groups based on whether they had received oral IgG to treat diarrhea. Sixteen pediatric kidney transplant recipients required hospitalization for diarrhea over 3 years. Median age at admission was 9.25 years (IQR:12.54). Fifty‐six percent of recipients were male, and 81% were white. Four patients received oral IgG for prolonged diarrhea. Oral IgG recipients had longer diarrheal duration before admission (median (days) 14.5 vs1; P .02), a trend for greater weight loss at admission (median (kilogram) 1.4 vs 0.2; P .3), and a trend for higher acute kidney injury (>75% reduction in glomerular filtration rate: 100% vs 42%; P .36). Diarrhea resolved completely in 3 (75%) oral IgG recipients and 7 (58%) non‐oral IgG patients by discharge (P .99). One oral IgG recipient showed partial improvement but also had biopsy evidence of mycophenolate‐induced colitis. All patients tolerated oral IgG well. No patients required re‐hospitalization within 30 days of discharge. Oral IgG may be used safely and effectively to treat prolonged diarrhea in pediatric kidney transplant recipients. A larger, randomized, prospective study is needed to further assess the efficacy of oral IgG in the treatment of diarrhea.     

Variability of Pneumocystis jirovecii prophylaxis use among pediatric solid organ transplant providers

Pneumocystis jirovecii pneumonia (PJP) prophylaxis after pediatric solid organ transplant (SOT) is routinely recommended, but practice varies. Online survey was sent in 2018 to 707 members of the International Pediatric Transplant Association. A total of 105 responded, representing 47 institutions in 18 countries consisting of transplant physicians (66%), transplant surgeons (19%), nurse practitioners (6%), infectious disease physicians (5%), or pharmacists (4%). PJP prophylaxis was reported by 88%, while 12% did not routinely give prophylaxis. The majority not using PJP prophylaxis performed renal transplants (67%) citing low incidence of PJP (62%). Trimethoprim/sulfamethoxazole was first‐line agent (95%). PJP prophylaxis for 4‐6 months was the most frequent duration following kidney (48%, 27/56), liver (42%, 13/31), and heart (40%, 10/25) transplant. Abdominal multivisceral providers equally gave 10‐12 months (47%) or lifelong (47%); most lung transplant providers gave lifelong prophylaxis (85%). Across all organs, 21% provided lifetime prophylaxis. After completion of prophylaxis, 32% do not restart for any reason; majority of the rest would restart for treatment of acute graft rejection. 83% reported no PJP cases in the prior 12 months; 14% reporting 1‐5 infections. Only 3% reported a case of PJP infection on prophylaxis; none in SOT. PJP prophylaxis is routinely provided to pediatric SOT patients though practice and duration vary by center and organ type. Durations of 4‐6 months were most common for renal, liver, and heart transplant recipients, while 10‐12 months or lifelong prophylaxis were commonly reported for abdominal multivisceral recipients and most lung transplant recipients are given lifelong prophylaxis.     

Physical activity experiences in children post–liver transplant: Developing a foundation for rehabilitation interventions

Physical Activity (PA) plays an important role in the physical and psychosocial health of children and is beneficial in the treatment and prevention of comorbidities associated with transplantation. Despite this, PA participation in pediatric liver transplant recipients remains low compared to healthy peers. This qualitative‐focused mixed‐methods study explored the PA experiences and parental perception of these experiences, including perceived facilitators and barriers to PA in children post–liver transplant. Eighteen participants (9 children [median age 10.8 years] and 9 parents) took part in semi‐structured interviews and completed the PedsQL Multidimensional Fatigue Scale and PAQ. Most children reported they were physically active (PAQ median 3.08 [IQR] 2.60‐3.51), participating in PA for its enjoyment, regardless of their level of motor proficiency. Levels of fatigue (median 65.28 [IQR] 56.25‐90.97) were higher than healthy norms and impacted PA participation in some children. Children and parents perceived PA as central to post‐transplant recovery and valued its social and mental health benefits; however, parents struggled with ongoing uncertainty and perceived physical vulnerability of their child. This study indicates the need for continuing PA support and education and provides valuable information for family‐centered interventions to increase PA and improve health outcomes in children post‐transplant.     

Donor‐derived strongyloidiasis in a Saudi pediatric kidney transplant recipient: A case report and mini‐review

S. stercoralis infection has been identified as a donor‐derived infection in cases of solid organ transplant among recipients with no prior risk factor for parasitic exposure. Worldwide and regional reports from the adult kidney transplant population highlight this indirect method of infection and caution about delayed diagnosis, severe complications, and death related to donor‐derived S. stercoralis infection. We report a deceased‐donor‐derived S. stercoralis infection in a 12‐year‐old Saudi girl who underwent kidney transplantation. This is the first pediatric case reported outside the United States of America. Although she presented with mild bouts of gastrointestinal symptoms, the need for additional immune suppression put her at risk of serious complications. A literature review highlights the importance of awareness about S. stercoralis infections and complications in kidney transplant recipients, pretransplant screening of donors based on risk assessment, and the challenges with treatment availability and duration in this vulnerable population.     

Use of public health service increased risk kidneys in pediatric renal transplant recipients

With the opioid epidemic and expansion of “IR” classification, 25% of deceased donors are categorized PHS‐IR. Studies have assessed utilization of PHS‐IR organs among adults, but little is known about pediatric recipients. This retrospective cohort study from 2004‐2016 (IR period) aimed to: (a) assess IR kidney utilization patterns between adults and children; (b) identify recipient factors associated with transplant from IR donors among pediatric kidney recipients; and (c) determine geography's role in IR kidney utilization for children. The proportion of pediatric recipients receiving IR kidneys was significantly lower than adults (P < 0.001), even when stratified by donor mechanism of death (non‐overdose/overdose) and era. In mixed effects models accounting for clustering within centers and regions, older recipient age, later era (post‐PHS‐IR expansion), and blood type were associated with significantly higher odds of receiving an IR kidney (17 years era 5: OR 5.16 [CI 2.05‐13.1] P < 0.001; 18‐21 years era 5: OR 2.72 [CI 1.05‐7.06] P = 0.04; blood type O: OR 1.32 [CI 1.06‐1.64] P = 0.013). The median odds ratio for center within region was 1.77 indicating that when comparing two patients in a region, the odds of receiving an IR kidney were 77% higher for a patient from a center with higher likelihood of receiving an IR kidney. Utilization of PHS‐IR kidneys is significantly lower among pediatric recipients versus adult counterparts. More work is needed to understand the reasons for these differences in children in order to continue their access to this life‐prolonging therapy.     

Valganciclovir dosing using area under the curve calculations in pediatric solid organ transplant recipients

Pediatric valganciclovir dosing recommendations have not been extensively validated for prevention or treatment for CMV infection. As such, we performed a pharmacokinetic study to compare different valganciclovir dosing regimens and the potential benefits of individualized dose adjustments in children following organ transplantation. Ganciclovir AUCs were calculated from four plasma drug levels in pediatric SOT recipients aged six months through three yr receiving valganciclovir suspension by mouth. Of the 28 ganciclovir AUC calculations performed, 11 (39%) were outside the therapeutic target range of 40–60 mcg h/L leading to a valganciclovir dose adjustment. Current manufacturer‐recommended dosing based on BSA and CrCl was estimated to result in therapeutic AUCs in fewer patients than the simple weight‐based formula used in our institution (4 vs. 13; p = 0.017). An AUC calculation using only the two‐ and five‐h measurements was strongly correlated with the AUC using all four time measurements (R² = 0.846; p < 0.001). A simple weight‐based dosing approach gives a higher probability for therapeutic AUCs compared to the manufacturer‐recommended dosing in pediatric transplant patients aged six months through three yr with normal renal function. An AUC calculated using two sample times might allow for fewer blood draws in the future.     

Solid tumors following kidney transplantation in children

Kidney transplant recipients have an increased risk of cancer. Data on non‐LPD malignancies (solid tumors) in pediatric renal transplant recipients are limited. We performed a cohort study using the NAPRTCS transplant registry to describe the incidence of non‐LPD malignancy compared with the general pediatric population. The observed incidence rate of non‐LPD malignancy in the NAPRTCS transplant registry was 72.1 per 100 000 person‐years (SIR 6.7; 95% CI, 5.3, 8.5); a 6.7‐fold increased risk compared with the general pediatric population (10.7 cases per 100 000 person‐years). Non‐LPD malignancy was diagnosed in 35 subjects at a median of 726 days post‐transplant. The most common type of malignancy was renal cell carcinoma. The increased risk of non‐LPD malignancy was seen in all patients regardless of age, gender, race, etiology of end‐stage kidney disease, and transplant era. The specific type of immunosuppression was not identified as a risk factor. In this first large‐scale study of North American pediatric renal transplant recipients, we observed a 6.7‐fold increased risk of non‐LPD malignancy compared with the general pediatric population. Further examination of this unique patient population may provide greater insight into the impact of transplant and immunosuppression on malignancy risk.     

Perceived barriers to medication adherence remain stable following solid organ transplantation

Perceived barriers to adherence have previously been investigated in SOT to identify plausible intervention targets to improve adherence and transplant outcomes. Fifteen centers in CTOTC enrolled patients longitudinally. Patients >8 years completed Adolescent Scale(AMBS) at two visits at least 6 months apart in the first 17 months post‐transplant while their guardians completed PMBS. Differences over time for pre‐identified AMBS/PMBS factors were analyzed. Perceived barrier reporting impact on subsequent TAC levels was assessed. A total of 123 patients or their guardians completed PMBS or AMBS. Twenty‐six were 6‐11 years and 97 were ≥12. The final cohort consisted of kidney (66%), lung (19%), liver (8%), and heart (7%) recipients. Unadjusted analysis showed no statistically significant change in reported barriers from visit 1 (median 2.6 months, range 1.2‐3.7 post‐transplant) to visit 2 (median 12, range 8.9‐16.5). Of 102 patients with TAC levels, 74 had a single level reported at both visits. The factor of “Disease frustration” was identified through the PMBS/AMBS questions about fatigue around medication and disease. Each point increase in “disease frustration” at visit 1 on the AMBS/PMBS doubled the odds of a lower‐than‐threshold TAC level at visit 2. No clear change in overall level of perceived barriers to medication adherence in the first year post‐transplant was seen in pediatric SOT. However, disease frustration early post‐transplant was associated with a single subtherapeutic TAC levels at 12 months. A brief screening measure may allow for early self‐identification of risk.     

Health‐related quality of life among siblings of kidney transplant recipients

Studies are increasingly recognizing health‐related quality of life (HRQOL) as a key pediatric outcome in both clinical and research settings and an essential health outcome measure to assess the effectiveness of medical treatment. However, it has not yet been studied among the healthy siblings of kidney transplant recipients. The aim of this study, therefore, is to examine HRQOL among this population. We asked the following three groups to complete a validated measure of HRQOL among children (KIDSCREEN‐52 ) : siblings of children who had received kidney transplants (n = 50), kidney transplant recipients (n = 43), and a healthy control group (n = 84). We found that siblings of kidney transplant patients exhibited lower scores for financial resources and autonomy than kidney transplant recipients. They also served lower on physical well‐being, financial resources, autonomy, and parent relations/home life than the control group. However, they scored higher on social acceptance than kidney transplant recipients. Our study underscores the importance of assessing HRQOL in families including a child diagnosed with a chronic illness. Siblings require social and psychological support to promote coping and adaptation.     

Generalized and specific anxiety in adolescents following heart transplant

Mental health concerns are associated with worse outcomes after adult heart transplant. Illness‐specific anxiety is associated with worsened psychological well‐being after other solid organ transplants but has never been characterized after pediatric heart transplant. This single‐center cross‐sectional study aimed to evaluate illness‐specific and generalized anxiety after heart transplantation in adolescents. A novel 12‐item PHTF, GAD‐7, and the PedsQL were administered. Univariate associations of demographics, clinical features, and medication adherence as measured by immunosuppression standard deviation with the PHTF and GAD‐7 scores were evaluated. Internal consistency and validity of the PHTF were examined. In total, 30 patients participated. The most common illness‐specific fears were retransplantation, rejection, and more generally post‐transplant complications. The PHTF had good internal consistency (Cronbach α = .88). Construct validity was demonstrated between PHTF and GAD‐7 (r = .62) and PedsQL (r = ?.54 to ?.62). 23% endorsed moderate to severe generalized anxiety symptoms. More severe symptoms were associated with older age at survey (P = .03), older age at listing (P = .01) and having post‐transplant complications (P = .004). Patients with moderate or severe symptoms were more likely to report late immunosuppression doses (P = .004). Illness‐specific and generalized anxiety may be prevalent after pediatric heart transplant. Screening for anxiety in adolescents post‐transplant may identify those at risk for adverse outcomes including non‐adherence. The PHTF is a brief, valid, and reliable instrument identifying illness‐specific anxiety in this population.     

Non‐invasive staging of chronic kidney allograft damage using urine metabolomic profiling

Chronic kidney allograft damage is characterized by IFTA and GS. We sought to identify urinary metabolite signatures associated with severity of IFTA and GS in pediatric kidney transplant recipients. Urine samples (n = 396) from 60 pediatric transplant recipients were obtained at the time of kidney biopsy and assayed for 133 metabolites by mass spectrometry. Metabolite profiles were quantified via PLS‐DA. We used mixed‐effects regression to identify laboratory and clinical predictors of histopathology. Urine samples (n = 174) without rejection or AKI were divided into training/validation sets (75:25%). Metabolite classifiers trained on IFTA severity and %GS showed strong statistical correlation (r = .73, P < .001 and r = .72; P < .001, respectively) and remained significant on the validation sets. Regression analysis identified additional clinical features that improved prediction: months post‐transplant (GS, IFTA); and proteinuria, GFR, and age (GS only). Addition of clinical variables improved performance of the %GS classifier (AUC = 0.9; 95% CI = 0.85‐0.96) but not for IFTA (AUC = 0.82; 95% CI = 0.71‐0.92). Despite the presence of potentially confounding phenotypes, these findings were further validated in samples withheld for rejection or AKI. We identify urine metabolite classifiers for IFTA and GS, which may prove useful for non‐invasive assessment of histopathological damage.     

Bortezomib in the treatment of antibody‐mediated rejection in pediatric kidney transplant recipients: A multicenter Midwest Pediatric Nephrology Consortium study

Antibody‐mediated rejection leads to allograft loss after kidney transplantation. Bortezomib has been used in adults for the reversal of antibody‐mediated rejection; however, pediatric data are limited. This retrospective study was conducted in collaboration with the Midwest Pediatric Nephrology Consortium. Pediatric kidney transplant recipients who received bortezomib for biopsy‐proven antibody‐mediated rejection between 2008 and 2015 were included. The objective was to characterize the use of bortezomib in pediatric kidney transplant recipients. Thirty‐three patients received bortezomib for antibody‐mediated rejection at nine pediatric kidney transplant centers. Ninety percent of patients received intravenous immunoglobulin, 78% received plasmapheresis, and 78% received rituximab. After a median follow‐up of 15 months, 65% of patients had a functioning graft. The estimated glomerular filtration rate improved or stabilized in 61% and 36% of patients at 3 and 12 months post‐bortezomib, respectively. The estimated glomerular filtration rate at diagnosis significantly predicted estimated glomerular filtration rate at 12 months after adjusting for chronic histologic changes (P .001). Fifty‐six percent of patients showed an at least 25% reduction in the mean fluorescence intensity of the immune‐dominant donor‐specific antibody, 1‐3 months after the first dose of bortezomib. Non‐life‐threatening side effects were documented in 21 of 33 patients. Pediatric kidney transplant recipients tolerated bortezomib without life‐threatening side effects. Bortezomib may stabilize estimated glomerular filtration rate for 3‐6 months in pediatric kidney transplant recipients with antibody‐mediated rejection.     

Non‐invasive differentiation of non‐rejection kidney injury from acute rejection in pediatric renal transplant recipients

Acute kidney injury (AKI) is a major concern in pediatric kidney transplant recipients, where non‐alloimmune causes must be distinguished from rejection. We sought to identify a urinary metabolite signature associated with non‐rejection kidney injury (NRKI) in pediatric kidney transplant recipients. Urine samples (n = 396) from 60 pediatric transplant participants were obtained at time of kidney biopsy and quantitatively assayed for 133 metabolites by mass spectrometry. Metabolite profiles were analyzed via projection on latent structures discriminant analysis. Mixed‐effects regression identified laboratory and clinical predictors of NRKI and distinguished NRKI from T cell–mediated rejection (CMR), antibody‐mediated rejection (AMR), and mixed CMR/AMR. Urine samples (n = 199) without rejection were split into NRKI (n = 26; ΔSCr ≥25%), pre‐NRKI (n = 35; ΔSCr ≥10% and <25%), and no NRKI (n = 138; ΔSCr <10%) groups. The NRKI discriminant score (dscore) distinguished between NRKI and no NRKI (AUC = 0.86; 95% CI = 0.79‐0.94), confirmed by leave‐one‐out cross‐validation (AUC = 0.79; 95% CI = 0.68‐0.89). The NRKI dscore also distinguished between NRKI and pre‐NRKI (AUC = 0.82; 95% CI = 0.71‐0.93). In a linear mixed‐effects regression model to account for repeated measures, the NRKI dscore was independent of concurrent rejection, but there was a non‐statistical trend for higher dscores with rejection severity. A second exploratory classifier developed to distinguish NRKI from clinical rejection had similar test characteristics (AUC = 0.81, 95% CI = 0.70‐0.92, confirmed by LOOCV). This study demonstrates the potential of a urine metabolite classifier to detect NRKI in pediatric kidney transplant patients and non‐invasively discriminate NRKI from rejection.     

Across all solid organs,adolescent age recipients have worse transplant organ survival than younger age children: A US national registry analysis

Univariate analyses suggest that adolescents have worse long‐term allograft survival versus younger children across different SOT. This study's objective was to determine whether multivariate analyses of a large national database recording all deceased SOT (KI; LI; HR; LU) also show worse adolescent allograft survival in the different organs. Using data from the national Scientific Registry for Transplant Recipients in the USA for pediatric primary SOT from 1989 to 2010, we calculated median half‐lives and constructed K–M graft survival curves. Recipient age at transplant (<12 or adolescent 12–17 yr) was fitted with other identical covariates into multivariate Cox proportional hazards models. In all SOT recipients, unadjusted graft survival curves demonstrated better graft survival for adolescents initially, followed by crossing of the lines, such that adolescent SOT recipients had worse survival after one yr (KI), 4.6 yr (LI), 4.4 yr (HR), and 1.6 yr (LU). Multivariate models of the post‐cross period showed a significantly higher AHR for worse graft survival in adolescent age across all four SOTs: AHR 1.400 (KI), 1.958 (LI), 1.414 (HR), and 1.576 (LU). Improving adolescent long‐term outcomes across all four organs will be a defining issue in the future.     

Educational and learning morbidity in pediatric heart transplant recipients: A pediatric heart transplant society study

Educational development is an important component of quality of life for children with heart transplant. Aims include determining prevalence of and risk factors for modified education placement in a large representative sample of pediatric heart transplant recipients. Participants included 1495 patients (age 6‐18 years) from the PHTS database. Data on education placement and clinical predictors were collected at listing and at 1 and 3 years post‐transplant. At listing, 88% of patients were in typical education placement, while 12% were in modified education. Males (P = .02), those with CHD (P < .0001), those with non‐private insurance (P < .0001), and those with longer hospital stay (P = .001) were more likely to be in a modified education placement at time of listing. Age, race, listing status, mechanical support, and waitlist time were not significantly associated with placement. The prevalence of typical education placement was similar (87% at 1‐year and 86% at 3‐year) post‐transplant. Predictors of modified education placement at 3‐year follow‐up included placement at listing (OR = 12.9 [95% CI 7.6‐21.9], P < .0001), non‐private insurance (OR = 2.0 [95% CI 1.3‐3.2], P = .001), CHD (OR = 1.8 [95% CI 1.1‐2.7, P = .01), history of post‐transplant infection (OR = 1.9 [95% CI 1.2‐2.9, P = .007), and number of post‐transplant infections (OR = 1.3 [95% CI 1.1‐1.5, P = .002). Among pediatric heart transplant recipients, males, those with non‐private insurance, those with CHD, and those who experience post‐transplant infections are at greatest risk for modified academic placement, which persists for several years post‐transplant and deserves targeted intervention.