Four pediatric patients with autosomal recessive polycystic kidney disease developed new‐onset diabetes after renal transplantation

NODAT is increasingly prevalent. Compared with adult recipients, NODAT is less prevalent in pediatric renal transplant recipients; however, some risk factors for its development in young patients have been defined. We report four pediatric renal transplant recipients with ARPKD who developed NODAT. We review the current pediatric NODAT literature and hypothesize that ARPKD may be an additional risk factor for NODAT.     

New‐onset diabetes mellitus after pediatric liver transplantation

In the first five yr after liver transplant, approximately one in 10 pediatric recipients will develop NODAT. Factors associated with higher risk for NODAT have been difficult to identify due to lack of uniformity in reporting and data collection. Limited studies have reported higher risk in those who are at an older age at transplant, those with high‐risk ethnic backgrounds, and in those with particular underlying conditions, such as CF and primary sclerosing cholangitis. Immunosuppressive medications, including tacrolimus, cyclosporine A, GC, and sirolimus, have been implicated as contributing to NODAT, to varying degrees. Identifying those at highest risk, appropriately screening, and diagnosing NODAT is critical to initiating timely treatment and avoiding potential complications. In the pediatric population, treatment is limited primarily to insulin, with some consideration for metformin. Children with NODAT should be monitored carefully for complications of DM, including microalbuminuria, hypertension, hyperlipidemia, and retinopathy.     

Lymphocyte‐depleting induction therapy lowers the risk of acute rejection in African American pediatric kidney transplant recipients

The use of lymphocyte‐depleting induction immunosuppression has been associated with a reduction in risk of AR after KT among adult recipients, particularly among high‐risk subgroups such as AAs. However, data on induction regimen and AR risk are lacking among pediatric KT recipients. We examined outcomes among 7884 first‐time pediatric KT recipients using SRTR data (2000‐2014). Characteristics were compared across race using Wilcoxon rank‐sum tests for continuous and chi‐square tests for categorical variables. Risk of AR was estimated using modified Poisson regression, stratified by recipient race, adjusting for recipient age, gender, BMI, primary diagnosis, number of HLA mismatches, maintenance immunosuppression, and donor type. Risk of AR within 1 year was lower in AA recipients receiving lymphocyte‐depleting induction (ATG or alemtuzumab; RR, 0.66; 95% CI, 0.52‐0.83 P < .001) compared to AA recipients receiving anti‐IL‐2 receptor antibody induction. This difference was not seen in non‐AA recipients receiving lymphocyte‐depleting induction (RR, 0.93; 95% CI, 0.81‐1.06, P = .26) compared to IL‐2 induction. These findings support a role for lymphocyte‐depleting induction agents in AA pediatric patients undergoing KT and continued use of IL‐2 inhibitor induction in non‐AA pediatric KT recipients.     

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.     

Prediction of medication non‐adherence and associated outcomes in pediatric kidney transplant recipients

Studies have continued to evaluate risk factors associated with post‐transplant non‐adherence in pediatric patients. However, many of these studies fail to evaluate how risk factors can be utilized to predict MNA. The aims of this study were to (i) determine salient risk factors associated with MNA to develop an adequate predictive risk model and (ii) assess transplant outcomes based on the presence of MNA in a large, diverse cohort of pediatric KTX recipients. One hundred and seventy‐five solitary pediatric KTX recipients transplanted from 1999 to 2013 were included. AA, males, older patients, those who lived in urban environments, had legal issues, and lived shorter distances from the transplant center were more likely to have MNA. Using logistic regression, a parsimonious model applying nine risk factors together was developed for predicting MNA, demonstrating a PPV of 69% and a NPV of 81%. Patients with MNA had more than twice the risk of biopsy proven acute rejection, 1.6 times the risk of hospitalization, and 1.8 times the risk of graft loss. Utilization of a predictive model to determine risk of MNA after pediatric KTX may offer clinicians the ability to efficiently and effectively monitor MNA following transplant.     

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.     

Comparison of outcomes with low-dose anti-thymocyte globulin, basiliximab or no induction therapy in pediatric kidney transplant recipients: a retrospective study

It is unclear which induction therapy yields the best outcomes in pediatric kidney transplantation. Retrospective data of 88 children receiving a renal allograft between November 1996 and October 2003 were analyzed. Patients received ATGI (n = 12), BI (n = 29), or NAI (n = 47). The mean ATG dose was 5.1 +/- 2.1 mg/kg. At 12 months, graft survival rates were 91.7%, 100%, and 97.9% for ATGI, BI, and NAI groups, respectively. Acute rejection rates at 12 months were 0 (ATGI), 20.6% (BI), and 10.7% (NAI). The mean GFR for ATGI (42.4 +/- 25.9 mL/min) was lower than for BI (78.3 +/- 27.2 mL/min), and NAI (66 +/- 28.3 mL/min) at 12 months (p < 0.05). One ATGI patient developed CMV pneumonia but none developed post-transplant lymphoproliferative disorder. Although there was no renal allograft survival benefit with either ATGI or BI, relative to NAI, the absence of acute rejection and equivalent rates of viral infections in the higher-risk ATGI recipient group suggests that the treatment strategy is promising. A large prospective study is needed to better define the role of ATGI in pediatric kidney transplantation.     

Pediatric risk to orthotopic heart transplant (PRO) score: Insights from United Network for Organ Sharing (UNOS) waitlist mortality findings

Background

Pediatric heart transplant candidates on the waitlist have the highest mortality rate among all solid organ transplants. A risk score incorporating a candidate's individual risk factors may better predict mortality on the waitlist and optimize organ allocation to the sickest of those awaiting transplant.

Methods

Using the United Network for Organ Sharing (UNOS) database, we evaluated a total of 5542 patients aged 0–18 years old on the waitlist for a single, first time, heart transplant from January 2010 to June 2019. We performed a univariate analysis on two-thirds (N = 3705) of these patients to derive the factors most associated with waitlist mortality or delisting secondary to deterioration within 1 year. Those with a p <0.2 underwent a multivariate analysis and the resulting factors were used to build a prediction model using the Fine-Grey model analysis. This predictive scoring model was then validated on the remaining one-third of the patients (N = 1852).

Results

The Pediatric Risk to OHT (PRO) scoring model utilizes the following unique patient variables: blood type, diagnosis of congenital heart disease, weight, presence of ventilator support, presence of inotropic support, extracorporeal membrane oxygenation (ecmo) status, creatinine level, and region. A higher score indicates an increased risk of mortality. The PRO score had a predictive strength of 0.762 as measured by area under the ROC curve at 1 year.

Conclusion

The PRO score is an improved predictive model with the potential to better assess mortality for patients awaiting heart transplant.     

Long‐term outcomes of pediatric kidney transplant recipients with a pretransplant malignancy

A childhood malignancy can rarely progress to ESRD requiring a KT. To date, few reports describe long‐term outcomes of pediatric KT recipients with a pretransplant malignancy. Between 1963 and 2015, 884 pediatric (age: 0‐17 years old) recipients received 1055 KTs at our institution. KT outcomes were analyzed in children with a pretransplant malignancy. We identified 14 patients who had a pretransplant malignancy prior to KT; the majority were <10 years old at the time of KT. Ten (71%) patients received their grafts from living donors, the majority of which were related to the recipient. Wilms' tumor was the dominant type of pretransplant malignancy, seen in 50% of patients. The other pretransplant malignancy types were EBV‐positive lymphoproliferative disorders, non‐EBV‐positive lymphoma, leukemia, neuroblastoma, soft‐tissue sarcoma, and ovarian cancer. Ten of the 14 patients received chemotherapy as part of their pretransplant malignancy treatment. Graft survival at 1, 3, and 5 years was 93%, 83%, and 72%, respectively. Patient survival at 1, 5, and 10 years was 100%, 91%, and 83%, respectively. Six (40%) patients suffered AR following KT; half of them had their first episode of AR within 1 month of KT. Our single‐center experience demonstrates that pediatric KT recipients with a previously treated pretransplant malignancy did not exhibit worse outcomes than other pediatric KT patients.     

New‐onset diabetes after pediatric heart transplantation: A review of the Pediatric Heart Transplant Study

NDT is a well‐defined complication after solid organ transplantation. Little has been published describing the incidence, risk factors, and effect on outcome after pediatric heart transplantation. We performed a retrospective evaluation of pediatric patients from the PHTS registry from 2004 to 2014. Group comparison, associated factors, incidence using Kaplan‐Meier method, and risk factor and outcome analysis for NDT at 1 year post‐transplant. Of the 2185 recipients, 1756 were alive and followed at 1 year. Overall freedom from NDT was 98.9%, 94.7%, and 92.6% at 1, 5, and 10 years, respectively. Patients with NDT were more likely to be black (non‐Hispanic; P = 0.002), older at time of transplant (P < 0.0001), and have a higher BMI percentile at time of transplant (P < 0.0001). Adjusted risk factors for NDT at 1 year were older age at transplant (years; >12 years, OR: 8.8 and 5‐12 years, HR: 8.0), obese BMI percentile at time of transplant (OR: 3.8), and steroid use at 30 days after transplant (OR: 4.7). Though uncommon, NDT occurs with a constant hazard after pediatric heart transplant; it occurs more often in older patients at transplant, those who are of black race, those who are obese, and those who use steroids. Therefore, targeted weight reduction and selective steroid use in at‐risk populations could reduce the incidence of early NDT. Further data are needed to determine the risk imparted by transplantation, factors that predict late‐onset NDT, and whether NDT alters the outcome after transplant.     

Antibody‐mediated rejection with the presence of glomerular crescents in a pediatric kidney transplant recipient: A case report

Glomerular crescents in kidney transplantation are indicative of severe glomerular injury and constitute a hallmark of RPGN. Their concurrence with ABMR has been rarely described only in adult patients. We report a case of 10‐year‐old boy with compound heterozygous Fin‐major Finnish‐type congenital nephrotic syndrome, who had received a deceased‐donor kidney transplant 5 years before onset of acute kidney injury and nephrotic range proteinuria without hematuria. Kidney allograft biopsy illustrated 6 glomeruli with global sclerosis and 6 with remarkable circumferential or segmental cellular crescents. Negative glomerular immunofluorescence for immune‐complex deposits and the absence of serum ANCA eliminated the presence of immune‐mediated and ANCA‐positive pauci‐immune crescentic glomerulonephritis. Diagnosis of ABMR was based on the high levels of HLA class II DSA and the histological evidence of glomerulitis, peritubular capillaritis, and acute tubular injury with positive linear peritubular capillary C4d staining. The patient despite plasmapheresis and enhanced immunosuppressive treatment progressed to end‐stage renal disease. We conclude that glomerular crescents may represent a finding of AMBR and possibly a marker of poor allograft prognosis in pediatric patients.     

Analysis of rabbit anti‐thymocyte globulin vs basiliximab induction in pediatric liver transplant recipients

Literature is limited comparing induction immunosuppression in pediatric liver transplant (LTx) recipients. This is a single‐center, retrospective cohort study of primary pediatric liver transplants at our center between 2005 and 2016 who received either basiliximab (BSX) or rabbit anti‐thymocyte globulin (rATG) induction. Maintenance immunosuppression consisted of tacrolimus ± a corticosteroid taper. Exclusions included receipt of an ABO‐incompatible graft, retransplantation, and multi‐organ transplantation. Primary outcomes were incidence of treated biopsy‐proven acute rejection (tBPAR) and PTLD within the first year and infections within 90 days of LTx. Secondary outcomes included graft and patient survival, time to first tBPAR, and incidence of steroid‐resistant rejection (SRR) within the first year post‐LTx. A total of 136 patients were included in the final analysis of which 57 patients (42%) received BSX induction. Patients who received rATG induction with or without a 2‐week corticosteroid taper experienced significantly more tBPAR compared to those who received BSX induction with a 6‐month corticosteroid taper (55.7% vs 33.3%, P = .01). There were no differences in the incidence of PTLD, infections, SRR, graft or patient survival, or time to first tBPAR between the two groups . Induction with rATG either with or without a short corticosteroid taper was associated with significantly more tBPAR in primary pediatric LTx recipients when compared to BSX induction with a prolonged corticosteroid taper in the setting of maintenance immunosuppression with tacrolimus.     

T-cell infiltrate intensity is associated with delayed response to treatment in late acute cellular rejection in pediatric liver transplant recipients

Background

Late acute cellular rejection (ACR) is associated with donor-specific antibodies (DSA) development, chronic rejection, and allograft loss. However, accurate predictors of late ACR treatment response are lacking. ACR is primarily T-cell mediated, yet B cells and plasma cells (PC) also infiltrate the portal areas during late ACR. To test the hypothesis that the inflammatory milieu is associated with delayed response (DR) to rejection therapy, we performed a single-center retrospective case-control study of pediatric late liver ACR using multiparameter immunofluorescence for CD4, CD8, CD68, CD20, and CD138 to identify immune cell subpopulations.

Methods

Pediatric liver transplant recipients transplanted at <17 years of age and treated for biopsy-proven late ACR between January 2014 and 2019 were stratified into rapid response (RR) and DR based on alanine aminotransferase (ALT) normalization within 30 days of diagnosis. All patients received IV methylprednisolone as an initial rejection treatment. Immunofluorescence was performed on archived formalin-fixed paraffin embedded (FFPE) liver biopsy tissue.

Results

Liver biopsies from 60 episodes of late ACR in 54 patients were included in the analysis, of which 33 were DR (55%). Anti-thymocyte globulin was only required in the DR group. The frequency of liver-infiltrating CD20⁺ and CD8⁺ lymphocytes and the prevalence of autoantibodies were higher in the DR group. In univariate logistic regression analysis, serum gamma-glutamyl transpeptidase (GGT) level at diagnosis, but not ALT, Banff score or presence of DSA, predicted DR.

Conclusions

Higher serum GGT level, presence of autoantibodies, and increased CD8⁺ T-cell infiltration portends DR in late ACR treatment in children.     

Impact of active antibody‐mediated rejection treatment on donor‐specific antibodies in pediatric kidney transplant recipients

AMR is a major cause of graft loss after kidney transplantation. We evaluated a retrospective cohort of 13 pediatric kidney transplant patients diagnosed with active AMR. All 13 patients were treated with plasmapheresis (PP), IVIg, and rituximab. Anti‐HLA DSAs were measured at the time of transplantation, AMR diagnosis, 30 days post‐rejection treatment, 90 days post‐rejection treatment, and 24 ± 12 months post‐AMR. A total of 68 DSAs were identified from 13 patients at the time of active AMR diagnosis. The primary objective of this study was to differentiate treatment response rates between class I and class II anti‐HLA DSA post‐AMR treatment. Overall, DSAs were significantly reduced at 30 days, and the reduction was sustained at 90 days post‐treatment, even for class II anti‐HLA and strongly positive DSAs. A significant difference between class I and class II anti‐HLA DSA was observed at 30 days; however, between class significance was lost at 90‐day follow‐up due to continued class II anti‐HLA DSA treatment response. Low DSA strength was predictive of treatment response. eGFR demonstrated significant improvement 90 days after AMR diagnosis compared to the initial value at the time of AMR, and the effect was sustained for 12 months. These results suggest that the AMR treatment is effective in pediatric kidney transplant recipients with an early diagnosis of active AMR across both class I and class II anti‐HLA DSAs.     

GCV/VCVG prophylaxis against CMV DNAemia in pediatric renal transplant patients: A systematic review and meta‐analysis

CMV disease continues to stand as a significant threat to the longevity of renal transplants in children. More pediatric recipients are CMV‐negative with CMV‐positive donor serologies resulting in a HR mismatch. The length of prophylaxis with GCV or VGCV required to optimally prevent recurrence of CMVDNAemia remains unknown. This study is a meta‐analysis comparing GCV/VGCV prophylaxis regimens provided for <6 months, from 6 to <12 months, and ≥12 months after transplant in order to prevent CMVDNAemia. The search conducted involved PubMed, EMBASE, ISI Web of Science, and Cochrane Central Register from inception through December 2017. Search terms Kidney Transplantation, CMV, GCV, and VGCV provided 204 studies for abstract review. Studies excluded were those which did not itemize pediatric data separately, single case reports, and duplicate studies. Pooled analysis of five retrospective studies and one prospective study identified that there is no statistically significant difference in the incidence of CMV DNAemia when comparing <6 months of prophylaxis and >12 months of prophylaxis (23% and 15%, respectively, P = 0.23). Regardless of the length of prophylaxis, there was no statistical difference in the incidence of CMV DNAemia in the HR patients (6 to <12 months vs <6 months, P = 0.62; 6 to <12 months vs ≥12 months, P = 0.78; ≥12 months vs <6 months, P = 0.83). This study identifies no optimal length of prophylaxis for HR mismatch pediatric renal transplant patients as many develop CMV DNAemia.     

Clinical significance of anti‐HLA antibodies associated with ventricular assist device use in pediatric patients: A United Network for Organ Sharing database analysis

While VAD use in pediatric patients has previously been associated with anti‐HLA antibody production, the clinical significance of these antibodies is unclear. We investigated the clinical impact of anti‐HLA antibodies associated with VAD use in a large cohort of pediatric HTx recipients. From 2004 to 2011, pediatric cardiomyopathy patients post‐HTx (N=1288) with pre‐HTx PRA levels were identified from the United Network for Organ Sharing database. PRA levels were compared between VAD patients and those with no history of MCS. Incidence of rejection and overall survival were compared between VAD and non‐MCS groups after stratification by PRA and age. VAD recipients were more likely to produce anti‐HLA antibodies than non‐MCS patients (25.5% vs 10.5% had PRA>10%, P<.0001). Sensitized VAD patients (PRA>10%) had a higher incidence of rejection within 15 months of HTx compared to sensitized non‐MCS patients (57.1% vs 35.9%, P=.02). There was no intergroup difference in 15‐month mortality. Among pediatric cardiomyopathy patients supported with a VAD, the presence of anti‐HLA antibodies prior to HTx is associated with an increased risk of rejection. The mechanism of the association between VAD‐associated antibodies and early rejection is unclear and warrants further investigation.     

The impact of intercurrent EBV infection on ATP levels in CD4+ T cells of pediatric kidney transplant recipients

Abstract: ImmuKnow^® measures ATP (ng/mL) in PHA‐activated CD4+ T cells from patient’s whole blood. According to published reports, median ImmuKnow^® is 258 ng/mL in stable pediatric kidney transplant (PKT) recipients ≥12 yr, and 165 ng/mL in those <12 yr. However, data on the effect of infection or AR on ImmuKnow^® are scarce. We studied the effect of Epstein‐Barr virus (EBV) viremia on ImmuKnow^® in PKT with GD. Twenty‐eight PKT with GD were reviewed. Group 1 has 19 PKT ≥12 yr, and group 2 has nine PKT <12 yr. Mean follow‐up was 19.4 ± 12 months. All ImmuKnow^® values discussed in this study were measured during GD ± fever. None had ImmuKnow^® pretransplant. EBV DNA was isolated from patient blood by real‐time PCR. Group 1 has eight boys and 11 girls (mean age = 16.6 ± 2.4 yr). Group 2 has two boys and seven girls (mean age = 6 ± 3.1 yr). Median ImmuKnow^® was 292 ng/mL in group 1, and 370 ng/mL in group 2. Nine children developed EBV viremia: two in group1 (median ImmuKnow^® = 273 ng/mL), and seven in group 2 (median ImmuKnow^® = 475 ng/mL). Overall mean ImmuKnow^® in the nine EBV viremic patients was higher than that in the 19 non‐viremic ones (422 ± 176 ng/mL, and 302 ± 113 ng/mL, respectively, unequal variance t‐test, p = 0.08). Eight children developed AR (all in G1, median ImmuKnow^® = 272 ng/mL). In group 1, one patient developed concurrent EBV viremia and rejection, while another patient developed EBV viremia six months following a rejection episode. In group 2, none developed simultaneous AR, CMV, or BK virus infection with EBV viremia. None developed post‐transplant lymphoproliferative disease. In summary, EBV viremia was paradoxically associated with high ImmuKnow^® in PKT <12 yr. This suggests strong co‐stimulation of PHA‐activated CD4+ T cells by EBV‐transformed B cells.