Helen Pizzo

Background: Choice of induction agent at the time of pediatric kidney transplantation is primarily influenced by recipient characteristics and center practice. The economic implications of this choice have not been reported in a pediatric cohort. Methods: This is a retrospective study of merged data from North American Pediatric Renal Trials and Collaborative Studies transplant registry with data in the Pediatric Health Information Systems. We estimated costs of the kidney transplant admission analyzed for association with induction agent and clinical factors. Participants were grouped by induction agent: interleukin‐2 receptor blocker (IL2RB), anti‐thymocyte globulin (ATG), and alemtuzumab. We also estimated inpatient care and other hospital‐based services during the first year after transplantation. Results: A total of 831 children and young adults < 21 years who received a kidney transplant between January 2010 through 2019 were identified. Among these, 50.5% received ATG, 31.3% received IL2RB only, and 18.2% received alemtuzumab. Among clinical characteristics studied, sex and likelihood of pre‐emptive transplant were similar among the groups. Though unadjusted index hospitalization costs (IHC) were significantly different among the induction groups, induction choice was not associated with IHC in multivariable analysis. Younger age at the time of transplantation and delayed graft function (DGF) were independently associated with higher IHC. Unadjusted hospital‐based costs incurred after discharge from the transplant procedure through the first year after transplantation were similar among induction groups. Conclusion: Among pediatric and young adult kidney transplant recipients, IHC was comparable across induction agents. Younger age at transplantation and DGF were associated with significantly higher IHC.

Background: Donor‐derived cell‐free DNA (dd‐cfDNA) is increasingly used as a noninvasive marker of kidney allograft injury, but adult‐derived cutoffs may not be applicable to pediatric recipients, particularly in the setting of donor–recipient size mismatch. We evaluated dd‐cfDNA levels in stable pediatric kidney transplant (KT) recipients and assessed variation by recipient weight and donor body mass index (BMI). Methods: Retrospective data were collected from seven U.S. pediatric KT centers. Clinically stable recipients < 18 years of age (no de novo donor specific antibody, biopsy‐proven rejection or BK viremia/nephropathy), with ≥ 2 dd‐cfDNA measurements per year were included. Recipients were stratified by weight at dd‐cfDNA collection (< 20 kg, 20–50 kg, > 50 kg). Donor BMI was categorized as underweight (≤ 18.5), normal (18.6–24.9), overweight (25–29.9), or obese (≥ 30). Comparisons were performed using linear mixed‐effects models. Results: Among 178 recipients, mean dd‐cfDNA did not differ by recipient weight (< 20 kg: 0.51 ± 0.44; 20–50 kg: 0.65 ± 1.28; > 50 kg: 0.49 ± 0.70). Median dd‐cfDNA was similar across donor BMI categories. However, among obese donors, recipients < 20 kg had 1.3‐fold higher dd‐cfDNA ( p = 0.044). Donor–recipient body surface area mismatch > 1.5 was associated with 1.083‐fold higher dd‐cfDNA up to 5 years post‐transplant ( p = 0.016). Conclusions: In stable pediatric KT recipients, dd‐cfDNA levels were well below the adult‐derived 1% cutoff, reinforcing the generalizability of this cutoff to the pediatric population. Recipients < 20 kg with donor BMI > 30 kg/m ² or in the setting of a donor‐recipient BSA mismatch > 1.5 were associated with higher dd‐cfDNA levels.

Background: Alemtuzumab is an induction immunosuppressive agent effective in preventing hyperacute rejection; however, it can result in prolonged lymphocyte depletion. Here we assessed the dosing, tolerability, and outcomes with alemtuzumab induction via IV vs. SQ route in pediatric kidney transplantation. Methods: A multicenter analysis of 119 patients < 21 years old who received alemtuzumab induction immunosuppression. Total dose (mg) and dose by body weight (mg/kg) were assessed. Tolerability was defined by the development of leukopenia (WBC < 3.0 × 10 ³ /uL) or neutropenia (ANC < 1.5 × 10 ³ /uL). Outcomes in the first year post‐transplant were defined by eGFR, hospitalizations, infections, development of de novo DSA, and rejection. Results: A total of 83 and 36 recipients received alemtuzumab IV and SQ, respectively. SQ group was slightly older, 14.0 y. (SD 5.5) vs. 11.9 y. (SD 6.1) ( p = 0.07), and had more highly sensitized recipients, 14 (38.9%) vs. 10 (12.1%) ( p = 0.002). Total dose and dose by weight were higher in the SQ group, 22.3 mg (SD 8.9) vs. 14.9 mg (SD 9.5), and 0.57 mg/kg (SD 0.21) vs. 0.36 mg/kg (SD 0.18 mg), respectively ( p = 0.0001 and p < 0.0001). SQ group experienced more leukopenia and resultant medication dose reduction; however, there were no differences between the groups in eGFR, infections, hospitalizations, and rejection in the year following transplant. Conclusion: Despite the higher dose of alemtuzumab and rates of leukopenia in the SQ group, there were no other differences in tolerability and outcomes compared to IV alemtuzumab. Overall, alemtuzumab is well tolerated during the first year post‐transplant as an induction immunosuppression agent in the pediatric population.

Background: Varicella zoster (VZV) vaccination pre-kidney transplant (Tx) can help prevent severe disseminated VZV in immunosuppressed recipients; however, studies have shown loss of humoral immunity post-Tx. Methods: A retrospective analysis of 45 pediatric kidney Tx recipients with positive pre-Tx VZV IgG (>1.09 index). VZV IgG was assessed annually and compared with the induction agent used, the number of VZV vaccines received, and the interval between the last dose of VZV vaccine and Tx. Results: Median age at Tx was 16.7 years (IQR 12.7–18.5). 11 of 45 (24.4%) patients lost immunity to VZV at a median of 12.6 months post-Tx. Those who lost VZV immunity were younger at the time of Tx, 12.4 years vs. 17.3 years ( P = 0.05) and more likely to be on steroid-based immunosuppression 81.8% vs. 32.4% ( P = 0.006). There were no differences between the induction agents used and the ability to maintain VZV IgG antibodies. Subjects who required ≥3 doses of VZV vaccine to develop VZV IgG seropositivity were at a higher risk for losing their anti-varicella antibody post-Tx (HR 3.81, 95% CI 1.09–13.30, P = 0.04). Receiving VZV vaccination <1 year prior to kidney Tx was associated with a higher risk for losing anti-varicella antibody after Tx (HR 6.97, 95% CI 2.08–23.34). Conclusion: In this small cohort, pediatric kidney Tx recipients are more likely to lose VZV IgG in those who were younger at the time of Tx, on steroid-based immunosuppression, required 3 or more doses of VZV vaccination to seroconvert, or received VZV vaccine <1 year before Tx. Graphical

Hyperuricemia is a common finding in kidney transplant recipients, often associated with calcineurin inhibitor or diuretic use, obesity, metabolic syndrome, dyslipidemia, high purine intake, and reduced allograft function. We report a unique case of hyperuricemia leading to acute kidney injury associated with the use of cimetidine for treatment of mosaic warts in a 12-year-old female pediatric kidney transplant patient. With the reduction in the patient’s serum uric acid levels, there was concurrent marked improvement in her eGFR. Subsequently, her uric acid remained low, suggesting the cessation of cimetidine maintained her baseline uric acid level. This case highlights the significance of monitoring uric acid levels post-transplant and the importance of attention to potential drug interactions.

Background: Varicella zoster (VZV) vaccination pre-kidney transplant (Tx) can help prevent severe disseminated VZV in immunosuppressed recipients, however, studies have shown loss of humoral immunity post-Tx. Methods: A retrospective analysis of 45 pediatric kidney Tx recipients with positive pre-Tx VZV IgG (>1.09 index). VZV IgG was assessed annually and compared with the induction agent used, number of VZV vaccines received, and the interval between the last dose of VZV vaccine and Tx. Results: Median age at Tx was 16.7 years (IQR 12.7-18.5). 11 of 45 (24.4%) patients lost immunity to VZV at a median of 12.6 months post-Tx. Those who lost VZV immunity were younger at the time of Tx, 12.4 years vs. 17.3 years (P=0.05) and more likely to be on steroid-based immunosuppression 81.8% vs. 32.4% (P=0.006). There were no differences between the induction agents used and the ability to maintain VZV IgG antibodies. Subjects who required ³3 doses of VZV vaccine to develop VZV IgG seropositivity were at a higher risk for losing their anti-varicella antibody post-Tx (HR 3.81, 95%CI 1.09-13.30, P=0.04). Receiving VZV vaccination <1 year prior to kidney Tx was associated with a higher risk for losing anti-varicella antibody after Tx (HR 6.97, 95%CI 2.08-23.34). Conclusion: In this small cohort, pediatric kidney Tx recipients are more likely to lose VZV IgG in those who were younger at the time of Tx, on steroid-based immunosuppression, required 3 or more doses of VZV vaccination to seroconvert, or received VZV vaccine <1 year before Tx.

Background: Studies in adults have demonstrated a risk for allograft rejection or development of donor‐specific antibodies (DSA) following SARS‐CoV‐2 vaccination. We examined the incidence of acute rejection and de novo DSA following COVID‐19 vaccination or infection among pediatric kidney transplant patients. Method: Retrospective analysis of 23 pediatric kidney transplant recipients without prior history of rejection, DSA, or COVID‐19 infection who received the SARS‐CoV‐2 mRNA vaccine. Risk for rejection was evaluated via monitoring of serum creatinine, DSA, and donor‐derived cell‐free DNA per center protocol. Results concerning for rejection prompted allograft biopsy, graded by the Banff classification system. Results: Eight of 23 (34.8%) received two doses of SARS‐CoV‐2 mRNA vaccine, 15 (65.3%) received three doses. Two (8.7%) had rejection; one with de novo DSA, another without. There was no difference in the number of doses of COVID‐19 vaccine received in those with rejection vs. no rejection ( p = 0.53). 13 (56.5%) developed SARS‐CoV‐2 infection, with no difference in the number of vaccines received between those infected with COVID‐19 vs. those who were not ( p = 0.69). No adjustments were made to the maintenance immunosuppression during SARS‐CoV‐2 infection, and there was no evidence of rejection or DSA formation after infection. Median follow‐up time was 29.9 months (IQR 25.0–33.4 months) after the first vaccine dose. Conclusion: In our small single‐center cohort, SARS‐CoV‐2 vaccination or infection is unlikely to increase the risk for rejection or de novo DSA in pediatric kidney transplant recipients. Larger prospective studies with a control group are needed to further understand the immune effects of the COVID‐19 vaccine and disease in this population.

Background: Current kidney transplant (KT) policies offer advantages in waiting time and organ allocation priority to pediatric patients waitlisted before 18 years old. This study evaluates the effects of this policy for patients who are on dialysis before, but not waitlisted until after, age 18.Methods: Patients aged 11–25 years and waitlisted between 2001 and 2022 for KT were identified in the OPTN STAR data file for analysis. Cohorts were defined by age and dialysis status at time of listing: Peds if < 18 yo, young adult (YA) if ≥ 18 yo; NYOD—not yet on dialysis or OD—on dialysis at time of listing, with YA groups further segregated by age at dialysis initiation. Cumulative incidence of transplant was calculated for waitlisted patients. Graft survival was assessed using Kaplan–Meier analysis and multivariable Cox proportional hazards modeling. p values < 0.01 were significant.Results: Amongst 35 764 KT registrations, candidates who initiated dialysis as pediatric patients but were not waitlisted until after turning 18 years old (YA + OD < 18) have the highest rate of nontransplantation (33.5%) and longest time on dialysis (median: 2103 days) before deceased donor (DD) KT. YA + OD < 18 patients were sixfold less likely than Peds + OD patients to undergo DDKT at 5 years after listing. YA + OD < 18 recipients had the worst post‐KT graft survival of all groups at 5 years with adjusted hazard ratio of 1.477 (95% confidence interval: 1.218–1.792) compared to Peds‐NYOD (p < 0.001).Conclusions: Current allocation policies significantly disadvantage candidates who initiate dialysis before, but are not listed until after age 18, and should be re‐examined to address these inequities.

Background: Adult kidney transplant recipients (KTRs) fully vaccinated against COVID‐19 have substantial morbidity and mortality related to SARS‐CoV‐2 infection compared with the general population. However, little is known regarding the safety and efficacy of the COVID‐19 vaccination series in pediatric KTRs.Methods: A multicenter, retrospective observational study was performed across nine pediatric transplantation centers. Eligible KTRs fully vaccinated against COVID‐19 were enrolled and data were collected pertaining to SARS‐CoV‐2 infection incidence and severity, graft outcomes and post‐vaccination safety profile, as well as overall patient survival.Results: A total of 247 patients were included in this investigation with a median age at transplantation of 11 years (IQR 5–15). SARS‐CoV‐2 infection was observed in 30/110 (27.27%) of fully vaccinated patients, tested post‐transplant, within the defined follow‐up period. Of these patients, 6/30 (18.18%) required hospitalization and 3/30 (12.12%) required reduction in immunosuppression, with no reported deaths. De novo donor‐specific antibodies (DSAs) were found in 8/86 (9.30%) of DSA‐tested patients with two experiencing rejection and subsequent graft loss. The overall incidence of rejection and graft loss among the total cohort was 11/247 (4.45%) and 6/247 (3.64%), respectively. A 100% patient survival was observed.Conclusions: Observationally, infectious outcomes of SARS‐CoV‐2 in fully vaccinated pediatric KTRs are excellent, with a low incidence of infection requiring hospitalization and no associated deaths. Though de novo DSAs were observed, there was minimal graft rejection and graft loss reported in the total cohort.

Background: An accurate, rapid estimate of glomerular filtration rate (GFR) in kidney transplant patients affords early detection of transplant deterioration and timely intervention. This study compared the performance of serum creatinine (Cr) and cystatin C (CysC)-based GFR equations to measured GFR (mGFR) using iohexol among pediatric kidney transplant recipients. Methods: CysC, Cr, and mGFR were obtained from 45 kidney transplant patients, 1–18 years old. Cr- and CysC-estimated GFR (eGFR) was compared against mGFR using the Cr-based (Bedside Schwartz, U25-Cr), CysC-based (Gentian CysC, CAPA, U25-CysC), and Cr-CysC combination (CKiD Cr-CysC, U25 Cr-CysC) equations in terms of bias, precision, and accuracy. Bland–Altman plots assessed the agreement between eGFR and mGFR. Secondary analyses evaluated the formulas in patients with biopsy-proven histological changes, and K/DOQI CKD staging. Results: Bias was small with Gentian CysC (0.1 ml/min/1.73 m²); 88.9% and 37.8% of U25-CysC estimations were within 30% and 10% of mGFR, respectively. In subjects with histological changes on biopsy, Gentian CysC had a small bias and U25-CysC were more accurate—both with 83.3% of and 41.7% of estimates within 30% and 10% mGFR, respectively. Precision was better with U25-CysC, CKiD Cr-CysC, and U25 Cr-CysC. Bland–Altman plots showed the Bedside Schwartz, Gentian CysC, CAPA, and U25-CysC tend to overestimate GFR when > 100 ml/min/1.72 m². CAPA misclassified CKD stage the least (whole cohort 24.4%, histological changes on biopsy 33.3%). Conclusions: In this small cohort, CysC-based equations with or without Cr may have better bias, precision, and accuracy in predicting GFR. Graphical