Advances in immunosuppression have improved graft survival in pediatric kidney transplant recipients; however, treatment‐related toxicities need to be balanced against the possibility of graft ...rejection. Several immunosuppressive agents are available for use in transplant recipients; however, the optimal combinations of agents remain unclear, resulting in variations in institutional protocols. Lymphocyte‐depleting antibodies, specifically ATG, are the most common induction agent used for pediatric kidney transplantation in the US. Basiliximab may be used for induction in immunologically low‐risk children; however, pediatric data are scarce. CNIs and antiproliferative agents (mostly Tac and mycophenolate in recent years) constitute the backbone of maintenance immunosuppression. Steroid‐avoidance maintenance regimens remain controversial. Belatacept and mTOR inhibitors are used in children under specific circumstances such as non‐adherence or CNI toxicity. This article reviews the indications, mechanism of action, efficacy, dosing, and side effect profiles of various immunosuppressive agents available for pediatric kidney transplantation.
Background
Corticosteroids have been an integral part of maintenance immunosuppression for pediatric kidney transplantation. However, prolonged steroid therapy is associated with significant ...toxicities resulting in several SW/avoidance strategies in recent years.
Method/Objective
This comprehensive review aims to discuss steroid‐related toxicities and the safety, efficacy, and benefit of steroid avoidance/withdrawal immunosuppression in pediatric kidney transplant recipients.
Results
Initial studies of SW/avoidance conducted in the setting of CSA and AZA showed an increased incidence of AR but no increase in graft loss or mortality with SW/avoidance maintenance immunosuppression. Studies performed under modern immunosuppression (induction therapy, Tac, and MMF) show no significant increase in AR or graft loss with SW/avoidance immunosuppression. Furthermore, SW/avoidance immunosuppression is associated with significant improvement in growth, BMI, BP control, and lipid profile in pediatric kidney transplant recipients. Despite these data, SW/avoidance remains controversial, and only 40% of pediatric kidney transplant recipients in the United States are currently on SW/avoidance maintenance immunosuppression.
Conclusion
SW/avoidance maintenance immunosuppression is safe and associated with fewer side effects compared with steroid‐inclusive maintenance immunosuppression in pediatric kidney transplant recipients.
Human cytomegalovirus (CMV) remains one of the most common opportunistic infections following solid organ transplantation in children. CMV causes morbidity and mortality through direct ...tissue-invasive disease and indirect immunomodulatory effects. In recent years, several new agents have emerged for the prevention and treatment of CMV disease in solid organ transplant recipients. However, pediatric data remain scarce, and many of the treatments are extrapolated from the adult literature. Controversies exist about the type and duration of prophylactic therapies and the optimal dosing of antiviral agents. This review provides an up-to-date overview of treatment modalities used to prevent and treat CMV disease in solid organ transplant (SOT) recipients.
Continuous kidney replacement therapy (CKRT) is increasingly used in youths with critical illness, but little is known about longer-term outcomes, such as persistent kidney dysfunction, continued ...need for dialysis, or death.
To characterize the incidence and risk factors, including liberation patterns, associated with major adverse kidney events 90 days after CKRT initiation (MAKE-90) in children, adolescents, and young adults.
This international, multicenter cohort study was conducted among patients aged 0 to 25 years from The Worldwide Exploration of Renal Replacement Outcomes Collaborative in Kidney Disease (WE-ROCK) registry treated with CKRT for acute kidney injury or fluid overload from 2015 to 2021. Exclusion criteria were dialysis dependence, concurrent extracorporeal membrane oxygenation use, or receipt of CKRT for a different indication. Data were analyzed from May 2 to December 14, 2023.
Patient clinical characteristics and CKRT parameters were assessed. CKRT liberation was classified as successful, reinstituted, or not attempted. Successful liberation was defined as the first attempt at CKRT liberation resulting in 72 hours or more without return to dialysis within 28 days of CKRT initiation.
MAKE-90, including death or persistent kidney dysfunction (dialysis dependence or ≥25% decline in estimated glomerular filtration rate from baseline), were assessed.
Among 969 patients treated with CKRT (529 males 54.6%; median IQR age, 8.8 1.7-15.0 years), 630 patients (65.0%) developed MAKE-90. On multivariable analysis, cardiac comorbidity (adjusted odds ratio aOR, 1.60; 95% CI, 1.08-2.37), longer duration of intensive care unit admission before CKRT initiation (aOR for 6 days vs 1 day, 1.07; 95% CI, 1.02-1.13), and liberation pattern were associated with MAKE-90. In this analysis, patients who successfully liberated from CKRT within 28 days had lower odds of MAKE-90 compared with patients in whom liberation was attempted and failed (aOR, 0.32; 95% CI, 0.22-0.48) and patients without a liberation attempt (aOR, 0.02; 95% CI, 0.01-0.04).
In this study, MAKE-90 occurred in almost two-thirds of the population and patient-level risk factors associated with MAKE-90 included cardiac comorbidity, time to CKRT initiation, and liberation patterns. These findings highlight the high incidence of adverse outcomes in this population and suggest that future prospective studies are needed to better understand liberation patterns and practices.
In clinical trials, the early or accelerated continuous renal replacement therapy (CRRT) initiation strategy among adults with acute kidney injury or volume overload has not demonstrated a survival ...benefit. Whether the timing of initiation of CRRT is associated with outcomes among children and young adults is unknown.
To determine whether timing of CRRT initiation, with and without consideration of volume overload (VO; <10% vs ≥10%), is associated with major adverse kidney events at 90 days (MAKE-90).
This multinational retrospective cohort study was conducted using data from the Worldwide Exploration of Renal Replacement Outcome Collaborative in Kidney Disease (WE-ROCK) registry from 2015 to 2021. Participants included children and young adults (birth to 25 years) receiving CRRT for acute kidney injury or VO at 32 centers across 7 countries. Statistical analysis was performed from February to July 2023.
The primary exposure was time to CRRT initiation from intensive care unit admission.
The primary outcome was MAKE-90 (death, dialysis dependence, or persistent kidney dysfunction >25% decline in estimated glomerular filtration rate from baseline).
Data from 996 patients were entered into the registry. After exclusions (n = 27), 969 patients (440 45.4% female; 16 (1.9%) American Indian or Alaska Native, 40 (4.7%) Asian or Pacific Islander, 127 (14.9%) Black, 652 (76.4%) White, 18 (2.1%) more than 1 race; median IQR patient age, 8.8 1.7-15.0 years) with data for the primary outcome (MAKE-90) were included. Median (IQR) time to CRRT initiation was 2 (1-6) days. MAKE-90 occurred in 630 patients (65.0%), of which 368 (58.4%) died. Among the 601 patients who survived, 262 (43.6%) had persistent kidney dysfunction. Of patients with persistent dysfunction, 91 (34.7%) were dependent on dialysis. Time to CRRT initiation was approximately 1 day longer among those with MAKE-90 (median IQR, 3 1-8 days vs 2 1-4 days; P = .002). In the generalized propensity score-weighted regression, there were approximately 3% higher odds of MAKE-90 for each 1-day delay in CRRT initiation (odds ratio, 1.03 95% CI, 1.02-1.04).
In this cohort study of children and young adults receiving CRRT, longer time to CRRT initiation was associated with greater risk of MAKE-90 outcomes, in particular, mortality. These findings suggest that prospective multicenter studies are needed to further delineate the appropriate time to initiate CRRT and the interaction between CRRT initiation timing and VO to continue to improve survival and reduce morbidity in this population.
Perturbations in phosphate and vitamin D homeostasis impacts skeletal health in children and adults. Study of inherited and acquired hypophosphatemic syndromes led to the discovery of fibroblast ...growth factor 23 (FGF23) as a potent regulator of phosphate and vitamin D metabolism, and advanced our understanding of the pathophysiology of mineral and bone disorder in chronic kidney disease (CKD-MBD). Here, we review a recently approved therapy for patients with X-linked hypophosphatemia (XLH) using a novel anti-FGF23 antibody, burosumab, and discuss the implications of such targeted therapy in CKD.
In children and adults with XLH, burosumab treatment significantly increased renal tubular phosphate reabsorption and normalized serum phosphorus concentrations. Prolonged treatment with burosumab showed a favorable safety profile, improved healing of rickets in children, and fractures and pseudofractures in adults. FGF23 excess in CKD is independently associated with left ventricular hypertrophy and cardiovascular mortality. Research strategies to lower FGF23 in animal models of CKD are rapidly advancing and a question that remains to be answered is whether FGF23 blockade will offer a new targeted intervention for disordered mineral metabolism in CKD.
Findings from recently concluded clinical trials in adults and children with XLH provide evidence for improved skeletal health with burosumab therapy with normalization of phosphate and vitamin D metabolism. Targeted anti-FGF23 antibody treatment of XLH has emerged as a novel therapeutic strategy to treat an inherited disorder of FGF23 excess.
Posttransplant anemia (PTA) is a common complication of pediatric kidney transplantation, with a prevalence ranging from 22 to 85%. PTA is categorized as early (within 6 months posttransplant) and ...late (>6 months posttransplant). Early PTA is typically associated with surgical blood losses and iron deficiency. Late PTA primarily results from graft dysfunction; however, iron deficiency, drug toxicity, and posttransplant inflammation also play a role. PTA is more severe compared with the anemia in glomerular-filtration-rate matched patients with native chronic kidney disease. Treatment of PTA is directed toward the underlying cause. Erythropoiesis stimulating agents (ESA) are effective; however, their use is limited in the transplant setting. Timely diagnosis and treatment of PTA are vital to prevent long-term adverse outcomes in pediatric transplant recipients.
The purpose of this review is to highlight recent studies that have emerged on the topic of ANCA-associated vasculitis with some historical context. The review also discusses how the adult data is ...relevant to pediatric patients.
Pediatric studies on AAV are lacking. Therapies targeted to the inflammatory cascade specifically implicated in AAV, such as MPO inhibitors and complement mediators, are emerging. The PEXIVAS study recently called into question the routine use of plasma exchange (PLEX) in severe AAV, with no difference in ESKD or mortality found between patients who did or did not receive PLEX. Longer maintenance duration of nearly 48 months is preferred as compared with shorter duration in patients who are not on dialysis because of higher relapse rates in children with AAV.
Current treatment in AAV includes corticosteroids, rituximab, and cyclophosphamide for induction. Maintenance therapy commonly consists of azathioprine or rituximab. Plasma exchange (PLEX) is no longer recommended for induction therapy for AAV but some experts still consider this as an option for patients who are not responding to therapy or have severe disease at presentation. However, emerging novel therapies may be on the horizon.
Background
Pediatric data on risk factors and the clinical course of BK DNAemia are limited. We aimed to determine the effects of BK DNAemia on transplant outcomes and delineate the safety and ...efficacy of various treatment approaches.
Methods
This retrospective‐cohort study included 161 transplants (age ≤ 21 years) performed at a single center between 1/1/2012 and 1/1/2020. We used Cox proportional models to evaluate the effects of BK DNAemia on patient survival (PS), graft survival (GS), and acute rejection (AR), using BK as a time‐dependent covariate. We also assessed the effects of pharmacological intervention on BK DNAemia duration using intervention as a time‐dependent covariate.
Results
BK‐free survival was 69.1% at 1‐year and 54.6% at 3‐year posttransplant. After multivariate adjustment, BK DNAemia was associated with young age at transplant (aHR, age 5–<12 vs. ≥12 (years): 2.5 (1.4–4.5); p = .001) and steroid‐based immunosuppression (IS) (aHR: 2.2 1.1–4.5; p = .03). We found no effect of DNAemia on AR (aHR: 1.25; p = .5), PS (aHR: 2.85; p = .22), and GS (aHR: 0.56; p = .41). Of 70 patients with DNAemia, 22 (31.4%) received no treatment, 20 (28.6%) received IS reduction alone, and 28 patients (40%) received treatment with at least one pharmacological agent (leflunomide, IVIG, ciprofloxacin, cidofovir). Sixty‐three patients (90%) cleared DNAemia with median time to resolution of 2.4 months (IQR:1.4–5.6). We found no significant effect of BK‐directed pharmacological treatment on time to resolution (aHR: 0.64;p = .13). BK‐directed agents were well tolerated.
Conclusions
BK DNAemia is associated with a young age at transplant and steroid‐based maintenance IS. We found no effect of BK DNAemia on AR, GS, and PS.
