Prevention of post-transplant lymphoproliferative disorder in pediatric kidney transplant recipients.

BACKGROUND: Post-transplant lymphoproliferative disorder (PTLD) is a devastating complication of immunosuppressive treatment in both solid organ transplantations (SOT) and hematopoietic stem cell transplantations (HSCT). Epstein-Barr virus (EBV) infection precedes PTLD in 90% of patients. Rituximab, a monoclonal anti-CD20 antibody, depletes B-lymphocytes, which are the ultimate reservoir for EBV. Although rituximab therapy is commonly used as a preventive measure for PTLD in high-risk HSCT, it is not established in SOT. METHODS: Pediatric kidney transplant recipients (PKTR) underwent routine EBV-PCR surveillance. Patients with increasing viral loads, despite immunosuppressive dose reduction, were managed with preventive rituximab therapy. RESULTS: Between 2012 and 2023, we identified eight episodes of asymptomatic EBV-PCR-positive blood tests in seven out of 65 PKTR (11%) under our care. EBV DNAemia emerged 120-720 days post-transplantation. Five of seven patients with EBV DNAemia (71%) were EBV-seronegative prior to transplantation. All five patients did not respond to MMF dose reduction and were therefore treated with preventive rituximab therapy. Following this treatment, EBV PCR clearance was observed in all patients with only minimal complications. CONCLUSIONS: PKTR who are EBV-naïve prior to transplantation are expected to have a higher prevalence of EBV DNAemia. We found that PKTR who were EBV seronegative prior to transplantation were less likely to achieve EBV clearance in response to immunosuppression dose reduction. We suggest that rituximab therapy in PKTR may be safe and effective in EBV clearance and PTLD prevention.

Youth-onset type 2 diabetes in Israel: A national cohort.

BACKGROUND: Prevalence of youth-onset type 2 diabetes (T2D) has increased worldwide, paralleling the rise in pediatric obesity. Occurrence and clinical manifestations vary regionally and demographically. OBJECTIVES: We assessed the incidence, and clinical and demographic manifestations of youth-onset T2D in Israel. METHODS: In a national observational study, demographic, clinical, and laboratory data were collected from the medical records of children and adolescents, aged 10-18 years, diagnosed with T2D between the years 2008 and 2019. RESULTS: The incidence of youth-onset T2D in Israel increased significantly from 0.63/100,000 in 2008 to 3.41/100,000 in 2019. The study cohort comprised 379 individuals (228 girls [59.7%], 221 Jews [58.3%], mean age 14.7 ± 1.9 years); 73.1% had a positive family history of T2D. Mean body mass index (BMI) z-score was 1.96 ± 0.7, higher in Jews than Arabs. High systolic (≥ 130 mmHg) and diastolic blood pressure (≥ 85 mmHg) were observed in 33.7% and 7.8% of patients, respectively; mean glycosylated hemoglobin (A1c) level at diagnosis was 8.8 ± 2.5%. Dyslipidemia, with high triglyceride (>150 mg/dl) and low HDL-c (<40 mg/dl) levels, was found in 45.6% and 56.5%, respectively. Microalbuminuria and retinopathy were documented at diagnosis, 15.2% and 1.9%, respectively) and increased (36.7% and 4.6%, respectively) at follow-up of 2.9 ± 2.1 years. Criteria of metabolic syndrome were met by 224 (62.2%) patients, and fatty liver documented in 65%, mainly Jews. Psychosocial comorbidity was found in 31%. Treatment with metformin (45.6%), insulin (20.6%), and lifestyle modification (18%) improved glycemic control. CONCLUSION: Youth-onset T2D in Israel has increased significantly and presents a unique profile.

Protocolized polyoma BK viral load monitoring and high-dose immunoglobulin treatment in children after kidney transplant.

Background: BKPyV virus nephropathy (BKPyVAN) is diagnosed in 5%-16% of pediatric renal transplant recipients (PRTR) and preceded by BKPyV-viruria and DNAemia. Despite the risk of irreversible transplant damage associated with BKPyVAN, evidence-based consensus guidelines for BKPyVAN prevention are still lacking. In this retrospective study, we examined the safety and efficacy of high-dose intravenous immunoglobulin (HD-IVIG) therapy for prevention of BKPyVAN in PRTR with significant BKPyV-viruria/DNAemia. Methods: Between January 2013 and December 2022, all PRTR under our care underwent routine urine and blood testing for BKPyV viral load, using specific polymerase chain reaction (PCR). BKPyV DNAemia, with <103 copies/mL, with BKPyV viruria <107 copies/mL, with no evidence of BKPyVAN, were managed with 50% dose reduction of mycophenolate mofetil (MMF). Patients showing no decline in BKPyV viral load within two months of MMF dose reduction were managed with HD-IVIG (2 g/kg). Results: Seventy patients were recruited during a ten-year period and 31/70 patients (44%) demonstrated significant post-transplantation BKPyV-viruria/DNAemia, while 13/31 (42%) patients were unresponsive to MMF dose reduction, and were administered HD-IVIG. Of these, 12/13 (92%) patients achieved BKPyV viral clearance within six months from completion of HD-IVIG therapy and 1/13 patient (8%) was unresponsive to HD-IVIG therapy, showing increased BKPyV viral load. There were no major adverse events associated with HD-IVIG, and none of our patients developed BKPyVAN during the study period. Conclusions: Prophylactic HD-IVIG therapy in PRTR with significant BKPyV-viruria/DNAemia unresponsive to MMF dose reduction is safe and might be effective in preventing BKPyVAN. Our findings remain to be established by large-scale prospective studies.

Management and long-term outcome of recurrent idiopathic FSGS in pediatric kidney transplant recipients.

Focal segmental glomerulosclerosis (FSGS) is a major cause of pediatric kidney failure. Most cases of FSGS in children are idiopathic and have a high risk of post-transplantation recurrence and graft loss. Common treatments for recurrent FSGS (rFSGS) post-transplantation include plasmapheresis, immunoadsorption, and/or immunomodulatory therapy. This study retrospectively evaluated the efficacy and safety of early plasmapheresis followed by rituximab for inducing and maintaining remission in rFSGS. Between 2014 and 2023, 8 of 65 pediatric kidney transplant recipients at our center were diagnosed with idiopathic FSGS. rFSGS was diagnosed based on nephrotic range proteinuria with no other cause and managed with plasmapheresis. Rituximab therapy was used for those who did not achieve complete remission with prolonged plasmapheresis or remained plasmapheresis dependent. 6 of 8 (75%) transplant recipients with idiopathic FSGS experienced rFSGS. All patients achieved partial or complete remission with plasmapheresis, with response times ranging from 8 to 379 days (median 13 days). Rituximab therapy was introduced for 5 plasmapheresis-dependent patients, leading to sustained remission and cessation of plasmapheresis in 3 patients, while 2 showed improved proteinuria and reduced plasmapheresis frequency. Adverse effects included rituximab-induced serum sickness in one patient and one mild allergic reaction. One patient experienced graft loss due to humoral rejection, but no grafts were lost to rFSGS, and all other grafts remained functional over an average follow-up of 50 months. Early plasmapheresis followed by rituximab therapy effectively induces remission in most post-transplantation rFSGS cases, is well tolerated, and prevents graft loss. Larger studies are needed to confirm these findings.