Ryszard Grenda

Key Points: Among 72 patients with childhood-onset ANCA-associated vasculitis, kidney transplant survival was good (86%). ANCA-associated vasculitis relapse occurred in 8 patients (11%), a median of 71 months after transplantation and resulted in graft failure in only one case. Positive ANCA at the time of transplantation did not predict graft failure but was associated with a higher risk of relapse and worse graft function. Background: ANCA-associated vasculitis (AAV) is rare in children, and results in kidney failure in up to one third of cases. There is very limited knowledge on kidney transplantation in childhood-onset AAV. We assessed kidney transplantation outcomes and prognostic factors in a multicenter cohort of patients with childhood-onset AAV. Methods: Patients diagnosed with AAV during childhood (≤18 years) who received a kidney transplant were included in this retrospective study. We determined patient and graft survival, rates of chronic graft dysfunction (defined as eGFR 2 for ≥3 months) and AAV relapse, and assessed determinants of outcome with logistic regression models. Patients were matched 1:2 for age, sex, and era of transplantation with non-AAV recipients from the Hospital for Sick Children in Toronto, Canada, and their graft survival was compared. Results: We included 72 patients, of whom 53 (74%) had microscopic polyangiitis and 19 (26%) granulomatosis with polyangiitis. Their median age (interquartile range at the time of diagnosis and transplantation was 12 (9–14) and 14 (12–16) years, respectively. After a median post-transplant follow-up of 53 months (interquartile range, 25–97), 70 patients (97%) were alive, 62 (86%) had a functioning graft, 28 (39%) had developed chronic graft dysfunction, and 8 (11%) had experienced AAV relapse. Graft survival was comparable between AAV and non-AAV recipients. Acute rejection was the only independent predictor of graft failure (hazard ratio [HR], 12.11; 95% confidence interval [CI], 1.19 to 122.49). Positive ANCA at the time of transplantation was significantly associated with a chronic graft dysfunction (HR, 4.16; 95% CI, 1.71 to 10.13) and AAV relapse (HR, 23.1; 95% CI, 2.67 to 200.28). Conclusions: Patients with childhood-onset AAV show good overall and graft survival after kidney transplantation and a low rate of post-transplant relapse. Further studies are warranted to confirm whether positive ANCA at the time of transplantation is associated with poorer graft outcomes.

Background: Pediatric acute liver failure (PALF) is one of the most demanding emergencies in hepatology, intensive care, and for transplant team. This report describes the clinical pattern, diagnostic and therapeutic modalities in children with ALF considered at risk of death without liver transplantation, basing on a long‐term experience of the pediatric transplant center.Materials and Methods: Between 1990 and 2022, 104 children aged 7 days–17 years (median 8 years), with body weight 3.1 to 77 kg (median 32 kg), were qualified for LT due to ALF, and finally 81 (78%) of them were transplanted (9% of all 899 LT performed in children in the same period).Results: A total of 23 children were not transplanted: 15 (14.4%) died while awaiting transplantation. In 8 (7.7%) patients liver function recovered. Before transplantation 45 (43.3%) children developed circulatory failure, in 66 (63.5%) mechanical ventilation was necessary, 18 patients presented acute kidney injury (17.3%), and encephalopathy higher than stage I was present in 60 (57.7%) patients. In 63 children, various kidney/liver assist procedures were performed: CVVHD (continuous veno‐venous hemodiafiltration in 22 (21.2%) patients, albumin dialysis (MARS; molecular adsorbent recirculating system) in 39 (37.5%) patients, therapeutic plasma exchange (TPE) in 13 (12.5%) patients. Twenty (24.7%) children died after LT including 15 (18.5%) in the early posttransplant period, and 5 (6.1%) in the late follow‐up.Conclusions: Treatment of children with ALF in the peritransplant period is very difficult and require an experienced, multidisciplinary team. Despite continued advances in the care of children with ALF, patient survival remains lower than for elective indications for liver transplantation, and timely qualification and transplantation still are the most important factors of survival of these children.

There are specific indications to use modern monoclonal antibodies in selected patients after kidney transplantation, such as desensitization, treatment of humoral rejection, management of post-transplant recurrence of nephrotic syndrome, therapy of lymphoproliferative disease (PTLD) for rituximab, and a prophylaxis/treatment of recurrence of the atypical hemolytic uremic syndrome (aHUS) for eculizumab. The use of rituximab, a depleting antibody against B_CD20 cells is related to hypogammaglobulinemia and late-onset neutropenia, which increases the risk of secondary viral, bacterial, and fungal infections. Pneumocystis jiroveci-related pneumonia is the most severe complication. Eculizumab, as a blocker of the complement system, predominantly increases the risk of meningococcal infections; however, some associations with other types of infections, like cryptococcal and JC-virus-related infections have also been reported. The use of both monoclonals includes specific mandatory prophylaxis, with trimethoprim/sulfamethoxazole (TMP-SMX) in rituximab and anti-meningococcal vaccination/penicillin administration in eculizumab-treated patients. There are specific issues associated with the use of both monoclonals in terms of COVID-19-related infections, as administration of rituximab is related to the prolonged failure of response to relevant vaccinations (including the third, booster dose), whereas blocking of the complement system may ameliorate the COVID-19-infection-related cytokine storm. Keywords: monoclonal antibodies rituximab/eculizumab related infections transplantation

Therapy of immune-mediated kidney diseases has evolved during recent decades from the non-specific use of corticosteroids and antiproliferative agents (like cyclophosphamide or azathioprine), towards the use of more specific drugs with measurable pharmacokinetics, like calcineurin inhibitors (cyclosporine A and tacrolimus) and mycophenolate mofetil, to the treatment with biologic drugs targeting detailed specific receptors, like rituximab, eculizumab or abatacept. Moreover, the data coming from a molecular science revealed that several drugs, which have been previously used exclusively to modify the upregulated adaptive immune system, may also exert a local effect on the kidney microstructure and ameliorate the functional instability of podocytes, reducing the leak of protein into the urinary space. The innate immune system also became a target of new therapies, as its specific role in different kidney diseases has been de novo defined. Current therapy of several immune kidney diseases may now be personalized, based on the detailed diagnostic procedures, including molecular tests. However, in most cases there is still a space for standard therapies based on variable protocols including usage of steroids with the steroid-sparing agents. They are used as a first-line treatment, while modern biologic agents are selected as further steps in cases of lack of the efficacy or toxicity of the basic therapies. In several clinical settings, the biologic drugs are effective as the add-on therapy.

De novo Donor Specific Antibodies (dnDSA) are associated with inferior graft outcomes. Standard immunosuppression is expected to prevent dnDSA production in low-risk patients. We have evaluated a cumulative effect of a triple immunosuppression (CNI/MMF/Pred), as well as TAC concentration and coefficient of variation on the incidence of dnDSA production. Overall, 67 transplanted patients were evaluated in retrospective (dnDSA for-cause; n = 29) and prospective (dnDSA by protocol; n = 38) groups. In the retrospective group, the eGFR value at first dnDSA detection (median interval—4.0 years post-transplant) was 41 mL/min/1.73 m²; 55% of patients presented biopsy-proven cAMR, and 41% lost the graft within next 2.4 years. Patients from the prospective group presented 97% graft survival and eGFR of 76 mL/min/1.73 m² at 2 years follow-up, an overall incidence of 21% of dnDSA and 18% of acute (T cell) rejection. None of the patients from the prospective group developed cAMR. Median value of Vasudev score within 2 years of follow-up was not significantly higher in dsDSA negative patients, while median value of TAC C₀ > 1–24 months post-transplant was 7.9 in dnDSA negative vs. 7.1 ng/mL in dnDSA positive patients (p = 0.008). Conclusion: dnDSA-negative patients presented a higher exposure to tacrolimus, while not to the combined immunosuppression.

Non-Hodgkin lymphoma (NHL) that develops after kidney transplantation belongs to post-transplant lymphoproliferative disorders (PTLD) occurring with an incidence of 2–3%. Most pediatric cases are related to primary infection with Epstein-Barr virus (EBV), able to transform and immortalize B cells and widely proliferate due to the lack of relevant control of cytotoxic T cells in patients receiving post-transplant immunosuppression. NHL may develop as a systemic disease or as a localized lesion. The clinical pattern is variable, from non-symptomatic to fulminating disease. Young age of transplant recipient, seronegative EBV status at transplantation, and EBV mismatch between donor and recipient (D+/R-) are regarded as risk factors. Immunosuppression impacts the development of both early and late NHLs. Specific surveillance protocols, including monitoring of EBV viral load, are used in patients at risk; however, detailed histopathology diagnosis and evaluation of malignancy staging is crucial for therapeutic decisions. Minimizing of immunosuppression is a primary management, followed by the use of rituximab in B-cell NHLs. Specific chemotherapeutic protocols, adjusted to lymphoma classification and staging, are used in advanced NHLs. Radiotherapy and/or surgical removal of malignant lesions is limited to the most severe cases. Outcome is variable, depending on risk factors and timing of diagnosis, however is positive in pediatric patients in terms of graft function and patient survival. Kidney re-transplantation is possible in survivors who lost the primary graft due to chronic rejection, however may be performed after at least 2–3 years of waiting time, careful verification of malignancy-free status, and gaining immunity against EBV.

The aim of the study was to evaluate the influence of the intensity of mesangial C3 deposits in kidney biopsy and the serum C3 level on the clinical course and outcomes of IgAN in children. The study included 148 children from the Polish Pediatric IgAN Registry, diagnosed based on kidney biopsy. Proteinuria, creatinine, IgA, C3 were evaluated twice in the study group, at baseline and the end of follow-up. Kidney biopsy was categorized using the Oxford classification, with a calculation of the MEST-C score. The intensity of IgA and C3 deposits were rated from 0 to +4 in immunofluorescence microscopy. The intensity of mesangial C3 > +1 deposits in kidney biopsy has an effect on renal survival with normal GFR in children with IgAN. A reduced serum C3 level has not been a prognostic factor in children but perhaps this finding should be confirmed in a larger group of children.