Safety and infectious outcomes in pediatric kidney transplant recipients after COVID-19 vaccination: A pediatric nephrology research consortium study.

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.

CMV-associated collapsing focal segmental glomerulosclerosis after kidney transplant in a pediatric patient.

BACKGROUND: Cytomegalovirus (CMV) is a significant cause of morbidity among immunocompromised patients who have undergone kidney transplantation and is known to rarely induce collapsing focal segmental glomerulosclerosis (FSGS) among adults. METHODS: We present the first reported case of CMV-induced collapsing FSGS in a pediatric patient after kidney transplant. RESULTS: Our patient underwent a deceased donor kidney transplant due to end-stage renal disease secondary to lupus nephritis. Approximately 4 months after transplantation, he developed signs of worsening kidney function in the setting of CMV viremia and was found to have collapsing features of FSGS on kidney transplant biopsy. He was managed with a prompt escalation of antiviral therapy along with a reduction of immunosuppression and recovered without significant complication. At follow-up, he continued to have undetectable CMV titers, creatinine within normal limits, and no significant proteinuria. CONCLUSION: This report demonstrates CMV as a cause of collapsing FSGS and should be considered among pediatric transplant recipients who present with acute kidney injury, as should early assessment of APOL1 genetic status in both donor and recipient.

Use of ofatumumab and eplerenone in post-transplant recurrence of FSGS.

BACKGROUND: Focal segmental glomerulosclerosis (FSGS) predisposes patients for risk of recurrent disease in allografts. METHODS: We report a case of a recipient of an unrelated living donor renal transplant and discuss considerations for utilization of ofatumumab and eplerenone in treatment for recurrent FSGS. RESULTS: The recipient was initially managed with scheduled plasmapheresis, intravenous immunoglobulin (IVIG), and rituximab post-transplant during index hospitalization. With notable recurrence of FSGS noted on kidney transplant biopsy, she was initially treated with additional plasmapheresis sessions leading to downtrend in proteinuria. The patient was then transitioned to LDL-A pheresis, which resulted again in uptrend in proteinuria. This prompted return to scheduled plasmapheresis sessions weekly, leading again to a downtrend in proteinuria. Albumin levels remained within normal range throughout her course. Following initiation of eplerenone and ofatumumab, the patient demonstrated normalization of urine protein:creatinine ratio and remission of FSGS recurrence without need for additional apheresis. CONCLUSIONS: With notable risk of recurrence of FSGS in kidney transplants leading to allograft failure, the use of ofatumumab and eplerenone in conjunction should be considered for management to induce remission.

Rare Presentation of Atypical Hemolytic Uremic Syndrome in a Child With Acute Lymphocytic Leukemia and Pancreatitis.

Atypical hemolytic uremic syndrome (aHUS) is associated with significant mortality and morbidity, including acute renal injury, anemia and thrombocytopenia. Rare cases of aHUS in a child with acute leukemia before diagnosis or during chemotherapy have been reported. We report a pediatric case of B-cell acute lymphoblastic leukemia complicated by pancreatitis with concomitant aHUS following induction chemotherapy.

Considerations for utilizing medullary sponge kidney allografts in pediatric patients.

BACKGROUND: Medullary sponge kidney (MSK) disease predisposes patients to recurrent nephrolithiasis, which affects one in every 5000 people in the United States. METHODS: We report a rare case of a pediatric recipient of a living donor MSK transplant and discuss considerations when discussing risks and benefits of accepting MSK allografts for this population. RESULTS: The recipient was admitted due to concerns for nephrolithiasis, hydronephrosis, and urinary tract infection at 1-month post-transplant. The hydronephrosis was resolved by surgical removal of an encrusted ureteral stent; this was followed by supplementation with oral medications to prevent future episodes of nephrolithiasis. The recipient did not have any further episodes after this as seen at a 1-year follow-up. The donor has remained well through this period. CONCLUSIONS: With increasing organ shortages, the use of variety of donors may need to be considered to enlarge the organ pool.

Re-transplantation in pediatric patients with failure of primary transplant due to recurrent focal segmental glomerulosclerosis: A pediatric nephrology research consortium study.

INTRODUCTION: Recurrent focal and segmental glomerulosclerosis (FSGS) in kidney transplant recipients is associated with lower graft survival and increased morbidity. There are limited data to guide the decision to re-transplant patients with transplant failure due to FSGS recurrence. We aimed to evaluate outcomes in patients re-transplanted after having initial graft failure due to recurrent FSGS and to study physician attitudes and practice patterns. METHODS: Retrospective data from 10 centers were collected on 20 patients transplanted between January 1997 and September 2018. A survey was sent to nephrologist members of the Pediatric Nephrology Research Consortium. RESULTS: Mean patient age (years) was 9.8 ± 4.8 at first transplant and 15.9 ± 4.9 at re-transplantation. Pre-transplant plasmapheresis was used in 1 (5.3%) primary transplant vs. 7 (38.9%) re-transplants (p = .03). Nephrotic syndrome recurred in 14 patients (70%) after re-transplantation and was severe in 21.1% vs. 64.7% after first transplant (p = .04). Graft survival was significantly higher in the second transplant (p .009) with 70% having functioning grafts at a median of 25.2 months. Thirty-one physicians from 21 centers completed the survey, 94% indicated they would re-transplant such patients, 44.4% preferred a minimum waiting period before re-transplantation, 36.4% preferred living donors, and 22.2% indicated having protocols for re-transplantation at their centers. CONCLUSIONS: Consideration for re-transplantation is high among pediatric nephrologists. Pre-transplant plasmapheresis was more frequent in re-transplanted patients. Nephrotic syndrome recurrence was less severe, with better graft survival. More data and a larger population are necessary to further evaluate outcome determinants and best practices in this special population.

Treatment of borderline infiltrates with minimal inflammation in kidney transplant recipients has no effect on allograft or patient outcomes.

In 2005, the Banff committee expanded the "borderline changes" category to include lesions with minimal (<10%) inflammation: "i0" borderline infiltrates. Clinical significance and optimal treatment of i0 borderline infiltrates are not known. Data suggest that i0 borderline infiltrates may have a more favorable prognosis than borderline infiltrates with higher grades of interstitial inflammation. In this single-center, retrospective, observational study, we assessed 90 renal transplant recipients with i0 borderline infiltrates on biopsies indicated for graft dysfunction. We studied the impact of treatment with corticosteroids on allograft function, allograft survival, and patient survival. We found no differences between treated and untreated groups with respect to eGFR at 4 weeks and 6 months after biopsy. Follow-up biopsies, available in 67% of patients, were negative for rejection in almost half of all cases, regardless of treatment status. The frequencies of persistent borderline infiltrates (38%) and higher-grade T cell-mediated rejection (1A or greater, 14%) on follow-up biopsies were similar between the two groups. There were no differences in rejection-free allograft survival, death-censored graft failure, or patient mortality among treated vs non-treated i0 borderline patients. Our findings suggest that the natural history of i0 borderline infiltrates, in relatively low immunologic risk patients, is not affected by corticosteroid treatment.

Apheresis therapy in children: an overview of key technical aspects and a review of experience in pediatric renal disease.

Although there is less experience with its use in children than adults, apheresis can be a life-saving treatment modality in certain pediatric diseases. With attention to specific technical aspects of the treatment, especially circuit volume, apheresis can be safely performed in children of any age or size. Even in pediatric diseases where it is recognized as an important part of therapy, apheresis is unfortunately still underutilized in North America and there needs to be increased awareness of its role and its availability within the pediatric community. Apheresis has been used particularly in children with certain renal diseases, notably ANCA-associated nephritis, anti-GBM disease, and atypical HUS. In addition, it can improve outcomes in transplantation of children with FSGS and can be part of a pre-transplant strategy for children who are highly sensitized and at high risk for graft failure.

Implementation and Feasibility of Clinical Genome Sequencing Embedded Into the Outpatient Nephrology Care for Patients With Proteinuric Kidney Disease.

Introduction: The diagnosis and management of proteinuric kidney diseases such as focal segmental glomerulosclerosis (FSGS) are challenging. Genetics holds the promise to improve clinical decision making for these diseases; however, it is often performed too late to enable timely clinical action and it is not implemented within routine outpatient nephrology visits. Methods: We sought to test the implementation and feasibility of clinical rapid genome sequencing (GS) in guiding decision making in patients with proteinuric kidney disease in real-time and embedded in the outpatient nephrology setting. Results: We enrolled 10 children or young adults with biopsy-proven FSGS (9 cases) or minimal change disease (1 case). The mean age at enrollment was 16.2 years (range 2-30). The workflow did not require referral to external genetics clinics but was conducted entirely during the nephrology standard-of-care appointments. The total turn-around-time from enrollment to return-of-results and clinical decision averaged 21.8 days (12.4 for GS), which is well within a time frame that allows clinically relevant treatment decisions. A monogenic or APOL1-related form of kidney disease was diagnosed in 5 of 10 patients. The genetic findings resulted in a rectified diagnosis in 6 patients. Both positive and negative GS findings determined a change in pharmacological treatment. In 3 patients, the results were instrumental for transplant evaluation, donor selection, and the immunosuppressive treatment. All patients and families received genetic counseling. Conclusion: Clinical GS is feasible and can be implemented in real-time in the outpatient care to help guiding clinical management. Additional studies are needed to confirm the cost-effectiveness and broader utility of clinical GS across the phenotypic and demographic spectrum of kidney diseases.

Clinical Predictors and Prognosis of Recurrent IgA Nephropathy in the Kidney Allograft.

Introduction: Although IgA nephropathy (IgAN) is the most common recurrent glomerulonephritis encountered in the kidney allograft, the clinical and immunogenetic characteristics remain poorly understood. We sought to study determinants and prognosis of recurrent IgAN with special focus on HLA antigens. Materials and Methods: Between 2005 and 2019, we identified 282 transplanted patients with failure secondary to IgAN from two North American and one European Medical Centers, including 80 with recurrent IgAN and 202 without recurrence. Prevalence of HLA antigens was compared to external healthy controls of European ancestry (n=15,740). Graft survival was assessed by Kaplan-Meier method and log rank test. Cox proportional hazards were used for multivariable analyses. Results: Compared to external controls of European ancestry, kidney transplant recipients of European ancestry with kidney failure secondary to IgAN had higher frequency of HLA-DQ5 (42% vs. 30%, OR=1.68, P=0.002) and lower frequency of HLA-DR15 (15% vs. 28%, OR=0.46, P<0.001) and HLA-DQ6 (32% vs. 45%, OR=0.59, P=0.003); however, the frequency of these HLA antigens were similar in recurrent versus non-recurring IgAN. Younger recipient age at transplantation was an independent predictor of recurrence. HLA-matching was an independent predictor for recurrent IgAN only in recipients of living-related but not deceased or living unrelated transplants. Recurrent IgAN was an independent predictor of allograft failure, along with acute rejection. In patients with recurrent IgAN, serum creatinine at biopsy, degree of proteinuria, and concurrent acute rejection were associated with inferior allograft survival. Discussion/ Conclusion: Recurrent IgAN negatively affects allograft survival. Younger recipient age at transplantation is an independent predictor of recurrent IgAN, while the presence of HLA antigens associated with IgAN in the native kidney and HLA-matching in recipients of deceased or living unrelated transplants are not.

Risk factors for chronic kidney disease following acute kidney injury in pediatric allogeneic hematopoietic cell transplantation.

Risk factors associated with the progression of acute kidney injury to chronic kidney disease in pediatric allogeneic hematopoietic cell transplantation (AlloHCT) recipients are not well described. We retrospectively investigated the risk factors for the progression to CKD in 275 AlloHCT recipients. AKI and CKD grading was defined according to the Kidney Disease Improving Global Outcomes classification. PRI90 was defined as persistent renal insufficiency (estimated GFR < 90 ml/min/1.73 m2) 90 days after the first episode of AKI. The median age was 9.1 years. Incidence of stages 1, 2, and 3 AKI were 43%, 41%, and 15%, respectively. 86.1% met our study criteria for PRI90. Of the 236 PRI90 patients, 213 and 152 patients were evaluable for CKD at 1 and 3 years, respectively. The incidence of CKD at 1 and 3 years was 63.1% and 62.9%, respectively. On multivariable analysis, estimated GFR at initial episode of AKI (<80 ml/min/1.73 m2) and estimated GFR (<70 ml/min/1.73 m2) at PRI90 was a risk factor associated with CKD development and both risk factors were associated with significantly lower overall survival. To conclude, eGFR at the time of AKI and PRI90 may be considered for screening pediatric AlloHCT recipients at risk for the progression to CKD.

AKI in COVID-19-Associated Multisystem Inflammatory Syndrome in Children (MIS-C).

Background: Multisystem inflammatory syndrome in children (MIS-C) is a recently identified entity in association with COVID-19. AKI has been widely reported in patients with primary COVID-19 infection. However, there is a paucity of literature regarding renal injury in MIS-C. We aim to characterize AKI in MIS-C in this cohort identified at a major children's hospital in New York City during the COVID-19 pandemic. Methods: We conducted a retrospective cohort study of children 0-20 years old admitted to Morgan Stanley Children's Hospital (MSCH) between April 18th and September 23rd, 2020. Patients were included if they met criteria for MIS-C on the basis of CDC guidelines. All patients were evaluated for the presence of AKI, and AKI was staged according to KDIGO criteria. Results: Of the 57 children who met inclusion criteria, 46% (26 of 57) were found to have AKI. The majority of patients (58%; 15 of 26) were classified as KDIGO stage 1. AKI was present upon admission in 70% of those identified. All patients had resolution of AKI at discharge, with 61% achieving recovery by day 2. One patient required dialysis. When compared with those without renal injury, the AKI cohort was older (P<0.001) and had higher median peak values of CRP (P<0.001), IL-6 (P=0.02), ferritin (P<0.001), and procalcitonin (P=0.02). More patients with AKI had left ventricular systolic dysfunction (P<0.001) and lymphopenia (P=0.01) when compared with those without AKI. No differences in body mass index or sex were found. Conclusions: Although children with MIS-C may develop AKI, our study suggests that most experience mild disease, swift resolution, and promising outcome. Older age, increased inflammation, and left ventricular systolic dysfunction may be risk factors. Our study highlights the substantial differences in epidemiology and outcomes between AKI associated with pediatric MIS-C versus primary COVID-19 infection.

Microfluidic mazes to characterize T-cell exploration patterns following activation in vitro.

The migration of T-cell subsets within peripheral tissues is characteristic of inflammation and immunoregulation. In general, the lymphocyte migratory response is assumed directional and guided by local gradients of chemoattractants and/or chemorepellents. However, little is known about how cells explore their tissue environment, and whether lymphocyte activation may influence speed and exploratory patterns of migration. To probe migration patterns by T-cells we designed a microfluidic maze device that replicates critical features of a tissue-like microenvironment. We quantified the migration patterns of unstimulated and mitogen-activated human T-cells at single cell resolution and found significant differences in exploration within microfluidic mazes. While unstimulated lymphocytes migrated in a directed manner, activated T-cells migrated through large areas of the mazes in an exploratory pattern in response to the chemoattractants RANTES (CCL5) and IP-10 (CXCL10). The analysis of migration enabled by the microfluidic devices help develop new methods for determining how human circulating T-cells function in vivo to seek out antigens in health and disease states.