Antibody-mediated rejection in pediatric kidney transplant recipients: A report from the Pediatric Nephrology Research Consortium.

BACKGROUND: Antibody-mediated rejection (AMR) is a major cause of kidney allograft loss. There is a paucity of large-scale pediatric-specific data regarding AMR treatment outcomes. METHODS: Data were obtained from 14 centers within the Pediatric Nephrology Research Consortium. Kidney transplant recipients aged 1-18 years at transplant with biopsy-proven AMR between 2009 and 2019 and at least 12 months of follow-up were included. The primary outcome was graft failure or an eGFR <20 mL/min/1.73 m2 at 12 months following AMR treatment. AMR treatment choice, histopathology, and DSA class were also examined. RESULTS: We reviewed 123 AMR episodes. Median age at diagnosis was 15 years at a median 22 months post-transplant. The primary outcome developed in 27.6%. eGFR <30 m/min/1.73 m2 at AMR diagnosis was associated with a 5.6-fold higher risk of reaching the composite outcome. There were no significant differences in outcome by treatment modality. Histopathology scores and DSA class at time of AMR diagnosis were not significantly associated with the primary outcome. CONCLUSIONS: In this large cohort of pediatric kidney transplant recipients with AMR, nearly one-third of patients experienced graft failure or significant graft dysfunction within 12 months of diagnosis. Poor graft function at time of diagnosis was associated with higher odds of graft failure.

Effect of pre-emptive rituximab on EBV DNA levels and prevention of post-transplant lymphoproliferative disorder in pediatric kidney transplant recipients: A case series from the pediatric nephrology research consortium.

BACKGROUND: There are scant data on the effect of rituximab on EBV DNA levels and prevention of post-transplant lymphoproliferative disorder (PTLD) in pediatric kidney transplant recipients with EBV DNAemia. METHODS: Kidney transplant recipients with EBV DNAemia treated with rituximab to prevent PTLD between 7/1999 and 7/2019 at five pediatric centers were included. Those with confirmed PTLD at the onset of rituximab were excluded. Primary outcomes included percentage change in EBV DNAemia and occurrence of PTLD post rituximab. RESULTS: Twenty-six pediatric kidney transplant recipients were included. Median age at transplant was 4 years (IQR 2.1-10.3). EBV DNA load monitoring by qPCR was performed at 1-3 month intervals. EBV DNAemia onset occurred at a median of 73 days post-transplant (IQR 52-307), followed by DNAemia peak at a median of 268 days (IQR 112-536). Rituximab was administered at a median of 9 days post peak (IQR 0-118). Rituximab regimens varied; median dose 375 mg/m2 (IQR 375-439) weekly for 1-4 doses per course. Following rituximab, EBV DNA load decreased to <10% of baseline at 120 days in 20/26 patients; however, only 30% achieved complete resolution at last follow-up (median 2094 days post-transplant [IQR 1538-3463]). Two (7%) developed PTLD at 915 and 1713 days post rituximab. All recipients had functioning grafts. One death occurred in a child with PTLD following remission due to unrelated reasons. CONCLUSIONS: In the largest pediatric kidney transplant recipient case series with EBV DNAemia given rituximab to prevent PTLD, rituximab achieved a short-term reduction in DNA load; however, recurrent DNAemia is common.

Outcomes of granulocyte colony-stimulating factor use in pediatric kidney transplant recipients: A Pediatric Nephrology Research Consortium study.

BACKGROUND: Neutropenia is common in the first year after pediatric kidney transplant and is associated with an increased risk of infection, allograft loss, and death. Granulocyte colony-stimulating factor (G-CSF) increases neutrophil production, but its use in pediatric solid organ transplant recipients remains largely undescribed. METHODS: We performed a multicenter retrospective cohort study of children with neutropenia within the first 180 days after kidney transplant. Multivariable linear regression and Poisson regression were used to assess duration of neutropenia and incidence of hospitalization, infection, and rejection. RESULTS: Of 341 neutropenic patients, 83 received G-CSF during their first episode of neutropenia. Median dose of G-CSF was 5 mcg/kg for 3 (IQR 2-7) doses. G-CSF use was associated with transplant center, induction immunosuppression, steroid-free maintenance immunosuppression, hospitalization, and decreases in mycophenolate mofetil, valganciclovir, and trimethoprim-sulfamethoxazole dosing. Absolute neutrophil count nadir was also significantly lower among those treated with G-CSF. G-CSF use was not associated with a shorter duration of neutropenia (p = .313) and was associated with a higher rate of neutropenia relapse (p = .002) in adjusted analysis. G-CSF use was associated with a decreased risk of hospitalization (aIRR 0.25 (95%CI 0.12-0.53) p < .001) but there was no association with incidence of bacterial infection or rejection within 90 days of neutropenic episode. CONCLUSION: G-CSF use for neutropenia in pediatric kidney transplant recipients did not shorten the overall duration of neutropenia but was associated with lower risk of hospitalization. Prospective studies are needed to determine which patients may benefit from G-CSF treatment.

Low-Dose Antithymocyte Globulin Has No Disadvantages to Standard Higher Dose in Pediatric Kidney Transplant Recipients: Report From the Pediatric Nephrology Research Consortium.

INTRODUCTION: Rabbit antithymocyte globulin (rATG) dosing strategies for induction in pediatric kidney transplantation vary between centers. It is not known whether a lower rATG induction dose provides safe and effective immunosuppression compared with a "standard" higher dose. METHODS: We performed a retrospective multicenter study of all isolated first-time kidney transplant recipients <21 years old who received rATG induction between 1 January 2010 and 31 December 2014 at 9 pediatric centers. An a priori cutoff of a 4.5-mg/kg cumulative rATG dose was used to identify low (≤ 4.5 mg/kg) and standard (> 4.5 mg/kg) exposure groups. Outcomes examined included 12 months posttransplant graft function (estimated glomerular filtration rate [eGFR]); the occurrence of acute rejection, donor-specific antibody (DSA), neutropenia, and viral infection (cytomegalovirus [CMV], Epstein-Barr virus [EBV], and BK virus); and 24-month outcomes of posttransplant lymphoproliferative disorder (PTLD) occurrence and patient and graft survival. RESULTS: Two hundred thirty-five patients were included. Baseline features of the low and standard rATG dose groups were similar. By 12 months, the rATG dose group had no significant impact on the occurrence of neutropenia, positive DSA, or viral polymerase chain reaction (PCR). Graft function was similar. Acute rejection rates were similar at 17% (low dose) versus 19% (standard dose) (P = 0.13). By 24 months, graft survival (96.4% vs. 94.6%) and patient survival (100% vs. 99.3%) were similar between the low- and standard-dose groups (P = 0.54 and 0.46), whereas the occurrence of PTLD trended higher in the standard-dose group (0% vs. 2.6%, P = 0.07). CONCLUSION: A low rATG induction dose ≤ 4.5 mg/kg provided safe and effective outcomes in this multicenter low immunologic risk pediatric cohort. Prospective studies are warranted to define the optimal rATG induction dose in pediatric kidney transplantation.

De novo collapsing glomerulopathy in a pediatric kidney transplant recipient with COVID-19 infection.

The negative impact of COVID-19 on adults with underlying chronic kidney disease, including kidney transplant recipients, has been well documented. Children have a less severe presentation and better prognosis compared to adults. However, little is known regarding the spectrum of COVID-19 infection in children and adolescents with underlying autoimmune disorders necessitating solid organ transplant and long-term immunosuppressive therapy. Case Report. An adolescent male developed end-stage kidney disease secondary to microscopic polyangiitis requiring a living-donor kidney transplant. Six years later, he developed antibody-mediated rejection of his kidney transplant. During his rejection treatment course, he contracted SARS-CoV-2 and developed new-onset nephrotic syndrome with severe acute kidney injury. Kidney transplant biopsy revealed de novo collapsing focal segmental glomerulosclerosis on a background of chronic active antibody mediated rejection. Immunostaining for SARS-CoV-2 on the biopsy specimen demonstrated positive staining of the proximal tubular epithelium consistent with intra-renal viral infection. Pulse corticosteroids, intravenous immunoglobulin, and temporary reduction of anti-metabolite therapy resulted in successful recovery with return of graft function back to pre-infection baseline. This case highlights the clinical conundrum of treating kidney transplant recipients with active rejection in the midst of the COVID-19 pandemic. Pediatric kidney transplant recipients can develop severe COVID-19-related kidney complications. Judicious immunosuppression modulation is necessary to balance infection and rejection risk.

Emerging monitoring technologies in kidney transplantation.

Non-invasive technologies to monitor kidney allograft health utilizing high-throughput assays of blood and urine specimens are emerging out of the research realm and slowly becoming part of everyday clinical practice. HLA epitope analysis and eplet mismatch score determination promise a more refined approach to the pre-transplant recipient-donor HLA matching that may lead to reduced rejection risk. High-resolution HLA typing and multiplex single antigen bead assays are identifying potential new offending HLA antibody subtypes. There is increasing recognition of the deleterious role non-HLA antibodies play in post-transplant outcomes. Donor-derived cell-free DNA detected by next-generation sequencing is a promising biomarker for kidney transplant rejection. Multi-omics techniques are shedding light on discrete genomic, transcriptomic, proteomic, and metabolomic signatures that correlate with and predict allograft outcomes. Over the next decade, a comprehensive approach to optimize kidney matching and monitor transplant recipients for acute and chronic graft dysfunction will likely involve a combination of those emerging technologies summarized in this review.

Reassessing Rabbit Antithymocyte Globulin Induction in Kidney Transplantation (RETHINK): An Analysis of the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) Registry.

BACKGROUND: There is no consensus on rabbit antithymocyte globulin (rATG) dose used for induction immunosuppression in pediatric kidney transplants. We aimed to identify whether a lower rATG dose provides safe and effective immunosuppression compared with a higher dose. METHODS: We retrospectively analyzed all first-time kidney transplant recipients (aged <21 y) in the North American Pediatric Renal Trials and Collaborative Studies registry since 1998 on mycophenolate mofetil- and tacrolimus-based immunosuppression with rATG induction. An a priori cutoff of 7.5 mg/kg cumulative rATG dose was used to identify low (<7.5 mg/kg) and high (≥7.5 mg/kg) exposure groups. Primary outcome was time to first-acute rejection episode. Secondary outcomes included graft function, patient survival, hospitalizations due to infections, and time to first-posttransplant lymphoproliferative disorder episode. RESULTS: Four hundred fifty-five patients met inclusion criteria (59% male, 49% whites, 26% blacks, 38% living donor source). Median cumulative rATG dose was 6.8 mg/kg with a median of 5 doses and a median 1.5 mg/kg/dose introduced at a median of postoperative 0 days. Sixty-four percent received <7.5 mg/kg total rATG. There was no difference in age at transplant, gender, race, end-stage renal disease causes, or HLA mismatch among groups. Time to first-acute rejection was similar (P = 0.07). There was no significant difference in graft or patient survival or time to posttransplant lymphoproliferative disorder. Hospitalization for infection rates was similar. CONCLUSIONS: These data demonstrate a wide variation in cumulative rATG induction dose. A smaller rATG dose <7.5 mg/kg may provide effective and safe immunosuppression compared with a higher dose.

Pediatric Immunization Practices in Nephrotic Syndrome: An Assessment of Provider and Parental Knowledge.

Background: Children with nephrotic syndrome (NS) are at high risk for vaccine-preventable infections due to the immunological effects from the disease and concurrent treatment with immunosuppressive medications. Immunizations in these patients may be deferred due to their immunosuppressive treatment which may increase the risk for vaccine-preventable infections. Immunization practices in children with NS continue to vary among pediatric nephrologists. This raises the question of whether children with NS are receiving the recommended vaccinations at appropriate times. Therefore, it is critical to understand the practices and patient education provided by physicians to patients on the topic of vaccinations. Methods: After informed consent, parents/guardians of 153 pediatric patients (<18 years old) diagnosed with NS from 2005 to 2018 and 50 pediatric nephrologists from 11 participating centers completed anonymous surveys to evaluate immunization practices among pediatric nephrologists, assess the vaccine education provided to families of children with NS, assess the parental knowledge of immunization recommendations, and assess predictors of polysaccharide pneumococcal vaccine adherence. The Advisory Committee on Immunization Practices (ACIP) Immunization 2019 Guideline for those with altered immunocompetence was used to determine accuracy of vaccine knowledge and practices. Results: Forty-four percent of providers self-reported adherence to the ACIP guidelines for inactive vaccines and 22% to the guidelines for live vaccines. Thirty-two percent of parents/guardians reported knowledge that aligned with the ACIP guidelines for inactive vaccines and 1% for live vaccines. Subjects residing in the Midwest and provider recommendations for vaccines were positive predictors of vaccine adherence (p < 0.001 and p 0.02, respectively). Conclusions: Vaccine recommendation by medical providers is paramount in vaccine adherence among pediatric patients with NS. This study identifies potential educational opportunities for medical subspecialty providers and family caregivers about immunization recommendations for immunosuppressed patients.

Treatment Patterns Among Adults and Children With Membranous Nephropathy in the Cure Glomerulonephropathy Network (CureGN).

INTRODUCTION: The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guidelines for Glomerulonephritis recommend that patients with membranous nephropathy (MN) at risk for progression receive immunosuppressive therapy (IST), usually after 6 months of observation. A cyclophosphamide (CYC) or calcineurin inhibitor (CNI)-based regimen is recommended as first-line IST. However, the extent to which KDIGO recommendations are adopted in practice remains largely unknown. METHODS: We evaluated prescribing practice among patients with primary MN (diagnosed 2010-2018) enrolled in the Cure Glomerulonephropathy Network (CureGN) cohort study. We also evaluated the availability of testing for phospholipase A2 receptor (PLA2R) in the contemporary era. RESULTS: Among 361 patients (324 adults and 37 children) with MN who were IST-naïve at biopsy and had at least 6 months of follow-up, 55% of adults and 58% of children initiated IST <6 months after biopsy. Of these, 1 in 5 had no indication for (i.e., urine protein-to-creatinine ratio [uPCR] <4 g/g) or an apparent contraindication to (i.e., an estimated glomerular filtration rate [eGFR] <30 ml/min per 1.73 m2) IST. As first-line IST, half of treated patients received either CYC (16% of adults; 0% of children) or a CNI (40% and 46%, respectively), whereas 1 in 5 received corticosteroid monotherapy (20% and 27%, respectively) and 1 in 6 rituximab (15% and 15%, respectively). More than 80% of surveyed centers had access to PLA2R testing. CONCLUSION: These findings suggest that providers are not aware of, or lack confidence in, current KDIGO guidelines for MN. Treatment patterns observed in this cohort might critically inform the drafting of planned updates to KDIGO guidelines.

Prevalence of Cardiovascular Disease Risk Factors in Childhood Glomerular Diseases.

Background Cardiovascular disease is a major cause of morbidity and mortality in children with chronic kidney disease. We sought to determine the prevalence of cardiovascular risk factors in children with glomerular disease and to describe current practice patterns regarding risk factor identification and management. Methods and Results Seven-hundred sixty-one children aged 0 to 17 years with any of 4 biopsy-confirmed primary glomerular diseases (minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and IgA nephropathy/vasculitis) were enrolled at a median of 16 months from glomerular disease diagnosis in the multicenter prospective Cure Glomerulonephropathy Network study. Prevalence of traditional (hypertension, hypercholesterolemia, and obesity) and novel (proteinuria, prematurity, and passive smoke exposure) cardiovascular risk factors were determined at enrollment and compared across glomerular disease subtypes. Frequency of screening for dyslipidemia and prescribing of lipid-lowering or antihypertensive medications were compared across glomerular disease subtype, steroid exposure, and remission status groups. Compared with the general population, all traditional risk factors were more frequent: among those screened, 21% had hypertension, 51% were overweight or obese, and 71% had dyslipidemia. Children who were not in remission at enrollment were more likely to have hypertension and hypercholesterolemia. Fourteen percent of hypertensive children were not receiving antihypertensives. Only 49% underwent screening for dyslipidemia and only 9% of those with confirmed dyslipidemia received lipid-lowering medications. Conclusions Children with primary glomerular diseases exhibit a high frequency of modifiable cardiovascular risk factors, particularly untreated dyslipidemia. Lipid panels should be routinely measured to better define the burden of dyslipidemia in this population. Current approaches to screening for and treating cardiovascular risk factors are not uniform, highlighting a need for evidence-based, disease-specific guidelines.

Early identification of transplant glomerulopathy in pediatric kidney transplant biopsies: A single-center experience with electron microscopy analysis.

Banff 2013 criteria recommend performing ultrastructural studies with electron microscopy (EM) in kidney transplant biopsies if the technology is available. We sought to determine the impact of EM on enhancing diagnostic findings in pediatric kidney transplant biopsies and the prognostic information gained from the additional findings. All kidney transplant biopsies since routine EM use started on June 1, 2014, until October 31, 2016, were reviewed. Primary outcome measures included the positive yield frequency of EM use defined as an upgraded diagnosis based on EM findings relative to light microscopy, and 12-month kidney allograft outcome of progression to ESRD or doubling of serum creatinine stratified by transplant glomerulopathy (TG) status on EM. Eighty unique kidney transplant biopsies were reviewed. EM studies were completed for 61 biopsies (76%). Complication rate was low (3.7%). In 61 biopsies where EM was completed, EM findings included foot process fusion (62%), endothelial cell swelling (38%), subendothelial lucencies (31%), and glomerular basement membrane duplication (41%). EM confirmed FSGS recurrence in three cases. In the remaining 58 cases, there was a positive yield of 31% where 18 biopsies were upgraded to a worse category after TG identification on EM. Kidney allograft outcome was poor regardless whether TG was detected early on EM or advanced on LM. Routine EM use in analyzing pediatric kidney transplant biopsies proved safe and provided valuable additional diagnostic information in almost one-third of cases. Additional studies are needed to determine if clinical interventions for early TG identified on EM can improve long-term outcomes.

Non-immunologic allograft loss in pediatric kidney transplant recipients.

Non-immunologic risk factors are a major obstacle to realizing long-term improvements in kidney allograft survival. A standardized approach to assess donor quality has recently been introduced with the new kidney allocation system in the USA. Delayed graft function and surgical complications are important risk factors for both short- and long-term graft loss. Disease recurrence in the allograft remains a major cause of graft loss in those who fail to respond to therapy. Complications of over immunosuppression including opportunistic infections and malignancy continue to limit graft survival. Alternative immunosuppression strategies are under investigation to limit calcineurin inhibitor toxicity. Finally, recent studies have confirmed long-standing observations of the significant negative impact of a high-risk age window in late adolescence and young adulthood on long-term allograft survival.

Fibroblast growth factor-23 and chronic allograft injury in pediatric renal transplant recipients: a Midwest Pediatric Nephrology Consortium study.

The chronic kidney disease-mineral bone disorder (CKD-MBD) produces fibroblast growth factor-23 (FGF-23) and related circulating pathogenic factors that are strongly associated with vascular injury and declining kidney function in native CKD. Similarly, chronic renal allograft injury (CRAI) is characterized by vascular injury and declining allograft function in transplant CKD. We hypothesized that circulating CKD-MBD factors could serve as non-invasive biomarkers of CRAI. We conducted a cross-sectional, multicenter case-control study. Cases (n = 31) had transplant function >20 mL/min/1.73 m(2) and biopsy-proven CRAI. Controls (n = 31) had transplant function >90 mL/min/1.73 m(2) and/or a biopsy with no detectable abnormality in the previous six months. We measured plasma CKD-MBD factors at a single time point using ELISA. Median (range) FGF23 levels were over twofold higher in CRAI vs. controls [106 (10-475) pg/mL vs. 45 (8-91) pg/mL; p < 0.001]. FGF23 levels were inversely correlated with transplant function (r(2) = -0.617, p < 0.001). Higher FGF23 levels were associated with increased odds of biopsy-proven CRAI after adjusting for transplant function, clinical, and demographic factors [OR (95% CI) 1.43 (1.23, 1.67)]. Relationships between additional CKD-MBD factors and CRAI were attenuated in multivariable models. Higher FGF23 levels were independently associated with biopsy-proven CRAI in children.

Sexually transmitted infection screening and reproductive health counseling in adolescent renal transplant recipients: Perceptions and practice patterns. A study from the Midwest Pediatric Nephrology Consortium.

We wanted to identify practice patterns and perceived barriers among pediatric nephrologists regarding STI screening and reproductive health counseling in adolescent renal transplant recipients. We created an online Likert-scaled survey. Response rate was 54%. The majority (83%) believed STI risk in their patients was similar to or higher than healthy teens. Interestingly, while 67% felt moderately or very confident in asking about sexual activity and counseling about safer sex, only 43% routinely or always inquired about sexual activity, and only 42% routinely or always counseled about safer sex. Fifty-four percent routinely or always discussed contraceptive options and implications of unintentional pregnancy. Fifty-one percent routinely or always referred patients to a gynecologist or adolescent provider for contraception prescription. The most common counseling mechanism was informal discussions in clinic (87%). Ten percent had no mechanism in place. Major barriers included time limitations, adolescents' fear regarding confidentiality, and lack of professional training. This is the first report of perceptions and practice patterns of pediatric nephrologists regarding STI screening and reproductive health counseling. Providers seem to recognize the importance of counseling; however, translation into practice remains low. Professional training in this area and increased encounter time could improve counseling delivery and thereby reduce risk in this population.

Arteriovenous access monitoring with ultrasound dilution in a pediatric hemodialysis unit.

BACKGROUND: Permanent arteriovenous (AV) access is the preferred access for dialysis delivery in children and adolescents requiring chronic hemodialysis (HD). Ultrasound dilution (UD) monitoring of AV access flow is widely used in adult HD units for the early detection of stenosis but experience in pediatrics is limited. METHODS: We monitored all maintenance HD patients with AV access using a noninvasive screening algorithm based on UD access flow. We assessed the effectiveness of this algorithm by comparing it to fistulagrams and its impact on AV access-related morbidity. RESULTS: AV access thrombosis rates fell from 13.5 per 100 patient-months on HD during the baseline period to 3.5 per 100 patient-months on HD during the screening period (p < 0.04). The mean blood flow rate by UD measurement was lower in AV accesses that went on to thrombose compared to those without thrombosis (1,203 ml/min/1.73 m(2) vs. 1,683 ml/min/1.73 m(2), p < 0.001). When compared to fistulagrams, the screening algorithm was 94% sensitive and 77% specific in detecting hemodynamically significant stenosis, with positive and negative predictive values of 83 and 91% respectively. CONCLUSIONS: A noninvasive UD screening algorithm of AV access flow is very sensitive in detecting hemodynamically significant stenosis and can decrease AV access thrombosis rates.

Rejection and regulation: a tight balance.

PURPOSE OF REVIEW: Achieving allograft tolerance is the holy grail of transplantation. However, tolerance and rejection are two extreme ends of a scale that can be tipped in either direction. We review the novel effector and regulatory mechanisms involved and factors that tip the balance in favor of rejection or regulation. RECENT FINDINGS: It is increasingly recognized that established T-cell phenotypes could change their commitments. New data point to the plasticity of Th17 cells in vivo with a reciprocal balance of Th17 cells and regulatory T cells (Tregs) driven by the local cytokine environment. Treg-cell profiles have been linked to acute and chronic allograft outcomes, and emerging data also indicate a novel role of a regulatory B-cell population. Current research efforts are looking into factors that tip the balance toward allograft tolerance by targeting cytokines, novel costimulatory pathways such as T-cell immunoglobulin mucin molecules, and components of innate immunity, particularly dendritic cells. SUMMARY: The balance of effector and regulatory mechanisms contributing to allograft outcome is very complex. It is likely that targeting multiple pathways will be required to achieve tolerance. Further studies are warranted to define this balance and identify optimal combination of therapeutic interventions.

Eruption hematoma as a possible oral sign of infantile scurvy.

Scurvy, vitamin C deficiency, is uncommon in industrialized societies today. Although supplementation of food with vitamin C has diminished its incidence, scurvy continues to occur in specific economically and nutritionally disadvantaged populations. The purpose of this report was to describe the case of infantile scurvy in a 20-month-old male with multisystem involvement including significant oral manifestations. Following an extensive initial evaluation, the multidisciplinary approach to diagnosis and management is discussed. This case demonstrates the need for heightened awareness of severe and multiplefood allergies in children and highlights disease conditions caused by nutritional deficiencies in this population.