An integrated machine learning model enhances delayed graft function prediction in pediatric renal transplantation from deceased donors.

BACKGROUND: Kidney transplantation is the optimal renal replacement therapy for children with end-stage renal disease; however, delayed graft function (DGF), a common post-operative complication, may negatively impact the long-term outcomes of both the graft and the pediatric recipient. However, there is limited research on DGF in pediatric kidney transplant recipients. This study aims to develop a predictive model for the risk of DGF occurrence after pediatric kidney transplantation by integrating donor and recipient characteristics and utilizing machine learning algorithms, ultimately providing guidance for clinical decision-making. METHODS: This single-center retrospective cohort study includes all recipients under 18 years of age who underwent single-donor kidney transplantation at our hospital between 2016 and 2023, along with their corresponding donors. Demographic, clinical, and laboratory examination data were collected from both donors and recipients. Univariate logistic regression models and differential analysis were employed to identify features associated with DGF. Subsequently, a risk score for predicting DGF occurrence (DGF-RS) was constructed based on machine learning combinations. Model performance was evaluated using the receiver operating characteristic curves, decision curve analysis (DCA), and other methods. RESULTS: The study included a total of 140 pediatric kidney transplant recipients, among whom 37 (26.4%) developed DGF. Univariate analysis revealed that high-density lipoprotein cholesterol (HDLC), donor after circulatory death (DCD), warm ischemia time (WIT), cold ischemia time (CIT), gender match, and donor creatinine were significantly associated with DGF (P < 0.05). Based on these six features, the random forest model (mtry = 5, 75%p) exhibited the best predictive performance among 97 machine learning models, with the area under the curve values reaching 0.983, 1, and 0.905 for the entire cohort, training set, and validation set, respectively. This model significantly outperformed single indicators. The DCA curve confirmed the clinical utility of this model. CONCLUSIONS: In this study, we developed a machine learning-based predictive model for DGF following pediatric kidney transplantation, termed DGF-RS, which integrates both donor and recipient characteristics. The model demonstrated excellent predictive accuracy and provides essential guidance for clinical decision-making. These findings contribute to our understanding of the pathogenesis of DGF.

Incidence, risk factors, management strategies, and outcomes of antibody-mediated rejection in pediatric kidney transplant recipients-a multicenter analysis of the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN).

BACKGROUND: This study by the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) was designed to determine the incidence, risk factors, current management strategies, and outcomes of antibody-mediated rejection (ABMR) in pediatric kidney transplant recipients (pKTR). METHODS: We performed an international, multicenter, longitudinal cohort study of data reported to the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) registry. Three hundred thirty-seven pKTR from 21 European centers were analyzed. Clinical outcomes, including kidney dysfunction, rejection, HLA donor-specific antibodies, BK polyomavirus-associated (BKPyV) nephropathy, and allograft loss, were assessed through 5 years post-transplant. RESULTS: The cumulative incidence of de novo donor-specific class I HLA antibodies (HLA-DSA) post-transplant was 4.5% in year 1, 8.3% in year 3, and 13% in year 5; the corresponding data for de novo class II HLA-DSA were 10%, 22.5%, and 30.6%, respectively. For 5 years post-transplant, the cumulative incidence of acute ABMR was 10% and that of chronic active ABMR was 5.9%. HLA-DR mismatch and de novo HLA-DSA, especially double positivity for class I and class II HLA-DSA, were significant risk factors for ABMR, whereas cytomegalovirus (CMV) IgG negative recipient and CMV IgG negative donor were associated with a lower risk. BKPyV nephropathy was associated with the highest risk of graft dysfunction, followed by ABMR, T-cell mediated rejection, and older donor age. CONCLUSIONS: This study provides an estimate of the incidence of de novo HLA-DSA and ABMR in pKTR and highlights the importance of BKPyV nephropathy as a strong risk factor for allograft dysfunction.

Kidney transplantation in children and adolescents with C3 glomerulopathy or immune complex membranoproliferative glomerulonephritis: a real-world study within the CERTAIN research network.

BACKGROUND: Complement 3 glomerulopathy (C3G) and immune complex membranoproliferative glomerulonephritis (IC-MPGN) are ultra-rare chronic kidney diseases with an overall poor prognosis, with approximately 40-50% of patients progressing to kidney failure within 10 years of diagnosis. C3G is characterized by a high rate of disease recurrence in the transplanted kidney. However, there is a lack of published data on clinical outcomes in the pediatric population following transplantation. METHODS: In this multicenter longitudinal cohort study of the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) registry, we compared the post-transplant outcomes of pediatric patients with C3G (n = 17) or IC-MPGN (n = 3) with a matched case-control group (n = 20). RESULTS: Eleven of 20 children (55%) with C3G or IC-MPGN experienced a recurrence within 5 years post-transplant. Patients with C3G or IC-MPGN had a 5-year graft survival of 61.4%, which was significantly (P = 0.029) lower than the 5-year graft survival of 90% in controls; five patients with C3G or IC-MPGN lost their graft due to recurrence during this observation period. Both the 1-year (20%) and the 5-year (42%) rates of biopsy-proven acute rejection episodes were comparable between patients and controls. Complement-targeted therapy with eculizumab, either as prophylaxis or treatment, did not appear to be effective. CONCLUSIONS: These data in pediatric patients with C3G or IC-MPGN show a high risk of post-transplant disease recurrence (55%) and a significantly lower 5-year graft survival compared to matched controls with other primary kidney diseases. These data underscore the need for post-transplant patients for effective and specific therapies that target the underlying disease mechanism.

Detection of Subclinical Rejection in Pediatric Kidney Transplantation: Current and Future Practices.

INTRODUCTION: The successes in the field of pediatric kidney transplantation over the past 60 years have been extraordinary. Year over year, there have been significant improvements in short-term graft survival. However, improvements in longer-term outcomes have been much less apparent. One important contributor has been the phenomenon of low-level rejection in the absence of clinical manifestations-so-called subclinical rejection (SCR). METHODS: Traditionally, rejection has been diagnosed by changes in clinical parameters, including but not limited to serum creatinine and proteinuria. This review examines the shortcomings of this approach, the effects of SCR on kidney allograft outcome, the benefits and drawbacks of surveillance biopsies to identify SCR, and new urine and blood biomarkers that define the presence or absence of SCR. RESULTS: Serum creatinine is an unreliable index of SCR. Surveillance biopsies are the method most utilized to detect SCR. However, these have significant drawbacks. New biomarkers show promise. These biomarkers include blood gene expression profiles and donor derived-cell free DNA; urine gene expression profiles; urinary cytokines, chemokines, and metabolomics; and other promising blood and urine tests. CONCLUSION: Specific emphasis is placed on studies carried out in pediatric kidney transplant recipients. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03719339.

Over Three Decades of Growth Hormone Treatment in Children With Chronic Kidney Disease-Associated Growth Failure Before and After Kidney Transplantation.

BACKGROUND: Growth retardation and short final height is a common complication of chronic kidney disease (CKD) beginning in childhood, with profound deleterious effects on quality of life, mental health, and social achievement. Despite optimal treatments of causative factors for growth retardation in children with CKD, more than 50% of patients reach end-stage renal failure with a height >2 SD below the mean, and most do not demonstrate "catch-up" growth after receiving a kidney transplant. Four decades ago, recombinant human growth hormone (rhGH) treatment was introduced after studies showed increased growth velocity and improved height SDS in uremic subjects. Since then, an abundance of published data showed significant improvements in health-related quality of life, and most studies revealed no significant adverse effects. Clinical practice guidelines recommended rhGH treatment in CKD Stages 3-5D and after transplantation. Despite these guidelines, this therapy remained underutilized. Most commonly cited barriers to the implementation of rhGH treatment were the need for daily injections, financial challenges, physicians' unfamiliarity with guidelines, and fear of adverse events. CONCLUSIONS: rhGH has been shown to improve growth and final height in short children with CKD, with minimal adverse effects. Despite data of its successful use generated over 3 decades, this treatment is underutilized. More judicious utilization of the treatment should emphasize educating patients, their care givers, and members of the multidisciplinary treating team. Additional studies are needed to assess the longer-term rhGH treatment in larger cohorts of patients, leading to additional supportive data and clearer recommendations.

BK polyomavirus DNAemia, allograft rejection, and de novo donor-specific antibodies after lowering target tacrolimus levels in pediatric kidney transplant recipients.

BACKGROUND: BK polyomavirus (BKV) DNAemia is a challenging infectious complication after kidney transplant (KT). Reduction of immunosuppression is the mainstay of management, and tacrolimus is often the first immunosuppressive medication adjusted upon the diagnosis of BKV DNAemia. This study aimed to evaluate the impact of a new institutional protocol with lower target tacrolimus levels on BKV DNAemia, allograft rejection, and de novo donor-specific antibodies (dnDSA) among pediatric KT recipients. METHODS: We conducted a retrospective chart review of all KT episodes between January 2013 and December 2018. The new protocol with lower target tacrolimus levels was implemented in March 2015. One hundred twenty-seven patients were included in primary analysis. All patients received induction with basiliximab and methylprednisolone and were maintained on a steroid-based immunosuppressive regimen. RESULTS: In the post-intervention cohort, cumulative incidence of BKV DNAemia at 100 days (13.4% vs. 17.8%, p = .605) and 18 months post-KT (34.1% vs. 26.7%, p = .504) was not significantly different from the pre-intervention cohort. Biopsy-proven rejection rate did not change. However, we observed a trend toward earlier development of dnDSA in the post-intervention cohort using the Kaplan-Meier survival analysis (log-rank p = .06). Younger recipient age at the time of transplant was found to slightly increase the risk of BKV DNAemia (OR: 1.09, 95% CI [1.01, 1.16], p = .024). There was an association between BKV DNAemia and biopsy-proven rejection of any type (adjustedOR: 2.77, 95% CI [1.26, 6.23], p = .012), especially acute T-cell-mediated rejection grade 1A and above (adjustedOR: 2.95, 95% CI [1.06, 8.30], p = .037), after adjusted for recipient age at the time of transplant. CONCLUSIONS: Targeting lower tacrolimus levels did not decrease the incidence of BKV DNAemia within 100 days or 18 months post-KT, nor did it increase the risk of biopsy-proven rejection among pediatric KT recipients in our center. However, there was a trend toward earlier development of dnDSA, which may portend worse long-term graft outcome post-KT. Our findings highlight the need for individualized immunosuppressive regimens based on immunologic and infectious risk factors and the importance of implementing innovative biomarkers to guide therapy and improve outcomes.

Utilization of donor-derived Cell-Free DNA in pediatric kidney transplant recipients: A single center study.

High donor-derived cell-free DNA (dd-cfDNA) levels indicate transplant allograft injury and can identify graft rejection in kidney transplant recipients. Here, we evaluated the use of dd-cfDNA in pediatric kidney transplant rejection monitoring and treatment. METHODS: Forty-two pediatric kidney transplant patients were enrolled between February 2020 and August 2021. Dd-cfDNA was tested before and after biopsy/rejection treatment. There was a total of 61 allograft biopsies (44 for-cause, 17 surveillance). RESULTS: Graft rejection was found in 35/61 biopsies. Rejection was more common in basiliximab induction compared to rATG (77.1% vs. 22.9%, p = .0121). Median dd-cfDNA was higher in those with rejection (1.2% [0.34-3.12] vs. 0.24% [0.08-0.78], p < .0001). Dd-cfDNA was highest in biopsies with AMR and mixed AMR/TCMR. In addition, dd-cfDNA in basiliximab induction was higher compared to rATG (0.92% [0.27-1.8] vs. 0.26% [0.08-2], p = .0437). Median change in dd-cfDNA after rejection treatment was -0.57% (-1.67 to 0.05). Median time to dd-cfDNA <1% post-rejection treatment was 8.5 days (3.0-19.5). Dd-cfDNA in AMR was higher compared to TCMR or mixed rejection, and levels remained higher in AMR after treatment. In surveillance biopsies, 4/17 had rejection. Median dd-cfDNA was not different in those with versus without rejection (0.48% vs. 0.28%, p = .2342). Those without rejection all had dd-cfDNA <1%. In those with rejection, only one patient had dd-cfDNA >1%, and all had TCMR. CONCLUSIONS: Our findings support dd-cfDNA as a useful indicator of graft rejection and response to treatment. Additional studies are needed to determine the role of dd-cfDNA in graft health surveillance.

Current management of symptomatic vesicoureteral reflux in pediatric kidney transplantation-A European survey among surgical transplant professionals.

BACKGROUND: Vesicoureteral reflux (VUR) is common in children and adolescents undergoing kidney transplantation (KTx) and may adversely affect allograft kidney function. METHODS: To explore the current management of symptomatic native and allograft VUR in pediatric KTx recipients, an online survey was distributed to European surgical transplant professionals. RESULTS: Surgeons from 40 pediatric KTx centers in 18 countries participated in this survey. Symptomatic native kidney VUR was treated before or during KTx by 68% of the centers (all/selected patients: 33%/67%; before/during KTx: 89%/11%), with a preference for endoscopic treatment (59%). At KTx, 90% favored an anti-reflux ureteral reimplantation procedure (extravesical/transvesical approach: 92%/8%; preferred extravesical technique: Lich-Gregoir [85%]). Management strategies for symptomatic allograft VUR included surgical repair (90%), continuous antibiotic prophylaxis (51%), bladder training (49%), or noninterventional surveillance (21%). Redo ureteral implantation and endoscopic intervention for allograft VUR were equally reported (51%/49%). CONCLUSIONS: This survey shows uniformity in some surgical aspects of the pediatric KTx procedure. However, with regard to VUR, there is a significant variation in practice patterns that need to be addressed by future well-designed and prospective studies. In this way, more robust data could be translated into consensus guidelines for a more standardized and evidence-based management of this common condition in pediatric KTx.

Anesthesia and intensive care unit care in pediatric kidney transplantation: An international survey.

BACKGROUND: Despite the high perioperative risk profile, international guidelines for anesthesia and intensive care unit (ICU) care in pediatric kidney transplantation do not exist. Optimizing hemodynamics can be challenging in these patients, while scientific data to guide decisions in hemodynamic monitoring, hemodynamic targets, and perioperative fluid management are lacking. The limited annual number of pediatric kidney transplantations, even in reference centers, necessitates the urge for international collaboration to share knowledge and develop research and guidelines. The aim of this study was to collect data on current perioperative anesthesia and ICU care practices in pediatric kidney transplantation. METHODS: An international survey with an anonymized link was sent from a validated electronic data capture system (Castor). Inclusion criteria were: medical doctor in anesthesia, (ICU), or pediatric nephrology working in a pediatric kidney transplantation specialized center; and signed informed consent. Data were analyzed using descriptive statistics. RESULTS: Thirty-three records were analyzed. Responders were anesthesiologists (58%), pediatric nephrologists (30%), and pediatric intensivists (12%), representing 13 countries worldwide. About half of the centers (48%) performed more than 10 pediatric kidney transplantations a year. Perioperative hemodynamic support was guided by intra-arterial blood pressure (88%), central venous pressure (CVP; 88%), and cardiac output (CO; 39%). The most variation was seen in the hemodynamic targets CVP and CO, fluid administration, and inotrope/vasopressor use. The protocolized use of furosemide (46%) and mannitol (61%) also varied between centers. Postoperative care for the youngest recipients occurred in the pediatric intensive care unit at all centers. CONCLUSION: The results of this survey reveal a large variation in anesthesia and ICU care in pediatric kidney transplantation centers worldwide, particularly in CVP and CO targets, hemodynamic therapy, and the use of furosemide and mannitol. These data identify areas for further research and can be a starting point for international research collaboration and guideline development.

The Barriers Assessment Tool-A Patient-Centered Measure of Adherence Barriers in Pediatric Kidney Transplantation.

OBJECTIVE: Assessing barriers to adherence provides helpful information to clinicians. The objective of this study was to describe the clinical utility of the Barriers Assessment Tool (BAT) using clinical data for a large, midwestern U.S. pediatric kidney transplant program. METHODS: Focus group and clinical data were obtained during post-transplant medical visits. Qualitative and quantitative assessment methods were utilized to describe patient and caregiver feedback on the BAT, clinical utility, concordance between reporters, and the effect of interventions on subsequent assessment and electronically measured adherence. RESULTS: Patients were willing to discuss adherence issues with their care team. There was substantial agreement between patients and caregivers at two timepoints. If a barrier was not addressed, 89.6% (43/48) of patients and 85.9% (67/78) of caregivers reported the same BAT scores from the first to second assessment. When barriers were addressed with a clinic-based intervention, 82% of caregivers reported no adherence barriers. No significant change was found for patient-reported barriers. CONCLUSIONS: Standardized assessment of barriers to medication adherence provides actionable information to clinicians. Standardized assessment of adherence barriers may give clinicians opportunities to help patients and caregivers overcome these barriers which can decrease risk of rejection.

A pre-transplantation risk assessment tool for graft survival in Dutch pediatric kidney recipients.

Background: A prediction model for graft survival including donor and recipient characteristics could help clinical decision-making and optimize outcomes. The aim of this study was to develop a risk assessment tool for graft survival based on essential pre-transplantation parameters. Methods: The data originated from the national Dutch registry (NOTR; Nederlandse OrgaanTransplantatie Registratie). A multivariable binary logistic model was used to predict graft survival, corrected for the transplantation era and time after transplantation. Subsequently, a prediction score was calculated from the ß-coefficients. For internal validation, derivation (80%) and validation (20%) cohorts were defined. Model performance was assessed with the area under the curve (AUC) of the receiver operating characteristics curve, Hosmer-Lemeshow test and calibration plots. Results: In total, 1428 transplantations were performed. Ten-year graft survival was 42% for transplantations before 1990, which has improved to the current value of 92%. Over time, significantly more living and pre-emptive transplantations have been performed and overall donor age has increased (P < .05).The prediction model included 71 829 observations of 554 transplantations between 1990 and 2021. Other variables incorporated in the model were recipient age, re-transplantation, number of human leucocyte antigen (HLA) mismatches and cause of kidney failure. The predictive capacity of this model had AUCs of 0.89, 0.79, 0.76 and 0.74 after 1, 5, 10 and 20 years, respectively (P < .01). Calibration plots showed an excellent fit. Conclusions: This pediatric pre-transplantation risk assessment tool exhibits good performance for predicting graft survival within the Dutch pediatric population. This model might support decision-making regarding donor selection to optimize graft outcomes. Trial registration: ClinicalTrials.gov Identifier: NCT05388955.

Vesicoureteral Reflux Causes Interstitial Inflammation in Pediatric Kidney Allograft: A Clinicopathological Analysis of 1-Year Protocol Biopsies.

INTRODUCTION: At present, there is limited evidence of the histological impact of vesicoureteral reflux (VUR) on pediatric kidney allografts. In this study, we aimed to investigate the relationship between VUR diagnosed by voiding cystourethrography (VCUG) and 1-year protocol biopsy results. METHODS: One hundred thirty-eight pediatric kidney transplantations were performed in Toho University Omori Medical Center between 2009 and 2019. We included 87 pediatric transplant recipients who were evaluated for VUR by VCUG prior to or at the time of the 1-year protocol biopsy and underwent a 1-year protocol biopsy after transplantation. We evaluated the clinicopathological findings of the VUR and non-VUR groups, and histological scores were evaluated using the Banff score. Tamm-Horsfall protein (THP) within the interstitium was identified by light microscopy. RESULTS: Of the 87 transplant recipients, 18 cases (20.7%) were diagnosed with VUR by VCUG. The clinical background and findings were not significantly different between the VUR and non-VUR groups. The pathological findings revealed a significantly higher Banff total interstitial inflammation (ti) score in the VUR group than in the non-VUR group. Multivariate analysis indicated a significant relationship between the Banff ti score and THP within the interstitium, and VUR. The 3-year protocol biopsy results (n = 68) revealed a significantly higher Banff interstitial fibrosis (ci) score in the VUR group than in the non-VUR group. CONCLUSION: VUR caused interstitial fibrosis in the 1-year pediatric protocol biopsies, and interstitial inflammation at the 1-year protocol biopsy may affect interstitial fibrosis at the 3-year protocol biopsy.

Systematic use of magnetic double J stent in pediatric kidney transplantation: A single-center experience.

BACKGROUND: The intraoperative insertion of a double J stent (DJS) is known to reduce urological complications and is broadly accepted in kidney transplant (KTx) patients. The magnetic ureteral DJS (mDJS) represents a valid alternative device as it can be removed without cystoscopy, using a transurethral magnet. This is of particular importance in the pediatrics, allowing us to avoid cystoscopy requiring general anesthesia (GA) in this population. To date, few data are available on the systematic use of mDJS in pediatric patients undergoing KTx. METHODS: We report a retrospective analysis of 32 consecutive pediatric KTx at our center from July 2020 to December 2021. RESULTS: Ureteral stents remained in place for a median of 35 days (range: 12-76). Non-surgical magnetic removal of the mDJS was attempted in all cases without complications. In most cases (69%), the removal procedure was performed in an outpatient clinic. In 10 cases, the mDJS was removed in the operating room under sedation before removal of the abdominal Tenckhoff catheter. All patients were clinically followed (range: 3-15 months). CONCLUSIONS: We confirm the safety and feasibility of systematic use of mDJS in the setting of pediatric KTx. The systematic use of this device contributes to reduce the need for GA and the rate of hospital admission.

Limited Sampling Strategies to Predict Ganciclovir Exposure after Valganciclovir Administration and to Reduce Monitoring Constraints in Renal Transplant Children.

Valganciclovir, the ganciclovir prodrug, is an antiviral agent used to prevent cytomegalovirus infection in renal transplant children. Therapeutic drug monitoring is still necessary to ensure optimal therapeutic area under the concentration-time curve from 0 to 24 h (AUC0-24) of 40 to 60 µg·h/mL since valganciclovir presents a high pharmacokinetic variability. To calculate ganciclovir AUC0-24 with the trapezoidal method, 7 samples are needed. The objective of this study was to develop and validate a reliable and clinically applicable limited sampling strategy (LSS) for individualizing valganciclovir dose in renal transplant children. Rich pharmacokinetic data from ganciclovir plasmatic dosages measured in renal transplant children who received valganciclovir to prevent cytomegalovirus infection at Robert Debré University Hospital were collected retrospectively. Ganciclovir AUC0-24s were calculated using the trapezoidal method. The LSS was developed using a multilinear regression approach to predict AUC0-24. The patients included were divided into two groups for model development (50 patients) and validation (30 patients). A total of 80 patients were included between February 2005 and November 2018. Multilinear regression models were developed on 50 pharmacokinetic profiles (50 patients) and validated with an independent group of 43 pharmacokinetic profiles (30 patients). Regressions based on samples collected at T1h-T4h-T8h, T2h-T4h-T8h, or T1h-T2h-T8h presented the best AUC0-24 predictive performances with an average difference between reference and predicted AUC0-24 of -0.27, 0.34, and -0.40 µg·h/mL, respectively. In conclusion, valganciclovir dosage adaptation was required in children to achieve the target AUC0-24. Three LSS models using three pharmacokinetic blood samples instead of seven will be useful for individualizing valganciclovir prophylaxis in renal transplant children.

Relationships and dynamics in families with a child with a kidney transplant-A study of parents' everyday life experiences.

BACKGROUND: Paediatric kidney transplantation is often the best choice of treatment for kidney failure with replacement therapy and represents an important change in the child's well-being. There are, however, still a number of challenges in addition to the parental role. The magnitude of intensive parental caregiving and support required by children with a kidney transplant could be disruptive to family relationships and dynamics. OBJECTIVE: To explore the experiences of family relationships and dynamics among parents of a child with a kidney transplant. DESIGN: An explorative study using a qualitative method. PARTICIPANTS: Twelve parents (seven mothers and five fathers) of seven children with a kidney transplant were included. APPROACH: A phenomenological-hermeneutic approach was applied. METHOD: Semistructured, individual interviews were conducted. The data were analysed using Ricoeur's theory of interpretation on three levels: naïve reading, structural analysis and critical interpretation and discussion. FINDINGS: Three themes were generated: Emotions during ups and downs in everyday life; Balancing different needs among children; and Opportunities and having consideration in the family. CONCLUSION: Relationships between parents that are based on mutual emotional support are significant and essential during periods of severe illness in a child. Parents who are alone or emotionally marked by their child's disease history feel vulnerable and struggle to overcome challenges. Different health situations among siblings lead to challenges in bringing up the children and emotional dilemmas among parents that impact family dynamics. Resilience in parents is a shifting phenomenon that can influence how they deal with family relationships and dynamics.

Use of organs from increased infectious risk deceased donors in pediatric kidney transplantation.

Living donors are the main source of transplanted kidneys for children and young people in many countries, but there still remains a significant need for deceased donor kidney transplantation. Given the waiting times associated with deceased donor kidney transplantation and the morbidity or mortality that can occur in those on the waiting list, it is essential that the utilization of kidneys from deceased donors is optimized. The use of organs from deceased donors at increased risk of transmitting human immunodeficiency virus, hepatitis B virus, or hepatitis C virus is relatively common in adults, but far less so in children. The risks and benefits of the use of kidneys from increased infectious risk donors (IIRD) are discussed. The variation of definitions of IIRD between countries is explored as is the need for pediatric nephrologists and transplant surgeons to have an understanding of the prevalence of viral diseases within the country in which they work. The role of screening tests such as nucleic acid tests is examined, along with the concept of residual risk. Finally, considerations in acquiring informed consent in the use of kidneys from IIRDs in children and young people are discussed.

Precise clinicopathologic findings for application of genetic testing in pediatric kidney transplant recipients with focal segmental glomerulosclerosis/steroid-resistant nephrotic syndrome.

BACKGROUND: Establishing a molecular genetic diagnosis of focal segmental glomerulosclerosis (FSGS)/steroid-resistant nephrotic syndrome (SRNS) can be useful for predicting post-transplant recurrence. Monogenic causes are reportedly present in approximately 20-30% of patients with FSGS/SRNS. However, the characteristics of patients who are likely to have a monogenic cause remain to be determined. METHODS: Pediatric recipients with SRNS and/or biopsy-proven FSGS who underwent their first kidney transplantation at our center between 1999 and 2019 were analyzed. Patients with secondary FSGS/SRNS were excluded. The recipients were divided into three groups: familial/syndromic, presumed primary, and undetermined FSGS/SRNS. Patients who met all of the following criteria were categorized as having presumed primary FSGS/SRNS: (i) nephrotic syndrome, (ii) complete or partial remission with initial steroid therapy and/or additional immunosuppressive therapies, and (iii) diffuse foot process effacement on electron microscopy in the native kidney biopsy. All patients underwent genetic testing using next-generation sequencing. RESULTS: Twenty-four patients from 23 families were analyzed in this study. Pathogenic or likely pathogenic variants in FSGS/SRNS-related genes were identified in four of four families, zero of eight families, and 10 of 11 families with familial/syndromic, presumed primary, and undetermined FSGS/SRNS, respectively. Post-transplant recurrence only occurred in patients with presumed primary FSGS/SRNS. CONCLUSIONS: Our systematic approach based on precise clinicopathological findings including nephrotic syndrome, treatment responses, and diffuse foot process effacement might be useful to differentiate pediatric kidney transplant recipients with FSGS/SRNS who are likely to have a monogenic cause from patients who are not, and to predict post-transplant recurrence. A higher resolution version of the Graphical abstract is available as Supplementary information.

Emulation of the control cohort of a randomized controlled trial in pediatric kidney transplantation with Real-World Data from the CERTAIN Registry.

BACKGROUND: Randomized controlled trials in pediatric kidney transplantation are hampered by low incidence and prevalence of kidney failure in children. Real-World Data from patient registries could facilitate the conduct of clinical trials by substituting a control cohort. However, the emulation of a control cohort by registry data in pediatric kidney transplantation has not been investigated so far. METHODS: In this multicenter comparative analysis, we emulated the control cohort (n = 54) of an RCT in pediatric kidney transplant patients (CRADLE trial; ClinicalTrials.gov NCT01544491) with data derived from the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) registry, using the same inclusion and exclusion criteria (CERTAIN cohort, n = 554). RESULTS: Most baseline patient and transplant characteristics were well comparable between both cohorts. At year 1 posttransplant, a composite efficacy failure end point comprising biopsy-proven acute rejection, graft loss or death (5.8% ± 3.3% vs. 7.5% ± 1.1%, P = 0.33), and kidney function (72.5 ± 24.9 vs. 77.3 ± 24.2 mL/min/1.73 m2 P = 0.19) did not differ significantly between CRADLE and CERTAIN. Furthermore, the incidence and severity of BPAR (5.6% vs. 7.8%), the degree of proteinuria (20.2 ± 13.9 vs. 30.6 ± 58.4 g/mol, P = 0.15), and the key safety parameters such as occurrence of urinary tract infections (24.1% vs. 15.5%, P = 0.10) were well comparable. CONCLUSIONS: In conclusion, usage of Real-World Data from patient registries such as CERTAIN to emulate the control cohort of an RCT is feasible and could facilitate the conduct of clinical trials in pediatric kidney transplantation. A higher resolution version of the Graphical abstract is available as Supplementary information.