Pediatric Renal Transplant Recipients Research Articles

Management strategies for common viral infections in pediatric renal transplant recipients.

Viral infections have been considered as a major cause of morbidity and mortality after kidney transplantation in pediatric cohort. Children are at high risk of acquiring virus-related complications due to immunological immaturity and the enhanced alloreactivity risk that led to maintenance of high immunosuppressive regimes. Hence, prevention, early detection, and prompt treatment of such infe ctions are of paramount importance. Among all viral infections, herpes viruses (herpes simplex virus, varicella zoster virus, Epstein-Barr virus, cytomegalovirus), hepatitis B and C viruses, BK polyomavirus, and respiratory viruses (respiratory syncytial virus, parainfluenza virus, influenza virus and adenovirus) are common in kidney transplant recipients. These viruses can cause systemic disease or allograft dysfunction affecting the clinical outcome. Recent advances in tech nology and antiviral therapy have improved management strategies in screening, monitoring, adoption of prophylactic or preemptive therapy and precise trea tment in the immunocompromised host, with significant impact on the outcome. This review discusses the etiology, screening and monitoring, diagnosis, pre vention, and treatment of common viral infections in pediatric renal transplant recipients.

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

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

Therapeutic drug monitoring of mycophenolic acid (MPA) using volumetric absorptive microsampling (VAMS) in pediatric renal transplant recipients: ultra-high-performance liquid chromatography-tandem mass spectrometry analytical method development, cross-validation, and clinical application

BackgroundMycophenolic acid (MPA) is widely used in posttransplant pharmacotherapy for pediatric patients after renal transplantation. Volumetric absorptive microsampling (VAMS) is a recent approach for sample collection, particularly during therapeutic drug monitoring (TDM). The recommended matrix for MPA determination is plasma (PL), and conversion between capillary-blood VAMS samples and PL concentrations is required for the appropriate interpretation of the results.MethodsThis study aimed to validate and develop a UHPLC-MS/MS method for MPA quantification in whole blood (WB), PL, and VAMS samples, with cross and clinical validation based on regression calculations. Methods were validated in the 0.10–15 µg/mL range for trough MPA concentration measurement according to the European Medicines Agency (EMA) guidelines. Fifty pediatric patients treated with MPA after renal transplantation were included in this study. PL and WB samples were obtained via venipuncture, whereas VAMS samples were collected after the fingerstick. The conversion from VAMSMPA to PLMPA concentration was performed using formulas based on hematocrit values and a regression model.ResultsLC–MS/MS methods were successfully developed and validated according to EMA guidelines. The cross-correlation between the methods was evaluated using Passing-Bablok regression, Bland–Altman bias plots, and predictive performance calculations. Clinical validation of the developed method was successfully performed, and the formula based on regression was successfully validated for VAMSMPA to PLMPA concentration and confirmed on an independent group of samples.ConclusionsThis study is the first development of a triple matrix-based LC–MS/MS method for MPA determination in the pediatric population after renal transplantation. For the first time, the developed methods were cross-validated with routinely used HPLC–DAD protocol.Graphical

Intraoperative management of pediatric renal transplant recipients: An opportunity for improvement.

Optimal organ perfusion at the time of pediatric renal transplantation is a commonly agreed upon goal. Intraoperative conditions such as fluid balance and arterial pressure determine the success of this goal. Sparse literature guides the anesthesiologist in accomplishing this. We, therefore, hypothesized that significant variability exists in the methods used to optimize renal perfusion during transplantation. A literature search was performed to assess what guidelines currently exist to optimize intraoperative renal perfusion. The intraoperative practice pathways of six large children's hospitals in North America were obtained to compare suggested guidelines. A retrospective chart review of anesthesia records was performed of all pediatric renal transplants over 7 years at the University of North Carolina. There did not appear to be agreement between the various publications in terms of standard intraoperative monitoring, specific blood pressure or central venous pressure goals, and fluid management. The practice pathways of six children's hospitals showed significant variation and lack of a consensus-driven approach. The chart review demonstrated significant variation between anesthesiologists in terms of invasive monitoring, fluid management, hemodynamic goals, vasopressor use, and analgesic choices. However, children <30 kg were significantly more likely to have arterial lines and epidural catheters placed prior to surgery. Significant variation exists across centers of expertise and even within centers of expertise with regard to the intraoperative management of pediatric kidney transplant recipients. In the era of enhanced recovery after surgery, this presents an opportunity to develop consensus on an evidence-based approach to optimize initial organ perfusion during surgery.

Coronavirus disease 2019 vaccine in pediatric post-kidney transplantation.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and the resulting disease, coronavirus disease 2019 (COVID-19), have spread to millions of persons worldwide. Many vaccines have been developed; however, their efficacy in pediatric solid organ transplant recipients is yet to be determined. This is a prospective observational, non-interventional single-center study on the safety and efficacy of a COVID-19 vaccine (BNT162b2) in pediatric kidney transplant recipients. The primary aim of this study was to evaluate immunogenicity according to SARS-CoV-2-specific neutralizing antibody titer after two vaccine doses. The secondary aims were to investigate the safety of the vaccines, solicited local and systemic adverse reactions, incidence of COVID-19 post-vaccination, and effects on transplant graft function. Baseline investigations were conducted on pediatric renal transplant recipients, and recruited participants were advised to have the Comirnaty® mRNA vaccine according to protocol. A total of 48 patients (male, n=31, 64.6%; female, n=17, 35.4%), median age 14 [12-16] years were included, and all received two doses of the vaccine. The vaccine had a favorable safety and side-effect profile. The S-antibody titer of all patients ranged between .4 and 2,500 U/ml and was>50 U/ml in 89% of the patients. No difference in the measured antibody immune response was noted between infected and uninfected children. No major side effects were reported. The vaccine had a favorable safety profile in 12- to 15-year-old kidney transplant recipients, producing a greater measured antibody response than that in older transplant recipients.

Evaluation of pediatric renal transplant recipients admitted to the intensive care unit: A retrospective cohort study

Background/Aim: The best course of treatment for children with end-stage kidney disease (ESKD) is renal transplantation (RT), but some pediatric RT recipients are admitted to an intensive care unit (ICU) post-transplant. In the early and late post-operative phases, clinical data about pediatric RT recipients who are admitted to ICU are available. In this study, we aimed to evaluate demographic features, main reasons, and outcomes of pediatric RT patients admitted to the ICU during the early and late post-operative phases. Methods: This study was a cohort study. We analyzed the medical records of pediatric RT recipients (&lt;18 years of age) who were admitted to the ICU between May 30, 2011, and October 16, 2021, at our center, retrospectively. Patients ≥18 years of age and those without available data were excluded. We obtained the following data from ICU follow-up records and hospital medical records. The median (minimum-maximum) for continuous variables, frequencies, and percentages for categorical variables were used. The Chi-square test was used to compare categorical variables. We created graphs using percentages and frequencies to summarize the results. Results: Nineteen (16.5%) of the 115 pediatric patients who underwent RT were admitted to the ICU during the study period. Thirteen patients (68.4%) were male, and the mean age was 10.2 (4.9) years. Hypertension (21.2%) was the most common comorbidity. Eighteen (94.7%) received transplants from living donors. Cystic-hereditary-congenital disorders (42.1%, n=8) and congenital anomalies of the kidney and urinary tract (26.3%, n=5) were among the etiologies of ESKD. Ten patients (52.6%) were admitted to the ICU &gt;6 months after transplantation. Epileptic seizure (n=6, 31.6%), respiratory failure (n=4, 21.1%), and cardiac diseases (n=2, 10.5%) were among the main reasons for ICU admission. During ICU follow-up, invasive mechanical ventilation was needed for five patients (26.3%), and renal replacement treatment was needed for four patients (21.1%). The mean length of ICU was 12.4 (28.5), and the mean hospital stay was 25.8 (29.4) days. The ICU and hospital survival rates were 78.9% and 97%, respectively, while 3.5% was the hospital mortality rate. Hemorrhagic cerebrovascular disease, acute hepatic failure, and cardiogenic shock secondary to pericardiocentesis were the causes of death in the ICU. Conclusion: Patients mostly had ICU admissions because of epileptic seizures and acute respiratory failure. A multidisciplinary approach involving pediatric nephrologists, transplant surgeons, and an intensive care team successfully manages pediatric RT recipients admitted to the intensive care unit.

De novo Donor-specific Anti-human Leukocyte Antigen Antibody and Its Outcome in Pediatric Renal Transplant Recipients: A Single-center Experience in India

Development of de novo donor-specific anti-HLA antibody (dnDSA) is associated with poor graft survival in adults. However, there is a paucity of data about its prevalence and outcome in Indian children. We retrospectively assessed the proportion and spectrum of dnDSA and its outcome on antibody-mediated rejection (ABMR) and graft function. Children ≤18 years who were transplanted between November 2016 and October 2019 were included in this study. Pretransplant donor-specific antibody (DSA) was screened by complement-dependent cytotoxicity, flow cytometry crossmatch, and single antigen bead (SAB) class I and II by Luminex platform. Either antithymocyte globulin or basiliximab was used as induction. Tacrolimus, mycophenolate, and prednisolone were used for the maintenance of immunosuppression. SAB screening was done at 1, 3, 6 months, and yearly in seven children and at the time of acute graft dysfunction in eight. Mean fluorescence intensity ≥1000 was considered positive. Protocol biopsies were done at 3, 6, and 12 months and annually thereafter in seven children. Fifteen children, all males with a median age (interquartile range) of 13 years (11; 15.5) were analyzed. Only one child had pretransplant DSA who developed dnDSA posttransplant. Overall, 8 (53%) developed dnDSA over a median follow-up of 18 months. Seven (87%) had Class II, one Class I and 3 (37%) both Class I and II. Six had dQ and two had DR. All children with dnDSA had ABMR, of these two had subclinical rejection. DSAs persisted despite treatment, though graft function improved. Children with DSA and ABMR had lower graft function than those without DSA. The proportion of dnDSA was high in our study, majority against DQ. The detection of dnDSA prompted early diagnosis and treatment of ABMR.

Therapeutic challenges of tacrolimus dose requirement and trough level in an indian pediatric renal transplant recipient with extensive metabolizer (Cytochrome P450 3A5*1)

Pediatric patients need a higher dose of tacrolimus for posttransplant immunosuppression due to its high clearance. In addition, genetic polymorphism in cytochrome P450 (CYP) 3A5 enzyme (CYP3A5*1/*3) is an important determinant for its serum concentration. Substantial data exist about the requirement of higher doses of tacrolimus in patients with the CYP3A5*1 genotype (extensive metabolizer). Ketoconazole, an inhibitor of CYP, leads to the reduction of the tacrolimus dose while maintaining therapeutic levels in transplant recipients. However, very few studies have mentioned coadministration of ketoconazole and tacrolimus in pediatric renal transplant recipients. Herein, we present a case of a 10-year-old boy with end-stage renal disease due to posterior urethral valves who underwent a living-related kidney transplant. We also emphasize the importance of CYP3A5 genotype evaluation in deciding the course of the treatment and maintaining therapeutic levels of tacrolimus in pediatric transplant recipients.

Pediatric kidney transplants with multiple renal arteries show no increased risk of complications compared to single renal artery grafts.

Kidney allografts with multiple renal arteries (MRA) are not infrequent and have been historically associated with a higher risk of developing vascular and urologic complications. Reports of kidney transplantation using MRA allografts in the pediatric population remain scarce. The aim of this study was to evaluate if transplantation of allografts with MRA with a surgical intent of creating a single arterial inflow using vascular reconstruction techniques when required, and without the routine use of surgical drains or ureteral stents, is associated with an increased risk of complications when compared to single renal artery (SRA) grafts. We retrospectively analyzed all pediatric renal transplant recipients performed by a single surgeon at our center between January 2015 and June 2022. Donor and recipient demographics, intraoperative data, and recipient outcomes were included. Recipients were divided into two groups based on SRA vs. MRA. Baseline variables were described using frequency distributions for categorical variables and means and standard errors for continuous variables. Comparisons of those distributions between the two groups were performed using standard chi-squared and t-tests. Time-to-event distributions were compared using the log-rank test. Forty-nine pediatric transplant recipients were analyzed. Of these, 9 had donors with MRA (Group 1) and 40 had donors with SRA (Group 2). Native kidney and liver mobilization was performed in 44.4% (4/9) of Group 1 vs. 60.0% (24/40) of Group 2 cases (p = 0.39). There were no cases of delayed graft function or graft primary nonfunction. No surgical drainage or ureteral stents were used in any of the cases. One patient in Group 2 developed a distal ureter stricture. The geometric mean serum creatinine at 6- and 12-months posttransplant was 0.7 */ 1.2 and 0.9 */ 1.2 mg/dl in Group 1 and 0.7 */ 1.1 and 0.7 */ 1.1 mg/dl in Group 2. Two death-censored graft failures were observed in Group 2, with no significant difference observed between the two groups (p = 0.48). Our study demonstrates that pediatric renal transplantation with MRA grafts, using a surgical approach to achieve a single renal artery ostium, can be safely performed while achieving similar outcomes as SRA grafts and with a low complication rate.

Retroperitoneal kidney transplantation with liver and native kidney mobilization: a safe technique for pediatric recipients

BackgroundPediatric kidney transplant (KT) using larger, deceased or living donor adult kidneys can be challenging in the pediatric population due to limited space in the retroperitoneum. Liver and native kidney (L/NK) mobilization techniques can be used in smaller and younger transplant recipients to aid in retroperitoneal placement of the renal allograft. Here, we compare the clinical outcomes of pediatric retroperitoneal KT with and without L/NK mobilization.MethodsWe retrospectively analyzed pediatric renal transplant recipients treated between January 2015 and May 2021. Donor and recipient demographics, intraoperative data, and recipient outcomes were included. Recipients were divided into two groups according to the surgical technique utilized: with L/NK mobilization (Group 1) and without L/NK mobilization (Group 2). Baseline variables were described using frequency distributions for categorical variables and means and standard errors for continuous variables. Tests of association with the likelihood of using L/NK mobilization were performed using standard χ2 tests, t tests, and the log-rank test.ResultsForty-six pediatric recipients were evaluated and categorized into Group 1 (n = 26) and Group 2 (n = 20). Recipients in Group 1 were younger (6.7 ± 0.8 years vs. 15. 3 ± 0.7, P < 0.001), shorter (109.5 ± 3.7 vs. 154.2 ± 3.8 cm, P < 0.001) and weighed less (21.4 ± 2.0 vs. 48.6 ± 3.4 kg, P < 0.001) than those in Group 2. Other baseline characteristics did not differ between Groups 1 and 2. One urologic complication was encountered in Group 2; no vascular or surgical complications were observed in either group. Additionally, no stents or drains were used in any of the patients. There were no cases of delayed graft function or graft primary nonfunction. The median follow-up of the study was 24.6 months post-transplant. Two patients developed death-censored graft failure (both in Group 2, P = 0.22), and there was one death with a functioning graft (in Group 2, P = 0.21).ConclusionsRetroperitoneal liver/kidney mobilization is a feasible and safe technique that facilitates implantation of adult kidney allografts into pediatric transplant recipients with no increased risk of developing post-operative complications, graft loss, or mortality.

Frequency of Bacteremia and Urinary Tract Infection in Pediatric Renal Transplant Recipients.

Our primary goal was to determine the frequency of bacteremia and urinary tract infections (UTI) in pediatric renal transplant recipients presenting with suspected infection within 2 years of transplant and to identify clinical and laboratory factors associated with bacteremia. We conducted a retrospective cross-sectional study for all pediatric ( < 18 years old) renal transplant recipients seen at 3 large children's hospitals from 2011 to 2018 for suspected infection within 2 years of transplant date, defined as pyrexia ( > 38°C) or a blood culture being ordered. Patients with primary immunodeficiencies, nontransplant immunosuppression, intestinal failure, and patients who had moved out of the local area were excluded. The primary outcome was bacteremia or UTI; secondary outcomes included pneumonia, bacterial or fungal meningitis, respiratory viral infections, and antibiotic resistance. The unit of analysis was the visit. One hundred fifteen children had 267 visits for infection evaluation within 2 years of transplant. Bacteremia (with or without UTI) was diagnosed in 9/213 (4.2%) and UTIs in 63/189 (33.3%). Tachycardia and hypotension were present in 66.7% and 0% of visits with documented bacteremia, respectively. White blood cell (12,700 cells/mm 3 vs. 10,900 cells/mm 3 ; P = 0.43) and absolute neutrophil count (10,700 vs. 8200 cells/mm 3 ; P = 0.24) were no different in bacteremic and nonbacteremic patients. The absolute band count was higher in children with bacteremia (1900 vs. 600 cells/mm 3 ; P = 0.02). Among Gram-negative pathogens, antibiotic resistance was seen to 3rd (14.5%) and 4th (3.6%) generation cephalosporins, 12.7% to semisynthetic penicillins, and 3.6% to carbapenems. Bacteremia or UTIs were diagnosed in one-quarter of all pediatric renal transplant recipients presenting with suspected infection within 2 years of transplant. Evaluations were highly variable, with one-third of visits not having urine cultures obtained. No single demographic, clinical or laboratory variable accurately identified patients with bacteremia, although combinations of findings may identify a high-risk population.

248.10: COVID-19 Infections in Pediatric Renal Transplant Recipients

248.10: COVID-19 Infections in Pediatric Renal Transplant Recipients

332.3: Preoperative Systemic Immune-Inflammation Index, Platelet-Lymphocyte Ratio and Neutrophil-Lymphocyte Ratio in Predicting the Delayed Graft Function in Pediatric Renal Transplant Recipients: A Single Centre Study

332.3: Preoperative Systemic Immune-Inflammation Index, Platelet-Lymphocyte Ratio and Neutrophil-Lymphocyte Ratio in Predicting the Delayed Graft Function in Pediatric Renal Transplant Recipients: A Single Centre Study

243.4: Evolution of Polyomavirus BK and JC Viral Load in Pediatric Renal Transplant Recipients

Introduction: Polyomavirus-associated nephropathy (PVAN) occurs in 5% of renal transplant recipients (RTR) and is caused by Polyomavirus BK (BKPyV) and JC (JCPyV), at a very low rate. This disease causes a progressive impairment of renal function and ultimate graft loss. Monitoring of viral load with pre-emptive reduction of immunosuppression is the only proved preventive strategy to reduce the risk of PVAN. The aim of this study was to describe the evolution of BKPyV and JCPyV viral load in de novo pediatric RTR. Method: A prospective observational study was carried out in a pediatric RTR. Paired samples of serum and urine were collected at baseline (on the day of transplantation), then monthly for at least 9 months post transplantation (PostTx). Viral load of BKPyV and JCPyV was determined by a Multiplex Real Time PCR assay (transferred by Fedele CG,2012). Results: Fourteen patients were enrolled, the median age of the group was 13 years old (8-19) and 11 were male. The monitoring period was from 9 to 20 months (media 16). None of the patients developed PVAN during the study, but 11 (78%) of them tested positive, which were divided into three groups: 1.BKPyV positive (n=7) - they showed a pattern of viruria with a maximum between the 2nd and 7th month PostTx (median 8.5.108copies/ml), after this peak viral load diminished significantly over the time getting undetectable in 4 cases. Two patients had higher values at the maximum in coincidence with impairment of renal function. Viremia was detectable in all cases, but with intermittences and it has not shown a well-defined profile, the highest values were around 104copies/ml. 2.JCPyV positive (n=2) - both cases had JCPyV viruria without viremia with similar patterns: viral load was detectable from 2nd month PostTx and continued along the time with tendency to increase. 3.BKPyV and JCPyV dual positive (n=2) - BKPyV viruria and viremia were detected at low rates at the beginning, then appeared JCPyV viruria simultaneously but with higher viral load, and from 10th month PostTx to the end (17th month) only JCPyV viruria was detectable with the same upward trend as group two. Conclusion: We detected active infection of BKPyV in 64% (9/14) of the cases, although there was no occurrence of any case of PVAN. However, in cases with impair renal function it were observed a significant increase of viruria. There are different proposed algorithms for monitoring BKPyV viral load to identify patients at risk of PVAN. We found a characteristic pattern of BKPyV viral shedding in urine. Based on this finding we would recommend to strengthen controls between 2nd to 7th month PostTx to be more sensitive to detect patients with viruria higher than 107copies/ml, thus at more risk to develop viremia and consequently PVAN. Finaly, when PVAN is suspected and BKPyV is undetectable, JCPyV diagnose should be made, since it can cause PVAN as well although with low frequency, and we demonstrated its presence in 29% of the cases. Cesare Giovanni Fedele.

Incidence and outcome of SARS-CoV-2 infection in a pediatric kidney transplant recipient cohort from a single center in Northern Italy.

BackgroundConcern about SARS‐CoV‐2 infection has increased over the possible effects on immunocompromised patients. Among them, recipients of solid organ transplantation deserve special attention. Data from the adult population suggest they may be at high risk for developing severe COVID‐19, but little data are available for pediatric solid organ transplantation recipients.MethodsFrom March 2020 to April 2021, KT recipients aged <21 years, routinely managed at our center, who underwent RT‐PCR testing with nasopharyngeal swabs to detect SARS‐CoV‐2 infection, were studied. Tests were performed according to clinical and/or epidemiological criteria.ResultsOne hundred one transplanted patients were managed at our center during the observation period. Among this population, 57 patients were tested for SARS‐CoV‐2 infection with a RT‐PCR test and were subsequently enrolled. A total of 111 swabs were performed. Twelve out of the 57 patients tested (21.1%) had a positive RT‐PCR test result. Among the positive patients, eight were symptomatic (66.7%). Median duration of symptoms and RT‐PCR positivity was two days (IQR 1–2.25) and 17 days (IQR 11–27.25), respectively. No patients required specific treatment or IS therapy reduction; no one was admitted to hospital.ConclusionsOur data show that pediatric renal transplant recipients are at low risk of clinically relevant COVID‐19, as is the healthy age‐related population. On the contrary, our results differed substantially from those seen in adult SOT recipient populations that have a high incidence and an even earlier and higher mortality rate.

Long term tolerability and clinical outcomes associated with tocilizumab in the treatment of refractory antibody mediated rejection (AMR) in pediatric renal transplant recipients.

Treatment options for antibody-mediated rejection (AMR) are limited. Recent studies have shown that inhibition of interleukin-6 (IL-6)/interleukin-6 receptor (IL-6R) signaling can reduce inflammation and slow AMR progression. We report our experience using monthly tocilizumab (anti-IL6R) in 25 pediatric renal transplant recipients with AMR, refractory to IVIg/Rituximab. From January 2013 to June 2019, a median (IQR) of 12 (6.019.0) doses of tocilizumab were given per patient. Serial assessments of renal function, biopsy findings, and HLA DSA (by immunodominant HLA DSA [iDSA] and relative intensity score [RIS]) were performed. Median (IQR) time from transplant to AMR was 41.4 (24.367.7) months, and time from AMR to first tocilizumab was 10.6 (8.317.6) months. At median (IQR) follow up of 15.8 (8.435.7) months post-tocilizumab initiation, renal function was stable except for 1 allograft loss. There was no significant decrease in iDSA or RIS. Follow up biopsies showed reduction in peritubular capillaritis (p=.015) and C4d scoring (p=.009). The most frequent adverse events were cytopenias. Tocilizumab in pediatric patients with refractory AMR was well tolerated and appeared to stabilize renal function. The utility of tocilizumab in the treatment of AMR in this population should be further explored.

Pharmacokinetics of free and total mycophenolic acid in paediatric and adult renal transplant recipients: Exploratory analysis of the effects of clinical factors and gene variants.

Clinical and genetic influencing factors on free fraction of mycophenolic acid (MPA) have rarely been discussed. The present study investigated whether the clinical and genetic factors could explain the variability in the pharmacokinetics of free MPA (fMPA) and total MPA (tMPA) in Chinese paediatric and adult renal transplant recipients. Twenty-eight paediatric and 31 adult patients were enrolled, and the concentrations of tMPA and fMPA were determined at 0 h (predose) and 0.5, 1, 1.5, 2, 4, 5, 8, 9, 10 and 12 h after mycophenolate mofetil administration. Genetic polymorphisms of UGTs (rs671448, rs1042597, rs2741049, rs62298861, rs7439366, rs12233719) and ABCC2 (rs717620) were simultaneously determined. The clinical and genetic data were analysed and reported. tMPA and fMPA concentrations adjusted for dose per body weight were consistently higher in adults than in paediatric patients. In the paediatric group, only albumin and time after transplantation correlated significantly with the MPA-free fraction variation, which could explain 32.4% of the variability. Besides, ABCC2 polymorphism, albumin and time after transplantation correlated significantly with the MPA-free fraction variation in adults, which could explain 56.9% of the variability. The influencing factors in the paediatric group are different from those in adults, which may be due to age-related transporter expression.

The Role of Platelet-Lymphocyte Ratio and Neutrophil-Lymphocyte Ratio in Predicting the Delayed Graft Function in Pediatric Renal Transplant Patients.

Delayed graft function is a common adverse outcome after renal transplant. Attempts for early prediction and prevention of delayed graft function are often challenging and misleading. Herein, we investigated for the first time the correlation between delayed graft function and preoperative noninvasive hematologic parameters to predict the possible adverse outcomes for renal transplant in pediatric patients. In this study, preoperative hematologic parameters of 51 pediatric renal transplant recipients followed between 2015 and 2021 were analyzed retrospectively. The selected 16 renal transplant patients with delayed graft function and 35 patients without delayed graft function had no concomitant comorbidities. The cutoff values for platelet-to-lymphocyte ratio of <5 and neutrophilto- lymphocyte ratio of <175 were considered low. We retrospectively evaluated a total of 51 (male/female, 33/18) pediatric kidney transplant recipients with a median age of 12 (interquartile range, 8-18) years. Median level of circulating lymphocytes was significantly higher in patients with delayed graft function compared with patients without delayed graft function (2 vs 1, P = .040). The preoperative low values for platelet-to-lymphocyte ratio and neutrophil-to-lymphocyte ratio were more prevalent in recipients who developed delayed graft function versus those who did not develop delayed graft function (68.8% vs 31.4% [P = .014] and 68.8% vs 34.3% [P = .023], respectively). Pretransplant low platelet-to-lymphocyte ratio and neutrophil-to-lymphocyte were associated with increased number of delayed graft dysfunction. These novels and noninvasive inflammatory biomarkers may contribute to an early prediction of delayed graft function in pediatric kidney transplant recipients.

Effects of tacrolimus intrapatient variability and CYP3A5 polymorphism on the outcomes of pediatric kidney transplantation.

The intrapatient variability (IPV) of tacrolimus (Tac) is associated with the long-term outcome of kidney transplantation. The CYP3A single-nucleotide polymorphism (SNP) may affect the IPV of Tac. We investigated the impact of IPV and genetic polymorphism in pediatric patients who received kidney transplantation. A total of 202 pediatric renal transplant recipients from 2000 to 2016 were analyzed retrospectively. The IPV was calculated between 6 and 12months after surgery. Among these patients, CYP3A5 polymorphism was analyzed in 67 patients. The group with high IPV had a significantly higher rate of de novo donor-specific human leukocyte antigen antibodies (dnDSA) development (35.7% vs. 16.7%, p=.003). The high IPV group also had a higher incidence of T-cell-mediated rejection (TCMR; p<.001). The high IPV had no significant influence on Epstein-Barr virus, cytomegalovirus, and BK virus viremia but was associated with the incidence of posttransplant lymphoproliferative disorders (p=.003). Overall, the graft survival rate was inferior in the high IPV group (p<.001). The CYP3A5 SNPs did not significantly affect the IPV of Tac. In the CYP3A5 expressor group, however, the IPV was significantly associated with the TCMR-free survival rate (p<.001). The IPV of Tac had a significant impact on dnDSA development, occurrence of acute TCMR, and graft failure in pediatric patients who received renal transplantation. CYP3A5 expressors with high IPV of Tac showed worse outcomes, while the CYP3A5 polymorphism had no impact on IPV of Tac.

Treatment of post-transplant recurrent FSGS in children using plasmapheresis and augmentation of immunosuppression

BackgroundUp to 60% of pediatric renal transplant recipients with end-stage renal disease due to primary focal and segmental glomerulosclerosis (FSGS) may develop recurrent disease. Such recurrence is associated with poor prognosis if no remission is achieved. We report a single center experience with a protocol based on plasmapheresis and increased immunosuppression that resulted in a high long-lived remission rate.MethodsThis retrospective cohort study included consecutive pediatric renal transplant patients with recurrent FSGS treated with a standardized protocol using plasmapheresis and cyclophosphamide to supplement usual post-transplant immunosuppression with calcineurin inhibitors and steroids. Relapse was defined as urinary protein/creatinine ratio > 1.0 g/g and remission as < 0.5 g/g.ResultsSeventeen patients with FSGS recurrence post-transplant were treated. All had therapy resistant FSGS in native kidneys and had been on dialysis from 4 to 10 years. Of the 17, one died perioperatively from a pulmonary thromboembolism. Fifteen others achieved a complete remission within 3 months of treatment for FSGS recurrence. After a median follow-up period of 4 years, there were no recurrences of significant proteinuria. One patient achieved remission with rituximab.ConclusionThe addition of plasmapheresis and cyclophosphamide to a calcineurin- and steroid-based immunosuppression regime was highly successful in inducing high remission rates with recurrent FSGS. Prospective trials are needed to evaluate further the efficacy of increased immunosuppression along with plasmapheresis in this setting.