Machine learning models to predict post-dialysis blood pressure in children and young adults on maintenance hemodialysis.

Hypertension is associated with significant cardiovascular morbidity. Blood pressure (BP) control on maintenance hemodialysis (HD) is strongly impacted by volume status. The objective of this study was to assess whether machine learning (ML) is effective in predicting post-HD BP in children and young adults on HD. We collected data on BP, IDWG, pulse, and weights for patients on maintenance HD (> 3 months). Input features included DW, pre-post weight difference, IDWG and pre-HD BP. Seven models were trained and tuned using open-source libraries. Model performance was evaluated using time-series cross-validation on a rolling basis (3-12 month training, 1-day testing). Various regression scores were compared between models. Data for 35 patients (14,375 HD sessions) were analyzed. Extreme gradient boosting (XGB) and vector autoregression with exogenous regressors (VARX) achieved better accuracy in predicting post-dialysis systolic BP than K-nearest neighbor, support vector regression (SVR) with radial basis function kernel and random forest (p < 0.001 for each). The differences in accuracy between XGB, VARX, SVR with linear kernel, random forest and linear regression were not significant. Using clinical parameters, ML models may be useful in predicting post-HD BP, which may help guide DW adjustment and optimizing BP control for maintenance HD patients.

Design and Methods of the Validating Injury to the Renal Transplant Using Urinary Signatures (VIRTUUS) Study in Children.

Lack of noninvasive diagnostic and prognostic biomarkers to reliably detect early allograft injury poses a major hindrance to long-term allograft survival in pediatric kidney transplant recipients. METHODS: Validating Injury to the Renal Transplant Using Urinary Signatures Children's Study, a North American multicenter prospective cohort study of pediatric kidney transplant recipients, aims to validate urinary cell mRNA and metabolite profiles that were diagnostic and prognostic of acute cellular rejection (ACR) and BK virus nephropathy (BKVN) in adult kidney transplant recipients in Clinical Trials in Organ Transplantation-4. Specifically, we are investigating: (1) whether a urinary cell mRNA 3-gene signature (18S-normalized CD3ε, CXCL10 mRNA, and 18S ribosomal RNA) discriminates biopsies with versus without ACR, (2) whether a combined metabolite profile with the 3-gene signature increases sensitivity and specificity of diagnosis and prognostication of ACR, and (3) whether BKV-VP1 mRNA levels in urinary cells are diagnostic of BKVN and prognostic for allograft failure. RESULTS: To date, 204 subjects are enrolled, with 1405 urine samples, including 144 biopsy-associated samples. Among 424 urine samples processed for mRNA, the median A260:280 ratio (RNA purity) was 1.91, comparable with Clinical Trials in Organ Transplantation-4 (median 1.82). The quality control failure rate was 10%. Preliminary results from urine supernatant showed that our metabolomics platform successfully captured a broad array of metabolites. Clustering of pool samples and overlay of samples from various batches demonstrated platform robustness. No study site effect was noted. CONCLUSIONS: Multicenter efforts to ascertain urinary biomarkers in pediatric kidney transplant recipients are feasible with high-quality control. Further study will inform whether these signatures are discriminatory and predictive for rejection and infection.

School and sports participation post-transplant.

Pediatric recipients of life-saving organ transplants are living longer, with improved graft and overall survivals. After successful transplant, children are encouraged to return to "normal life," with school attendance and participation in age-appropriate physical activities. This transition may cause stress to the recipients, parents, teachers, and other participating caregivers and staff. Planning for school reentry and assuring education for and open lines of communication with the school staff can help alleviate some of this discomfort and ease the process for the patient and the family. Cardiovascular disease has emerged as the leading cause of death in survivors of pediatric transplantation and is contributed to by modifiable risk factors such as obesity, hypertension, and the MS. Physical activity is a proven tool in decreasing surrogate markers of this risk. Sports participation is an important way to promote an enjoyment of physical activity that can ideally persist into adulthood, but conflicting advice and opinions exist regarding type and participation in physical activity. Moreover, specific recommendations are likely not applicable to all recipients, as certain degrees of rehabilitation may be needed depending on degree and length of illness. In general, a program of rehabilitation and increased physical activity has been shown to be safe and effective for most pediatric transplant recipients. Focusing on optimizing the "normal" childhood activities of going to school and participating in sports can improve the physical, social, cognitive, and mental health outcomes of this population after transplant and should be prioritized.

Varicella infection following vaccination in a pediatric kidney transplant recipient.

Live viral vaccines have historically been avoided in children after solid organ transplantation. Multiple reports of safety and immunogenicity, largely in the pediatric liver transplant population, have led to a reconsideration of this recommendation. Here, we report the case of a 4-year-old boy who inadvertently received the live attenuated MMR-varicella vaccine (MMRV) at a routine well-child visit 16 months after receiving a living donor kidney transplant. This was not known until after he was admitted with rash and documented disseminated varicella infection 5 weeks later. He was treated with intravenous acyclovir followed by oral therapy and recovered fully. This case and its discussion illustrate what is still unknown about the risk-to-benefit ratio of live viral vaccination in any individual transplant recipient. Criteria to determine which patients should receive these vaccines should be evaluated before their use after transplant becomes routine, and all recipients and their families should be counseled to have a low threshold to seek medical care for any febrile illness or rash after live viral vaccination.

Impact of preoperative hyponatraemia on paediatric perioperative mortality.

BACKGROUND: Preoperative hyponatraemia is an independent risk factor for postoperative mortality in adults. To our knowledge, this has not been investigated in children. METHODS: Using data from the 2014 and 2015 data sets of the American College of Surgeons National Surgical Quality Improvement Program-Pediatric (NSQIP-P), we conducted a retrospective study of children undergoing surgery. The primary outcome was 30-day all-cause mortality. The secondary outcomes of interest were postoperative seizure within 30 days and prolonged length of stay. To identify any independent association between preoperative hyponatraemia, defined as mild (serum sodium of 131-135 mEq L-1) or severe (≤130 mEq L-1), and death, postoperative seizures, or prolonged length of stay, multivariable logistic regression models were generated. RESULTS: A total of 152 894 patients were identified, and of these 35 291 were included in the final analysis. Preoperative hyponatraemia was present in 5422 patients or 15.4% of the final cohort. There were 432 (0.80%) deaths at 30 days. Compared with patients with a normal preoperative sodium concentration, those with mild (P=0.003; odds ratio [OR]: 1.59; 95% confidence interval [CI]: 1.17-2.18) and severe (P=0.002; OR: 2.16; 95% CI: 1.32-3.54) hyponatraemia had increased rates of death, after adjusting for co-morbidity and procedural complexity. Both mild (P<0.001; OR: 1.53; 95% CI: 1.42-1.65) and severe (P<0.001; OR: 1.51; 95% CI: 1.19-1.93) hyponatraemia were independently associated with prolonged length of stay, after adjusting for relevant co-variates. CONCLUSIONS: This retrospective analysis identified an association between preoperative hyponatraemia and perioperative mortality and length of stay in paediatric patients.

Utility of thrombophilia screening in pediatric renal transplant recipients.

Thrombosis after kidney transplantation may result in catastrophic outcomes, including graft loss. Thrombophilia has been implicated in post-transplant thrombosis; data, however, are inconclusive on the impact of acquired and inherited thrombophilia and resultant thrombosis in renal graft recipients. We aimed to evaluate whether identifying children with thrombophilia during the pretransplant evaluation predicted post-transplant outcomes. We reviewed 100 kidney transplants performed in 100 children, aged 1-18 years, in a single-center retrospective study. Routine pretransplant comprehensive thrombophilia evaluation was completed. Thrombophilia was demonstrated in 36% patients (N = 36). TEs occurred in 11 patients before kidney transplant. Low PS and antithrombin were found in 9/86 (10.5%) and 2/89 (2.2%) children, respectively. Heterozygosity for FLV and PGM were found in 5/81 (6.2%) and 1/93(1.1%) children, respectively. A post-transplant thrombotic event occurred in 10 children (10%); six involved the renal transplant. The association between a history of a pretransplant thrombotic event and post-operative renal graft thrombosis approached, but did not reach significance (P = 0.071). There was no association between preoperative screening abnormalities and post-operative TEs. Graft loss due to a thrombotic event occurred in two patients; none had underlying thrombophilia. Our data suggest that the utility of universal, comprehensive preoperative thrombophilia testing is not beneficial in determining risk of post-operative graft thrombosis. Thrombophilia testing may be considered in a select population with a history of pretransplant thrombotic event.

BK polyomavirus infection in pediatric heart transplant recipients: a prospective study.

BKV infection and nephropathy complicate pediatric HTx, but the incidence and time course of the disease are unknown. We assessed the incidence of BKV infection and its association with kidney dysfunction in pediatric HTx recipients. A single center prospective study compared pediatric (<18 years) HTx recipients, with and without BKV infection, who received an allograft between September 2013 and December 2014. Screening of urine for BKV was performed prior to transplant, and at week 1, and at months 3, 6, 9, 12, and 15 months post-transplantation. Serum for BKV DNA was assayed if BK viruria was present. Statistics included Fisher's exact test and Student's t test. Twelve patients were enrolled. Two patients were removed per parent request. Two (20%) had BK viruria and one (10%) had BK viremia. No patients developed BKVN. BK viruria was present within 2 months following transplantation. There were no identifiable risk factors for BKV infection and no statistically significant difference in renal function between the groups; however, there was a trend toward worsening renal function in those with BKV infection. BKV infection can occur early following heart transplantation. Screening for BK viruria should be considered in HTx recipients.

Prevalence of BK polyomavirus infection and association with renal dysfunction in pediatric heart transplant recipients.

BACKGROUND: BK polyomavirus (BKV) infection and nephropathy complicate renal allografts; however, their effect in the native kidneys of pediatric heart transplant (HTx) recipients is unknown. We assessed the prevalence of BKV infection and its association with kidney dysfunction in survivors of pediatric HTx. METHODS: A single-center retrospective study compared pediatric (aged <18 years ) HTx recipients, with and without BKV (controls), who received an allograft from May 1989 to July 2013. Screening of urine for BKV was performed in patients with chronic kidney disease (CKD) stage ≥2 since 2006, and since April 2012 in all HTx recipients at least at an annual evaluation. Serum for BKV DNA was assayed if BK viruria was present. Data collected included recipient and donor demographics, the immunosuppressive regimen, and history of Epstein-Bar virus (EBV) and cytomegalovirus infection. Statistics included Fisher's exact test, chi-square test, Student's t-test, and multivariate logistic regression. RESULTS: Of 98 eligible recipients, 83 (85%) were screened: 28 (34%) had BK viruria, and 7 had BK viremia. One viremic patient had biopsy-proven BKV nephropathy that progressed to end-stage renal disease. Risk factors for BK viruria were (1) longer duration since HTx (6.02 vs 2.95 years; p = 0.01), (2) worsening estimated glomerular filtration rate (71.3 vs 86.3 ml/min/1.73 m(2), p = 0.03), (3) history of EBV infection (p = 0.0002), and (4) use of sirolimus (p = 0.0003). After multivariate logistic-regression, only history of EBV infection remained associated with BKV infection (p = 0.015). CONCLUSIONS: BKV may lead to BK viremia and BK nephropathy in pediatric HTx patients. Routine screening for BK viruria should be considered.

Clinical grand rounds: atypical hemolytic uremic syndrome.

Atypical hemolytic uremic syndrome (aHUS) is a rare, lifethreatening, chronic, genetic disease of uncontrolled alternative pathway complement activation. The understanding of the pathophysiology and genetics of this disease has expanded over recent decades and promising new developments in the management of aHUS have emerged. Regardless of the cause of aHUS, with or without a demonstrated mutation or autoantibody, blockade of terminal complement activation through C5 is of high interest as a mechanism to ameliorate the disease. Eculizumab, an existing monoclonal antibody directed against C5 with high affinity, prevents the perpetuation of the downstream activation of the complement cascade and the damage caused by generation of the anaphylotoxin C5a and the membrane attack complex C5b-9, by blocking C5 cleavage. We report the successful use of eculizumab in a patient after kidney transplantation and discuss the disease aHUS.

The primary hyperoxalurias.

The primary hyperoxalurias (PHs) are rare autosomal-recessive inborn errors of metabolism. In the most severe form (type 1), recurrent kidney stones and progressive nephrocalcinosis lead to the loss of kidney function, accompanied by systemic oxalosis, and often requires dialysis and/or transplantation. The variety of genetic mutations leading to PH increasingly are being defined, resulting in the ability to diagnose most patients accurately via minimally invasive means. During and after definitive diagnosis, supportive therapies with pyridoxine supplementation, urinary crystallization inhibitors, and hydration should be used, but have varying success. Emerging information about the renal tubular and intestinal transport of oxalate is leading to increasing evidence to support the use of oxalate-degrading bacteria (probiotics) and enzymes in the treatment of PH. Organ transplantation historically has offered the only potential cure for PH, and may include kidney-alone, combined liver-kidney, or pre-emptive liver-alone transplantation. Exciting new approaches in the treatment of type 1 PH, however, are under investigation. These include the restoration of defective enzymatic activity through the use of chemical chaperones, hepatocyte cell transplantation, or enzyme replacement by recombinant gene therapy. These novel approaches illustrate the goal for the ideal treatment of PH: correcting the genetic defect without exposing patients to the life-long risks associated with organ transplantation.

Hyperoxaluria and systemic oxalosis: current therapy and future directions.

Excessive urinary oxalate excretion, termed hyperoxaluria, may arise from inherited or acquired diseases. The most severe forms are caused by increased endogenous production of oxalate related to one of several inborn errors of metabolism, termed primary hyperoxaluria. Recurrent kidney stones and progressive medullary nephrocalcinosis lead to the loss of kidney function, requiring dialysis or transplantation, accompanied by systemic oxalate deposition that is termed systemic oxalosis. For most primary hyperoxalurias, accurate diagnosis leads to the use of therapies that include pyridoxine supplementation, urinary crystallisation inhibitors, hydration with enteral fluids and, in the near future, probiotic supplementation or other innovative therapies. These therapies have varying degrees of success, and none represent a cure. Organ transplantation results in reduced patient and organ survival when compared with national statistics. Exciting new approaches under investigation include the restoration of defective enzymatic activity through the use of chemical chaperones and hepatocyte cell transplantation, or recombinant gene therapy for enzyme replacement. Such approaches give hope for a future therapeutic cure for primary hyperoxaluria that includes correction of the underlying genetic defect without exposure to the life-long dangers associated with organ transplantation.