Cynthia Wong

CKiD (CKD in Children) Prospective Cohort Study: A Review of Current Findings

Chronic kidney disease (CKD) is a life-long condition associated with substantial morbidity and premature death due to complications from a progressive decrease in kidney function. The incidence and prevalence of all stages of CKD in children continues to increase worldwide. Between 2000 and 2008, the kidney replacement therapy incidence rate in those aged 0-19 years increased 5.9% to 15 per million population, highlighting the importance of CKD research in children. Many comorbid conditions seen in adults with CKD, including cardiovascular disease and cognitive impairment, also are highly prevalent in children, implicitly demonstrating the crucial need for initiating therapy early to improve health outcomes in children with CKD. The CKiD (Chronic Kidney Disease in Children) Study is a prospective cohort study of 586 children aged 1-16 years with an estimated glomerular filtration rate of 30-90 mL/min/1.73 m(2). Since its inception, CKiD has identified risk factors for CKD progression and cardiovascular disease in children with CKD and highlighted the effects of CKD on outcomes unique to children, including neurocognitive development and growth. This review summarizes the findings to date, illustrating the spectrum of CKD-associated complications in children and emphasizing areas requiring further investigation. Taken in sum, these elements stress that initiating treatment at an early age is essential for reducing long-term morbidity and mortality in children with CKD.

Steroid-Free Immunosuppression Since 1999: 129 Pediatric Renal Transplants with Sustained Graft and Patient Benefits

Despite early promising patient and graft outcomes with steroid‐free (SF) immunosuppression in pediatric kidney transplant recipients, data on long‐term safety and efficacy results are lacking. We present our single‐center experience with 129 consecutive pediatric kidney transplant recipients on SF immunosuppression, with a mean follow‐up of 5 years. Outcomes are compared against a matched cohort of 57 concurrent recipients treated with steroid‐based (SB) immunosuppression. In the SF group, 87% of kidney recipients with functioning grafts remain corticosteroid‐free. Actual intent‐to‐treat SF (ITT‐SF) and still‐on‐protocol SF patient survivals are 96% and 96%, respectively, actual graft survivals for both groups are 93% and 96%, respectively and actual death‐censored graft survivals for both groups are 97% and 99%, respectively. Unprecedented catch‐up growth is observed in SF recipients below 12 years of age. Continued low rates of acute rejection, posttransplant diabetes mellitus (PTDM), hypertension and hyperlipidemia are seen in SF patients, with sustained benefits for graft function. In conclusion, extended enrollment and longer experience with SF immunosuppression for renal transplantation in low‐risk children confirms protocol safety, continued benefits for growth and graft function, low acute rejection rates and reduced cardiovascular morbidity.

Donor-specific antibody against denatured HLA-A1: Clinically nonsignificant?

Pre-transplant screening of a woman with end-stage renal disease (ESRD) showed no anti-human leukocyte antigen (HLA) alloantibodies by anti-human globulin-complement-dependent cytotoxicity (AHG-CDC; class I) or enzyme-linked immunosorbent assay (class II). Following a negative AHG-CDC crossmatch, an HLA*01:01+ deceased donor (DD) kidney was transplanted in September 2005. Subsequent screening of pre-transplant serum by LABScreen Single Antigen (SA) array showed strong reactivity versus A*01:01. Despite that reactivity, at 5 years post-transplant, the patient has a serum creatinine of 1.6 mg/dl and has never experienced humoral or cellular rejection. Retrospective flow-cytometric crossmatch of pre- and post-transplant sera versus DD cells was negative. Rescreening of multiple pre- and post-transplant sera revealed anti-A1 reactivity persisting from the first through the last samples tested. The patients anti-A1 was almost two fold more reactive with denatured A*01:01 FlowPRA SA beads after denaturation with acid treatment (pH 2.7) than with untreated beads. Parallel results were observed with pH 2.7 treated versus untreated A1+ T cells in FXM. These data highlight the difficulty in interpreting screening results obtained using bead arrays, because of antibodies that appear to recognize denatured but not native class I HLA antigens. We suggest that such bead-positive, flow cytometric crossmatch negative antibodies are not associated with humoral rejection, may not necessarily be detrimental to a graft, and deserve further evaluation before becoming a barrier to transplantation.

Casual Blood Pressure and Neurocognitive Function in Children with Chronic Kidney Disease: A Report of the Children with Chronic Kidney Disease Cohort Study

BACKGROUND AND OBJECTIVES Children with chronic kidney disease (CKD) are at risk for cognitive dysfunction, and over half have hypertension. Data on the potential contribution of hypertension to CKD-associated neurocognitive deficits in children are limited. Our objective was to determine whether children with CKD and elevated BP (EBP) had decreased performance on neurocognitive testing compared with children with CKD and normal BP. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This was a cross-sectional analysis of the relation between auscultatory BP and neurocognitive test performance in children 6 to 17 years enrolled in the Chronic Kidney Disease in Children (CKiD) project. RESULTS Of 383 subjects, 132 (34%) had EBP (systolic BP and/or diastolic BP ≥90(th) percentile). Subjects with EBP had lower mean (SD) scores on Wechsler Abbreviated Scales of Intelligence (WASI) Performance IQ than those with normal BP (normal BP versus EBP, 96.1 (16.7) versus 92.4 (14.9), P = 0.03) and WASI Full Scale IQ (97.0 (16.2) versus 93.4 (16.5), P = 0.04). BP index (subjects BP/95(th) percentile BP) correlated inversely with Performance IQ score (systolic, r = -0.13, P = 0.01; diastolic, r = -0.19, P < 0.001). On multivariate analysis, the association between lower Performance IQ score and increased BP remained significant after controlling for demographic and disease-related variables (EBP, β = -3.7, 95% confidence interval [CI]: -7.3 to -0.06; systolic BP index, β = -1.16 to 95% CI: -2.1, -0.21; diastolic BP index, β = -1.17, 95% CI: -1.8 to -0.55). CONCLUSIONS Higher BP was independently associated with decreased WASI Performance IQ scores in children with mild-to-moderate CKD.

Role of Twenty-Four-Hour Ambulatory Blood Pressure Monitoring in Children on Dialysis

BACKGROUND AND OBJECTIVES Pre- or postdialysis BP recordings are imprecise, can be biased, and have poor test-retest reliability in children on dialysis. We aimed to examine the possible differences between pre- and postdialysis BP levels and 24-hour ambulatory BP monitoring (ABPM) in diagnosis of hypertension (HTN). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Twenty-four children on dialysis had 24-hour ABPM in the interdialytic period, and values were compared with average pre- and postdialysis systolic BP (SBP) and diastolic BP (DBP) recordings that week. Each patient had an echocardiogram to determine presence of left ventricular hypertrophy (LVH). RESULTS By ABPM, 8% of patients had white coat HTN and 12% had masked HTN. There was no significant difference in diagnosis of systolic HTN based on ABPM daytime SBP mean or load and postdialysis SBP. However, only 15% of patients had diastolic HTN based on postdialysis measures, whereas 46% of patients had significantly elevated daytime DBP loads and 71% had high nighttime DBP loads on ABPM. Forty-eight percent of patients were SBP nondippers. Children with LVH had higher daytime and nighttime SBP loads, significantly higher daytime and nighttime DBP loads, and lesser degree of nocturnal dipping of SBP compared with those who did not. CONCLUSION ABPM is more informative than pre- and postdialysis BPs and improves the predictability of BP as a risk factor for target organ damage. Diagnosis and treatment monitoring of HTN among pediatric dialysis patients is enhanced with addition of ABPM.

Severe cryptosporidiosis in a seven-year-old renal transplant recipient – Case report and review of the literature

Abstract:  Cryptosporidium is an intracellular protozoa that can cause gastroenteritis in humans. In immunocompromised hosts, infection can be severe, leading to life‐threatening persistent diarrhea. There is limited experience in treating this infection in solid organ transplants. Although newer drugs active against Cryptosporidium exist, they are only licensed in the USA for treatment of immunocompetent hosts. Here we describe a seven‐year‐old renal transplant recipient with severe cryptosporidiosis. He had a protracted course of diarrhea of up to 2 L/day. He was successfully managed with combination antimicrobial therapy including nitazoxanide, paromomycin, and azithromycin. In conjunction with this regimen, he had a reduction in immunosuppression and complete bowel rest. His stool pattern normalized in four weeks and he has had no recurrence after six months of follow up.

Patient selection critical for calcineurin inhibitor withdrawal in pediatric kidney transplantation

Abstract:  CNI withdrawal may be employed as a “rescue” strategy for patients with established renal allograft injury and/or declining allograft function, with the aim at eliminating CNI‐associated nephrotoxic effects. This analysis reviews outcomes in a pediatric population and identifies risk factors for adverse events post‐CNI withdrawal. We performed a retrospective analysis of 17 pediatric renal transplants who underwent CNI withdrawal, with conversion to sirolimus and MMF. Mean CrCl decreased from 64.3 ± 22 to 59.38 ± 28.6 mL/min/1.73 m2 (p = 0.04) at six months and 57.46 ± 31.1 mL/min/1.73 m2 (p = 0.02) at 12 months post‐withdrawal. Forty‐one percent of patients experienced AR. Increased risk for AR was associated with prior AR history, lower sirolimus trough levels, and lower CNIT biopsy scores. Graft loss (24%) was associated with worse CrCl, proteinuria, and histologic chronicity. Proteinuria (spot protein/creatinine ratio) increased from 0.75 ± 1.0 to 1.71 ± 2.0 (p = 0.03), unrelated to de novo sirolimus use. Four patients returned to CNI‐based immunosuppression due to AR (n = 3) and gastrointestinal side effects (n = 1). Careful selection of pediatric candidates for CNI withdrawal is recommended. Worsening graft function and graft loss may be minimized by selecting patients with high CNIT scores and low biopsy chronicity and excluding patients with prior AR history.

Implementation of standardized follow-up care significantly reduces peritonitis in children on chronic peritoneal dialysis.

The Standardizing Care to improve Outcomes in Pediatric End stage renal disease (SCOPE) Collaborative aims to reduce peritonitis rates in pediatric chronic peritoneal dialysis patients by increasing implementation of standardized care practices. To assess this, monthly care bundle compliance and annualized monthly peritonitis rates were evaluated from 24 SCOPE centers that were participating at collaborative launch and that provided peritonitis rates for the 13 months prior to launch. Changes in bundle compliance were assessed using either a logistic regression model or a generalized linear mixed model. Changes in average annualized peritonitis rates over time were illustrated using the latter model. In the first 36 months of the collaborative, 644 patients with 7977 follow-up encounters were included. The likelihood of compliance with follow-up care practices increased significantly (odds ratio 1.15, 95% confidence interval 1.10, 1.19). Mean monthly peritonitis rates significantly decreased from 0.63 episodes per patient year (95% confidence interval 0.43, 0.92) prelaunch to 0.42 (95% confidence interval 0.31, 0.57) at 36 months postlaunch. A sensitivity analysis confirmed that as mean follow-up compliance increased, peritonitis rates decreased, reaching statistical significance at 80% at which point the prelaunch rate was 42% higher than the rate in the months following achievement of 80% compliance. In its first 3 years, the SCOPE Collaborative has increased the implementation of standardized follow-up care and demonstrated a significant reduction in average monthly peritonitis rates.

Rituximab treatment for recurrence of nephrotic syndrome in a pediatric patient after renal transplantation for congenital nephrotic syndrome of Finnish type

Chaudhuri A, Kambham N, Sutherland S, Grimm P, Alexander S, Concepcion W, Sarwal M, Wong C. Rituximab treatment for recurrence of nephrotic syndrome in a pediatric patient after renal transplantation for congenital nephrotic syndrome of Finnish type.

Depressive Symptoms in Children with Chronic Kidney Disease

OBJECTIVE To assess depression in children with chronic kidney disease and to determine associations with patient characteristics, intellectual and educational levels, and health-related quality of life (HRQoL). STUDY DESIGN Subjects aged 6-17 years from the Chronic Kidney Disease in Children cohort study completed the Childrens Depression Inventory (CDI), Wechsler Abbreviated Scales of Intelligence, Wechsler Individual Achievement Test-II-Abbreviated, and the Pediatric Inventory of Quality of Life Core Scales 4.0. Regression analyses determined associations of CDI score and depression status with subject characteristics, intellectual and educational levels, and HRQoL. A joint linear mixed model and Weibull model were used to determine the effects of CDI score on longitudinal changes in glomerular filtration rate and time to renal replacement therapy. RESULTS A total of 344 subjects completed the CDI. Eighteen (5%) had elevated depressive symptoms, and another 7 (2%) were being treated for depression. In adjusted analyses, maternal education beyond high school was associated with 5% lower CDI scores (estimate, 0.95; 95% CI, 0.92-0.99). Depression status was associated with lower IQ (99 vs 88; P = .053), lower achievement (95 vs 77.5; P < .05), and lower HRQoL by parent and child reports (effect estimates, -15.48; 95% CI, -28.71 to -2.24 and -18.39; 95% CI, -27.81 to -8.96, respectively). CDI score was not related to change in glomerular filtration rate. CONCLUSION Children with depression had lower psychoeducational skills and worse HRQoL. Identifying and treating depression should be evaluated as a means of improving the academic performance and HRQoL of children with chronic kidney disease.