Barbara A. Fivush

Growth failure, risk of hospitalization and death for children with end-stage renal disease

Abstract Growth failure remains a significant problem for children with chronic renal insufficiency and end-stage renal disease (ESRD). We examined whether growth failure is associated with more-frequent hospitalizations or higher mortality in children with kidney disease. We studied data on prevalent United States pediatric patients with ESRD in 1990 who were followed through 1995. Patients were categorized according to the standard deviation score (SDS) of their incremental growth during 1990: severe (<–3 SDS), moderate growth failure (>–3 and <–2 SDS), and normal growth (>–2 SDS). Among 1,112 prevalent pediatric dialysis and transplant patients (<17 years, Tanner I–IV), those with severe and moderate growth failure had higher hospitalization rates {relative risk (RR) 1.14 [95% confidence interval (CI) 1.1, 1.2] and 1.24 [95% CI 1.2, 1.3]} respectively than those with normal growth after adjustment for age, gender, race, cause and duration of ESRD, and treatment modality (dialysis or transplant) in 1990. Kaplan-Meier survival analysis showed 5-year survival of 85% and 90% for patients with severe and moderate growth failure, respectively, compared with 96% for patients with normal growth (P<0.001, log-rank). Cox proportional hazards analysis revealed that those with severe (RR 2.9, 95% CI 1.6, 5.3) and moderate growth failure (RR 2.01, 95% CI 1.1, 3.6) had an increased risk of death compared with youths with normal growth, after adjustment. A higher proportion of deaths in the severe and moderate growth failure groups were attributed to infectious causes (22% and 18.7%, respectively) than in the normal growth group (15.6%). We conclude that growth failure is associated with a more-complicated clinical course and increased risk of death for children with kidney failure.

Racial Differences in Access to the Kidney Transplant Waiting List for Children and Adolescents With End-Stage Renal Disease

Context. Renal transplantation is the treatment of choice for pediatric patients with end-stage renal disease (ESRD). Black patients wait longer for kidney transplants than do white patients. Objective. To determine whether the increased time to transplantation for black pediatric patients is attributable not only to a shortage of suitable donor organs, but also to racial differences in the time from a childs first treatment for ESRD until activation on the cadaveric kidney transplant waitlist. Design. National longitudinal cohort study. Setting. US Medicare-eligible, pediatric ESRD population. Patients. Children and adolescents ≤19 years old at the time of their first dialysis for ESRD between 1988 and 1993, followed through 1996. Patients who received living donor renal transplants were excluded from study. Main Outcome Measures. Time from first dialysis for ESRD until activation on the kidney transplant waiting list, relative hazard of activation on the waiting list for black compared with white pediatric patients. Results. Comparisons of the time from first dialysis for ESRD to waitlisting among the 2162 white (60.7%) and 1122 black (31.5%) patients studied using survival analysis revealed that blacks were less likely to be waitlisted at any given time in follow-up. In multivariate analysis, even after controlling for patient age, gender, socioeconomic status, geographic region, incident year of renal failure, and cause of ESRD, blacks were 12% less likely to be waitlisted than were whites at any point in time (relative hazard: .88: 95% confidence interval: .79–.97). Conclusions. Racial disparities in access to the renal transplant waiting list exist in pediatrics. Whether these disparities are attributable to differences in time of presentation to a nephrologist, physician bias in identification of transplant candidates, or patient preferences warrants further study.

Risk factors for urolithiasis in children on the ketogenic diet

Abstract Kidney stones have been associated with use of the ketogenic diet in children with refractory seizure disorders. We performed a case-control study examining risk factors for the development of stones on the ketogenic diet, and prospectively followed children initiating the ketogenic diet to evaluate the incidence of urolithiasis. Clinical characteristics of 18 children presenting with stones (8 uric acid stones, 6 mixed calcium/uric acid stones, 1 calcium oxalate/phosphate stone, 3 stones not evaluated) were compared with characteristics of non-stone-forming children initiating the ketogenic diet at Johns Hopkins since July 1996. Since July 1996, 112 children initiating the ketogenic diet have been followed for development of stones. Follow-up times on the diet range from 2 months to 2.5 years. Of 112 children, 6 have developed stones (3 uric acid, 3 mixed calcium/uric acid stones) (0.8 children developing stones/ 100 patient-months at risk). Comparisons of children presenting with stones on the ketogenic diet with characteristics of the entire cohort initiating the ketogenic diet suggest younger age at diet initiation and hypercalciuria are risk factors for the development of stones. Prospective evaluation of children initiating the ketogenic diet revealed that almost 40% of patients had elevated fasting urine calcium: creatinine ratios at baseline; this increased to 75% after 6 months on the diet. Median urine pH was 5.5 at diet initiation, and remained at 6.0 thereafter. In a subset of patients tested, urinary citrate excretion fell from a mean of 252 mg/24 h pre diet initiation to 52 mg/24 h while on the diet. Uric acid excretion remained normal. Patients maintained on the ketogenic diet often have evidence of hypercalciuria, acid urine, and low urinary citrate excretion. In conjunction with low fluid intake, these patients are at high risk for both uric acid and calcium stone formation.

Chronic renal insufficiency in children and adolescents: The 1996 annual report of NAPRTCS

Abstract. The 1996 annual report of the Chronic Renal Insufficiency Arm of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) summarizes descriptive data and highlights important features on 1,725 patients from 130 centers. This database contains information on patients with an estimated glomerular filtration rate (GFR) ≤75 ml/min per 1.73 m2 as calculated by the Schwartz formula, who were treated on or after 1 January 1994. Thus this report reflects 2 years of data entry. Analysis of the data revealed that nearly two-thirds of patients registered had a structural anomaly. On average, patients were 1.5 standard deviations below age- and sex-specific norms for height, and 0.6 standard deviations below weight norms. Mean serum creatinine for the entire group was 2.4 mg/dl and 68% of patients had a baseline GFR of at least 25 ml/min per 1.73 m2. The mean hematocrit for all children at registration was 33.3±6.3%, and did not vary among age groups. Overall, 30.9% of patients had a hematocrit <30%. Only 12.8% of patients were receving Epoetin therapy. Although still in infancy, the Chronic Renal Insufficiency Arm of the NAPRTCS database in providing important insights into this disorder.

Assessing associations between medication adherence and potentially modifiable psychosocial variables in pediatric kidney transplant recipients and their families.

Abstract:  Post‐transplant immunosuppressant (IS) medication adherence is essential for long‐term graft survival and relatively little is known about psychosocial barriers that interfere with optimum medication adherence in pediatric kidney transplant patients. The objective of this prospective observational cohort study was to assess the impact of modifiable psychosocial variables on medication adherence. Our hypothesis was that parental stress, dysfunctional parent–child interactions and child behavior problems would be associated with poorer medication adherence. Thirteen pediatric kidney transplant patients and their caregivers were enrolled. Transplant recipients who were able to read and caregivers of all the transplant recipients completed behavioral and attitudinal surveys. A subgroup of seven families dispensed their primary IS medication from an electronic monitoring vial (MEMS Smart Cap). For these patients, medication adherence was calculated by computing a ratio of the medication taken divided by the prescribed dose. In addition, for the entire group, serial IS levels were reviewed by two board certified pediatric nephrologists who categorized all 13 transplant recipient families as either ‘probably adherent (PA)’ or ‘possibly non‐adherent (PNA)’. Pearson correlation coefficients and independent samples Student t‐tests were used to assess the association between medication adherence and psychosocial variables measured by standardized questionnaires. In this study, elevated parental stress, dysfunctional parent–child interactions, and child behavior problems were associated with poorer medication adherence. In addition, we found evidence to support the relationship between subjective dissatisfaction with appearance and poorer medication adherence. These findings suggest that pre‐transplant recipient evaluations of risk factors for poor adherence are warranted.

Accelerated growth rates in children treated with growth hormone after renal transplantation.

To determine the usefulness of growth hormone treatment among children with renal allografts, we treated nine children with functioning renal transplants who were less than 16 years of age and had poor growth. The nine children, who were aged 12.6 +/- 4.0 years, had (1) heights greater than 2.5 SD less than the mean for age, (2) growth rates less than or equal to 5 cm/yr, and (3) additional growth potential, as assessed by bone age (8.9 +/- 2.8 year). Insulin-like growth factor I, thyrotropin, and thyroid hormone levels were normal for age in all children. Growth hormone treatment increased growth rates from 1.9 +/- 1.1 cm/yr to 7.2 +/- 1.8 cm/yr without accelerating skeletal maturation and without advancing pubertal status. During growth hormone treatment, serum creatinine concentration rose from 140 +/- 50 to 190 +/- 80 mumol/L (1.6 +/- 0.6 to 2.1 +/- 0.9 mg/dl) (p less than 0.05), and creatinine clearances decreased from 0.79 +/- 0.37 to 0.58 +/- 0.30 ml/sec per 1.73 m2 (47 +/- 22 to 35 +/- 18 ml/min per 1.73 m2) (p less than 0.05) but then remained stable. Growth rates of two patients returned to pretreatment rates when growth hormone treatment was discontinued after 5 and 7 months because of increased serum creatinine values. Growth hormone treatment may be useful as adjunctive therapy for increasing growth rates in selected children with renal allografts who have poor growth; however, serum creatinine concentrations should be closely monitored during such treatment.

Tacrolimus vs. cyclosporine A as primary immunosuppression in pediatric renal transplantation: a NAPRTCS study.

Abstract:  Using the North American Renal Transplant Cooperative Study (NAPRTCS) database, we performed a retrospective cohort study of 986 pediatric renal transplant recipients (index transplant 1997–2000) who were treated either with Cyclosporine A (CSA), Mycophenolate Mofetil (MMF) and steroids (n = 766) or tacrolimus (TAC), MMF and steroids (n = 220) to examine potential difference in clinical outcomes between these two groups. In the first year post‐transplant, time to first rejection (29.1% vs. 29%, p = 0.840), risk for rejection [Adjusted Relative Risk (aRR) 1.01, 95% Confidence Interval (CI) 0.77, 1.323], graft survival (96.8% vs. 97.9%, p = 0.607) and risk for graft failure (aRR 0.988, 95% CI 0.64, 1.928) were not significantly different in TAC and CSA‐treated patients. At 2 yr post‐transplant, there was also no difference in risk for rejection (aRR 0.918, 95% CI 0.669, 1.259), graft survival (91.4% vs. 95.1%, p = 0.152) and risk for graft failure (aRR 0.702, 95% CI 0.461, 1.762) in the subset of 391 CSA‐treated patients and 77 TAC‐treated patients on whom 2 yr follow data were available in the database. TAC‐treated patients were significantly less likely to require antihypertensive medication at 1 yr [aRR 0.74 (95% CI 0.454, 0.637)] and 2 yr post‐transplant [aRR 0.67 (95% CI 0.56, 0.793)]. At 1 yr post‐transplant, TAC‐treated patients enjoyed a higher mean GFR as estimated by the Schwartz formula [89.1 mL/min/1.73 m2 (SE 2.64) vs. 78.6 mL/min/1.73 m2 (SE 1.07), p = 0.0003]. In addition, in the subset of patients with 2 yr of follow‐up, TAC patients had a higher mean GFR at both 1 yr [98.6 mL/min/1.73 m2 (SE 3.83) vs. 78.0 mL/min/1.73 m2 (SE 1.44), p = 0.0003] and 2 yr post‐transplant [96.7 mL/min/1.73 m2 (SE 3.33) vs. 73.2 mL/min/1.73 m2 (SE 1.48), p < 0.0001]. In summary, TAC and CSA, in combination with MMF and steroids, produce similar rejection rates and graft survival in pediatric renal transplant recipients. However, TAC is associated with improved graft function at 1 and 2 yr post‐transplant. Further analysis as more patient data are obtained will be necessary to determine if this difference in graft function persists and translates into improved graft survival.

Assessing Health Status and Health Care Utilization in Adolescents with Chronic Kidney Disease

Few validated health status measures have been assessed in children with chronic kidney disease (CKD). The objective was to assess the validity of a generic health status measure, the Child Health and Illness Profile-Adolescent Edition (CHIP-AE), in adolescents with CKD. A case-control study was performed (1) to assess scores on the CHIP-AE in adolescents with CKD compared with two control groups of age-, socioeconomic-, and gender-matched peers and (2) to compare health of patients who had chronic renal insufficiency (CRI), were on dialysis, and were posttransplantation. Seven pediatric nephrology centers recruited 113 patients (mean age, 14 yr; 39 CRI, 21 dialysis, 53 posttransplantation). Compared with 226 control subjects, patients with CKD had lower overall satisfaction with health and more restriction in activity. Positively, patients with CKD had more family involvement, better home safety and health practices, and better social problem-solving skills and were less likely to participate in risky social behaviors or socialize with peers who engaged in risky behavior. Patients who received dialysis were less physically active and experienced more physical discomfort and limitations in activities than did transplant or CRI patients. It is concluded that patients with CKD have poorer functional health status than age-matched peers. Among CKD patients, dialysis patients have the poorest functional health status. These results suggest that the CHIP-AE can be used to measure functional health status in adolescent patients with CKD.

Central nervous system toxicity of cyclosporine in a rat model.

The central nervous system toxicity of cyclosporine, which is known to be neurotoxic clinically, was investigated in a rat model. Munich-Wistar rats were divided into 3 groups for a 2-week protocol. After baseline EEG and behavioral testing, group 1 (control) received a weight-adjusted volume of parenteral cyclosporine vehicle i.p., group 2 (low-dose) received 5 or 10 mg/kg/day i.p., and group 3 (high-dose) received 20 mg/kg/day i.p. Spontaneous behavior was observed, simple sensorimotor testing performed daily, and awake EEGs recorded 3 times per week. Four of 12 high-dose animals died during study, one after a witnessed tonic-clonic seizure, and two after recording of frankly epileptiform EEGs; there were no deaths in control or low-dose animals. Significant EEG abnormalities developed only at high-dose, with frankly epileptiform EEGs and/or seizures seen in 58 +/- 15% of these rats (P = 0.005, different from controls by life-table analysis). Although some high-dose animals demonstrated hyperirritability and dystonic posturing, behavioral changes were subtle, and animals were often still or rocking slightly during recording of frankly epileptiform EEGs. Walking latency and alley escape behaviors were delayed in high-dose rats, the latter correlating with abnormal EEGs. Serum urea nitrogens were mildly elevated in high-dose animals, but serum creatinine, electrolytes, bilirubin, body magnesium stores, and blood pressure remained normal in all groups. Kidneys showed only mild vacuolation histologically. The brain showed only very focal cortical injury sites related to electrode placement, which did not correlate with EEG changes or mortality. These results suggest that there may be a direct effect of cyclosporine on the central nervous system. This model system should prove useful in defining mechanisms of cyclosporine-related neurotoxicity.

Immune response to influenza vaccination in children with renal disease

Although immunization with influenza vaccine is recommended for children with chronic renal disease and after organ transplantation, the antibody response in these children has not been well described. We studied the response to the 1993–1994 trivalent influenza vaccine in children, aged 1–21 years, with chronic renal failure (n=15), end-stage renal disease requiring dislysis (n=10), and post renal transplantation (n=17). Each groups antibody response was compared with that of a control group (n=7). No significant differences were found in seroconversion rates, percentage of patients achieving protective hemagglutination-inhibition titers post vaccination or change in geometric mean titers from pre to post vaccination between study groups and controls. These results suggest that pediatric patients with renal disease will respond and therefore will benefit from currently recommended influenza immunization.