Robert S. Mathias

Outcomes of Dialysis Initiated During the Neonatal Period for Treatment of End-Stage Renal Disease: A North American Pediatric Renal Trials and Collaborative Studies Special Analysis

OBJECTIVE. We sought to determine the outcomes of initiating long-term dialysis of neonates and children aged >1 to 24 months with end-stage renal disease. PATIENTS AND METHODS. By querying the North American Pediatric Renal Trials and Collaborative Studies database, we obtained information on 193 neonates (≤1 month of age) and 505 children (>1–24 months of age) with a presumptive diagnosis of end-stage renal disease who initiated long-term dialysis. Dialysis characteristics and likelihood of hospitalization were compared using the χ2 test, and duration of hospitalization was compared using the Wilcoxon 2-sample test. Product limit methods were implemented, and the log rank test was used to compare time-to-event analyses. Multivariate analyses were performed using Cox proportional hazards models. RESULTS. Neonates with end-stage renal disease were more likely to receive peritoneal dialysis versus hemodialysis than older children with end-stage renal disease. Moreover, neonates who initiated dialysis during the first month of life were just as likely to terminate dialysis as were the older children. Rates of renal transplantation were significantly lower in the neonates compared with the older children, but neonates were more likely to recover function of the native kidney. Although neonates were more often hospitalized, their overall risk of mortality was similar to that observed in older children. CONCLUSIONS. Neonates with a presumptive diagnosis of end-stage renal disease may initiate long-term dialysis during the first month of life with outcomes comparable to those of patients who initiate dialysis later in infancy.

A Peripheral Blood Diagnostic Test for Acute Rejection in Renal Transplantation

Monitoring of renal graft status through peripheral blood (PB) rather than invasive biopsy is important as it will lessen the risk of infection and other stresses, while reducing the costs of rejection diagnosis. Blood gene biomarker panels were discovered by microarrays at a single center and subsequently validated and cross‐validated by QPCR in the NIH SNSO1 randomized study from 12 US pediatric transplant programs. A total of 367 unique human PB samples, each paired with a graft biopsy for centralized, blinded phenotype classification, were analyzed (115 acute rejection (AR), 180 stable and 72 other causes of graft injury). Of the differentially expressed genes by microarray, Q‐PCR analysis of a five gene‐set (DUSP1, PBEF1, PSEN1, MAPK9 and NKTR) classified AR with high accuracy. A logistic regression model was built on independent training‐set (n = 47) and validated on independent test‐set (n = 198)samples, discriminating AR from STA with 91% sensitivity and 94% specificity and AR from all other non‐AR phenotypes with 91% sensitivity and 90% specificity. The 5‐gene set can diagnose AR potentially avoiding the need for invasive renal biopsy. These data support the conduct of a prospective study to validate the clinical predictive utility of this diagnostic tool.

Increased incidence in post-transplant diabetes mellitus in children: a case-control analysis.

Abstract. There is limited information regarding the incidence and features of post-transplant diabetes mellitus (PTDM) in pediatric renal transplant recipients. We noted a recent increased frequency of PTDM and reviewed charts of children who underwent renal transplantation from 1 September 1986 to 31 August 1999 to characterize the risk factors and natural history of PTDM. Sixteen children were identified with PTDM, and were each matched with two transplanted controls who did not develop PTDM. Clinical presentation varied from asymptomatic hyperglycemia to hyperosmolar dehydration or diabetic ketoacidosis. The mean time from transplantation to PTDM presentation was 1.2 years (range 1 day to 6.2 years). Significant risk factors for PTDM included: first degree family history of type 2 DM [odds ratio (OR) 23.9]; second degree family history of type 2 DM (OR 5.8); tacrolimus use (OR 9.1 versus cyclosporin); and hyperglycemia in the 2 weeks immediately after transplantation (OR 4.7). Seven of eight children with persistent PTDM continue to receive insulin. Patients with persistent PTDM had later onset disease (mean 1.9 years) compared to those with transient PTDM (0.3 years), suggesting different pathophysiologic processes. We suggest that all children undergoing renal transplantation be screened routinely for PTDM after transplantation, and that such patients may benefit from the avoidance of tacrolimus, as it may cause permanent beta-cell injury.

Complete Steroid Avoidance Is Effective and Safe in Children With Renal Transplants: A Multicenter Randomized Trial With Three‐Year Follow‐Up

To determine whether steroid avoidance in pediatric kidney transplantation is safe and efficacious, a randomized, multicenter trial was performed in 12 pediatric kidney transplant centers. One hundred thirty children receiving primary kidney transplants were randomized to steroid‐free (SF) or steroid‐based (SB) immunosuppression, with concomitant tacrolimus, mycophenolate and standard dose daclizumab (SB group) or extended dose daclizumab (SF group). Follow‐up was 3 years posttransplant. Standardized height Z‐score change after 3 years follow‐up was –0.99 ± 2.20 in SF versus –0.93 ± 1.11 in SB; p = 0.825. In subgroup analysis, recipients under 5 years of age showed improved linear growth with SF compared to SB treatment (change in standardized height Z‐score at 3 years –0.43 ± 1.15 vs. –1.07 ± 1.14; p = 0.019). There were no differences in the rates of biopsy‐proven acute rejection at 3 years after transplantation (16.7% in SF vs. 17.1% in SB; p = 0.94). Patient survival was 100% in both arms; graft survival was 95% in the SF and 90% in the SB arms (p = 0.30) at 3 years follow‐up. Over the 3 year follow‐up period, the SF group showed lower systolic BP (p = 0.017) and lower cholesterol levels (p = 0.034). In conclusion, complete steroid avoidance is safe and effective in unsensitized children receiving primary kidney transplants.

Hyperammonemia in urea cycle disorders: Role of the nephrologist

Hyperammonemia associated with inherited disorders of amino acid and organic acid metabolism is usually manifested by irritability, somnolence, vomiting, seizures, and coma. Although the majority of these patients present in the newborn period, they may also present in childhood, adolescence, and adulthood with failure to thrive, persistent vomiting, developmental delay, or behavioral changes. Persistent hyperammonemia, if not treated rapidly, may cause irreversible neuronal damage. After the diagnosis of hyperammonemia is established in an acutely ill patient, certain diagnostic tests should be performed to differentiate between urea cycle defects and other causes of hyperammonemic encephalopathy. In a patient with a presumed inherited metabolic disorder, the aim of therapy should be to normalize blood ammonia levels. Recent experience has provided treatment guidelines that include minimizing endogenous ammonia production and protein catabolism, restricting nitrogen intake, administering substrates of the urea cycle, administering compounds that facilitate the removal of ammonia through alternative pathways, and, in severe cases, dialysis therapy. Initiation of dialysis in the encephalopathic patient with hyperammonemia is indicated if the ammonia blood level is greater than three to four times the upper limit of normal. Hemodialysis is the most effective treatment for rapidly reducing blood ammonia levels. Continuous hemofiltration and peritoneal dialysis are also effective modalities for reducing blood ammonia levels. An improved understanding of the metabolism of ammonia and neurological consequences of hyperammonemia will assist the nephrologist in providing optimal care for this high-risk patient population.

The Clinical Impact of Humoral Immunity in Pediatric Renal Transplantation

The development of anti-donor humoral responses after transplantation associates with higher risks for acute rejection and 1-year graft survival in adults, but the influence of humoral immunity on transplant outcomes in children is not well understood. Here, we studied the evolution of humoral immunity in low-risk pediatric patients during the first 2 years after renal transplantation. Using data from 130 pediatric renal transplant patients randomized to steroid-free (SF) or steroid-based (SB) immunosuppression in the NIH-SNSO1 trial, we correlated the presence of serum anti-HLA antibodies to donor HLA antigens (donor-specific antibodies) and serum MHC class 1-related chain A (MICA) antibody with both clinical outcomes and histology identified on protocol biopsies at 0, 6, 12, and 24 months. We detected de novo antibodies after transplant in 24% (23% of SF group and 25% of SB group), most often after the first year. Overall, 22% developed anti-HLA antibodies, of which 6% were donor-specific antibodies, and 6% developed anti-MICA antibody. Presence of these antibodies de novo associated with significantly higher risks for acute rejection (P=0.02), chronic graft injury (P=0.02), and decline in graft function (P=0.02). In summary, antibodies to HLA and MICA antigens appear in approximately 25% of unsensitized pediatric patients, placing them at greater risk for acute and chronic rejection with accelerated loss of graft function. Avoiding steroids does not seem to modify this incidence. Whether serial assessments of these antibodies after transplant could guide individual tailoring of immunosuppression requires additional study.

The Comprehensive Assessment of Physical Fitness in Children Following Kidney and Liver Transplantation

Background. Pediatric organ transplant recipients may have elevated cardiovascular (CV) risk. Low cardiorespiratory fitness (CRF) may contribute to CV risk; however, studies of CRF in children following kidney transplantation (KTx) and liver transplantation (LTx) are limited. Methods. Laboratory testing included assessment of CRF (VO2peak), muscle strength, and body composition (%fat). Field testing (FITNESSGRAM) included the PACER, curl-up, and sit-and-reach tests. Values obtained were compared to sex- and age-based criterion-referenced standards (Healthy Fitness Zone, HFZ). The Previous Day Physical Activity Recall was used to assess after-school physical activity (PA) participation. Independent t tests were used to compare groups. Results. Twenty-five KTx and 11 LTx recipients were tested. The groups were similar in all measures. Both groups demonstrated below normative values for VO2peak and muscle strength. Only 4% of the KTx and 9% of the LTx recipients achieved the HFZ for the PACER and 24% of the KTx and 45% of the LTx attained the HFZ for the curl-up test. Approximately 44% of both groups had percent fat greater than the upper criterion value of the HFZ. Both groups reported spending only 8% of their after-school time participating in physical activity. Conclusions. Pediatric KTx and LTx recipients have significantly reduced CRF, muscle strength, and physical activity. Routine counseling and encouragement for increased physical activity is recommended as a part of routine care. A randomized clinical exercise intervention trial after pediatric solid organ transplantation is warranted to determine the impact of such lifestyle intervention on improving physical fitness and cardiovascular health.

Subclinical Inflammation and Chronic Renal Allograft Injury in a Randomized Trial on Steroid Avoidance in Pediatric Kidney Transplantation

Steroid avoidance is safe and effective in children receiving kidney transplants in terms of graft function and survival, but the effects on allograft histology are unknown. In this multicenter trial, 130 pediatric renal transplant recipients were randomized to steroid‐free (SF; n = 60) or steroid‐based (SB; n = 70) immunosuppression, and underwent renal allograft biopsies at the time of graft dysfunction and per protocol at implantation and 6, 12 and 24 months after transplantation. Clinical follow‐up was 3 years posttransplant. Subclinical acute rejection was present in 10.6% SF versus 11.3% SB biopsies at 6 months (p = 0.91), 0% SF versus 4.3% SB biopsies at 1 year (p = 0.21) and 0% versus 4.8% at 2 years (p = 0.20). Clinical acute rejection was present in 13.3% SF and 11.4% SB patients by 1 year (p = 0.74) and in 16.7% SF and 17.1% SB patients by 3 years (p = 0.94) after transplantation. The cumulative incidence of antibody‐mediated rejection was 6.7% in SF and 2.9% in SB by 3 years after transplantation (p = 0.30). There was a significant increase in chronic histological damage over time (p < 0.001), without difference between SF and SB patients. Smaller recipient size and higher donor age were the main risk factors for chronic histological injury in posttransplant biopsies.

Identification of the Calcium-Sensing Receptor in the Developing Tooth Organ

Calcium (Ca2+) is a critical component of tooth enamel, dentin, and the surrounding extracellular matrix. Ca2+ also may regulate tooth formation, although the mechanisms for such action are poorly understood. The Ca2+‐sensing receptor (CaR) that is expressed in the parathyroid gland, kidney, bone, and cartilage has provided a mechanism by which extracellular Ca2+ can regulate cell function. Because these tissues play an important role in maintaining mineral homeostasis and because Ca2+ is hypothesized to play a crucial role in tooth formation, we determined whether the CaR was present in teeth. In this study, using immunohistochemistry, CaR protein was detected in developing porcine molars localized in the predentin (pD), early secretory‐stage ameloblasts, maturation‐stage smooth‐ended ameloblasts (SA), and certain cells in the stratum intermedium. CaR protein and messenger RNA (mRNA) were detected also in an immortalized ameloblast‐like cell line (PABSo‐E) using immunofluorescence, reverse‐transcription polymerase chain reaction (RT‐PCR), and Northern analysis. Based on the observation that the CaR is expressed in cultured ameloblasts, we determined whether increments in medium Ca2+ concentration could activate the intracellular Ca2+ signal transduction pathway. In PABSo‐E cells, increasing extracellular Ca2+ in the medium from 0 (baseline) to 2.5mM or 5.0 mM resulted in an increase in intracellular Ca2+ above baseline to 534 ± 69 nM and 838 ± 86 nM, respectively. Taken together, these results suggest that the CaR is expressed in developing teeth and may provide a mechanism by which these cells can respond to alterations in extracellular Ca2+ to regulate cell function and, ultimately, tooth formation.

Oral Disease Burden and Utilization of Dental Care Patterns Among Pediatric Solid Organ Transplant Recipients

OBJECTIVES We conducted a study among pediatric renal (RTRs) and liver transplant recipients (LTRs) to determine: a) the overall burden of oral disease; and b) the frequency with which this population utilizes dental care services in relation to sociodemographic factors and oral disease burden. METHODS In this cross-sectional survey, study procedures included the completion of a standardized questionnaire (by parents/guardians), oral mucosal examination, assessment of caries, gingival enlargement, and plaque index. RESULTS The 142 children (82 RTRs and 60 LTRs) enrolled from April 2002 to November 2005 were predominantly Latino (41 percent) and Caucasian (34 percent). Forty-three percent had at least one carious surface (in either a deciduous or permanent tooth), 19 percent had five or more carious surfaces, and 25 percent had gingival enlargement. We found only one case of oral candidiasis. Even though 72 percent of parents/guardians reported their child had a regular source of dental care, only 49 percent had a dental cleaning and 44 percent had dental radiographs in the past year, reflecting a low prevalence of preventive dental care. Among children with no regular source of dental care, there were statistically significantly higher proportions of Latinos, younger children, and families with an annual household income <