Fibroblast growth factor-23 and chronic allograft injury in pediatric renal transplant recipients: a Midwest Pediatric Nephrology Consortium study.

The chronic kidney disease-mineral bone disorder (CKD-MBD) produces fibroblast growth factor-23 (FGF-23) and related circulating pathogenic factors that are strongly associated with vascular injury and declining kidney function in native CKD. Similarly, chronic renal allograft injury (CRAI) is characterized by vascular injury and declining allograft function in transplant CKD. We hypothesized that circulating CKD-MBD factors could serve as non-invasive biomarkers of CRAI. We conducted a cross-sectional, multicenter case-control study. Cases (n = 31) had transplant function >20 mL/min/1.73 m(2) and biopsy-proven CRAI. Controls (n = 31) had transplant function >90 mL/min/1.73 m(2) and/or a biopsy with no detectable abnormality in the previous six months. We measured plasma CKD-MBD factors at a single time point using ELISA. Median (range) FGF23 levels were over twofold higher in CRAI vs. controls [106 (10-475) pg/mL vs. 45 (8-91) pg/mL; p < 0.001]. FGF23 levels were inversely correlated with transplant function (r(2) = -0.617, p < 0.001). Higher FGF23 levels were associated with increased odds of biopsy-proven CRAI after adjusting for transplant function, clinical, and demographic factors [OR (95% CI) 1.43 (1.23, 1.67)]. Relationships between additional CKD-MBD factors and CRAI were attenuated in multivariable models. Higher FGF23 levels were independently associated with biopsy-proven CRAI in children.

Renin Angiotensin System Blocker Fetopathy: A Midwest Pediatric Nephrology Consortium Report.

OBJECTIVES: Fetuses continue to be exposed to renin angiotensin system (RAS) blockers despite their known teratogenicity and a black box warning. We hypothesized that fetopathy from in utero exposure to RAS blockers has a broader spectrum of clinical manifestations than described previously and that there are a variety of clinical scenarios leading to such exposures. STUDY DESIGN: This was a retrospective study performed through the Midwest Pediatric Nephrology Consortium. Cases of RAS blocker fetopathy were identified, with determination of renal and extrarenal manifestations, timing of exposure, and the explanation for the fetal exposure. RESULTS: Twenty-four cases were identified. RAS blocker exposure after the first trimester was associated with more severe renal manifestations. Chronic dialysis or kidney transplantation was required in 8 of 17 (47%) patients with RAS blocker exposure after the first trimester and 0 of 7 patients with exposure restricted to the first trimester (P = .05). Extrarenal manifestations, some not previously noted in the literature, included central nervous system anomalies (cystic encephalomalacia, cortical blindness, sensorineural hearing loss, arachnoid cysts) and pulmonary complications (pneumothorax, pneumomediastinum). RAS blocker exposure usually was secondary to absent or poor prenatal care or undiagnosed pregnancy. CONCLUSION: RAS blocker fetopathy continues to be a cause of considerable morbidity, with more severe renal manifestations associated with exposure after the first trimester. A variety of significant extrarenal manifestations occur in these patients. Clinicians should emphasize the risk of fetopathy when prescribing RAS blockers to women of childbearing age.

Occurrence of vitamin D deficiency in pediatric patients at high risk in West Virginia.

OBJECTIVES: Vitamin D deficiency is prevalent and is increasingly associated with the development of medical conditions both related and unrelated to bone metabolism. The purpose of this study was to examine vitamin D deficiency in patients of a pediatrics subspecialty practice. METHODS: The study consisted of a retrospective chart review of patients aged 2 to 18 years who were referred to the West Virginia University Physicians of Charleston pediatrics subspecialty group with a diagnosis of obesity, chronic kidney disease, diabetes, hypertension, or cystic fibrosis. All of the patients had 25-hydroxyvitamin D levels measured from 2007-2009. Seventy-six patients met inclusion criteria. RESULTS: A total of 23.7% of patients were vitamin D deficient (≤ 20 ng/mL). Children with vitamin D deficiency were older and had higher rates of obesity than those with nondeficient vitamin D levels. The comorbidities of cystic fibrosis, diabetes, hypertension, and chronic kidney disease did not associate with vitamin D deficiency. CONCLUSIONS: Vitamin D deficiency is common in children in West Virginia and is associated with increasing age and obesity. Vitamin D screening and supplementation should be considered in all children with chronic illness, particularly those who are overweight.

Cushing's syndrome due to ectopic production of corticotropin-releasing hormone in an infant with ganglioneuroblastoma.

OBJECTIVE: To report the first recognized case of Cushing's syndrome due to a corticotropin-releasing hormone (CRH)-secreting ganglioneuroblastoma, which was found in an 18-month-old boy with hypertensive encephalopathy. METHODS: The clinical, biochemical, and immunohistochemical characteristics of this rare syndrome are described, and the relevant literature is reviewed. RESULTS: An 18-month-old boy with a history of recent weight gain was admitted because of sudden onset of right fixed esotropia and left facial palsy after episodes of emesis. Magnetic resonance imaging showed old left frontal lobe and right hypothalamic infarcts. The patient had generalized obesity, decelerated linear growth, hypertrichosis, hypertension (144/103 mm Hg), hypokalemia, and proteinuria. The 24-hour urinary excretion of free cortisol, catecholamines, and metanephrines was increased. The serum cortisol concentration after a 1-mg overnight dexamethasone suppression test (DST) was 53.7 mg/dL (normal, <5). The serum adrenocorticotropic hormone (ACTH) concentration was 7 pg/mL (normal, 10 to 60), and the CRH level was 439 pg/mL (normal, 24 to 40). An overnight high-dose DST (8 mg) failed to suppress serum cortisol; however, both cortisol and ACTH were responsive to ovine CRH stimulation. Despite discordant dynamic endocrine testing and negative somatostatin receptor scintigraphy, computed tomography showed a right 3.6- by 3.0-cm extra-adrenal retroperitoneal mass with central calcification extending 7 cm cephalocaudally. The patient underwent exploratory laparotomy, followed by chemotherapy. Findings on light microscopic and immunohistochemical examination of the retroperitoneal mass were consistent with a ganglioneuroblastoma that expressed CRH, pro-opiomelanocortin, and ACTH. CONCLUSION: The evaluation of Cushing's syndrome is one of the most complex endocrine challenges. In this case, it was due to ectopic production of CRH by a ganglioneuroblastoma. Because most CRH-producing tumors also secrete ACTH, the ectopic production may represent a paracrine phenomenon in addition to an endocrine phenomenon. The ectopic CRH may also indirectly provoke pituitary ACTH secretion. This dual mechanism may explain the resistance of the tumor to feedback inhibition and a CRH-stimulation response indistinguishable from that observed in pituitary-dependent Cushing's syndrome.

Secondary hypertension in overweight and stage 1 hypertensive children: a Midwest Pediatric Nephrology Consortium report.

According to the Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents, stage 1 hypertension is often primary in origin and associated with overweight. In contrast, stage 2 hypertension is more often secondary in origin and, hence, requires more extensive evaluation according to task force recommendations. The objective of this retrospective study was to evaluate whether the presence of stage 1 hypertension in overweight pediatric patients precludes workup for secondary hypertension (SH). This study included children (5-18 years) with hypertension (defined and staged per task force recommendations) referred to 4 pediatric nephrology centers in the Midwest region. Of the 246 referred patients, 166 patients with primary hypertension (PH) and SH were included for body mass index and hypertension stage analysis. The study revealed no significant differences in the mean age at diagnosis (PH, 13.1+/-3.1 years; SH, 12.4+/-3.8 years), distribution of overweight (PH, 89.4% BMI >85th percentile; SH, 80% BMI >85th percentile), and stage 1 (PH, 45%; SH, 40%) or 2 hypertensive (PH,55%; SH, 60%) children between PH vs SH. Overweight and presence of stage 1 hypertension should not preclude evaluation for SH.

Obstacles to the prescribing of growth hormone in children with chronic kidney disease.

Despite its effectiveness, recombinant human growth hormone (rhGH) is under-utilized in short children with chronic kidney disease (CKD). We conducted a multicenter study to explore the obstacles preventing children with CKD from receiving rhGH. We investigated the use of rhGH in 307 children with CKD from seven pediatric nephrology centers. Among the 110 patients who fell below the 5th percentile, 56 (51%) had not received rhGH. The most common reasons given for these children not receiving rhGH were family refusal, secondary hyperparathyroidism, and non-compliance. However, no explanation was apparent for 25% of the short children with CKD. Boys were more likely than girls to receive rhGH (65% vs 31%; P = 0.002). Use of rhGH was similar in African Americans and non-Hispanic Whites. Children who had received rhGH achieved a 0.5 increase in height z-score in the first year after the initiation of rhGH therapy. Children who had not received rhGH achieved a 0.03 increase in height z-score during the first year after falling below the 5th percentile (P = 0.005 vs the children who had received rhGH). Waiting for insurance company approval led to a significant delay in the initiation of rhGH treatment in 18% of patients. The fact that more than 50% of short children with CKD did not receive rhGH is secondary to multiple factors, many of which may be amenable to intervention efforts.