Uri S. Alon

The role of bisphosphonates in diseases of childhood.

Bisphosphonates are synthetic analogues of pyrophosphate that inhibit bone resorption by their action on osteoclasts. In recent years, bisphosphonates have been used in children for treatment of a growing number of disorders associated primarily with generalized or localized osteoporosis, metabolic bone diseases, heterotopic calcification in soft tissues, and for resistant hypercalcemia. In the present review we discuss the pharmacological aspects of bisphosphonates and related bone pathophysiology, review the pediatric literature on the role of bisphosphonates in childhood diseases and our experience with these drugs. The theoretical concerns of possible adverse effects of these drugs on the growing skeleton have not materialized in the limited pediatric clinical experience. Bisphosphonates provide the pediatrician with an opportunity to treat mineral and bone disorders of childhood which until recently did not have satisfactory therapy, at the same time, being aware of the theoretical concerns on microdamage accumulation in bone, bone quality and teratogenic potential of these drugs

Ultrasound findings in juvenile nephronophthisis

The ultrasound finding of renal medullary cysts associated with increased echogenicity has been suggested to be diagnostic of juvenile nephronophthisis. The lack of cysts in several of our patients with juvenile nephronophthisis lead us to review the ultrasound findings at presentation in our patient population. Of 11 children with the diagnosis of juvenile nephronophthisis. 10 demonstrated increased echogenicity with loss of corticomedullary differentiation on initial ultrasound. Only 2 children had a single cyst each. On follow-up ultrasound, 2, 4.5, and 7 years later, 3 patients developed visible renal cysts. We conclude that at presentation the ultrasound finding consistent with the diagnosis of juvenile nephronophthisis is most often that of hyperechogenic kidneys without cysts; namely the lack of cysts does not rule out the diagnosis of juvenile nephronophthisis.

Success and safety of same-day kidney biopsy in children and adolescents

Abstract Renal biopsy is crucial for the diagnosis, management, and monitoring of many kidney diseases. Although percutaneous renal biopsy is considered a routine safe procedure in children, the optimal length of in-hospital observation following the procedure is not yet known. We prospectively studied two comparable groups of children to compare the success and safety of performing native renal biopsy as an outpatient procedure versus keeping the children hospitalized post biopsy. Doppler ultrasonography of the biopsied kidney was performed approximately 2 weeks after the procedure. For 40 children the biopsy was performed on a same-day basis (study group) and another 15 children were kept for overnight observation (control group). All biopsies yielded adequate tissue for histopathological diagnosis. There was no difference between the two groups in the amount of reported pain and analgesics used after the procedure. Only 1 child in the study group was readmitted 5 days after the biopsy for 48 h, but no major complications were detected. The incidence of post-biopsy intra- or perirenal hematoma detection by sonography was not statistically different between the two groups (39% study group, 43% control group). Follow-up imaging studies were performed on 10 of the 20 children who had an early post-biopsy hematoma and all were completely normal. Patients and their families appreciated being discharged home the same day. In addition, total charges for hospitalization were significantly less for the study group than the control group. We conclude that in selected patients, same-day discharge after renal biopsy may be performed safely without an increased risk of complications.

Recombinant human erythropoietin therapy in pediatric patients receiving long-term peritoneal dialysis

We evaluated the impact of (s.c.) recombinant human erythropoietin (r-HuEPO) therapy on the hematological status, exercise capacity, and dietary intake of nine pediatric patients (mean age 12.4±3.2 years) receiving long-term peritoneal dialysis. Five children without medical illness served as controls for the exercise testing portion of the study. Following 7.9±2.8 weeks of twice weekly r-HuEPO (50 units/kg per dose), the hematocrit increased from 21.9±3.5% to 31.3±2.5% (P<0.001). A further increase to 33.2±3.0% occurred after 2 months of once weekly therapy. The blood transfusion requirement decreased from 0.5 transfusions per patient-month to 0.05 transfusions per patient-month (P<0.01). Graded exercise testing demonstrated an increase in peak oxygen consumption from 17.8±5.2 to 24.0±7.6 ml/kg per min (P<0.01). The oxygen consumption at anaerobic threshold increased from 13.1±3.9 to 17.1±3.5 ml/kg per min (P<0.02). Treadmill time increased from 5.3±1.2 to 7.5±1.3 min (P<0.001). In each case, the percentage improvement was significantly greater than the improvement seen in the control population. Dietary evaluation revealed no significant change in caloric or protein intake, despite a subjectively improved appetite. r-HuEPO, given by the s.c. route, corrects the anemia and improves the exercise capacity of pediatric patients receiving long-term peritoneal dialysis.

A position statement on kidney disease from powdered infant formula-based melamine exposure in Chinese infants.

Melamine, a man-made non-nutritive substance containing nitrogen, can falsely elevate measures of protein content in foodstuffs. Several manufacturers of powdered infant formula in China apparently added melamine to raise the measured protein content and thereby exposed thousands of infants and young children to very high levels of melamine. Such exposure resulted in cases of acute kidney failure and nephrolithiasis. This Editorial from members of the world-wide Pediatric Nephrology community provides a common-sense approach to the care of infants who may have been exposed to powdered infant formula in 2007–2008.

Clinical practice: Fibroblast growth factor (FGF)23: a new hormone

Until a decade ago, two main hormones were recognized as directly affecting phosphate homeostasis and, with that, bone metabolism: parathyroid hormone and 1,25(OH)2 vitamin D (calcitriol). It was only a decade ago that the third major player hormone was found, linking gut, bone, and kidney. The physiologic role of fibrinogen growth factor (FGF)23 is to maintain serum phosphate concentration within a narrow range. Secreted from osteocytes, it modulates kidney handling of phosphate reabsorption and calcitriol production. Genetic and acquired abnormalities in FGF23 structure and metabolism cause conditions of either hyper-FGF23—manifested by hypophosphatemia, low serum calcitriol, and rickets/osteomalacia—or hypo-FGF23, expressed by hyperphosphatemia, high serum calcitriol, and extra-skeletal calcifications. In patients with chronic renal failure, FGF23 levels increase as kidney functions deteriorate and are under investigation to learn if the hormone actually participates in the pathophysiology of the deranged bone and mineral metabolism typical for these patients and, if so, whether it might serve as a therapeutic target. This review addresses the physiology and pathophysiology of FGF23 and its clinical applications.

Bilateral nephrectomy reverses hypothyroidism in congenital nephrotic syndrome

Abstract A state of biochemical hypothyroidism is commonly seen in infants with congenital nephrotic syndrome (NS) and therefore the current recommendation is to place all patients with congenital NS on supplemental thyroid preparations. We report our experience in five children with congenital NS in whom thyroid supplementation was discontinued following bilateral nephrectomy and initiation of renal replacement therapy. Immediately after nephrectomy, thyroid function tests normalized, except serum thyroid-stimulating hormone (TSH) concentration, which initially rose, but normalized later. This observation supports the hypothesis that hypothyroidism in these patients is secondary to the chronic massive proteinuria and is not the result of a defect intrinsic to the thyroid gland itself. Abatement of massive proteinuria enables discontinuation of thyroid supplementation, and a transient rise in TSH in the early post-nephrectomy stage should be potentially expected.

Hearing impairment in familial X-linked hypophosphatemic rickets

Hearing impairment in patients with X-linked dominant hypophosphatemic rickets (XLH) is likely part of the natural history of the disease, developing during adulthood. Therefore, whereas close follow up and hearing monitoring is recommended in adults, serial audiograms in children with XLH are not justified. Furthermore, in a child with XLH and hearing impairment, other etiologies should be explored. Hearing impairment in XLH patients has been reported a few times in the 1970s and 1980s [1, 2, 4, 5]; however, it was our impression that our pediatric XLH patients did not manifest clinical hearing impairment. Therefore, in order to better clarify the association between XLH and hearing status, and consequently provide information regarding patients’ management, we prospectively evaluated the hearing status in our XLH patients and their afflicted parents. Hearing evaluations including audiometry, tympanometry and stapedial reflex thresholds recording were performed in 16 children with XLH (age 1–18 years, median 9.0 years, six males) and all of their ten afflicted parents (age 22–55 years, three male). None had a history of treatment with ototoxic drugs, noise exposure, previous ear surgery or chronic ear disease. Of 16 children, 15 demonstrated normal hearing. One with bilateral profound hearing loss was found to have a Mondini congenital inner ear malformation, documented by a temporal bone CT scan. Two adult males and one female, all with severe XLH-related orthopedic manifestations, demonstrated sensorineural hearing loss. More than two decades passed since hearing impairment was first described in XLH [5]. Table 1 summarizes the main findings of previous studies that have reported on this association, showing evidence of hearing impairment in a significant percentage of adult XLH patients versus minimal incidence of hearing loss in children [1, 2, 4, 5]. We compared the hearing status in a relatively large group of XLH children in a wide range of ages with that of their afflicted parents. None of our children had a hearing impairment attributable to XLH. The only child with hearing impairment was the one with a Mondini inner ear malformation which is believed to result from a developmental arrest of the membranous labyrinth during the first trimester of pregnancy [3], and is not known to be associated with rickets which is a post-natal disease. In contrast to the normal hearingwe found in ourXLH children, three of their ten parents had sensorineural hearing loss. These patientswere under 52 years old; hence presbyacusis was ruled out. Since in all three etiologies other than the disease process were excluded and in the light of the fact that all had severe orthopedic manifestations of rickets, we suspect that their hearing impairment is part of the disease process. They were referred to adult otolaryngologists for further management. Even though two of the earlier studies [2, 5] found hearing impairment in a very few children, later studies which investigated much larger cohorts of children [1, 4] as well as ours, did not find evidence of XLH-related hearing impairment in childhood. Therefore, it cannot G. Fishman Department of Pediatric Otolaryngology, ‘‘Dana’’ Children’s Hospital, Tel-Aviv Medical Center, ‘‘Sackler’’ School of Medicine, Tel-Aviv University, Tel-Aviv, Israel

Sieving coefficient inaccuracies during hemodiafiltration in patients with hyperbilirubinemia

Abstract Hemodiafiltration has assumed an important role in the supportive therapy of critically ill patients. The viability of the filter used for hemodiafiltration can be monitored by estimating the sieving coefficient of small molecules such as creatinine and/or urea. We report on three patients with severe hyperbilirubinemia whose creatinine sieving coefficient was spuriously elevated as a result of discordance in the accuracy of creatinine measurement in plasma and ultrafiltrate respectively. This discordance was a consequence of lack of bilirubin clearance during hemodiafiltration. As a result, while the plasma creatinine determination by the kinetic Jaffe method was negatively influenced by the hyperbilirubinemia, the ultrafiltrate creatinine was not. This report is the first to document the lack of bilirubin clearance during hemodiafiltration and its impact on the calculation of sieving coefficient based on creatinine. The use of urea as the solute for determining the sieving coefficient allows for an accurate estimate and provides a valid means of monitoring this parameter in the setting of hyperbilirubinemia.

Serum 25(OH)-Vitamin D Level in Children Is There a Need to Change the Reference Range Based on 2011 Institute of Medicine Report?

Until now our clinical laboratory, in a children’s hospital, has reported the normal value for serum 25(OH)-vitamin D (25(OH)D) in children to be ≥30 ng/mL (75 nmol/L). The recent, 2011 Institute of Medicine (IOM) report recommends that serum 25(OH)D ≥20 ng/mL (50 nmol/L) should be considered acceptable for skeletal health including children. Although nutritional rickets can develop secondary to severe dietary calcium deprivation as is the case in infants and small children in some developing countries, in the majority of cases it is due to vitamin D deficiency. The hallmark of the latter is low serum level of 25(OH)D, which is the indicator of body stores of the fat-soluble vitamin. Insufficient calcium absorption from the gut because of the hypovitaminosis leads to an elevation in serum parathyroid hormone (PTH); frequently even before radiological manifestations of the rickets become apparent. Consequently, the IOM report states,