Short-Term Effect of Low and High Protein Intake on Renal Function in Children with Renal Disease

ABSTRACT. The short-term effect of different levels of protein intake on renal function was investigated in 18 children with moderately (51–85 ml/min/1.73 m² BSA) or severely (9–50 ml/min/1.73 m² BSA) reduced glomerular filtration rates (GFR). The GFR and effective renal plasma flow (ERPF), estimated as the clearances of respectively inulin and para-aminohippuric acid during uncontrolled (2-2.5 g/kg bw), low (1.2 g/kg bw for 12 days) and high (3–5 g/kg bw for 24 h) protein intake were determined by a standard clearance method employing continuous infusion and spontaneous voiding. There were no significant differences in GFR or ERPF during uncontrolled and low protein intake. During high protein intake the GFR and ERPF increased significantly in patients with GFRs above 50 ml/min/1.73 m² BSA and ERPFs above 150 ml/min/1.73 m² BSA. It is concluded that these findings might indicate a functional reserve capacity in children with only moderately reduced renal function.     

DOSAGE OF SALICYLATES FOR CHILDREN WITH JUVENILE RHEUMATOID ARTHRITIS A Prospective Clinical Trial with Three Different Preparations of Acetylsalicylic Acid

Abstract. 41 children with juvenile rheumatoid arthritis (JRA) and 6 with postinfectious arthropathies, aged 3–15 years, were treated with acetylsalicylic acid for 14 days during which time the patients were hospitalized. Three different acetylsalicylic acid preparations were used: a microencapsulated form, an enteric-coated form and standard acetylsalicylic acid tablets. Serum salicylate concentrations were measured by Trinder's photometric method. With doses of 90–120 mg/kg/day symptoms of salicylism appeared in about 50% of the cases. Daily doses of 2 g/m² (not exceeding 70 mg/kg) proved relatively safe in this study, whereas symptoms and signs of intoxication appeared at doses exceeding 3 g/m²/day. In this respect there were no significant differences between the three acetylsalicylic acid preparations used. The results of this study also suggest that the serum salicylate concentrations should not exceed 2000 μmol/1 (about 27 mg/100 ml). The symptoms of salicylism correlated closely with serum salicylate levels, which, in turn, correlated well with the dosage in g/m². Elevation of serum aspartate aminotransferase was noted in 1/3 of the cases. All of these had a dose exceeding 2 g/m², and the frequency of elevated enzyme activities increased with increasing dosage. In the group receiving enteric-coated form of acetylsalicylic acid, there were fewer positive benzidine tests (12%) than in the two other groups (22–28%).     

Neonatal plasma vitamin K1 levels following oral and intramuscular administration of vitamin K1

Vitamin K₁ levels were measured by high performance liquid chromatography in cord blood ( n = 33) and at the age of 97–120 h after administration of 2 mg of vitamin K_l orally ( n = 88) or 1 mg of vitamin K₁ by im injection ( n = 88). Vitamin K₁ levels were less than 0.05 μg/l in cord blood. The mean (range), SEM, mode and median values (μg/l) for the infants given oral vitamin K₁ were 17.99 (1–56), 1.25, 8 and 15.5 and those for the infants given im vitamin K_l 15.83(2–57), 1.01, 11and 14, respectively. The t- test showed no significant difference in the mean values ( p = 0.09) in the infants given oral or im vitamin K.     

Oral desmopressin treatment of central diabetes insipidus in children

To assess the efficacy of treatment with oral desmopressin (DDAVP), 20 patients, aged 5–20 y, with central diabetes insipidus were studied during 3 d of hospitalization and for 3 months at the outpatient clinic. At baseline the median rate of diuresis was 12. 7 ml kg^-1 h^-1. Urinary output decreased significantly under treatment with an increase in urinary osmolality, normalization of plasma osmolality and absence of nocturia. Patients were discharged from hospital with a median dose of 500μg d^-1 (100–1200μg d^-1). An adjustment in dosage was necessary in seven patients during follow-up, resulting in a final dose of 600μg d^-1. Body weight and DDAVP doses ( r = 0. 75, p = 0. 001) and body surface and DDAVP doses ( r = 0. 72, p < 0. 001) were significantly correlated. The average dosage was 474 ± 222μg m^-2 d^-1 (mean ± SD). The oral DDAVP treatment remained effective during the 3 months of follow-up. This therapy offers an alternative for the treatment of central diabetes insipidus in children.     

Persisting Glomerular Hyperfiltration in Short-term Diabetic Children without Microalbuminuria

ABSTRACT. The renal function in a group of diabetic children ( n =29; age: 4–17 yr; IDDM duration: 1.5–13 yr) was studied with a 3 year interval. At the first evaluation glomerular filtration rate (GFR) as assessed by inulin clearance was significantly increased compared to control values (167±32 vs. 124±18 ml/min/1.73 m²; p ≤0.01). Eighteen out of 29 children exhibited a glomerular hyperfiltration (GFR ≥ 160). Three years later mean GFR was identical (169±25 ml/min/1.73 m²) and 16 children were hyperfiltrating. Among them, 11 have had a persisting glomerular hyperfiltration over the 3-year period. Renal plasma flow (RPF) was positively correlated to GFR ( r =0.7; p ≤0.01) and remained elevated at both evaluations (794±163 and 812±157 ml/min/1.73 m², p ≤0.01 vs. control values). When the children were separated into 3 groups according to IDDM duration no significant differences were observed in the results for GFR and RPF. Mean urinary albumin excretion was comparable at the 3-year interval, and not significantly different from the control values (5.2±3.7 and 8.2±6.6 respectively vs. 8.65±4 |ig/min). None of the children demonstrated a persistent microalbuminuria. This study reveals a high proportion of diabetic children with a persisting glomerular hyperfiltration, without any other symmptom of incipiens nephropathy. If elevated GFR plays an important role in the development of diabetic nephropathy, this study emphasizes the value of regular evaluation of renal function in diabetic children.     

CEREBRAL BLOOD FLOW AND EXCHANGE OF OXYGEN, GLUCOSE, KETONE BODIES, LACTATE, PYRUVATE AND AMINO ACIDS IN INFANTS

Abstract. Cerebral blood flow (CBF) and cerebral av-differences of oxygen and circulating substrates were measured in normocapnic infants during general anaesthesia before elective surgery in order to study possible age-dependent variations. CBF was determined by a minor modification of the Kety-Schmidt technique from desaturation curves of nitrous oxide (N₂O) in arterial and cerebral venous blood (N₂O analysed by gas chromatography on 15 μl blood samples) after reduction of inhaled N₂O from 75 to 50%. The reproducibility was ±4.6%. Lactate, pyruvate and oxygen were determined in whole blood and amino acids in plasma by ion-exchange chromatography. Reliable av-differences of glucose, acetoacetate and d -β-hydroxybutyrate could be calculated from plasma values and hematocrits. Mean values from 12 infants (age II days-12 months) were: CBF 69 ml/100 g · min^-1; cerebral uptake (in μmoles/100 g · min^-1): oxygen 104, glucose 27, acetoacetate 0.9, d -β-hydroxybutyrate 2.3; cerebral release: lactate 2.4 and pyruvate 0.8. Significant uptake of amino acids was found only for histidine 0.95 and arginine 0.7. Significant correlations between arterial concentration and cerebral exchange were found for: ornithine, arginine, phenylalanine, aspartic acid, serine, glutamine and acetoacetate. CBF and substrate exchange were unrelated to age within the group. Infants had higher mean CBF and greater uptake of ketone bodies than has been reported in adults.     

Estimation of Digoxin Dosage in VLBW Infants Using Serum Creatinine Concentrations

ABSTRACT. Digoxin steady state plasma concentrations (C_ss) and the corresponding serum creatinine concentrations were studied in 17 VLBW infants. Birth weight was in the range of 760-1500 g (mean 1068 g), gestational age ranged from 26 to 32 weeks (mean 28.7 weeks). Digoxin steady state plasma concentrations were found in the range of 0.5-6.5 μg/ml (mean 1.88 μg/ ml) during maintenance therapy with 1.6-8.4 μg/kg BW/24 h (mean 4.4 μg/kg BW724 h) given in two divided doses intravenously. No digoxin-like immunoreactive substance could be detected in the plasma of 18 infants (10 patients with a birth weight <1500 g, 8 patients with a birth weight of 2100-4 730 g) that were not treated with digoxin. The calculated digoxin clearance ranged from 0.38-4.03 ml/min/kg BW. Serum creatinine concentrations were found in the range of 35-274 μmol/l (0.4-3.1 mg/100 ml). A hyperbolic correlation may be derived from the digoxin clearance and the corresponding serum creatinine concentration. A linear relationship was observed between the dose normalized digoxin concentrations (y=C_ss/dose in 24 h) and the respective creatinine concentrations x (v=0.52x-0.05; n=17; 5=0.24; r=0.86; p<0.01). According to this equation we suggest a dosing schedule for digoxin in VLBW infants with impaired renal function. Digoxin maintenance dose is derived from the digoxin target and the creatinine serum concentration. This dose recommendation proved reliable on four VLBW infants (birth weight 770-1260 g) with decreased renal function.     

Standardizing resistive indices in healthy pediatric transplant recipients of adult-sized kidneys

Gholami S, Sarwal MM, Naesens M, Ringertz HG, Barth RA, Balise RR, Salvatierra O. Standardizing resistive indices in healthy pediatric transplant recipients of adult-sized kidneys.
Pediatr Transplantation 2010: 14: 126–131. © 2009 John Wiley & Sons A/S.
Abstract:  Small pediatric recipients of an adult-sized kidney have insufficient renal blood flow early after transplantation, with secondary chronic hypoperfusion and irreversible histological damage of the tubulo-interstitial compartment. It is unknown whether this is reflected by renal resistive indices. We measured renal graft resistive indices and volumes of 47 healthy pediatric kidney transplant recipients of an adult-sized kidney in a prospective study for six months post-transplant. A total of 205 measurements were performed. The smallest recipients (BSA ≤0.75 m²) had higher resistive indices compared to recipients with a BSA between 0.75 and 1.5 m² (p < 0.0001) and to recipients with a BSA ≥ 1.5 m² (p < 0.0001). Resistive indices increased during the first six months in the smallest recipients (p = 0.02), but not in the two larger recipient groups (BSA 0.75–1.5 m² and ≥1.5 m²). All three BSA groups showed a reduction in renal volume after transplantation, with the greatest reduction occurring in the smallest recipients. In conclusion, renal transplant resistive indices reflect pediatric recipient BSA dependency. The higher resistance to intra-renal vascular flow and significant decrease in renal volume in the smallest group likely reflect accommodation of the size discrepant transplanted adult-sized kidney to the smaller pediatric recipient vasculature with associated lower renal artery flow.     

Neurologic effects of acyclovir after an allogenic marrow graft

On the 4th day of acyclovir treatment for Herpes simplex pneumonia, a 28 month-old girl who had received allogenic marrow transplant for stage IV neuroblastoma presented with severe neurologic disorders including coma and choreic movements. These symptoms disappeared 9 days after acyclovir was stopped. The disturbance in acyclovir kinetics because of acute renal failure and/or a cerebral cortex atrophy might explain the poor neurologic tolerance of acyclovir. This reversible neurologic involvement on a prone patient should be known as a differential diagnosis of Herpes simplex encephalitis.     

CONGENITAL RICKETS Study of the Evolution of Secondary Hyperparathyroidism

Abstract. A case of congenital rickets of nutritional origin is described in a light-for-date premature infant (gestational age 34 weeks, birthweight 1100 g). X-rays of the long bones showed spread, frayed and cupped metaphyses at birth and at the age of 16 days. Serum calcium was 8.2 mg/100 ml, phosphorus 3.4 mg/100 ml and alkaline phosphatase (A.P.): 323 IU/ml (N≤200) at the age of 3 days. Very high level of serum immunoreactive parathyroid hormone (iPTH) was found at the age of 16 days=295 μlEq/ml (N≤50). Evidence of maternal vitamin D deficiency was demonstrated by low plasma 25-hydroxycholecalciferol (25-OH-CC): 1.0 ng/ml (N: 13.2±4.2) soon after delivery; it was found to be normal (10.2 ng/ml) six months later. Ca infusion (15 mg/kg/3 h) resulted in a marked fall of serum iPTH (280 to 84 μlEq/ml). Administration of vitamin D₂ (2400 IU/day for 10 days) induced some healing of the metaphyses; A. P. remained elevated (400 IU/ml); plasma 25-OH-CC was normal 10.2 ng/ml and serum iPTH was 115 μlEq/ml. When 25-OH-CC was given orally for ten days (15 μg/day), plasma 25-OH-CC rose to 64.5 ng/ml with a minor change of serum iPTH (94 μlEq/ml); X-rays of the bones showed osteoporosis. These results suggest a reduced conversion of 25-OH-CC into 1–25-(OH)₂-CC.     

Pharmacokinetics of growth hormone-releasing hormone(1–29)-NH2 and stimulation of growth hormone secretion in healthy subjects after intravenous or intranasal administration

The growth hormone-releasing hormone analogue GHRH(1–29)-NH, was administered intravenously or intranasally to 30 healthy men aged 19–43 years. Intravenous injection of the lowest dose tested, 0.25 μg/kg body weight, elicited significant release of growth hormone (GH). Maximal release (mean GH peaks of about 90 mU/1) was obtained with a dose of 1–2 μg/kg. Although GHRH(1–29)-NH₂ was rapidly eliminated after intravenous injection, GH levels were elevated for about 3 hours. Absorption of GHRH(1–29)-NH₂ through the nasal mucosa was found to be low, and the bioavailability was only 3–5%. There was a dose-dependent release of GH after intranasal administration of GHRH(1–29)-NH₂, with the maximal response obtained with about 50 μg/kg; this dose was approximately as potent as 1 μg/kg injected intravenously. The GH response after repeated intranasal administration of GHRH(1–29)-NH₂ was sustained; there was no suppression of GH secretion during the night following a day when GHRH(1–29)-NH₂ had been given three times intranasally. Based on these findings and the obvious convenience of intranasal administration compared with injections, it would be justified to test intranasal therapy for treatment of short stature in children with GH deficiency caused by hypothalamic damage.     

GASTRIC EMPTYING IN INFANTS WITH CONGENITAL HEART DISEASE

ABSTRACT. Cavell, B. (Department of Paediatrics, University Hospital, Lund, Sweden). Gastric emptying in infants with congenital heart disease. Acta Paediatr Scand, 70: 517,.–Gastric emptying of infant formula using a marker dilution technique was studied in 8 infants with congenital heart disease aged 1 week to 5 months. Six infants were in heart failure and 4 failed to grow. Gastric emptying followed a linear pattern in 5 and a biphasic pattern with an initial slow phase in 2 infants. The amounts of meal emptied after 1 and 2 hours, 14.7 and 31.0 ml per 0.1 m² of body surface area, respectively, were significantly smaller than the corresponding amounts found in a group of healthy infants.     

The immunogenicity of Haemophilus influenzae: Meningococcal protein conjugate vaccine in Polynesian and non-Polynesian New Zealand infants

To examine the comparative immunogenicity of the Haemophilus influenzae type b-meningococcal protein (PRP-OMP) conjugate vaccine in Polynesian and non-Polynesian New Zealand infants.

Methodology:

Fifty-six Polynesian and 53 non-Polynesian infants aged 2–7 months recruited from primary health care settings in Auckland received a two-dose primary series of PRP-OMP. A sub-sample of 83 participants received a booster dose of PRP-OMP at 12–16 months of age. Anti-PRP antibody concentrations were measured in pre- and post-vaccination blood samples.

Results:

Antibody responses consistent with long-term protection (≥1.00 μg/mL) were observed in 72, 85 and 95% of children following the first, second and booster doses.

Conclusions:

Despite differences in disease epidemiology, PRP-OMP was highly immunogenic in Polynesian and non-Polynesian infants.     

Growth hormone (GH) profiles in response to continuous subcutaneous infusion of GH-releasing hormone(1— 29)-NH2 in children with GH deficiency

Six children presenting with partial growth hormone (GH) deficiency (mean GH peak in two different tests, 8.0 k1.3 μ g/l ) aged 8–10.3 years (mean, 2.7 ± 0.9 years) were treated for 6 months by continuous subcutaneous infusion of GH-releasing hormone(1–29)-NH, (GHRH(1–29)-NH₂); 24-hour GH profiles and height velocity were measured. A biphasic effect of GHRH(1–29)-NH₂ infusion was observed. After an early substantial increase in the 24-hour integrated concentration of GH, from 1.6 ± 0.1 to 3.5 ± 0.7 μg/l/minute, a subsequent consistent decrease occurred by 3 months, which was more pronounced after 6 months (mean 24-hour integrated concentration of GH, 1.9± 0.9 μg/l/minute). This effect reflects modification of both pulse amplitude and frequency of GH secretion. At the end of the study, one child had complete suppression of GH secretion and two others showed only one peak above 5 μg/1 during a 24-hour period. No correlation was found between these changes and height velocity. Three children did not grow significantly; the other three children who had a growth response to GHRH(1–29)-NH₂ were those with the lowest 24-hour integrated GH concentration at the end of the study. The possible mechanisms involved in this biphasic effect, including GHRH antibodies, changes in somatostatin levels and/or desensitization of pituitary GHRH receptors, have been investigated.     

THE CONCENTRATIONS OF TOTAL CORTISOL AND CORTICOSTERONE IN MIXED CORD PLASMA

ABSTRACT: Homoki, J., Teller, W. M., Tschürtz, D., and Fazekas, A. T. A. (Department of Paediatrics, Division of Endocrinology and Metabolism, University of Ulm/Donau, BRD). The concentrations of total Cortisol and corticosterone in mixed cord plasma. Acta Paediatr Scand, 64:587, 1975.–Cortisol and corticosterone were determined in mixed umbilical cord plasma of 43 healthy full-term newborns. The method consisted of a combined thin-layer chromatographic-ftuorimetric procedure which proved to be specific and reliable. The mean concentration in cord plasma of Cortisol was 10.6±4.9 μ.g/100 ml, of corticosterone 1.8±0.8 μg/100 ml. The mean ratio cortisol/corticosterone F/B was 6.3±2.5. Neither the duration nor the time of day of delivery appeared to influence the concentration of Cortisol or corticosterone in umbilical cord plasma. Also, there was no significant difference between male and female infants. In 18 instances of a pathological course of gestation and/or delivery the mean Cortisol level was 9.1±4.7 μg/ml, the mean corticosterone level 2.2±9 μg/100 ml. The mean F/B ratio was slightly but not significantly decreased (4.2±1.4 μg/100 ml; p >0.05). It is speculated that the high corticosterone concentration in umbilical cord plasma reflects a defect in Cortisol biosynthesis (17α-hydroxylase deficiency) in the newborn, compared with later life.     

Morphine pharmacokinetics in premature and mature newborn infants

The pharmacokinetics of a single dose of morphine was investigated in five term infants (gestational age 37–40 weeks) and eight preterm infants (gestational age 25–32 weeks). In the five term infants, median (range) volume of distribution at steady state (Vd_β) was 1758 (634–2700) ml/kg, plasma clearance (Cl) was 4.73 (1–75–6.61) ml/kg/min and terminal half-life (T1/2) was 224 (107–394) min. In the eight preterm infants, Vd_β was 2366 (1662–2876) ml/kg, Cl was 2.82 (1.88–6.60) ml/kg/min and T1/2 was 556 (248–834) min. No correlation was found between clearance and gestational age, but we found a significant negative correlation between T1/2 and gestational age. We conclude that there is considerable variation in the pharmacokinetic properties of morphine in both term and preterm newborn infants. Because of this variation, careful individual assessment of the clinical effect of therapy with morphine in newborn infants should be exercised.     

A Simplified Model for Adjustment of Gentamicin Dosage in Newborn Infants

ABSTRACT. In a retrospective study of 72 neonates during treatment with gentamicin, poor correlation was found between dosage based on body weight and gentamicin serum concentrations. Calculation of adequate gentamicin dosage regimen during steady-state based on individual pharmacokinetic parameters according to Gibaldi & Perrier (5) was then studied in 35 newborn infants during therapy. Predictions were based on gentamicin serum concentrations taken prior to and 1, 3, and 5 hours after the first ( n =8) or second ( n =12) dose (group A), or only prior to and one hour after dose (group B, n =15). Half-life ( t _1/2), apparent volume of distribution ( V_d ), body clearance (Cl_body) and elimination rate constant (β) were not significantly different when calculated after the first or second dose or during steady-state. The correlation between predicted and observed gentamicin concentration was high in both groups ( p < 0.005) and the slopes congruent with unity. After dose or interval correction, 73 % of the observed predose concentrations (mean 2.0 μg/ml) were within 1 μg/ml of predicted values. One hour after dose the predicted (mean 5.7 μg/ml) and observed (mean 6.2 μg/ml) values were not significantly different. Higher precision was noted when the predictions were based on 4 samples (group A) compared to 2 (group B). Since the calculations may be performed by a simple desk calculator rapid advice may be given to the clinical staff on adequate gentamicin dosage even in small severely ill preterm infants.     

Cerebral blood flow and plasma hypoxanthine in relation to surfactant treatment

We have previously reported reduction in EEG activity in preterm babies after tracheal instillation of Curosurf. To elucidate the cause of EEG depression, we have examined cerebral blood flow (CFB), amplitude-integrated EEG (aEEG), mean arterial blood pressure (MABP) and plasma hypoxanthine (Hx) concentration in a group of preterm babies before and immediately after administration of surfactant. No change occurred in CBF immediately after surfactant treatment despite a significant decrease in MABP. At 60 min after surfactant administration, a significant reduction in CBF occurred ( p < 0.05). However, when CBF values were corrected for changes in PaCO₂, no reduction in CBF was observed. Mean plasma Hx concentration was 11.6 (SD 7.3) μmol/l before surfactant therapy, which decreased significantly to 8.1 (5.8) μmol/l ( p < 0.05) 15–30 min after treatment. No correlations were found between plasma Hx concentration and FiO₂, a/A pO₂, PaCO₂, SaO₂, arterial blood pressure, CBF or the degree of EEG depression. This study indicates that EEG depression observed after surfactant instillation is not caused by cerebral ischemia.     

Glycerol carbon contributes to hepatic glucose production during the first eight hours in healthy term infants

The newborn infant must mobilize endogenous substrate stores to meet the requirements of glucose-dependent organs. High concentrations of free fatty acids and glycerol, and a rapid decrease in the respiratory quotient, indicate that lipids are an important fuel soon after birth. The purpose of the present study was to determine the onset of lipolysis and gluconeogenesis from glycerol in healthy, term, unfed infants. Eight infants were studied from a postnatal age of 3.5 ± 0.5 h to 7.4±0.2h using [6,6-²H₂]glucose and [2-¹³C]glycerol analysed by gas chromatography/mass spectrometry. Plasma concentrations of glucose, glycerol and insulin averaged 2.9±0.4mM, 369±89μM and 9.4 ±3.7 μU·ml^-1, respectively. The hepatic glucose production rate averaged 25.0±3.5 μmol·kg^-1 min^-1 (4.5 ±0.6mgkg^-1·min^-1) and the endogenous plasma appearance rate of glycerol 8.7±1.2/μmol·kg^-1min^-1. On average, 57.9±8.4% of the glycerol was converted to glucose, representing 11.1 ± 2.3% of hepatic glucose output. Thus, lipolysis and gluconeogenesis from glycerol are established within the first 8 h of life in term infants.     

COPPER DEFICIENCY AND HYPOCALCEMIC RICKETS IN A SMALL-FOR-DATE INFANT

ABSTRACT. A case of copper deficiency associated with hypocalcemia, radiological features of rickets and hyperparathyroidism is described in a small-for-date infant (gestational age 39 weeks, B.W. 1240 g). Neonatal serum copper (Cu) levels were found between 223 and 138 μmol/l. She was given daily 2 400 U of vitamin D₂ and a load dose of 80 000 IU at the age of 55 days. At the age of 79 days, X-rays of the legs and wrist showed spread, cupped and frayed metaphyses. Serum Ca was 1.35 mmol/1, P=0.99 mmol/1 with high alkaline phosphatases (A.P.) 590 II/ml. But plasma level of 25 hydroxycholecalciferol (25-OH-CC) was normal = 10.8 ng/ml. Serum Cu was low=3.14 μmol/l and serum immunoreactive parathormone (iPTH) level was elevated: 520 μlEq/ml (N±100). Administration of vitamin D₂ (15 mg) induced an immediate normalization of serum Ca, normal serum iPTH (68 μlEq/ml) in one month, normal X-rays in two months and normal A.P. in four months. Serum Cu and ceruloplasmin levels increased slowly without any supplementation to subnormal levels at the age of eight months (14.9 and 1.65 μmol/1. Serum Cu concentrations were found to be normal (16.0–33.7 μmol/1) in five children with hypocalcemic rickets. These results suggest a role of Cu deficiency in the occurrence of this transient vitamin D-resistant rickets.