Claus Peter Schmitt

Growth in children with chronic renal failure on intermittent versus daily calcitriol

Calcitriol (C) treatment strategies for secondary hyperparathyroidism remain controversial regarding efficacy and safety. In children, intermittent C administration has been suspected of impairing body growth. In a prospective, randomized multicenter study, we compared the effect of daily versus twice weekly C on plasma intact parathyroid hormone (iPTH) levels and growth in 24 prepubertal children with chronic renal insufficiency (mean creatinine clearance 20±9xa0ml/min per 1.73xa0m2). After a 3-week washout period, the patients were randomly assigned to 10xa0ng/kg per day or 35xa0ng/kg twice a week oral C. The C dose was kept constant for 2xa0months and could then be adapted to maintain an iPTH target range of 140–280xa0pg/ml. Median (range) baseline iPTH levels were 567 (114–1209)xa0pg/ml in the daily and 332 (93–614)xa0pg/ml in the intermittent treatment group (P=NS). After 12xa0months, iPTH had decreased to 255 (85–710) and 179 (51–443) pg/ml (P<0.01). The average weekly dose of C was 76±34 and 62±34xa0ng/kg (P=NS). Five episodes of calcium phosphate product≥70 occurred in the daily group and four in the intermittent group. The change in height standard deviation score during the study period was not affected by either treatment modality (−0.18±0.34 vs. −0.05±0.52, P=NS). Daily and intermittent C do not differentially affect growth rate and are equally effective in controlling secondary hyperparathyroidism in children with chronic renal failure.

The enigma of hyperparathyroidism in hypophosphatemic rickets.

Familial hypophosphatemic rickets (XLH) is caused by inactivating mutations of the cell surface metalloproteinase PHEX. It is characterized by low-normal serum levels of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], normocalcemia, and hypophosphatemia. Hyperparathyroidism is regularly seen in patients treated with phosphate supplements, although circulating serum phosphate levels do not reach the normal range. The mechanism is unknown. Decreased serum concentrations of ionized calcium following phosphate supplements might contribute to the development of hyperparathyroidism. Secondary and even tertiary hyperparathyroidism can, however, be observed in patients who have never received phosphate treatment. This points to an abnormal regulation of production and/or degradation of parathyroid hormone (PTH). Recently, the expression of the PHEX gene in hypertrophied parathyroid glands of a patient with XLH has been reported. It is unclear whether the mutant PHEX gene can induce hyperparathyroidism by abnormal regulation of peptidases.

Hydration measurement by bioimpedance spectroscopy and blood pressure management in children on hemodialysis

BackgroundHypertension is frequent in chronic hemodialyzed patients and usually treated by reducing extracellular fluid. Probing dry weight only based on a clinical evaluation may be hazardous, especially in case of volume independent hypertension.MethodsWe performed a 1-year retrospective study in three pediatric centers to define the relation between blood pressure (BP) and hydration status, assessed by whole-body bioimpedance spectroscopy (BIS). We analyzed 463 concomitant measurements of BP, relative overhydration (rel.OH), and plasma sodium (Napl) in 23 children (mean age 13.9u2009±u20095.1xa0years).ResultsPre-dialytic under-hydration (rel.OHu2009<u2009−7xa0%) was present in 5.4xa0% of the sessions, out of which 24xa0% showed hypertension. Normohydration (rel.OH −7 – +7xa0%) was observed in 62.4xa0% of the sessions, 45.3xa0% of them revealed hypertension. Moderate OH (rel.OH +7 – +15xa0%) was present in 21xa0% of the sessions, 47.4xa0% of them showed normal BP. In 11.2xa0% of the sessions, severe overhydration (rel.OHu2009>u2009+15xa0%) was assessed, however, the majority (73xa0%) showed normal BP. Patient-specific Napl setpoint could not be described. Mean dialysate sodium concentration was higher than mean Napl.ConclusionsHypertension is not always related to overhydration. Therefore, BIS should restrict the practice of “probing dry weight” in hypertensive children. Moreover, sodium dialytic balance needs to be considered to improve BP management.

Estrogen Receptor Alpha Expression in Podocytes Mediates Protection against Apoptosis In-Vitro and In-Vivo

Context/Objective Epidemiological studies have demonstrated that women have a significantly better prognosis in chronic renal diseases compared to men. This suggests critical influences of gender hormones on glomerular structure and function. We examined potential direct protective effects of estradiol on podocytes. Methods Expression of estrogen receptor alpha (ERα) was examined in podocytes in vitro and in vivo. Receptor localization was shown using Western blot of separated nuclear and cytoplasmatic protein fractions. Podocytes were treated with Puromycin aminonucleoside (PAN, apoptosis induction), estradiol, or both in combination. Apoptotic cells were detected with Hoechst nuclear staining and Annexin-FITC flow cytometry. To visualize mitochondrial membrane potential depolarization as an indicator for apoptosis, cells were stained with tetramethyl rhodamine methylester (TMRM). Estradiol-induced phosphorylation of ERK1/2 and p38 MAPK was examined by Western blot. Glomeruli of ERα knock-out mice and wild-type controls were analysed by histomorphometry and immunohistochemistry. Results ERα was consistently expressed in human and murine podocytes. Estradiol stimulated ERα protein expression, reduced PAN-induced apoptosis in vitro by 26.5±24.6% or 56.6±5.9% (flow cytometry or Hoechst-staining, respectively; both p<0.05), and restored PAN-induced mitochondrial membrane potential depolarization. Estradiol enhanced ERK1/2 phosphorylation. In ERα knockout mice, podocyte number was reduced compared to controls (female/male: 80/86 vs. 132/135 podocytes per glomerulus, p<0.05). Podocyte volume was enhanced in ERα knockout mice (female/male: 429/371 µm3 vs. 264/223 µm3 in controls, p<0.05). Tgfβ1 and collagen type IV expression were increased in knockout mice, indicating glomerular damage. Conclusions Podocytes express ERα, whose activation leads to a significant protection against experimentally induced apoptosis. Possible underlying mechanisms include stabilization of mitochondrial membrane potential and activation of MAPK signalling. Characteristic morphological changes indicating glomerulopathy in ERα knock-out mice support the in vivo relevance of the ERα for podocyte viability and function. Thus, our findings provide a novel model for the protective influence of female gender on chronic glomerular diseases.

No Difference in Intestinal Strontium Absorption After an Oral or an Intravenous 1,25(OH)2D3 bolus in Normal Subjects

It has been suggested that 1,25‐dihydroxyvitamin D3 (1,25(OH)2D3) stimulates intestinal calcium absorption less via the intravenous (iv) than the oral route, because the first avoids direct contact of the drug with the enterocytes. However, no study has addressed the issue directly. This investigation was designed to measure the effect of a single oral or iv dose of 1,25(OH)2D3 on calcium absorption, using stable strontium (Sr) as a surrogate for calcium, and measuring the Sr fractional absorbed dose (FAD%) over 240 minutes after Sr administration. In 10 healthy volunteers, five tests were performed in a cross‐over design, with a wash‐out period between two consecutive tests: Sr absorption without 1,25(OH)2D3 (test A); Sr absorption immediately after either oral (test B) or iv (test C) 1,25(OH)2D3 (1.5 μg/m2 of body surface area [BSA]); Sr absorption (24 hr after either oral (test D) or iv (test E) 1,25(OH)2D3 (1.5 μg/m2 BSA). The concurrent administration of 1,25(OH)2D3 and Sr (tests B and C) did not significantly change the area under the Sr FAD%–time curve with respect to test A (test A: 4090 ± 345; test B: 4510 ± 345; test C: 4210 ± 345), whereas Sr absorption was significantly increased (p < 0.001) when Sr was given 24 hr after either oral or iv 1,25(OH)2D3 (test D: 5710 ± 345; test E: 5510 ± 345). It was concluded that 1,25(OH)2D3 is likely to influence calcium absorption significantly only via its genomic effect, independent of its administration route.

Structural organization and biological relevance of oscillatory parathyroid hormone secretion

Parathyroid gland secretory activity exhibits seasonal and circadian fluctuations, which are in synchrony with changes in serum calcium, phosphate, and bone turnover. In addition, an ultradian rhythm exists, which comprises seven pulses per hour, accounts for 30% of basal parathyroid hormone (PTH) release, and is highly sensitive to changes in ionized calcium. Acute hypocalcemia induces a selective, severalfold increase in pulse frequency and amplitude, whereas hypercalcemia suppresses the pulsatile secretion component, as does prolonged calcitriol therapy. Chronic renal failure is associated with a GFR dependent decrease in metabolic PTH clearance accounting for a two- to threefold increase in plasma PTH concentrations, a consistent increase of PTH burst mass and frequency, and a markedly reduced capacity to counteract changes in ionized calcium by modulation of pulsatile PTH release. Continuous PTH excess destroys bone, whereas intermittent administration of pharmacological doses of PTH improves bone morphology and strength in experimental and clinical settings. The molecular mechanisms of the exposure pattern dependent, contrasting biological effects of PTH may involve differential regulation of osteoblastic G protein signaling feedback circuits. In this context, calcimimetic and calcilytic agents are promising new therapeutic tools allowing for tight control of plasma PTH and restoration of circadian PTH rhythmicity.

Effect of the Dialysis Fluid Buffer on Peritoneal Membrane Function in Children

BACKGROUND AND OBJECTIVESnDouble-chamber peritoneal dialysis fluids exert less toxicity by their neutral pH and reduced glucose degradation product content. The role of the buffer compound (lactate and bicarbonate) has not been defined in humans.nnnDESIGN, SETTING, PARTICIPANTS, & MEASUREMENTSnA multicenter randomized controlled trial in 37 children on automated peritoneal dialysis was performed. After a 2-month run-in period with conventional peritoneal dialysis fluids, patients were randomized to neutral-pH, low-glucose degradation product peritoneal dialysis fluids with 35 mM lactate or 34 mM bicarbonate content. Clinical and biochemical monitoring was performed monthly, and peritoneal equilibration tests and 24-hour clearance studies were performed at 0, 3, 6, and 10 months.nnnRESULTSnNo statistically significant difference in capillary blood pH, serum bicarbonate, or oral buffer supplementation emerged during the study. At baseline, peritoneal solute equilibration and clearance rates were similar. During the study, 4-hour dialysis to plasma ratio of creatinine tended to increase, and 24-hour dialytic creatinine and phosphate clearance increased with lactate peritoneal dialysis fluid but not with bicarbonate peritoneal dialysis fluid. Daily net ultrafiltration, which was similar at baseline (lactate fluid=5.4±2.6 ml/g glucose exposure, bicarbonate fluid=4.9±1.9 ml/g glucose exposure), decreased to 4.6±1.0 ml/g glucose exposure in the lactate peritoneal dialysis fluid group, whereas it increased to 5.1±1.7 ml/g glucose exposure in the bicarbonate content peritoneal dialysis fluid group (P=0.006 for interaction).nnnCONCLUSIONSnWhen using biocompatible peritoneal dialysis fluids, equally good acidosis control is achieved with lactate and bicarbonate buffers. Improved long-term preservation of peritoneal membrane function may, however, be achieved with bicarbonate-based peritoneal dialysis fluids.

Reversible end-stage renal disease in an adolescent patient with methylmalonic aciduria

Sirs, Methylmalonic aciduria (MMA) is an inborn error of metabolism, characterized by deficiency of the mitochondrial enzyme methylmalonyl-CoA mutase or by defects in the synthesis of 5-deoxyadenosylcobalamin, a cofactor of methylmalonyl-CoA mutase. Affected children suffer from lethargy, failure to thrive, and muscular hypotonia, and may have ketoacidotic, hypoglycemic, and hyperammonemic coma. Biochemically, the disease is characterized by accumulation of methylmalonate and, due to activation of alternative pathways of propionate oxidation, by accumulation of proprionate, 3-hydroxyproprionate, and 2-methylcitrate. Some of these organic acids have been suggested to act as endogenous toxins, inducing a synergistic inhibition of mitochondrial energy metabolism [1, 2]. Dietary and emergency therapy and thus outcome have substantially improved [3]. In brief, treatment is based on a restriction of natural protein and administration of precursor-free amino acid mixtures, as well as supplementation of carnitine. To avoid malnutrition and catabolism, affected patients require close monitoring during therapy. Secondary organ damage, however, remains insufficiently resolved, particularly if metabolic control is inadequate. Impairment of renal function is observed in a majority of patients [4]. It is characterized by tubulointerstitial nephritis with mononuclear cell infiltration, interstitial fibrosis, and tubular atrophy [5, 6, 7, 8]. Chronic renal failure (CRF) usually develops within the 1st or 2nd decade of life. However, adequate dietary control of protein metabolism is likely to slow the progression of renal disease, although this has not yet been investigated in prospective, observational studies. We report a 16-year-old male adolescent with vitamin B12-unresponsive MMA (mut ) and partially reversible end-stage renal disease, most likely due to improved metabolic control. In this patient, MMA was diagnosed shortly after birth, and a low-protein diet and carnitine supplementation was initiated. There were several episodes of metabolic decompensation due to inadequate metabolic control during infancy and childhood, resulting in neurological sequelae and CRF. Notably, a reduced glomerular filtration rate (GFR) was noted at 2.3 years of age. At 9 years of age, he developed spastic diplegia. CRF slowly progressed until puberty. At the age of 15 years, the patient was referred to our unit with a creatinine of 6.6 mg/dl and a GFR of 8 ml/min per 1.73 m (Fig. 1A). Transient hypercalcemia due to treatment of secondary hyperparathyroidism with 1, 25-dihydroxyvitamin D3 had resolved at the time of admission. Selective metabolic investigations revealed insufficient metabolic control, most likely due to inadequate adherence to the recommended dietary regimen. High-performance liquid chromatography analysis of plasma carnitine showed strongly elevated acylcarnitines, but free carnitine was within the normal range due to supplementation (Fig. 1B). Differentiation of acylcarnitines using tandem mass spectrometry of dried blood spots showed a predominant elevation of propionylcarnitine (Fig. 1B). Organic acid analysis of urine revealed a urinary excretion of methylmalonate, 2-methylcitrate, lactate, and pyruvate (Fig. 1C). ParathyC. P. Schmitt · O. Mehls · T. L. Weber Division of Pediatric Nephrology, Department of General Pediatrics, University Children’s Hospital, Heidelberg, Germany

BIOKID: Randomized controlled trial comparing bicarbonate and lactate buffer in biocompatible peritoneal dialysis solutions in children (ISRCTN81137991)

BackgroundPeritoneal dialysis (PD) is the preferred dialysis modality in children. Its major drawback is the limited technique survival due to infections and progressive ultrafiltration failure. Conventional PD solutions exert marked acute and chronic toxicity to local tissues. Prolonged exposure is associated with severe histopathological alterations including vasculopathy, neoangiogenesis, submesothelial fibrosis and a gradual loss of the mesothelial cell layer. Recently, more biocompatible PD solutions containing reduced amounts of toxic glucose degradation products (GDPs) and buffered at neutral pH have been introduced into clinical practice. These solutions contain lactate, bicarbonate or a combination of both as buffer substance. Increasing evidence from clinical trials in adults and children suggests that the new PD fluids may allow for better long-term preservation of peritoneal morphology and function. However, the relative importance of the buffer in neutral-pH, low-GDP fluids is still unclear. In vitro, lactate is cytotoxic and vasoactive at the concentrations used in PD fluids. The BIOKID trial is designed to clarify the clinical significance of the buffer choice in biocompatible PD fluids.Methods/designThe objective of the study is to test the hypothesis that bicarbonate based PD solutions may allow for a better preservation of peritoneal transport characteristics in children than solutions containing lactate buffer. Secondary objectives are to assess any impact of the buffer system on acid-base status, peritoneal tissue integrity and the incidence and severity of peritonitis.After a run-in period of 2 months during which a targeted cohort of 60 patients is treated with a conventional, lactate buffered, acidic, GDP containing PD fluid, patients will be stratified according to residual renal function and type of phosphate binding medication and randomized to receive either the lactate-containing Balance solution or the bicarbonate-buffered Bicavera® solution for a period of 10 months. Patients will be monitored by monthly physical and laboratory examinations. Peritoneal equilibration tests, 24-h dialysate and urine collections will be performed 4 times. Peritoneal biopsies will be obtained on occasion of intraabdominal surgery. Changes in small solute transport rates, markers of peritoneal tissue turnover in the effluent, acid-base status and peritonitis rates and severity will be analyzed.

Daily but not pulse calcitriol therapy improves growth in experimental uremia

Abstractu2002Calcitriol (C) pulse therapy is widely used to suppress secondary renal hyperparathyroidism. However, high C serum concentrations may have an antiproliferative effect on growth cartilage cells and may suppress growth rate. The study was designed to evaluate whether daily C and pulse C therapy have differential effects on growth in uremic rats. Female Sprague-Dawley rats (150 g, n=5–10 per group) underwent two-stage subtotal nephrectomy (U). The duration of uremia was 14–18 days. The animals were fed a standard diet or a diet with a low-calcium content. Rats on a low-calcium diet were randomized for recombinant human growth hormone (rhGH) treatment (2.5 IU/kg per day) or solvent. C was injected subcutaneous twice daily (15 pmol/day) or intraperitoneal (105 pmol) twice per week. Weight gain and length gain was determined weekly. After sacrifice, total body calcium was determined by total body neutron activation analysis. Bone micromorphometric analysis of third lumbar vertebra and double staining with tetracycline for determination of mineralization rate were performed. Whereas daily C significantly increased total body length gain within 2 weeks, pulse C did not (U solvent 4.0±0.3 cm, UC bolus 4.3±0.4 cm, UC daily 5.3±0.3 cm, P<0.05). A low-calcium diet reduced and rhGH increased basal length gain and weight gain; regardless of these preconditions, daily but not bolus C increased length gain significantly. C both daily and in bolus form reduced bone osteoid content, but daily C improved mineral apposition rate more than C bolus. Total body calcium corrected for body weight decreased with a low-calcium diet, was lowest with concomitant rhGH treatment, and was not improved by C. In conclusion, daily but not bolus C treatment improves growth in uremic rats.