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Biomedical subjects

O Mehls

Publications and source records attributed to O Mehls.

At least 37 records · Page 2Linked to original sources
PubMed2000

Experience with deflazacort in children and adolescents after renal transplantation.

Deflazacort (DFZ) has been proposed as an alternative drug for immunosuppression after renal transplantation (TX), with fewer side effects than conventional glucocorticoids. We investigated renal function, body growth, body fat, and bone mineral density (BMD) after switching from oral methylprednisolone (MPR) to equivalent doses of DFZ 1-9 years after TX in 20 patients aged 5-20 years, selected because of severe adverse effects from previous steroid therapy. At conversion the patients received a mean dose of 7.4 +/- 2.4 mg DFZ/m2 per day. The drug was continued for a mean of 3.7 (1.2-5.5) years. Under DFZ, the glomerular filtration rate dropped slightly (NS). A single rejection episode occurred. Growth velocity significantly improved in the 1st year on DFZ treatment and height standard deviation score (SDS) increased steadily after introduction of DFZ (from -2.64 to -1.96 after 4 years, P = 0.06). However, in 10 prepubertal children the height gain (+0.20 SDS in 2 years on DFZ) was not significant and the overall mean annual growth rate after TX was similar to that in 10 matched prepubertal TX children on continued MPR treatment. Relative obesity, estimated from mean body mass index corrected for height, was reduced from +1.11 SDS at the start of DFZ to +0.71 SDS after 2 years (P = 0.03) and to +0.39 SDS after 4 years (NS). BMD-SDS of the lumbar spine (L2-4) increased after 1 year on DFZ (P = 0.005). In conclusion, DFZ is well tolerated and safe in pediatric patients after TX. It improves relative obesity and bone mineralization. However, body growth is not significantly influenced pre puberty.

Adipose Tissue↗
PubMed2000

Effects of recombinant human growth hormone in catabolic adults with chronic renal failure.

Growth hormone (GH) has been used for the treatment of catabolism in a few pilot studies and in two placebo-controlled studies of 6 months duration. Treatment with GH in doses of 2-4 IU/m2/day (0.67-1.33 mg/m2/day) resulted in clear anabolic effects and a significant change in body composition. Lean body mass increased by more than 3 kg within 6 months, whereas fat mass was decreased by the same amount, resulting in a constant total body weight. As there were no major side-effects, controlled long-term studies are justified.

Adult↗
PubMed2000

Growth hormone receptor abundance in tibial growth plates of uremic rats: GH/IGF-I treatment.

BACKGROUND: Children with chronic renal failure (CRF) exhibit growth retardation and a disturbed growth hormone/insulin-like growth factor-I (GH/IGF-I) axis. Treatment of children with CRF with GH or GH/IGF-I can partially restore linear growth. The molecular basis for decreased longitudinal growth is not known but may involve an impaired action of GH. METHODS: We used the growth-retarded uremic rat model to determine the abundance and distribution of GH receptors (GHRs) in the tibial epiphyseal growth plate and the influence of GH, IGF-I, or combined GH/IGF-I treatment. Pair-fed rats were used as the control. RESULTS: While all treatment regimes increased body length and weight in both rat groups, only GH/IGF-I treatment increased the total growth plate width. This involved an increase in cell number in the hypertrophic zone, which could also be induced by IGF-I alone. Immunohistochemical analysis showed that uremic rats had decreased abundance of GHRs in the proliferative zone, and only GH/IGF-I therapy could overcome this decrease. These data thus suggest that growth retardation in uremic rats is, at least in part, due to a decrease in GHR abundance in chondrocytes of the proliferative zone of the tibial growth plate. This decreased GHR abundance can be overcome by combined GH/IGF-I therapy, thus enhancing generation and proliferation of hypertrophic zone chondrocytes and increasing growth-plate width. CONCLUSION: These studies point to a mechanism for the growth retardation seen in children with CRF, and suggest that combined GH/IGF-I treatment may provide more effective therapy for these patients than GH alone.

Animals↗
PubMed2000

No difference in intestinal strontium absorption after oral or IV calcitriol in children with secondary hyperparathyroidism. The European Study Group on Vitamin D in Children with Renal Failure.

BACKGROUND: Oral and intravenous calcitriol bolus therapy are both recommended for the treatment of secondary hyperparathyroidism, but it has been claimed that the latter is less likely to induce absorptive hypercalcemia. The present study was undertaken to verify whether intravenous calcitriol actually stimulates intestinal calcium absorption less than oral calcitriol and whether it is superior in suppressing parathyroid hormone (PTH) secretion. METHODS: Twenty children (16 males, age range of 5.1 to 16.9 years, mean creatinine clearance 21.9 +/- 11.5 mL/min/1.73 m2, range of 7.4 to 52.7) with chronic renal failure (CRF) and secondary hyperparathyroidism [median intact PTH (iPTH), 327 pg/mL; range 143 to 1323] received two single calcitriol boli (1.5 mg/m2 body surface area) orally and intravenously using a randomized crossover design. iPTH and 1,25(OH)2D3 levels were measured over 72 hours, and intestinal calcium absorption was measured 24 hours after the calcitriol bolus using stable strontium (Sr) as a surrogate marker. Baseline control values for Sr absorption were obtained in a separate group of children with CRF of similar severity. RESULTS: The peak serum level of 1,25(OH)2D3 and area under the curve baseline to 72 hours (AUC0-72h) were significantly higher after intravenous (IV) calcitriol (AUC0-72h oral, 1399 +/- 979 pg/mL. hour vs. IV 2793 +/- 1102 pg/mL. hour, P < 0.01), but the mean intestinal Sr absorption was not different [SrAUC0-240min during the 4 hours after Sr administration 2867 +/- 1101 FAD% (fraction of the absorbed dose) vs. 3117 +/- 1581 FAD% with oral and IV calcitriol, respectively]. The calcitriol-stimulated Sr absorption was more then 30% higher compared with control values (2165 +/- 176 FAD%). A significant decrease in plasma iPTH was noted 12 hours after the administration of the calcitriol bolus, which was maintained for up to 72 hours without any differences regarding the two routes of administration. CONCLUSIONS: These results demonstrate that under acute conditions, intravenous and oral calcitriol boli equally stimulate calcium absorption and had a similar efficacy in suppressing PTH secretion.

Administration, Oral↗
PubMed2000

Intermittent administration of parathyroid hormone (1-37) improves growth and bone mineral density in uremic rats.

BACKGROUND: Parathyroid hormone (PTH) is secreted in a pulsatile fashion. Continuous infusion of PTH(1-84) resulted in a net decrease in trabecular bone volume. Differential effects have been reported following an intermittent application of PTH. We investigated the effects of a continuous infusion and of an intermittent (2 times daily subcutaneously) administration of PTH(1-37) on growth and bone mineral density (BMD) in healthy and uremic rats. METHODS: Two-stage subtotal nephrectomy was performed on 130 g female Sprague-Dawley rats. PTH(1-37) or solvent was administered through minipumps in sham-operated and uremic rats (60 microg/kg x day for 2 weeks). The effect of intermittent administration was tested with a subcutaneous injection of solvent: 30 microg/kg PTH(1-37) two times per day, 100 pmol calcitriol (C)/kg two times per day, or both. The length (snout-tailtip) and BMD were measured at the start of uremia and at sacrifice. BMD was measured by peripheral quantitative computer tomography at the proximal tibia, 6 and 12 mm distal of the kneejoint space. Femur bone morphology was assessed by x-rays, and calcium content was measured by atomic absorption spectrophotometry. RESULTS: Length gain was not altered by the continuous infusion of PTH. In contrast, it was significantly increased by intermittent PTH (control solvent 5.35 +/- 0.37 cm vs. control PTH 6.19 +/- 0.47 cm; uremia solvent 4.78 +/- 0.20 cm vs. uremia PTH 6.17 +/- 0.36 cm; P < 0.05). Intermittent PTH but not C increased BMD in uremic rats (Delta total BMD 134 + 13.3 vs. 76.3 +/- 11.5 mg/mL; P < 0.05). X-rays revealed increased bone mass following treatment with PTH but not with C. Uremia decreased bone calcium content (64 +/- 0.3 vs. 73. 3 +/- 2.5 mg/mL), which was normalized by PTH (80 +/- 3.6 mg/mL, P < 0.05) but not by C (69 +/- 1.9 mg/mL). CONCLUSION: Pulsatile administration of PTH does not adversely affect, but improves longitudinal growth independent of concomitant treatment with C. At the same time PTH increases BMD and the calcium content of bone.

Animals↗
PubMed1999

Deaths within 90 days from starting renal replacement therapy in the ERA-EDTA Registry between 1990 and 1992.

BACKGROUND: Patients who die within 90 days of commencing renal replacement therapy (RRT) may be recorded by some centres and not others, and hence data on mortality and survival may not be comparable. However, it is essential to compare like with like when analysing differences between modalities, centres and registries. It was decided, therefore, to look at the incidence of deaths within 90 days in the ERA-EDTA Registry, and to try to define the characteristics of this group of patients. METHODS: Between 1 January 1990 and 31 December 1992, 78 534 new patients started RRT in 28 countries affiliated to the ERA-EDTA Registry. Their mean age was 54 years and 31% were over 65 years old. Eighty-two per cent of the patients received haemodialysis (HD), 16% peritoneal dialysis (PD) and 2% had preemptive transplantation as first mode of treatment. RESULTS: From January 1990 to March 1993 the overall incidence of deaths was 19% and 4% of all patients died within 90 days from the start of RRT. Among those dying within 90 days 59% were over 65 years compared to 53% over 65 years in those dying beyond this time (P<0.0001). The modality of RRT did not influence the distribution of deaths before and after 90 days. Vascular causes and malignancy were more common in those dying after 90 days, while there were more cardiac and social causes among the early deaths. Mortality from social causes was twice as common in the elderly, who had a significantly higher chance of dying from social causes within 90 days compared to those aged under 65 years. The overall incidence of deaths within 90 days was 3.9% but there was a wide variation between countries, from 1.8% to 11.4%. Finally, patient survival at 2 years was markedly influenced in different age groups when deaths within 90 days were taken into account. CONCLUSIONS: The incidence of deaths within 90 days from the start of RRT was 3.9%, with a marked variation between countries ranging from 1.8% to 11.4%, which probably reflects mainly differences in reporting these deaths, although variable selection criteria for RRT may contribute. Deaths within 90 days were significantly more frequent in elderly patients with more early deaths resulting from cardiac and social causes, while vascular causes of death and malignancy were more common in those dying after 90 days. Patient survival analyses should take into account deaths within 90 days from the start of RRT, particularly when comparing results between modalities, countries and registries.

Adolescent↗
PubMed1999

Improved survival in renal replacement therapy in Europe between 1975 and 1992. An ERA-EDTA Registry study.

BACKGROUND: The prevalence of Renal Replacement Therapy (RRT) is rising steadily, worldwide and in Europe. One reason for this is an increasing number of patients starting RRT, but improving survival on RRT may also be contributing. MATERIAL AND METHODS: In an ERA-EDTA Registry study we have examined survival of patients with Standard Primary Renal Disease, or Diabetes, aged 20 to 75 years, who started RRT with haemodialysis (HD) or peritoneal dialysis (PD) between 1975 and 1992. Altogether close to a quarter of a million patients were included in the analysis which included conventional survival analysis of comparable subgroups of the whole cohort as well as Cox regression. RESULTS: After accounting for age, mode of initial treatment, and diagnosis, an improvement in survival of RRT patients was evident. From Cox regression it was calculated the risk for death decreased by about 5% annually during the time period 1975 1992. Patients who started RRT using PD experienced a higher mortality than those starting with HD. According to Cox regression the relative risk ratio for death was 1.25 for the whole period. The difference in survival between patients starting with PD or HD diminished during the observation period (1975-1992). DISCUSSION: The survival prospects of a patient presenting with end stage renal disease were considerably better in the early 1990s compared to the mid 1970s. This is reassuring despite the fact that mortality on RRT remains high. The higher mortality of RRT patients who started with PD is probably an 'historical' observation as the techniques of this treatment modality have improved considerably since the 1980s which was the time period from which came most of the data for the analysis.

Adult↗
PubMed1999

Dialysis in neonates with inborn errors of metabolism.

BACKGROUND: Certain inborn errors of metabolism become manifest during the neonatal period by acute accumulation of neurotoxic metabolites leading to coma and death or irreversible neurological damage. Outcome critically depends on the immediate elimination of the accumulated neurotoxins. Recent technological progress provides improved tools to optimize the efficacy of neonatal dialysis. METHODS: We report our experience with continuous venovenous haemodialysis (CVVHD) in six neonates with hyperammonaemic coma due to urea-cycle disorders or propionic acidaemia and in one child with leucine accumulation due to maple-syrup urine disease (MSUD), in comparison with five patients managed by peritoneal dialysis (PD) (2 hyperammonaemia, 3 MSUD). Application of a new extracorporeal device specifically designed for use in small children permitted the establishment of stable blood circuits utilizing small-sized catheters, and the tight control of balanced dialysate flows over wide flow ranges. RESULTS: Plasma ammonia or leucine levels were reduced by 50% within 7.1 +/- 4.1 h by CVVHD and within 17.9 +/- 12.4 h by PD (P<0.05). Also, total dialysis time was shorter with CVVHD (25 +/- 21 h) than with PD (73 +/- 35 h, P<0.02). A comparison of the CVVHD results with published literature confirmed superior metabolite removal compared to PD, and suggested comparable efficacy as achieved with continuous haemofiltration techniques. Apart from accidental pericardial tamponade during catheter insertion in one case, no major complications were noted with CVVHD. In three of the five PD patients, dialysis was compromised by mechanical complications. None of the MSUD patients but four children with urea-cycle disorders died, two during the acute period and two later during the first year of life, with signs of severe mental delay. Of the eight children presenting with hyperammonaemic coma, the four with the most rapid dialytic ammonia removal rate (50% reduction in < 7 h) survived with no or moderate mental retardation, whereas slower toxin removal was always associated with a lethal outcome. Simulation studies showed that the efficacy of neonatal CVVHD is limited mainly by blood-flow restrictions. CONCLUSIONS: While CVVHD is the potentially most efficacious dialytic technique for treating acute metabolic crises in neonates, utmost care must be taken to provide an adequately sized vascular access.

Humans↗
PubMed1999

Area under the plasma concentration-time curve for total, but not for free, mycophenolic acid increases in the stable phase after renal transplantation: a longitudinal study in pediatric patients. German Study Group on Mycophenolate Mofetil Therapy in Pediatric Renal Transplant Recipients.

Mycophenolate mofetil, an ester prodrug of the immunosuppressant mycophenolic acid (MPA), is widely used for maintenance immunosuppressive therapy in pediatric renal transplant recipients. However, little is known about the pharmacokinetics of MPA in this patient population in the stable transplant phase, and dosage guidelines are preliminary. The authors therefore compared the pharmacokinetics of MPA, free MPA, and the renal metabolite MPA glucuronide (MPAG) in the initial (sampling at 1 and 3 weeks) and stable phases (sampling at 3 and 6 months) posttransplant in 17 children (age, 12.0 +/- 0.77 years; range, 5.9 to 15.8 years), receiving the currently recommended dose of 600 mg MMF/m2 body surface area (BSA) twice a day. Plasma concentrations of MPA and MPAG were measured by reverse phase HPLC. Because MPA is extensively bound to serum albumin and only the free drug is presumed to be pharmacologically active, the authors also analyzed the MPA free fraction by HPLC after separation by ultrafiltration. The intraindividual variability of the area under the concentration-time curves (AUC0-12) of MPA throughout the 12-hour dosing interval was high in the immediate posttransplant period, but declined in the stable phase, whereas the interindividual variability remained unchanged. The median MPA-AUC0-12 values increased 2-fold from 32.4 (range, 13.9 to 57.0) mg x h/L at 3 weeks to 65.1 (range, 32.6 to 114) mg x h/L at 3 months after transplantation, whereas the median AUC0-12 values of free MPA did not significantly change over time. This discrepancy can be attributed to a 35% decline of the MPA free fraction from 1.4% in the initial phase posttransplant to 0.9% (p < 0.01) in the stable phase. In conclusion, pediatric renal transplant recipients given a fixed MMF dose exhibit a 2-fold increase of the AUC0-12 of total MPA in the stable phase posttransplant and a 35% decrease of the MPA free fraction, whereas the AUC0-12 of free MPA remains unchanged over time. Because the latter pharmacokinetic variable is theoretically best predictive of the clinical immunosuppressive efficacy of MMF, these findings may have consequences for the dosing recommendations of MMF in renal transplant recipients.

Adolescent↗
PubMed1999

Hypoglycemic effects of insulin-like growth factor-1 in experimental uremia: can concomitant growth hormone administration prevent this effect?

The risk of hypoglycemia limits the clinical application of insulin-like growth factor-1 (IGF-1). Our studies aimed to evaluate the mode of occurrence as well as the prevention of this side effect. Acute administration (i.v. infusion) of IGF-1 in subtotal nephrectomized uremic (U), sham-operated ad libitum fed control (C) and sham-operated pair-fed control (P) rats led to hypoglycemia, though more expressed in P. Serum glucose levels decreased within 60 min after the IGF-1 administration by 40% in U, by 45% in C and by 52% in P (p < 0.05, U vs. P). Chronic administration (7 days) of 1, 4 and 8 mg/kg/day IGF-1 in U rats led to hypoglycemia in an increasing manner as the dose of IGF-1 increased. On the first day, 2 h after injection, serum glucose levels were 116.5 +/- 8.6, 110.4 +/- 12.4, 60,3 +/- 19.2 and 50.6 +/- 18.3 mg/dl, respectively (p < 0. 01). One week later, IGF-1 therapy proved to be less hypoglycemic in all the groups. On day 7, 2 h after injection the serum glucose levels were 118.9 +/- 23.8, 89.0 +/- 23.9 and 66.0 +/- 32.0, respectively (in comparison to day 1 for 4 and 8 mg/kg/day IGF-1 p < 0.05). The combined effect of 4 mg/kg/day IGF-1 and 10 IU/kg/day growth hormone (GH) was also studied in U and P animals. Two hours after the first injections of IGF-1 serum glucose levels decreased in U from 120.0 +/- 11.3 to 49.2 +/- 21.6 mg/dl, while IGF-1 plus GH decreased the glucose level from 122.0 +/- 15.5 to 81.3 +/- 24.7 mg/dl (p < 0.05 IGF-1 vs. IGF-1 + GH). The hypoglycemic effect of IGF-1 was less expressed by long-term treatment and simultaneous administration of GH overcame the glucose-lowering effect of IGF-1 (serum glucose levels on day 11 one hour after the injections: 73.7 +/- 15.3 mg/dl with IGF-1, and 111.0 +/- 7.8 mg/dl with IGF-1 + GH). Methylprednisolone (MP) did not significantly alter the former effects of IGF-1 and GH. In summary, IGF-1 leads to hypoglycemia in control and uremic rats in a dose-dependent manner. This effect becomes less expressed after prolonged administration. GH attenuates the hypoglycemic effect of IGF-1. This suggests that the combined GH and IGF-1 treatment is more effective and less dangerous in correcting uremic growth failure.

Animals↗
PubMed1999

Long-term outcome of paediatric patients with hereditary tubular disorders.

BACKGROUND: An increasing number of children with hereditary tubular disorders (HTD) reach adult life due to diagnostic and therapeutic advances which results in growing need to manage these patients by adult centres. Data on the prevalence and the late clinical problems of these patients are limited. METHODS: We observed 177 paediatric patients with isolated or complex HTD between 1969 and 1994. The median age at the time of diagnosis was 3 (range 0-18) years and the median observation period 10 (range 1-43) years. The long-term outcomes with respect to renal function, bone disease, and body growth were analyzed. RESULTS: The prevalence of HTD was 3.2% of all patients observed in our renal unit and 14% of those patients with chronic renal failure and/ or end-stage renal disease. The three most frequent disorders observed were nephropathic cystinosis (n = 34), X-linked hypophosphataemic rickets (n = 26), and idiopathic hypercalciuria (n = 17). At the last observation, 12% of the patients with isolated HTD and 30% of those with complex HTD had developed preterminal chronic renal failure; end-stage renal disease was observed in 5 and 25%, respectively (p < 0.001). Progressive disease occurred mainly in patients having cystinosis, primary hyperoxaluria, the syndrome of hypomagnesaemia/hypercalciuria, primary Fanconi syndrome, Fanconi-Bickel syndrome, and methylmalonic aciduria. Nephrocalcinosis was found in 42%, urolithiasis in 14%, bone deformities and/or fractures in 28%, and other extrarenal alterations in 29% of all patients. The median body height at last observation was 2.0 SD below the normal mean (range from -10.4 to +2. 6), and the adult height was subnormal in 48% of 67 grown-up patients. Growth retardation was more severe in complex than in isolated HTD. The mortality decreased from 17% in 1969-1981 to 12% in 1982-1994. CONCLUSION: Although HTD are rare nephropathies, their frequently progressive course associated with extrarenal complications requires the attention of nephrologists beyond the paediatric age.

Adolescent↗
PubMed1999

Synchronous fluctuations of blood insulin and lactate concentrations in humans.

Oscillatory organization is a universal mode of signal transduction in living organisms. In vitro studies suggest spontaneous pulsatile fluctuations of intracellular energy metabolism. It is possible that, in vivo, some of these processes are synchronized by the pulsatile release of insulin. We assessed a potential coupling among plasma insulin, glucose, and lactate concentrations, by frequent blood sampling for 24 h in 11 healthy volunteers. Insulin sensitivity was assessed using the euglycemic hyperinsulinemic clamp technique. Lactate concentrations exhibited pulsatile fluctuations at an average interval of 84 +/- 11 min, whereas sodium and pH were nonpulsatile. The lactate concentration pulses closely corresponded to insulin oscillations, which occurred with a periodicity of 86 +/- 11 min. Blood glucose also fluctuated during daytime at an interval of 89 +/- 32 min. During nighttime, the frequency and amplitude of glucose oscillations were lower. The daytime profiles showed significant temporal coupling and pattern synchrony among insulin, lactate, and glucose. Only the close temporal relationship between insulin and lactate release persisted during nighttime. The temporal coupling and pattern synchrony between insulin and lactate were correlated inversely with insulin sensitivity, and positively with the degree of abdominal obesity. Our results suggest that: 1) the concentration of lactate, an indicator of cellular energy metabolism, fluctuates periodically in vivo; 2) the lactate concentrations fluctuate in synchrony with insulin pulses; and 3) such coupling is more pronounced in obese, insulin-resistant individuals.

Adult↗
PubMed1999

No difference in intestinal strontium absorption after an oral or an intravenous 1,25(OH)2D3 bolus in normal subjects. For the European Study Group on Vitamin D in children with renal failure.

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 microg/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 microg/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.

Administration, Oral↗