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Biomedical subjects

G Filler

Publications and source records attributed to G Filler.

At least 55 records · Page 3Linked to original sources
PubMed1998

V2 vasopressin receptor dysfunction in nephrogenic diabetes insipidus caused by different molecular mechanisms.

Loss-of-function mutations in the V2 vasopressin receptor (AVPR2) gene have been identified as a molecular basis for X-linked nephrogenic diabetes insipidus (NDI). Herein, we describe a novel deletion mutation at nucleotide position 102 (delG102) found in a Russian family resulting in a frameshift and a truncated receptor protein. Furthermore, we analyzed the AVPR2 gene of two other unrelated boys with NDI from our patient clientele. These patients showed previously described mutations (R137H, R181C). In-depth characterization of the three mutant AVPR2s by a combination of functional and immunological techniques permitted further insight into molecular mechanisms leading to receptor dysfunction. Premature truncation of the AVPR2 (delG102) led to a drastically reduced receptor protein expression in transfected COS-7 cells and, as expected, precluded specific AVPR2 functions. As indicated by different ELISA and binding studies, the R137H mutant was almost completely retained in the cell interior. In contrast to previous studies, the few mutant receptors in the plasma membrane displayed a low (2.3-fold above basal) but significant ability to stimulate the Gs/adenylyl cyclase system. In contrast to the latter mutation, the R181C mutant is properly delivered to the cell surface but the mutation interferes with high affinity vasopressin binding. Impaired ligand binding is reflected in an about 100-fold shift of the concentration-response curve toward higher vasopressin concentrations with only slightly reduced agonist potency.

Amino Acid Sequence↗
PubMed1998

Dosing of MMF in combination with tacrolimus for steroid-resistant vascular rejection in pediatric renal allografts.

Steroid-resistant vascular rejection was treated in seven adolescent renal allograft recipients using the combination of mycophenolate mofetil (MMF) and tacrolimus (FK506). Since there are no published pediatric dose recommendations for MMF using this combination, trough concentrations and pharmacokinetic profiles were used for therapeutic drug monitoring. In order to keep the mycophenolic acid (MPA) concentrations between 2-5 micrograms/ml, mean MMF doses were reduced from 600 to 250 mg/m2 b.i.d. Apparent clearance of MPA decreased from 5 to 1 ml/min per kg within 2 weeks. Pharmacokinetic monitoring revealed substantial variability among patients of both MMF and FK506. The MPA dose ranged from 178 to 1008 mg/m2 per day to achieve an area under the curve (AUC) of 59.9 micrograms x h/ml +/- 10.5 SD (range 49-65 micrograms). FK506 dose ranged from 1.3 to 8.8 mg/m2 per day to achieve an AUC of 116 ng x h/ml +/- 27 SD (range 83-145). We recommend adjusting MMF doses using therapeutic drug monitoring.

Adolescent↗
PubMed1998

Slowly deteriorating insulin secretion and C-peptide production characterizes diabetes mellitus in infantile cystinosis.

UNLABELLED: Infantile cystinosis, a rare lysosomal storage disease of cystine, leads to Fanconi syndrome and end-stage renal failure. After renal transplantation, no recurrence of the disease occurs in the graft, but other organ involvement becomes evident later in life. Diabetes mellitus has been associated with cystinosis, but the mechanisms of impaired glucose tolerance have not yet been characterized. Here, we studied glucose tolerance, glucose constant decay (k-values), insulin and C-peptide by intravenous glucose tolerance test (IVGTT) in eight patients with infantile cystinosis (three with impaired GFR (CRF) and five after kidney transplantation (KTX)). For comparison, 15 age-matched children with CRF and 15 age-matched KTX patients were analysed. Both early and second insulin secretion phases were diminished in patients with infantile cystinosis, whereas in CRF, k-values were no different from control patients. After renal transplantation, k-values were significantly lower in cystinotic patients with a markedly reduced early insulin secretion phase. There was a significant negative correlation between k-values and age in patients with cystinosis. Repetitive IVGTTs in these patients demonstrated progressive but rather slow loss of first phase insulin secretion and C-peptide production, suggesting a slowly reducing secretion potential of the beta cell due to cystine storage. CONCLUSION: Unlike type I diabetes mellitus, glucose intolerance in patients with infantile cystinosis is characterized by a slow, progressive loss of insulin secretion and C-peptide production. For these patients, the data indicate a 50% risk of developing glucose intolerance by the age of 18 years. We recommend to perform intravenous glucose tolerance tests at 5-year intervals.

Adolescent↗
PubMed1998

Prophylactic oral ganciclovir after renal transplantation-dosing and pharmacokinetics.

Ganciclovir alone or in combination with hyperimmunoglobulin is replacing other treatment modalities for the prophylactic treatment of cytomegalovirus (CMV) infections. No dose recommendations are available for oral ganciclovir therapy in children with impaired renal function after renal transplantation of a kidney from a CMV IgG-positive donor. We undertook a pharmacokinetic study in 14 pediatric renal transplant recipients who were CMV IgG negative and had received a graft from a CMV IgG-positive donor. We estimated the daily dosage of oral ganciclovir in relation to the glomerular filtration rate (GFR). Oral ganciclovir was administered at a starting dose of 3 x 1 g for children with a weight above 50 kg, 3 x 750 mg for children between 50 and 37.5 kg, and 3 x 500 mg for children between 37.5 and 24 kg. The starting dose was reduced by 50% for GFR values < or = 50 ml/min per 1.73 m2 and by 75% for GFR values < or = 25 ml/min per 1.73 m2. The daily dose was divided into three daily doses unless GFR was < 40 ml/ min per 1.73 m2, when only two daily doses were given. Doses were adjusted according to the measured plasma trough concentrations (c) using the simple formula: c(ganciclovir)(measured)/c(ganciclovir)(desired) = dosage rate(used)/dosage rate(adjusted). Mean stable plasma trough concentration was 0.91 +/- 0.68 microg/ml. The dosage rate, adjusted to a trough concentration of 1.0 microg/ml, correlated with the GFR. The dose per day could be calculated according to a simple equation for a GFR < 100 ml/min per 1.73 m2: dosage per day (mg/kg per day) = GFR. No CMV disease developed in any of the patients during oral ganciclovir, but 1 patient developed an acute rejection episode and a positive pp65 antigen 5 weeks after discontinuation of ganciclovir. The drug was well tolerated and without side effects.

Administration, Oral↗
PubMed1998

Reversible diabetes mellitus during growth hormone therapy in chronic renal failure.

A 12-year-old girl with short stature due to idiopathic Fanconi syndrome and chronic renal failure was treated with recombinant human growth hormone (rhGH). There was no family history of diabetes mellitus and the glucose tolerance before treatment was normal. Intravenous glucose tolerance tests were performed before, during and after treatment. Two months after starting rhGH the early phase of insulin secretion (1-+3-min values) was diminished, and the patient developed manifest diabetes mellitus with hyperglycemia and an elevated hemoglobin A1c. Following discontinuation of rhGH, glucose tolerance slowly returned to normal.

Child↗
PubMed1998

Glucose tolerance and insulin secretion in children before and during recombinant growth hormone treatment.

This study evaluates glucose metabolism and insulin secretion in children with Ullrich-Turner syndrome (UTS), chronic renal failure (CRF) and kidney transplantation (KTx) with rh GH therapy using an intravenous glucose infusion test. Before treatment, glucose AUC was significantly increased in all patient groups when compared to normal controls. Both the early and second phases of insulin secretion were not altered. During treatment, elevated glucose AUC showed a further increase in patients with KTx but not in patients with CRF or UTS. Both the early and second insulin secretion phases rose significantly in UTS and were transiently elevated after 6 and 12 months of therapy in patients with CRF and KTx. We conclude that growth hormone therapy aggravates alteration of glucose metabolism in patients with KTx and not in children with CRF and UTS. Progressive hyperinsulinemia occurred only in patients with UTS.

Adolescent↗
PubMed1997

Pharmacokinetics of tacrolimus (FK 506) in children and adolescents with renal transplants.

BACKGROUND: Only few data exist on pharmacokinetics of tacrolimus in children. PATIENTS: In 1995 and 1996, 14 children (mean age 13 years, range 5-23 years) received tacrolimus after renal transplantation; 10 of these after biopsy-proven steroid-resistant rejection (2 with vascular rejection), two for cyclosporin A (CsA)-induced severe nephrotoxicity, one for untreatable gingival hyperplasia on CsA, and one child was treated primarily after transplantation because of severe liver involvement in nephronophthisis. Pharmacokinetic investigations were performed after establishing a stable maintenance dose with trough levels in the desired window of 5-12 ng/ml. RESULTS: Mean follow-up time was 6 months (range 3-25 months). Eleven patients are still on tacrolimus. Two were discontinued because of severe aggravation of chronic persistent hepatitis C (one of them also developed diabetes mellitus), and one patient was subsequently switched to conventional immunosuppression because of tacrolimus-associated nephrotoxicity. All tacrolimus levels were measured by a modified assay (MEIA, Tacrolimus, Abbott) with improved sensitivity. At the time of switch, median serum creatinine was 234 +/- 82 mumol/l and 6 months after switch 201 +/- 99 mumol/l. All grafts are still functioning. Mean FK-506 dose was 0.16 mg/kg body weight/day (range 0.036-0.30 mg/kg). Mean trough level was 7.1 +/- 2.6 ng/ml in the morning and 6.5 +/- 2.0 ng/ml in the evening. Median time of maximum concentration (tmax) was 120 min after application, and the mean maximum concentration (Cmax) was 15.2 +/- 6.7 ng/ml. Mean area under the curve (AUC) was 104 +/- 33 ng* h/ml, with a range from 65 yo 169 ng* h/ml. No patient had unsatisfactorily low trough levels during the study. There was only a weak but significant (P < 0.05) correlation between dose per kg body weight and AUC and, as expected, an excellent correlation (r2 = 0.73, P < 0.001) between AUC and trough level. CONCLUSION: Because of interindividual variation between patients, therapeutic drug monitoring of tacrolimus is mandatory. In this study, a daily dose of 0.15 mg/kg was sufficient in most patients. We recommend the performance of at least one pharmacokinetic study after establishing stable FK 506 trough levels to ascertain a safe profile.

Adolescent↗
PubMed1997

Renal transplantation from donors aged < 6 years into children yields equal graft survival when compared to older donors.

Several articles have shown inferior renal allograft survival in patients receiving kidneys from young cadaver donors. We therefore assessed the survival and function of the first cadaveric graft from donors aged under 6 years of age, transplanted after 1983. The results were compared with the outcome of children receiving kidneys from older donors. Graft survival and serum creatinine were analyzed retrospectively at various time intervals after first cadaveric transplantation in 35 pediatric recipients of renal transplants grafted between 1983 and 1996 from donors < 6 years of age. Their data were compared with those of 167 pediatric recipients of renal transplants grafted from older donors. The proportion of young donors remained constant throughout the observation period. Mean recipient age was 10.4 years (range 3.2-17.5 years) in the patients grafted from donors < 6 years of age, not much different from the mean age of the donors in the 6+ years group (12.5 years, range 2.3-18.6 years). Five-year patient survival did not differ between the two groups (89 vs. 90%). In 1983-1996, graft survival rate of kidneys from donors aged < 6 years after one year was 77% (donors aged 6+ years=76%), after 2 years 66% (donors aged 6+ years=68%), after 3 years 62% (donors aged 6+ years=66%), and after 5 years 55% (donors aged 6+ years=60%, n.s., Log-rank test). In 1994-1996, 2-year graft survival was 88% (controls 91%, n.s.). In children receiving a cadaveric graft from a donor aged < 6 years, mean serum creatinine fell from 132+/-101 (SD) micromol/l after 3 months to 101+/-66 micromol/l after 12 months, and was 110+/-52 micromol/l after 5 years. This compared with a serum creatinine of 131+/-108 micromol/l after 3 months, 132+/-97 micromol/l after 12 months and 143+/-81 micromol/l after 5 years in children receiving grafts from older donors. When transplanting renal allografts from young donors into children, there was no significant difference in graft survival between donors aged < 6 years and older donors or in graft function. We conclude that good results from young donors can be obtained in a specialized center, and therefore the restriction of kidney selection to donors aged > 6 years may not be justified.

Adolescent↗