Comparison of cyclosporine absorption profiles over a 12-month period in stable pediatric renal transplant recipients.

Evidence suggests that the pharmacokinetic (PK) profile of microemulsion- cyclosporine A (m-CsA) during the 4-hour absorption phase represents an accurate tool to estimate drug exposure. In addition, several reports suggest a close correlation between selected single CsA concentrations at 1, 2, or 3 hours post-dose (C(1), C(2), and C(3)) and the abbreviated area under the curve (AUC)(0-4) among pediatric renal transplant patients. However, it is still unclear whether these PK correlations remain stable and reliable over 12 months posttransplant. In this study, we obtained 4-hour pharmacokinetic profiles (AUC(0-4)) from stable pediatric renal transplant recipients (phase 1) with repeat measurements 12 months later (phase 2). In addition, we evaluated the optimal single sampling point that correlated with the AUC(0-4) during both phases of the study. Over 1 year there was no significant change in the AUC(0-4) of m-CsA in pediatric renal transplant recipients. The mean dose-normalized AUC(0-4) values changed by less than 2.5%, namely, 557 versus 545 ng x h/mL per unit dose, respectively. The C(1) value was the sampling point that showed the best correlation with AUC(0-4); C(0) displayed the weakest correlation. No changes in cyclosporine dosing or glomerular filtration rate estimates were observed throughout the study period. This study demonstrates the stability of drug measurements during m-CsA therapy.

Course of glomerular filtration rate after renal transplantation and the influence of hypertension.

INTRODUCTION: A gradual decline in the glomerular filtration rate (GFR) is a general problem in patients after renal transplantation that may be due to several factors. METHODS: The glomerular filtration rate (GFR) was estimated using the corrected Schwartz formula in 16 pediatric renal transplant recipients over a period of 5 years post-transplant. Several potential risk factors for graft outcome were analyzed. The mean age of the patients (8 female, 8 male) at the time of transplantation was 11.1 years (range: 2.7-17.3). All patients received a cadaveric renal graft for the first time. Immunosuppression consisted of cyclosporine in combination with steroids in all children treated; 3 patients received azathioprine in addition. Blood pressure (BP) was monitored regularly and its extent was expressed by an antihypertensive treatment (AHT) score. RESULTS: At the end of the first post-transplant year the mean GFR was 88 +/- 24 ml/min/1.73 m2. During the following 4 years the GFR declined to 68 +/- 29 ml/min/1.73 m2 representing an overall GFR loss of 20 ml/min/1.73 m2 (23%). With regard to the GFR loss, 2 groups could be distinguished. The first group of 7 patients showed a significant GFR decrease from 89 +/- 26 to 49 +/- 27 ml/min/1.73 m2 (p = 0.0025), whereas the second group of 9 patients had a relatively constant GFR during the 5 years (87 +/- 26 and 83 +/- 24 ml/min/1.73 m2). In each group, two acute rejections were observed in the first post-transplant year. Blood pressure, expressed by an AHT score, increased in Group 1 moresso than in Group 2 during the 5 years. CONCLUSION: During the course of a 5-year period post-transplant the GFR declined significantly in 7 of 16 patients. One of the factors responsible for GFR loss is probably the increase in blood pressure.

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.

Candidosis of the urinary tract with padding phenomenon of the renal pelvises in an infant with obstructive uropathy.

A male infant with obstructive uropathy developed yeast cell agglomerations which were detectable macroscopically and by image-generating techniques within both renal pelvises after Candida albicans infection of the urinary tract. Therapy with flucytosine induced excretion of 'fungal balls' via the urethra. Continuation of therapy with liposomal amphotericin B (AmBisome) prevented a relapse after development of fungal resistance against flucytosine. Sonographically or radiographically detectable formation of 'concrements' within the urinary tract of patients with an immature or compromised immune system and additional features such as obstructive urinary tract should suggest a localized or systemic mycosis, particularly in the context of long-term antibiotic treatment.

Response to sodium benzoate treatment in non-ketotic hyperglycinaemia.

Therapy with benzoic acid in a case of classic neonatal non-ketotic hyperglycinaemia (NKH) was successful in stopping seizures but not in promoting mental development. Serum glycine levels were normalizable even by administering low doses of 53 mg sodium benzoate/kg body mass (BM) per day. Despite giving a higher dosage (240 mg/kg BM per day) normalization of glycine concentration in cerebrospinal fluid (CSF) was not achieved. However, seizures ceased. Restriction of protein intake (< or = 2 g/kg BM per day) seemed to be profitable. CSF glycine concentrations below 100 mumol/L may be sufficient to prevent seizures in older infants who have adapted to neuronal glycine exposure. No toxicity of sodium benzoate treatment was detected when administering doses of up to 470 mg/kg BM per day but side effects such as itching and hyperactivity were obvious.

Blue rubber-bleb-nevus syndrome with predominant urinary bladder hemangiomatosis.

In a 2-year-old girl a blue rubber-bleb-nevus syndrome is described. Apart from cutaneous hemangiomas, pronounced hemangiomas of the urinary bladder were diagnosed and treated by laser surgery. The features of the disorder are discussed as a special clinical condition within the framework of this syndrome.

[Use and efficacy of extracorporeal detoxication procedures in poisoning in children]. / Einsatz und Effizienz extrakorporaler Detoxikationsverfahren bei Vergiftungen im Kindesalter.

We could demonstrate the possibilities and limitations of the extracorporal detoxications by accidental poisonings in children. The effective use of hemodialysis, hemoperfusion, and plasmapheresis in poisonings during childhood under special consideration of the parameters such as molecular weights, half time rate, proteinbinding, distribution volume, pattern of solubility, and metabolism is shown and critically discussed.

[The significance of erythrocyte morphology for the differential diagnosis of hematuria]. / Bedeutung der Erythrozytenmorphologie für die Differentialdiagnostik der Hämaturie.

Since 1984 we have investigated urine specimens of 129 patients by means of phase contrast microscopy. 51% of the children have an isomorphic, 43% a dysmorphic and 6% a mixed erythrocyturia. We have found a good correlation between dysmorphic erythrocyturia and glomerular diseases and between isomorphic erythrocyturia and nonglomerular changes. In 4.6% there were a discrepancy between the urinary findings and the diagnoses. Phase contrast microscopy is an advantage for diagnostics of hematuria provided that it will be done repeatedly.

[A protein restricted diet in conservative therapy of chronic renal failure in children]. / Proteinrestriktive Diät in der konservativen Therapie chronisch niereninsuffizienter Kinder.

A report about different kinds of protein restricted diet in conservative treatment of 10 children with renal failure in relation to determined parameter in blood serum and to the development of growth is given in this study. Protein restricted diet with supplementation of essential aminoacids or its ketoanalogues presents a favourable influence to the level of urea in serum and to the development of growth. Recommendations will be given for the praxis of protein restriction, especially in childhood.

[Metabolic changes in bones and modification of growth in children with chronic renal failure, dialyzed and with kidney transplant]. / Stoffwechselstörungen der Knochen und Wachstumsbeeinflussung chronisch niereninsuffizienter, dialysierter und transplantierter Kinder.

Forty to fifty percent of the children with chronic renal insufficiency show a growth retardation. The cause of this disorder is supposed on the cellular level of the target organ bone. Objective prospective studies on the growth characteristics of children with chronic renal insufficiency after dialysis and transplantation, respectively, are necessary in consideration of the internal milieu and external influences.

15N tracer kinetic investigations on the protein metabolism in a child with chronic renal failure fed a protein-restricted diet.

Administration of EAA and KA in patients with CRF on a protein-restricted diet led to a favourable influence on the plasma protein turnover. This was demonstrated by an increase in the half-life and a decrease in the breakdown rate of plasma proteins measured by the 15N tracer technique.

[15N-tracer kinetic studies on the utilization of urea in protein metabolism of infants]. / 15N-tracerkinetische Studien zur Utilisation des Harnstoffs im Eiweissstoffwechsel des Säuglings.

The virtual importance of the urea circuit is not clear. After a 3 to 21 day application of 100 mg [15N]-urea/l in 15 infants a [15N]-excess value of 0.06 in serum protein could be proven. Taking as a basis a protein content of 11.4% of the body mass and a regular distribution of the [15N] within the body one can calculate a retention of the urea nitrogen in the protein pool of 40.4% of the intake. Taking in account an amount of 11.4% urea nitrogen from the total nitrogen in mother's milk then the amount of urea nitrogen from the net protein accumulation comes to 6.5 (3.1-11.8)%.

[In vitro studies on microbial incorporation of nitrogen from [15N2] urea and [15N]ammonium chloride by human intestinal flora]. / In-vitro-Untersuchungen zur mikrobiellen Inkorporation von Stickstoff aus [15N2]Harnstoff und [15N2]Ammoniumchlorid durch die Intestinalflora des Menschen.

6 typical bacteria species of the human intestinal flora (E. coli, Klebsiella pneumoniae, Proteus vulgaris, Streptococcus faecalis, Bacteroides fragilis, Bifidobacterium sp.) were incubated in a liquid medium for 48 h with [15N2]-urea and [15N]-ammonium chloride. The rates of [15N]-incorporation were calculated. They depend reproducible on the species examined, on the kind of the offered NPN-substance and on the amount of NPN-substance in the medium. With [15N2]-urea the minimal rate of incorporation was 3.8% (E coli) and the maximal one 95.6% (Bifidobacterium sp.). With [15N]-ammonium chloride the corresponding figures were 31.0 (Proteus vulg.) and 98.0% (Bifidobacterium sp.). The findings are discussed with regard to a possible enteral detoxification in uremic patients by bacterial utilization and elimination of urea and ammonia.

Urea utilization by the intestinal flora, of infants fed mother's milk and a formula diet, as measured with the 15N-tracer technique.

15N-Incorporation by intestinal bacteria was measured under different feeding conditions in 16 infants after a single oral loading of 165 mg [15N2]urea X kg-1 body weight as a tracer. In five subjects on a mother's milk diet, the 15N-excess in the isolated intestinal bacteria was 1.08 (0.17-1.85) atom-%. The mean 15N-excess in the intestinal flora of five formula-fed subjects did not differ significantly from these values [0.63 (0.17-1.05) atom-%]. A trend to a higher incorporation of 15N from labeled urea by the intestinal flora was seen in four infants, who were adapted to an increased nutritional urea supply on a special formula, containing 14 g of milk protein, 80 g lactose, 36 g fat, and 0.35 g urea X L-1. The same observation was made in two infants with chronic renal failure. The incorporation of urea nitrogen by the putrefactive intestinal flora of infants on a formula diet as well as by the bifidobacterial flora of those on mother's milk feeding indicates the utilization of ureas as a source of bacterial protein and nucleic acid synthesis. The adaptive usage of urea for the bacterial metabolism can be considered as a sign of supportive detoxification by the intestinal flora.