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Biomedical subjects

G Filler

Publications and source records attributed to G Filler.

At least 19 recordsLinked to original sources
PubMed2006

Prevalence of complications in children with chronic kidney disease according to KDOQI.

The Kidney Disease Outcome and Quality Initiative (KDOQI) Group recommended guidelines for the monitoring and treatment of chronic kidney disease (CKD) in 2002. These recommendations were based on the prevalence of known complications as seen in adults. In children, the exact prevalence of these complications is unknown. We therefore conducted a cross-sectional study of 366 patients with CKD in a single center to analyze the prevalence of these complications across all stages of kidney disease. Patients were categorized to their KDOQI stage of CKD according to their estimated renal function as determined from serum cystatin C. Fifty seven percent of patients had CKD stage 1, 29.0% stage 2, 10.4% stage 3 and 4.1% stages 4+5. Uropathies (31%) were the most prevalent causes of CKD. Glomerular disease accounted for 27%. The overall prevalence of complications was as follows: hypertension 70.2%, anemia 36.6%, proteinuria 11.5%, and metabolic bone disease 16.9%. Metabolic bone disease and anemia occurred frequently, even with a glomerular filtration rate >60 ml/min/1.73 m2. Growth failure (11.5%) was also common and is not a component of the KDOQI guidelines for CKD in children. The prevalence of all complications increased with worsening stage of kidney disease (all P-values significant). In summary, this study supports the KDOQI guidelines in defining and staging CKD in children. This study also highlights the differences in the causes and complications that occur in CKD between adults and pediatrics. We recommend modification of the KDOQI guidelines for children to reflect the differences described in this paper.

Acidosis↗
PubMed2006

Value of therapeutic drug monitoring of MMF therapy in pediatric transplantation.

Therapeutic drug monitoring (TDM) is desirable whenever the desired drug effect cannot be predicted from a given dose, or when it is necessary to find a balance between the efficacy and toxicity of the drug. Children and adolescents particularly benefit from TDM, because dosing requirements are often not studied in the same detail as in adults. Also, drug-drug interactions are frequent. The gold standard for assessment of drug exposure is the area-under-the-curve (AUC) for a full pharmacokinetic profile. TDM for mycophenolic acid (MPA) is less well established. Monitoring of trough levels does not suffice because of enterohepatic recirculation of MPA after formation of its main metabolite, a glucoronide termed MPA-G. However, abbreviated sampling schemes specific to mycophenolate mofetil (MMF) correlate well with the AUC for MPA. Cyclosporine interacts with MPA by inhibiting the multidrug resistance-associated protein 2 (MRP2). Higher MPA concentrations result in a decreased two h concentration of cyclosporine, while higher cyclosporine exposure results in a lower MPA exposure. There are no drug interactions between tacrolimus and MPA, and lower doses of MMF are required in combination with tacrolimus. Steroids may induce the clearance of MPA, which could account in part for the increasing MPA exposure following transplantation. TDM has allowed for dosing recommendations of MMF in children, which could lead to improved efficacy and minimization of toxicities. It is important that these provisional target levels are validated in prospective studies. The above points clearly indicate that there is a role for TDM of MPA in pediatric transplant recipients.

Adolescent↗
PubMed2004

Resolution of severe, adolescent-onset hypophosphatemic rickets following resection of an FGF-23-producing tumour of the distal ulna.

Oncogenic hypophosphatemic osteomalacia (OHO) is an uncommon hypophosphatemic syndrome characterized by bone pain, proximal muscle weakness and rickets. It has been postulated that OHO results from overproduction of a humoral phosphaturic factor by an occult tumour. Recently, some OHO tumours have been shown to elaborate fibroblast growth factor-23 (FGF-23), which causes renal phosphate wasting when administered to mice. The purpose of this study was to undertake detailed investigations to confirm the diagnosis of OHO in a pediatric patient and to document the biochemical, radiographic and bone histological phenotype before and after tumour removal. We describe an 11-year-old, previously healthy girl with significant pain and functional disability associated with hypophosphatemic rickets. Circulating 1,25-(OH)(2) vitamin D was very low (14 pM; N: 40-140) while the FGF-23 serum level was markedly elevated [359.5 reference units (RU)/ml, N: 33-105]. An iliac bone biopsy revealed severe osteomalacia, but periosteocytic lesions, as are typical for X-linked hypophosphatemic rickets, were not seen. Sequence analyses of the PHEX and FGF23 genes were normal. A radiographic skeletal survey revealed a small exostosis of the left, distal ulnar metaphysis. A tumour was subsequently removed from this site and the pathology was consistent with benign, fibro-osseous tissue. Serum FGF-23 was normal when measured at 7 h post-operatively, while serum phosphate reached the low-normal range at 16 days following surgery. An iliac bone biopsy taken 5 months after the operation showed improvement, but not yet resolution, of the osteomalacia. Biochemical parameters of bone and mineral metabolism suggested that complete resolution of the osteomalacia was not achieved until 12 months following surgery. One year after tumour removal, the patient was pain-free and had resumed a normal level of activity. The rapid normalization of FGF-23 levels following removal of a benign tumour and the subsequent improvement in the biochemical and histological parameters of bone and mineral metabolism suggest that FGF-23 played a key role in this girl's disease.

Base Sequence↗
PubMed2004

Age-dependency of mycophenolate mofetil dosing in combination with tacrolimus after pediatric renal transplantation.

BACKGROUND: Dosing of mycophenolate mofetil (MMF) must be lower in combination therapy with Tacrolimus (Tac) than with Cyclosporine. One study with mostly adolescent recipients recommended an MMF dose of 250 mg/m2 BID. Because this dose resulted in low area-under-the-curve (AUC) in our infant population, we retrospectively analyzed all available pharmacokinetic (PK) profiles in pediatric renal transplant patients on MMF plus Tac therapy to propose appropriate MMF dosing in pediatric patients of all ages. PATIENTS AND METHODS: Forty-four PK profiles were performed in 27 patients (median age, 11.6 years; range, 1.8-20.7 years). The investigations were performed at a median of 299 days (range, 24-3424) after transplantation. Ten patients were converted to Tac plus MMF, all others received this as primary therapy. For patients with repeated measurements, we calculated the average AUC and doses. We used first-order PK modeling to calculate the doses for a mycophenolic acid (MPA) AUC of 60 ug*h/mL and a Tac AUC of 150 ng*h/mL. RESULTS: The mean Tac dose was 2.6 +/- 1.2 mg/m2/d or 0.086 +/- 0.038 mg/kg/d, resulting in an average AUC of 120.6 +/- 30.4 ng*h/mL. The MMF dose was not normally distributed; the median dose was 549 mg/m2/d (range, 146-1413) and the median MPA AUC was 49.8 ug*h/mL (range, 26.7-156.0). The mean dose for a Tac AUC of 150 ng*h/mL was 3.50 +/- 1.77 mg/m2/d (0.117 +/- 0.058 mg/kg) and was independent of age or time after transplantation. By contrast, we found a negative relationship between the dose per m2 (r2 = 0.29; P = 0.0038) or per kg (r2 = 0.58; P < .0001) required for an MPA AUC of 60 ug*h/mL and patient age. Converted and primary patients behaved identically. The dosing requirement decreased from 500 mg/m2 BID in 2-year-old patients to 250 mg/m2 in adolescents. There was substantial interpatient variability of 44%. CONCLUSIONS: Higher MMF doses are required for young children. Our data suggest a starting dose for infants of 500 mg/m2 BID, with PK monitoring of MPA due to substantial interpatient variability.

Adolescent↗
PubMed2003

Tissue HHV6 and 7 determination in pediatric solid organ recipients--a pilot study.

Herpes virus infections remain a major challenge in solid organ transplantation. HHV6 and 7 blood viral load was associated with pathology after renal transplantation. Little is known about the significance of tissue HHV6 and 7 infections. A total of 18 tissue biopsies (13 kidney, three GI and two BAL) from nine pediatric transplant patients (five kidney, two liver, one combined liver and kidney and one bone marrow transplant) were subjected to blood HHV6 IgG and IgM testing. In addition, tissue HHV6 and 7 semi-quantitative PCR analysis with subsequent detection by ELISA and quantitative methods were applied to the same samples. We also studied four native kidney biopsies of children with other kidney disease. The results of the biopsies were correlated with clinical data. Of the transplant patients, 78% were HHV6 IgG positive. Six of nine had a positive IgM on at least one occasion, however, only two of nine transplant patients were symptomatic with a mixed CMV/EBV septic picture of multi-organ failure. Only these two patients had a significant tissue viral load for HHV6. Additionally, a very significant tissue viral load for HHV6 was detected in an immunocompromised patient 3 wk after a roseola-like febrile illness. The HHV6 copies were 31, 88 and 206 per 10 microL of DNA, respectively. In the patient who also had the fourth positive ELISA for HHV6 PCR product, the Multiplex PCR and restriction enzyme assay on its PCR product revealed a significant contribution by HHV7, while the HHV6-B signal was rather weak. Significant tissue HHV6 loads can be found in tissue biopsies from organ recipients with significant illness and also in native kidneys after primary infection. This may explain the high prevalence of HHV6 in transplanted kidneys. Further studies on HHV6 and 7 using molecular techniques should be supported.

Adolescent↗
PubMed2003

Early dialysis in a neonate with intrauterine lisinopril exposure.

In general, angiotensin converting enzyme (ACE) inhibitors should be discontinued in pregnancy, as they can induce an ACE fetopathy. For the treatment of the latter, early peritoneal dialysis is recommended for in utero exposure to captopril and enalapril, although the outcome is poor. Early peritoneal dialysis has not previously been reported for lisinopril induced multiorgan failure. A case is reported in which treatment was given on postnatal day 3. The patient recovered from oligoanuria to almost normal renal function, and heart, brain, and musculoskeletal injury was reversible. This is despite relatively poor clearance of the drug through peritoneal dialysis. Analysis of the pharmacokinetic data suggests that haemodialysis or haemofiltration would be more efficacious for removal of the drug, and these treatments should be performed if available.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2002

Universal approach to pharmacokinetic monitoring of immunosuppressive agents in children.

Current data indicate that pharmacokinetic (PK) monitoring of cyclosporin microemulsion (CsA) should be performed using the 2-h concentration (C2), that tacrolimus (Tac) is commonly monitored using the trough level, and mycophenolate mofetil (MMF) should be monitored using the 1-h (C1), 2-h (C2) and 6-h (C6) concentrations. The three differing time-point requirements are cumbersome, and we aimed to develop universal guidelines for all three drugs using a large number of full PK profiles in children. One-hundred and twenty two stable pediatric patients, receiving either CsA (165 PK profiles, 69 patients, 24 with concomitant MMF) or Tac (122 PK profiles, 53 patients, 18 with MMF) were analyzed retrospectively. Pearson r for the CsA C2 was 0.90 [95% confidence interval(CI): 0.86-0.92], for Tac C2 r was 0.86 (95% CI: 0.80-0.90), and for MPA C2 r was 0.77 (95% CI: 0.68-0.83), respectively. For MPA, at least three time-points are required to accurately estimate the area under the concentration-time curve (AUC), and C1, C2 and C6 serve as best markers. Excellent AUC estimations could be obtained from a limited sampling strategy from C1, C2 and C6 or C0, C1, C2 and C4 with clinically acceptable errors for all three drugs. The AUC can be estimated with great precision by using an identical approach for all three drugs. Target AUCs for a given time-point after transplantation remain to be established.

Adolescent↗
PubMed2001

Renin angiotensin system gene polymorphisms in pediatric renal transplant recipients.

Genetic variability in the renin angiotensin system may modify renal responses to injury and disease progression. We therefore examined whether the insertion/deletion polymorphism of the angiotensin-converting enzyme (ACE) gene, the Met235-->Thr polymorphism of the angiotensinogen (AGT) gene, and the A1166-->C polymorphism of the angiotensin II type 1 receptor gene (ATR1) were associated with disease progression and outcome after renal transplantation (Tx) in 100 Caucasian pediatric renal transplant recipients. The observed allele frequencies were: DD 31%, DI 41% and II 28%, for ACE; MM 42%, MT 37% and TT 21%, for the methionine (Met)235-->threonine (Thr) polymorphism of AGT; and AA 51%, AC 38% and CC 11%, for the adenine (A)1166-->cytosine (C) gene polymorphism. The slope of 1/creatinine was determined by linear regression analysis of a median of 12 points before and after renal Tx, and the population was divided in two equal groups, according to the slope, both before and after Tx. There were no statistically significant differences for AGT, ACE, and ATR1 polymorphisms with regard to the slope of 1/creatinine before renal Tx. After renal Tx, the ACE II genotype (p = 0.024, chi-square test) and the presence of the I allele (p=0.033, chi-square test) were associated with a favorable slope of 1/creatinine. There was no association of the AGT or the ATR1 polymorphism with outcome after renal Tx, and none of the genotypes were associated with hypertension before or after renal Tx. We suggest that the beneficial association of disease progression after renal Tx with the II genotype and/or the presence of the I allele in our pediatric cohort might be explained by a lower activity of the circulating ACE enzyme associated with the I allele.

Adolescent↗
PubMed2001

Effect of cyclosporine on mycophenolic acid area under the concentration-time curve in pediatric kidney transplant recipients.

Mycophenolic acid (MPA), the active compound of mycophenolate mofetil (MMF), shows substantial interindividual and intraindividual variability. It was recently shown that in vitro calcineurin inhibitors alter the bioavailability of MPA by dose-dependent inhibition of MPA glucuronidation. The authors retrospectively analyzed full 10-point profiles for both MPA and cyclosporine (CyA) in 23 pediatric patients receiving MMF and cyclosporine microemulsion (Neoral; Novartis Pharmaceuticals Canada; Dorval, Quebec, Canada). Mycophenolic acid was measured using a commercially available EMIT (Novartis Pharmaceuticals, Canada) assay. As the majority of patients were treated with low doses of cyclosporine after adding MMF, the area under the concentration-time curve (AUC) for cyclosporine showed a wide scatter ranging from 296 to 6400 ng x h/mL. The mean cyclosporine dose was 100 +/- 76 mg/m2 per day (range: 28 to 331). There was no correlation between MPA AUC and MPA dose, and there was substantial interindividual variation. However, there was a significant negative correlation between dose-normalized MPA AUC and cyclosporine AUC ( r2 = 0.23, p < 0.0220). When dividing the MPA profiles into two groups (11 and 12 patients) with a CyA AUC less than or greater than 1600 ng x h/mL, there was a significantly higher 8-hour concentration in the patients with the lower CyA AUC, secondary to a higher second peak. The data demonstrate that the cyclosporine AUC is a determining factor for the MPA AUC and that MPA dose should be reduced when cyclosporine dose is reduced to achieve the same MPA AUC. The significantly higher peak in the group with a lower CyA profile supports the concept of a dose-dependent cyclosporine-induced inhibition of MPA glucuronidation.

Adolescent↗
PubMed2001

Analysis of cognitive and motor functioning during pubertal development: a new approach.

We investigated cognitive-motor abilities in 303 (156 female) school children from Zagreb, Croatia, in the age span 10 to 14 years using a newly developed chronometrical reactionmeter system (CRD). The following tests were applied: CRD-311 (simple visual discrimination of signal location), CRD-324 (short-term memory actualisation), CRD-21 (simple convergent visual orientation), and CRD-11 (arithmetically conceptualised/operationalised convergent thinking). In both gender a statistically significant age related improvement of the performance for time related parameters (minimum time of test item solving (MT), total ballast (TB), and total time of test solving (TT) was observed. In contrast, the number of errors (NE), which was the only non-time related parameter tested, did not significantly change with age. Significant differences between boys and girls were observed for the time related parameters TB and MT. TB was significantly lower in girls, whereas boys tended to be faster in MT measurements. In TT as a composed measure of the mentioned parameters, no major differences were observed. We conclude that the CRD system is a new useful tool for investigating the complexity of cognitive-motor abilities in children. Our cross-sectional study demonstrated that the time-related parameters were significantly affected by age and gender during puberty.

Adolescent↗
PubMed2001

Acute renal failure in children: aetiology and management.

This review evaluates the various causes and management of acute renal failure (ARF) in children. ARF is defined as an abrupt decline in the renal regulation of water, electrolytes and acid-base balance, and continues to be an important factor contributing to the morbidity and mortality of critically ill infants and children. The common causes of ARF in children include acute tubular necrosis secondary to various causes (including congestive heart failure and sepsis), haemolytic uremic syndrome, and glomerulonephritis and urinary tract obstruction. Ischaemia, toxins (including drugs) as well as primary parenchymal disease, have to be considered and ARF can also be a complication of systemic disease. The basic principles of management are avoidance of life-threatening complications, maintenance of fluid and electrolyte balance, and nutritional support. Only a few patients require specific management of the underlying disorder, although it is important to diagnose these conditions. Knowledge about the use of drugs for the prevention of ARF is scarce. Mannitol, low-dose dopamine, calcium channel antagonists, atrial natriuretic peptide and albumin have been evaluated and, where possible, meta-analyses are cited. Mannitol treatment appears to be warranted prophylactically after paediatric renal transplantation. Albumin infusion can reverse prerenal ARF in children with nephritic syndrome. For treatment of the complications of hyperkalaemia and volume overload, salbutamol, insulin and glucose infusion and diuretics such as furosemide and sodium bicarbonate, are discussed. All of the major dialysis modalities (peritoneal dialysis, haemodialysis and continuous haemofiltration) can be used to provide equivalent solute clearance and ultrafiltration. The indication for, and the choice of the modality depend on the patient requirements and on local resources, and should involve the care of a paediatric nephrologist. Peritoneal dialysis requires minimal equipment and infrastructure, is easy to perform and remains the favoured modality of renal replacement therapy in children. However, continuous haemofiltration is an excellent alternative to peritoneal dialysis in patients with ARF and severe fluid overload. Dialysis remains the most important tool to bridge the time needed for recovery of renal function. There is increasing evidence that more intense use of dialysis may improve the overall prognosis.

Acute Kidney Injury↗