Biomedical subjects

Udo Vester

Publications and source records attributed to Udo Vester.

17 recordsLinked to original sources

PubMed2006

Decreased systemic bioavailability of L-arginine in patients with cystic fibrosis.

BACKGROUND: L-arginine is the common substrate for nitric oxide synthases and arginases. Increased arginase levels in the blood of patients with cystic fibrosis may result in L-arginine deficiency and thereby contribute to low airway nitric oxide formation and impaired pulmonary function. METHODS: Plasma amino acid and arginase levels were studied in ten patients with cystic fibrosis before and after 14 days of antibiotic treatment for pulmonary exacerbation. Patients were compared to ten healthy non-smoking controls. RESULTS: Systemic arginase levels measured by ELISA were significantly increased in cystic fibrosis with exacerbation compared to controls (17.3 +/- 12.0 vs. 4.3 +/- 3.4 ng/ml, p < 0.02). Arginase levels normalized with antibiotic treatment. Plasma L-arginine was significantly reduced before (p < 0.05) but not after treatment. In contrast, L-ornithine, proline, and glutamic acid, all downstream products of arginase activity, were normal before, but significantly increased after antibiotic therapy. Bioavailability of L-arginine was significantly reduced in cystic fibrosis before and after exacerbation (p < 0.05, respectively). CONCLUSION: These observations provide further evidence for a disturbed balance between the L-arginine metabolic pathways in cystic fibrosis.

Journal Article↗

PubMed2006

Oedema with proteinuria in Gambian children--a descriptive study.

The clinical syndrome of oedema with proteinuria is an important cause of paediatric morbidity in sub-Saharan Africa. The aim of this study was to assess its prevalence, clinical presentation and outcome in The Gambia, where the syndrome is perceived to be common but has not previously been studied. All children admitted with oedema and proteinuria to three hospitals in the Western region of The Gambia between January 1995 and June 1998 were identified retrospectively. Hospital records were retrieved to assess admission characteristics. All traceable children were clinically reviewed, and urinalysis was performed between 3 months and 4 years after admission. Two hundred and two children who presented with proteinuria and oedema were identified, accounting for 1.2% of paediatric hospital admissions in The Gambia. Haematuria on dipstick testing was common (76.5%). Of 39 children who were traced, four (10.3%) were dead. Eighteen of the remaining 35 (51.4%) had proteinuria at follow up. Older age at first presentation was significantly associated with increased long-term morbidity. These preliminary data suggest that oedema with proteinuria may be common and could cause long-term morbidity and mortality in Gambian children. Further studies on its aetiology and treatment are warranted.

Adolescent↗

PubMed2006

Antiviral treatment of chronic hepatitis B with lamivudine in pediatric renal transplantation.

Renal transplantation in patients with chronic hepatitis B virus (HBV) infection is known to be associated with an increased risk for exacerbation of liver dysfunction. Lamivudine has been proven to be a potent inhibitor of hepatitis B virus replication in adults after kidney transplantation. Little is known about its efficacy and safety in pediatric renal transplant recipients. Three cases serve for the discussion to demonstrate the complexity of the clinical course and effective treatment of chronic hepatitis B in pediatric patients awaiting renal transplantation. Two patients on dialysis with a high HBV replication rate were treated with lamivudine before transplantation. After the viral load had decreased below the detection limit, they underwent transplantation successfully. Despite intensified immunosuppression to treat a rejection episode in one and a relapse of the nephrotic syndrome in the other patient, the viral load remained <2.5 pg/mL. Both patients developed a mutation in the YMDD motif of the HBV genome associated with an increase in the HBV replication rate >10,000 pg/mL without deterioration of the liver function. In a third patient with a chronic HBV infection with a low replication rate, lamivudine was started about nine months after kidney transplantation due to an increasing viral load after treatment of an acute rejection episode. Six months later, the HBV DNA was no longer detectable. The patient had no signs of liver dysfunction. Lamivudine in the treatment of chronic HBV infection in pediatric renal recipients seems to be safe and effective in preventing acute liver deterioration. Three clinical cases are discussed with regard to current options in monitoring and antiviral treatment of chronic HBV in pediatric renal transplant recipients.

Adolescent↗

PubMed2006

Outcome after kidney transplantation in children with thrombotic risk factors.

BACKGROUND: According to the data from the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS), vascular thrombosis accounts for 11.6% of graft losses in pediatric renal transplantation. In adults, inherited and acquired thrombophilic risk factors, e.g. factor V Leiden mutation, have been associated with early graft loss and increased rejection episodes. Data on the impact of these factors on the outcome of children after renal transplantation are rare. METHODS/PATIENTS: Sixty-six pediatric patients awaiting renal transplantation (mean age 10.1 yr) were screened for inherited and acquired risk factors for hypercoagulable disorders (protein C, S, and antithrombin III deficiency, antiphospholipid antibodies, factor V Leiden, prothrombin, and MTHFR mutation) in order to intensify anticoagulation in those with an increased risk for thrombophilia: intravenous heparin was administered with a partial prothrombin time (PTT) prolongation of 50 s for 14 days and switched to low-molecular-weight heparin for another 8 wk before aspirin was introduced for the first year. Patients without hypercoagulable risk factors were treated with heparin without PTT prolongation for 14 days and switched to aspirin immediately afterwards. The results on graft survival, incidence of acute rejection episodes, and long-term renal graft function were analyzed between recipients with and without hypercoagulable risk factors. RESULTS: Thrombophilic risk factors were identified in 27.3% of our patients. No thrombosis occurred. One serious bleeding complication led to a second surgical intervention. The rate of acute rejection episodes was not increased in patients with and without thrombotic risk factors after 90 days (16.7 vs. 25%), 1 yr (22.2 vs. 33.3%), and 3 yr (38.9 vs. 41.7%) of follow-up, respectively (p = n.s.). After a mean follow-up of 3 yr the kidney function was comparable in both groups, with 63.1 in recipients with and 69.8 mL/min/1.73 m(2) in recipients without hypercoagulable risk (p = n.s.). At latest follow-up, three graft losses were found not to be attributed to thrombotic risk factors. INTERPRETATION: Children with thrombophilic risk factors were identified and treated with an intensified anticoagulation regimen after renal transplantation. An increased risk for graft failure, acute rejection episodes, or impaired renal function for pediatric renal transplant recipients with hypercoagulable status was not found.

Anticoagulants↗

PubMed2005

Sirolimus rescue of renal failure in children after combined liver-kidney transplantation.

BACKGROUND: Calcineurin inhibitors (CNI) are the main immunosuppressive drugs in solid organ transplantation. However, their use is hampered by side effects like nephrotoxicity. We report an exceptional experience with three children treated with sirolimus after combined liver and kidney transplantation with prolonged renal failure and CNI-associated nephrotoxicity. PATIENTS AND RESULTS: Two girls experienced prolonged renal graft failure after combined liver-kidney transplantation for 11 and 12 weeks. Repeated biopsies did not show any rejection but did exhibit tubular damage and acute CNI-toxicity. A boy with hyperoxaluria after liver and (a third) renal transplantation experienced acute renal graft failure after an early steroid-resistant rejection. All children were switched to sirolimus-based immunosuppression and cessation of CNI therapy, which was followed by rapid improvement of renal function. Rejection of liver or kidney did not occur after CNI withdrawal. Sirolimus was commenced with 3 mg/m2/day in two doses and resulted in reasonable drug exposure. However, drug monitoring was required to adjust sirolimus dosage. SUMMARY: Prolonged renal failure after transplantation with severe CNI toxicity may be salvaged successfully with sirolimus-based immunosuppression.

Acute Disease↗

PubMed2005

The response to cyclophosphamide in steroid-sensitive nephrotic syndrome is influenced by polymorphic expression of glutathion-S-transferases-M1 and -P1.

Glutathione-S-transferases (GST) play a central role in the inactivation of toxic drugs like cyclophosphamide (CP). These enzymes depict several polymorphisms with altered activity, and it has been shown that different polymorphisms influence the risk of malignancies and the outcome after chemotherapy. To prove the hypothesis that CP efficacy in children with nephrotic syndrome is influenced by polymorphic expression of GSTs, the genotype of 26 patients was analyzed and correlated with the outcome after CP treatment. All 26 children with steroid-sensitive nephrotic syndrome and frequent relapses or steroid dependency were treated with CP at a mean age of 6.7+/-4.0 years. CP was given in a dose of 2 mg/kg/day for 12+/-1 week. GST-M1, GST-P1 and GST-T1 polymorphisms were detected by PCR. In patients with GST-M1 null polymorphism, a significantly better rate of sustained remission was seen than in patients with the heterozygous or homozygous GST-M1 wildtype (0 versus 29%, P <0.01). In contrast, children with GST-P heterozygous or homozygous polymorphism had a significantly lower rate of sustained remission compared to homozygous wildtype (7 versus 38%, P <0.02). The GST-T1 genotype did not influence the outcome after CP treatment (P =0.32). Patients with the combination of GST-M1 null and GST-P1 wildtype did not relapse in 50%, compared to 6% in other children (P <0.01). We conclude that the polymorphic expression of GST-M1 and -P1 did significantly influence the long-term remission rate after CP treatment of steroid-sensitive nephrotic syndrome in children. Whereas GST-M1 null will increase cyclophosphamide efficacy, GST-P1 polymorphism seems to be related to enhanced susceptibility to further relapses.

Adolescent↗

PubMed2005

Removal of metabolites, cytokines and hepatic growth factors by extracorporeal liver support in children.

BACKGROUND: Molecular Adsorbents Recirculating System (MARS)-mini has recently been approved and applied in children with hepatic failure. However, its indication, efficacy and capability to induce liver regeneration remain unclear. The aim of our pilot study in children was to analyse the impact of MARS on markers of detoxification and regeneration. METHODS: In children with fulminant Wilson's disease and bridged with MARSmini for liver transplantation, we analyzed toxic metabolites (bile acids, bilirubin, lactate, ammonia, tryptophan and copper), regulators of the inflammatory cascade [nitrate, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), methionine, cystine and hyaluronic acid] and hepatic growth factors [hepatocyte growth factor (HGF), epidermal growth factor (EGF), transforming growth factor-beta1 (TGF-beta1), cortisol, corticosteroid-binding globulin (CBG), insulin-like growth factor-1 (IGF-1), angiogenin, vascular endothelial growth factor (VEGF), IL-6 and TNF-alpha] from blood, albumin circuit and haemodialysate from four applications. RESULTS: In all four applications, transfer of toxic metabolites (6/6) and inflammatory mediators (6/6), but also of hepatic growth factors (9/10), into the albumin circuit of MARS was consistently detected. Corresponding blood levels were decreased for 3/6 metabolites, 3/6 inflammatory mediators and 1/10 growth factors and increased for 1/10 growth factors. Bridging for liver transplantation was successful with MARS. CONCLUSIONS: In our prospective study, substantial extraction of albumin-bound and water-soluble candidate substances was detected with variable effect on respective blood levels. Notably, essential factors inducing liver regeneration were simultaneously removed. These data provide a basis for evaluation of liver restoration and efficacy of liver support in children with liver failure to devise a collaborative, multicentre trial.

Adolescent↗

PubMed2005

Development of growth and body mass index after pediatric renal transplantation.

Suboptimal final height and marked weight gain after renal transplantation (RTx) are common and may result in obesity. Steroid free immunosuppression has been advocated to improve growth and limit weight gain. We evaluated retrospectively the evolution of growth and body mass index (BMI) after renal transplantation to study risk factors for weight gain under steroid based treatment. Sixty-four pediatric patients (age 9.9 +/- 5.0 yr) were included in the study. To allow comparison between different age groups, standard deviation scores (SDS) for height and BMI for height age were calculated at time of transplantation and 3, 6, 9, 12, 24, 36, 48 and 60 months later. Induction immunosuppression consisted of basiliximab, cyclosporine and prednisone. Growth retardation at time of RTx was obvious with a SDS for height of -2.20 +/- 1.34. Height during the first year improved to an SDS of -2.0 +/- 1.27 (p < 0.01) but did further not increase in year 2 and 3. More than 40% of all patients remained 2 SDS below normal mean. SDS BMI for height age at transplantation was -0.19 +/- 0.98 and increased significantly during the first 3 months after transplantation to +0.64 +/- 1.07 (p < 0.01). Thereafter, BMI remained stable but did not decline to pretransplant values. A SDS BMI for height age of more than 2 SDS was observed in 2, 6, 9 and 11% of children at RTx and 1, 2 and 3 yr later respectively. BMI gain over 3 yr was significantly enhanced in children whose parents (especially the mother) were overweight. No influence of gender, BMI at RTx, dialysis modality prior to RTx or rejection episodes could be detected. We conclude that after RTx children exhibit some improvement in growth but height remains suboptimal. The BMI does increase significantly during the first months after RTx and does not return to baseline values under steroid-based immunosuppression. Obesity (>2 SDS above normal) does not occur more often than in the normal population. The most predictive parameter of inappropriate weight gain during 3 yr is the BMI of the mother. We would speculate that steroids may play a major role in weight gain in the early phase after RTx. However, genetic or environmental factors predict the long-term weight development.

Antibodies, Monoclonal↗

PubMed2005

Clinical consequences of PKHD1 mutations in 164 patients with autosomal-recessive polycystic kidney disease (ARPKD).

BACKGROUND: ARPKD is associated with mutations in the PKHD1 gene on chromosome 6p12. Most cases manifest peri-/neonatally with a high mortality rate in the first month of life while the clinical spectrum of surviving patients is much more variable than generally perceived. METHODS: We examined the clinical course of 164 neonatal survivors (126 unrelated families) over a mean observation period of 6 years (range 0 to 35 years). PKHD1 mutation screening was done by denaturing high-performance liquid chromatography (DHPLC) for the 66 exons encoding the 4074 aa fibrocystin/polyductin protein. RESULTS AND CONCLUSION: This is the first study that reports the long-term outcome of ARPKD patients with defined PKHD1 mutations. The 1- and 10-year survival rates were 85% and 82%, respectively. Chronic renal failure was first detected at a mean age of 4 years. Actuarial renal survival rates [end point defined as start of dialysis/renal transplantation (RTX) or by death due to end-stage renal disease (ESRD)] were 86% at 5 years, 71% at 10 years, and 42% at 20 years. All but six patients (92%) had a kidney length above or on the 97th centile for age. About 75% of the study population developed systemic hypertension. Sequelae of congenital hepatic fibrosis and portal hypertension developed in 44% of patients and were related with age. Positive correlations could further be demonstrated between renal and hepatobiliary-related morbidity suggesting uniform disease progression rather than organ-specific patterns. PKHD1 mutation analysis revealed 193 mutations (70 novel ones; 77% nonconservative missense mutations). No patient carried two truncating mutations corroborating that one missense mutation is indispensable for survival of newborns. We attempted to set up genotype-phenotype correlations and to categorize missense mutations. In 96% of families we identified at least one mutated PKHD1 allele (overall detection rate 76.6%) indicating that PKHD1 mutation screening is a powerful diagnostic tool in patients suspected with ARPKD.

Adolescent↗

PubMed2004

Pseudotumor cerebri following cyclosporine A treatment in a boy with tubulointerstitial nephritis associated with uveitis.

An 11-year-old boy with recurrent nephritis due to tubulointerstitial nephritis associated with uveitis (TINU syndrome) was treated with cyclosporin A (CSA) to induce sustained remission. CSA was introduced as a steroid-sparing drug because of extreme obesity (body mass index 32 kg/m(2)). Although the boy did not complain of any clinical symptoms, eye inspection after 7 months revealed bilateral disk edema with retinal bleeding and the patient developed cerebrospinal hypertension. Pseudotumor cerebri was diagnosed by measuring the intracranial pressure (31 cm H(2)O) and normal computer tomography and brain magnetic resonance imaging. Cessation of CSA therapy and treatment with mycophenolate mofetil led to resolution within 12 weeks.

Adrenal Cortex Hormones↗

PubMed2004

The population-specific distribution and frequencies of genomic variants in the SLC3A1 and SLC7A9 genes and their application in molecular genetic testing of cystinuria.

Cystinuria is a common inherited aminoaciduria resulting in nephrolithiasis. Mutations in two genes, SLC3A1 and SLC7A9, have been identified in cystinuric patients. Considering the population-specific distribution of genetic variants in the SLC3A1 gene, we focused our study on mutations in SLC3A1 and SLC7A9 described more than once in the literature. We evaluated the usefulness of this restricted analysis as a diagnostic approach. Furthermore, the data obtained were used to estimate the frequency of heterozygote carriers of SLC3A1 mutations in the general European population. A total of 22 unclassified cystinuric patients were screened for genetic variants in four exons of both SLC3A1 and SLC7A9 in which the most common mutations have been identified. For screening, we used single strand conformation polymorphism analysis (SSCP), restriction assays, real-time PCR and direct sequencing. In total, we identified mutations in 17 of our 22 patients, including a new mutation (R365Q) as well as a novel polymorphism (c.1035G/A) within the SLC3A1 gene. An ethnic influence on the distribution of mutations was confirmed: T216M in SLC3A1 is the major mutation in south-eastern Europe, whereas M467T in SLC3A1 is mainly found in western Europe. A complex duplication in SLC3A1 is restricted to German patients. Generally, we could show that a stepwise analysis directed to the most common mutations in the two cystinuria genes is sufficient to detect variants in more than 75% of patients of European origin. The test consists of nine different PCR-based approaches and therefore represents a low-cost, reliable and timesaving diagnostic tool.

Amino Acid Transport Systems, Basic↗

PubMed2004

Absorption phase cyclosporine (C(2h)) monitoring in the first weeks after pediatric renal transplantation.

Cyclosporine (CsA) monitoring using abbreviated area under the curve or 2-h blood concentration (C(2h))has been shown to predict total drug exposure in adult renal transplantation. However, pediatric experience is limited. Since 1998, we have monitored C(2h) in 45 children (age 10.6+4.7 years) during the first 6 weeks after transplantation. In 22 a 4-h CsA profile (AUC(0-4h)) was available and C(2h) in the remaining 23 patients. In addition CsA profiles from 24 children transplanted before 1998 were used to calculate the correlation between single time points and AUC(0-4h). The best correlation between AUC(0-4h) and a single time point was seen with C(2h) (r(2)=0.89). Coh did not predict AUC(0-4h) reliably (r(2)=0.27). C(2h) showed the lowest prediction error (10.0+9.6%).No dependency on age could be detected. In the first 3 months following transplantation, rejection was ob-served in 9 of 45 patients (20%). Glomerular filtration rate remained stable within the first 5 years after trans-plantation. In conclusion, in the early phase after renal transplantation, C(2h) can be used to predict drug exposure within the whole pediatric age group and should be evaluated in prospective trials.

Absorption↗

PubMed2003

Cyclophosphamide in steroid-sensitive nephrotic syndrome: outcome and outlook.

Steroid-sensitive nephrotic syndrome often follows a relapsing course with a substantial number of patients requiring cytotoxic therapy with cyclophosphamide (CP). However, the long-term success of CP treatment is difficult to predict. We retrospectively evaluated 106 patients after CP to identify parameters associated with sustained remission. The overall rate of cumulative sustained remission was 24% after 10 years. No gender difference was found. Several factors were significantly correlated with the rate of sustained remission: age at CP therapy (remission 34% versus 9% in children older or younger than 5.5 years, P<0.01), frequently relapsing versus steroid-dependent status (54% versus 17%, P<0.05), leukopenia under CP treatment (44% in children with leukopenia versus 19% in children without leukopenia, P<0.05), and a cumulative dosage per body surface area (BSA) of more or less than 5,040 mg/m(2) (45% versus 11%, P<0.01). In contrast, the cumulative dosage per kilogram body weight had no significant influence on long-term remission (23% in children with >168 mg/kg versus 26% in children with <168 mg/kg, P>0.05). The current concept of CP treatment of steroid-sensitive nephrotic syndrome is less effective in preschool children. CP therapy should be re-evaluated on a BSA-adjusted regimen.

Adolescent↗

PubMed2003

Significant contribution of genomic rearrangements in SLC3A1 and SLC7A9 to the etiology of cystinuria.

BACKGROUND: Cystinuria is an inherited disorder of defective renal reabsorption of cystine and the dibasic amino acids. Recently, SLC3A1 and SLC7A9 have been identified as responsible genes. While point mutations in the two genes are well known to cause cystinuria, only a few studies are aimed on the identification of gross genomic alterations. Here, we report our results of a systematic screening for deletions and duplications in SLC3A1 and SLC7A9 by quantitative real-time polymerase chain reaction (PCR). METHODS: We screened a cohort of 49 cystinurics for copy number deviations in the genes SLC3A1 and SLC7A9 by quantitative real-time PCR assays using fluorogenic 5' nuclease chemistry. The detected duplication in SLC3A1 was analyzed in detail by further real-time assays, reverse transcription (RT)-PCR and direct sequencing. RESULTS: In seven patients, we could identify a large duplication in SLC3A1 spanning from intron 4 to intron 9. This tandem duplication was accompanied by a small inversion of 25 bp and a 2 bp deletion in intron 9. As a formation mechanism, we presume that the inversion in intron 9 and several Alu sequences neighbored to the affected region provoke a chromatin structure that stimulates the duplication event. In addition to the SLC3A1 duplication, we observed deletions in SLC7A9 in three patients. CONCLUSION: The frequency of genomic rearrangements in our patient population illustrates the significant contribution of large genomic alterations to the mutation spectrum in cystinuria. As we could show, quantitative real-time PCR is a reliable and effective tool for the identification of unbalanced genomic rearrangements.

Amino Acid Transport Systems, Basic↗

PubMed2002

Severe Fusobacteria infections (Lemierre syndrome) in two boys.

UNLABELLED: Abscess formation is a rare cause of febrile illness in childhood but always has to be considered in such clinical presentations. Belonging to the resident flora of the oropharyngeal region, Fusobacteria are known to cause local infections; from here they may extend to other sites via the bloodstream or are aspirated into the lung (Lemierre disease). We report on two boys with Lemierre disease due to infection by Fusobacteria in monoculture causing two different clinical phenotypes. Case 1 presented with a large subphrenic abscess and pneumonic infiltration of the right middle lobe. Primary focus of infection was periodontal disease. Case 2 presented with a life-threatening septicaemia due to a retropharyngeal abscess and perforated otitis media followed by osteomyelitis of the atlas and thrombosis of the left sigmoid sinus and internal jugular vein. CONCLUSION: Fusobacteria should be considered in any abscess formation in children. A thorough examination of the oropharyngeal region as a possible site of primary manifestation is mandatory.

Adolescent↗

PubMed2002

Dent's disease.

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Calcium↗

PubMed2002

Cystinuria in children: distribution and frequencies of mutations in the SLC3A1 and SLC7A9 genes.

BACKGROUND: Cystinuria is a common inherited disorder of defective renal reabsorption of cystine, ornithine, lysine and arginine leading to nephrolithiasis. Two responsible genes have been identified so far: Mutations in the SLC3A1 gene encoding the heavy chain rbAT of the renal cystine transport system rbAT/b(0,+)AT cause cystinuria type I, while variants in SLC7A9, the gene of its light chain b(0,+)AT, have been demonstrated in non-type I cystinuria. In this study, we searched for mutations in both genes in a cohort of children with cystinuria. METHODS: Twenty-one cystinuric children from 16 families were analyzed by mutational analysis of the genes SLC3A1 and the SLC7A9. The patients were classified by the urinary amino acid excretion profile of their parents. Additionally, 10 unclassified patients were screened for genomic variants. The screening techniques included single strand conformation polymorphism analysis, restriction assays and direct sequencing. RESULTS: Two novel mutations were identified in SLC3A1 and three in SLC7A9; three were missense mutations and two frameshift mutations. In the pediatric patients, mutations were found in 54% of type I (SLC3A1) and in 25% of non-type I (SLC7A9) chromosomes. For this group of patients a total detection rate of 46.6% for mutations in both genes was delineated. In the cohort of unclassified 10 patients, 70% of mutations were determined. M467T and G105R were the preponderant mutations in SLC3A1 and SLC7A9, respectively; T216M was the major mutation in Turkey and Greece. CONCLUSIONS: The detection rate for mutations in SLC3A1 and SLC7A9 in children was 54% in the SLC3A1 gene for type I chromosomes and 25% in the SLC7A9 gene for non-type I chromosomes. It was lower than that in 10 further patients with an unclassified cystinuria, although the clinical characterization in the first group was more stringent; additionally, different spectrums of mutations were observed. The lack of detectable mutations in many patients indicates the possibility of other yet unidentified genes involved in cystinuria. We could not correlate the severity of the disease to the type of cystinuria in the pediatric patients.

Adolescent↗