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  • 1
    Electronic Resource
    Electronic Resource
    Dithio-bis-mercaptoethanesulphonate (DIMESNA) does not prevent cellular damage by metabolites of ifosfamide and cyclophosphamide in LLC-PK1 cells (1994)
    Springer
    Pediatric nephrology 8 (1994), S. 458-465 
    Details
    ISSN: 1432-198X
    Keywords: Ifosfamide ; Cyclphosphamide ; Sodium-2-mercaptoethanesulphonate ; Fanconi syndrome ; LLC-PK1 cells
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Ifosfamide (IF) is an alkylating cytostatic with urotoxic (haemorrhagic cystitis) and nephrotoxic (Fanconi syndrome) side effects. Cyclophosphamide (CP), a structural isomer of IF, shows urotoxic but no nephrotoxic side effects. The development of haemorrhagic cystitis during therapy with IF or CP can be prevented by the uroprotective drug sodium-2-mercaptoethanesulphonate (MESNA). However, even in the presence of MESNA, Fanconi syndrome may still develop after therapy with IF. Using the renal tubular cell line LLC-PK1, we investigated whether there is a protective effect of either MESNA or of its major metabolite DIMESNA, in combination with metabolites of IF or CP, on thymidine incorporation, uridine incorporation or total protein. DIMESNA, the dimer of MESNA, is the dominant form of the molecule in the circulation; the proximal tubular cell must convert this back to MESNA at the expense of glutathione, before it can exert its uroprotective action. We did not find a protective effect of DIMESNA under any of the experimental conditions tested. LLC-PK1 cells exposed to 3 mmol/l DIMESNA did not convert DIMESNA to MESNA. The toxic effect of the CP metabolite 4-OOH-CP was more pronounced in the presence of DIMESNA than in its absence. MESNA completely prevented the toxic effects of acrolein and of 4-OOH-CP. The toxic effects of 4-OOH-IF and of chloracetaldehyde, two major metabolites of IF, were significantly reduced in the presence of MESNA. However, even at a 30-fold molar excess of MESNA over 4-OOH-IF, thymidine incorporation remained reduced by 40% compared with controls, indicating incomplete protection of tubular cells against metabolites of IF. Similarly, the effect of chloracetaldehyde was not completely reversed by MESNA. Our data indicate that DIMESNA is not metabolized sufficiently by LLC-PK1 cells. Moreover, DIMESNA may deprive the cell of glutathione and thus enhance the toxicity of 4-OOH-CP. The finding that MESNA does not protect LLC-PK1 cells completely against the toxic effects of IF metabolites may explain the difference in nephrotoxicity of IF and CP. It also explains the development of tubular damage in the presence of MESNA and in the absence of haemorrhagic cystitis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00856531
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  • 2
    Electronic Resource
    Electronic Resource
    Microproteins in amniotic fluid as an index of changes in fetal renal function during development (1987)
    Springer
    Pediatric nephrology 1 (1987), S. 574-580 
    Details
    ISSN: 1432-198X
    Keywords: Microproteins ; Amniotic fluid ; Fetal maturation ; Fetal kidney function
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Protein content and protein composition were studied in amniotic fluid obtained from 171 healthy pregnant women between the 16th and 38th week of gestation, using microgradient gel electrophoresis to separate proteins according to their molecular size into albumin (68 KD), proteins of low molecular weight (LMW proteins, 〈68 KD), and proteins of high molecular weight (HMW proteins, 〉68 KD). Additionally α-1-microglobulin (α-1-MG, 33 KD) and β-2-microglobulin (β-2-MG, 11,8 KD) were analysed as micromolecular marker proteins. Concentrations of LMW proteins were 0.15–0.22 g/l, of α-1-MG 28.4–34.5 mg/l, and of β-2-MG 7.2–11.6 mg/l during the second trimester of gestation, and thereafter decreased progressively to 0.03 g/l, 14.1 mg/l and 2.4 mg/l respectively near term. The same developmental trends were confirmed by calculating the protein/creatinine ratios in amniotic fluid. The concentrations of LMW proteins found in the first postnatal urine of 73 healthy infants born prematurely or at term were similar to those in amniotic fluid of corresponding fetal age. Concentrations of albumin and HMW proteins in postnatal urine were about 5% and 15% respectively when compared with amniotic fluid concentrations. No strong correlation existed between gestational age and either of the analysed proteins which would allow accurate assessment of fetal maturation by protein analysis in amniotic fluid. It is concluded that fetal urinary excretion is the major determinant of the microprotein content of amniotic fluid. Microproteins seem to reflect an increasing tubular reabsorption capacity, which accelerates rapidly after the second trimester of gestation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00853591
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  • 3
    Electronic Resource
    Electronic Resource
    Tubular toxicity of cyclosporine A and the influence of endothelin-1 in renal cell culture models (LLC-PK1 and MDCK) (1997)
    Springer
    Pediatric nephrology 11 (1997), S. 778-783 
    Details
    ISSN: 1432-198X
    Keywords: Key words: Bromodeoxyuridine incorporation ; Villin ; Uvomorulin ; Endothelin antagonists
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract. To evaluate the effect of cyclosporine A (CyA) at high concentrations (10–4 and 10–5 M) and the influence of endothelin-1 (ET-1) at physiological and pharmacological concentrations (10–14 to 10–6 M) on epithelial cell function, LLC-PK1 cells were studied as a model of the proximal tubule and MDCK cells as a model of the distal tubule/collecting duct. CyA caused time- and concentration-dependent acute toxicity. In LLC-PK1 cells, CyA caused a decrease in transepithelial resistance, indicating a loss of cell contacts, a release of lactate dehydrogenase (LDH) and villin into the supernatant, suggesting destruction of the apical membrane with loss of brush border, and finally release of uvomorulin, suggesting a disruption of the cell-cell adhesion, the zonula adherens. DNA synthesis, as evaluated by bromodeoxyuridine (BrdU) incorporation, was significantly affected at ≥10–5 M CyA. The toxicity of CyA was higher when given from the apical rather than the basolateral compartment. ET-1 alone was without effect, but in combination with CyA, ET-1 significantly enhanced toxicity. The ET-1 effect was partially inhibitable by an ETB, but not an ETA, antagonist. Immunofluorescence for α-catenin, another protein of the zonula adherens, demonstrated no change in polarity for this protein, and immunoprecipitation of the complex indicated relative stability of the zonula adherens despite loss of cadherin into the supernatant. In MDCK cells the effects were different. CyA was not associated with LDH release, but with an increase in transepithelial resistance, indicating increased paracellular resistance. Morphological alterations were significantly less, but BrdU incorporation was decreased. This pattern of toxicity is compatible with a direct toxic effect of CyA on cells of the proximal tubule, with predominant morphological destruction of the cells, with concomitant proximal tubular dysfunction, and a functional alteration in cells of the distal tubule associated with increased paracellular resistance, which may lead to solute and water loss.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004670050389
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  • 4
    Electronic Resource
    Electronic Resource
    Enterohemorrhagic Escherichia coli infections: following transmission routes (2000)
    Springer
    Pediatric nephrology 14 (2000), S. 73-83 
    Details
    ISSN: 1432-198X
    Keywords: Key words Enterohemorrhagic Escherichia coli ; Hemolytic uremic syndrome ; Transmission routes ; Epidemiology
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Infections with enterohemorrhagic Escherichia coli (EHEC) are the major cause of hemolytic-uremic syndrome (HUS ), the most-common cause of acute renal failure in childhood. The mortality rate of HUS (0%–5% in most recent series and 10%–30% in individual reports) and residual chronic renal sequelae (in up to 50% of patients in long-term follow-up studies) emphasize the seriousness of HUS for public health. Several studies have described possible sources of EHEC infection. However, in the majority of cases the pathogen cannot be identified in food or animals and the routes of transmission remain unclear. In this review article the hypothesized routes of transmission are summarized. The medical data bases ”Medline” and ”Current contents” were screened for the years January 1966 through November 1998. The difficulties in following the chain of EHEC infection are discussed. A precise evaluation of the environmental aspects of the patient is a precondition for further analysis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004670050018
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  • 5
    Electronic Resource
    Electronic Resource
    Lack of large, homozygous deletions of the nephronophthisis 1 region in Joubert syndrome type B (1998)
    Springer
    Pediatric nephrology 12 (1998), S. 16-19 
    Details
    ISSN: 1432-198X
    Keywords: Key words: Joubert syndrome ; Nephronophthisis ; Coloboma of the eye ; Cerebellar vermis aplasia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract. Joubert syndrome type B (JSB) is a developmental disorder of the nephronophthisis (NPH) complex with multiple organ involvement, including NPH, coloboma of the eye, aplasia of the cerebellar vermis, and the facultative symptoms of psychomotor retardation, polydactyly, and neonatal tachypnea. In isolated autosomal recessive NPH type 1 (NPH1), homozygous deletions have been described as causative in more than 80% of patients. Since different combinations of the extrarenal symptoms with NPH occur in JSB, a contiguous gene deletion syndrome in the NPH1 genetic region would seem a highly likely cause for JSB. We therefore examined 11 families with JSB for the presence of extended deletions at the NPH1 locus. Genomic DNA was examined using four consecutive polymerase chain reaction (PCR) markers that are deleted in NPH1 and three PCR makers flanking the NPH1 deletion. In all seven markers examined, there was no homozygous deletion detected in any of the 11 JSB families studied. Since these markers saturate the NPH1 deletion region at high density, this finding excludes the presence of large homozygous deletions of the NPH1 region in these JSB families, making it unlikely that deletions of the NPH1 region are a primary cause for JSB.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004670050394
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  • 6
    Electronic Resource
    Electronic Resource
    Sporadic case of X-chromosomal Alport syndrome in a consanguineous family (2000)
    Springer
    Pediatric nephrology 14 (2000), S. 758-761 
    Details
    ISSN: 1432-198X
    Keywords: Key words Alport syndrome ; Glomerular basement membrane ; Hereditary nephropathy ; De novo mutation ; Obstructive uropathy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Alport syndrome (AS) is a genetic disorder of basement membranes caused by mutations in type IV collagen genes that is characterized by chronic hematuria and progressive nephropathy leading to renal failure. The main extrarenal features include sensorineural hearing loss and ocular lesions. The mode of inheritance is X-linked dominant in about 80%–85% of the affected families, whereas autosomal transmission is rarely encountered. We report a male patient originating from a healthy consanguineous Lebanese family who presented with an unusual association of obstructive uropathy and AS. Hematuria and proteinuria were initially attributed to a suspected poststreptococcal glomerulonephritis (GN) and high-grade subpelvic ureteral stenosis. Persistence of symptoms after medical treatment of poststreptococcal GN and surgical correction of obstructive uropathy finally led to renal biopsy. The observed ultrastructural changes of the glomerular basement membrane were typical for AS.Molecular genetic studies revealed a previously undescribed de novo mutation in the COL4A5 gene, excluding maternal heterozygotic carrier status. This case report emphasizes the importance of hereditary nephritis in the differential diagnosis of chronic hematuria, and demonstrates the value of molecular studies for genetic counselling in AS.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/PL00013431
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  • 7
    Electronic Resource
    Electronic Resource
    Critical care in uraemic children (1992)
    Springer
    Pediatric nephrology 6 (1992), S. 88-95 
    Details
    ISSN: 1432-198X
    Keywords: Chronic kidney failure ; Respiratory therapy ; Dialysis ; Blood coagulation disorders ; Intracranial pressure ; Catecholamines ; Bacterial infections
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The special problems posed by renal disease have to be considered when a uraemic child requires intensive care. This report gives an overview on the problems of dialysis treatment, circulatory support, infectious complications, coagulation disorders and increased intracranial pressure.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00856850
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  • 8
    Electronic Resource
    Electronic Resource
    Toxicity of ifosfamide, cyclophosphamide and their metabolites in renal tubular cells in culture (1994)
    Springer
    Pediatric nephrology 8 (1994), S. 157-163 
    Details
    ISSN: 1432-198X
    Keywords: Ifosfamide ; Cyclophosphamide ; Nephrotoxicity ; Fanconi syndrome ; Chloracetaldehyde
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Ifosfamide (IF) and cyclophosphamide (CP) are highly effective alkylating cytostatic drugs. IF and CP have to be activated through a metabolic step in vivo; numerous metabolites are known. While both IF and its structural isomer CP have severe urotoxic side effects, only IF is also a nephrotoxic drug, causing tubular damage resulting in Fanconi syndrome in some cases. Little information is available regarding the pathogenic mechanism of tubular damage by IF. We used the renal epithelial cell line LLC-PK1, which has many properties of the proximal tubule, in order to investigate the toxicity of IF and CP and of their reactive metabolites 4-hydroxy-IF (4-OH-IF), 4-hydroxy-CP (4-OH-CP), acrolein and chloracetaldehyde (CAA). Protein content of monolayers, DNA and RNA synthesis were determined by standard techniques (thymidine and uridine incorporation). IF and CP had the lowest toxicities of all compounds tested. Both drugs inhibited thymidine incorporation by about 30% at a concentration of 300 μmol/l after 1 h incubation. 4-OH-IF and 4-OH-CP were significantly more toxic than the parent drugs. Thymidine incorporation, the most sensitive parameter, was reduced by about 70% by 300 μmol/l of either compound. In addition, 4-OH-CP reduced the total protein content of monolayers. 4-OH-IF did not effect protein content and RNA synthesis. Acrolein, the most toxic metabolite tested, reduced all three parameters significantly at concentrations of 50–75 μmol/l after 1 h. Incubation of cells with 100 μmol/l of acrolein showed an effect after only 1 min. CAA significantly damaged monolayers with a reduction of total protein at a concentration of 50–100 μmol/l. Thymidine incorporation was decreased only moderately by CAA, while uridine incorporation was stimulated, which may be interpreted to reflect a mechanism of repair. We conclude that both CP and IF and their metabolites are toxic in renal tubular cells in culture. CAA may play a larger role in the development of renal tubular damage after therapy with IF than was previously recognized.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00865466
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  • 9
    Electronic Resource
    Electronic Resource
    Urinary excretion of adenosine deaminase binding protein in neonates treated with tobramycin (1995)
    Springer
    Pediatric nephrology 9 (1995), S. 419-422 
    Details
    ISSN: 1432-198X
    Keywords: Tobramycin ; Cefotaxim ; Nephrotoxicity ; Adenosine deaminase binding protein ; Neonates
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The potential tubulotoxicity of tobramycin and cefotaxim were assessed in neonates by measuring the urinary level of adenosine deaminase binding protein (ABP) and urinary α1-microglobulin and β2-microglobulin. In a prospective study, 33 neonates who received tobramycin and cefotaxim for suspected neonatal sepsis were compared with 48 untreated newborns during the first 10 days of life. The urinary concentrations of ABP and its excretion rates, corrected for body weight and body surface area, were significantly increased from the 1st day of treatment. Urinary α1-microglobulin and β2-microglobulin were not elevated under tobramycin and cefotaxim during the first 2 days of treatment. We conclude that ABP may be a sensitive marker for the detection of proximal renal tubular injury during tobramycin and cefotaxim treatments of neonates. The increase in urinary ABP which occurs before an elevation of urinary α1-microglobulin and β2-microglobulin may reflect earlier structural than functional alterations. However, since none of the treated infants had signs of electrolyte disorders or glomerular dysfunction, the clinical relevance of ABP measurement should be reevaluated.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00866714
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  • 10
    Electronic Resource
    Electronic Resource
    A novel gene encoding an SH3 domain protein is mutated in nephronophthisis type 1 (1997)
    [s.l.] : Nature Publishing Group
    Nature genetics 17 (1997), S. 149-153 
    Details
    ISSN: 1546-1718
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Medicine
    Notes: [Auszug] Juvenile nephronophthisis (NPH), an autosomal recessive cystic kidney disease, is the primary genetic cause of chronic renal failure in children. About two thirds of patients with NPH carry a large homozygous deletion at the gene locus NPH1 on 2q13. We here identify a novel gene, NPHP1, which ...
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1038/ng1097-149
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