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Biomedical subjects

R P Wüthrich

Publications and source records attributed to R P Wüthrich.

At least 19 recordsLinked to original sources
PubMed2006

[The red urine].

The occurrence of red urine is a disconcerting sign for the patient. Hematuria is the most common cause for the red colour of the urine. However, certain drugs and food can also cause red urine. Visible blood in the urine is called macrohematuria; when blood is only detected by microscopic examination this is termed microhematuria. The cause of micro- or macrohematuria must be determined carefully. Both renal and extrarenal diseases can cause hematuria. Among the renal diseases certain glomerulonephritides (IgA nephropathy, Alport's syndrome) are frequent causes of asymptomatic microhematuria. Extrarenal causes include nephrolithiasis, tumours, or urinary tract infections. Microscopic analysis of the urinary sediment, ultrasound examination and other radiological tests are essential to establish a correct diagnosis. The diagnostic steps and differential diagnosis for a patient with red urine or microhematuria are described in detail in the present article.

Diagnosis, Differential↗
PubMed2004

Time course of serial cystatin C levels in comparison with serum creatinine after application of radiocontrast media.

BACKGROUND: The delayed increase of creatinine after radiocontrast application is a potential reason for overlooking radiocontrast nephrotoxicity. Cystatin C may be more useful to rapidly assess a decrease in glomerular filtration rate (GFR). We compared cystatin C and creatinine to examine their kinetics after application of radiocontrast media. PATIENTS AND METHODS: Forty-one patients (60.8 +/- 8.8 years, 68% males) with normal to subnormal GFR scheduled for coronary angiography (27% with angioplasty), were studied for serum cystatin C and creatinine levels before, 5 h, 24 h and 48 h after angiography. Furthermore, alpha1-microglobulin was checked for evidence of tubular damage. RESULTS: At 5 hours after angiography, there was no significant change compared to baseline in either serum creatinine nor cystatin C. In comparison with the value immediately before coronary angiography, the increase of cystatin C achieved a maximum at 24 h after the application of the contrast agent (+7.2%). Within 48 h, cystatin C decreased to the level before angiography. Serum creatinine increased at 24 h (+7.7%) and continued to increase at 48 h (+11.3%). CONCLUSION: Cystatin C increases earlier after radiocontrast application compared with creatinine. Therefore, cystatin C needs to be investigated as a potential early marker for nephrotoxicity, especially in the upcoming setting of short-time hospitalizations for coronary angiographies and interventions. Thus, further studies in patients with renal failure undergoing radiocontrast application are warranted to assess the usefulness of cystatin C in respect of an earlier detection of radiocontrast nephrotoxicity.

Aged↗
PubMed2002

Role of alveolar epithelial ICAM-1 in lipopolysaccharide-induced lung inflammation.

Intercellular adhesion molecule-1 (ICAM-1) is known to play a central role in lung inflammation. Limited information, however, is available regarding the expression and biological function of ICAM-1 in the alveolar epithelial compartment. The current report analyses the expression pattern of ICAM-1 in primary cultures of rat alveolar epithelial cells (AECs) and in the rat lung following instillation of bacterial endotoxin (lipopolysaccharide (LPS)) in order to better define the role of alveolar epithelial ICAM-1. AECs stimulated in vitro with LPS were evaluated for ICAM-1 and ICAM-1 messenger ribonucleic acid content. Adherence assays with neutrophils and macrophages were performed. Endotoxin-induced ICAM-1 upregulation on AECs was demonstrated in vivo by immunofluorescence staining. In addition, the effect of intratracheally-instilled anti-ICAM-1 was assessed. Significant upregulation of ICAM-1 occurred in vitro and in vivo on AECs after LPS stimulation. Adherence assays showed a 114% increase in adhesion of neutrophils to AECs. Antibody directed against ICAM-1 reduced this adhesion by 40%. A significant reduction in the number of neutrophils in bronchoalveolar lavage fluid and whole lung was seen under airway ICAM-1 blockade. These data indicate that intercellular adhesion molecule-1 participates in the inflammatory response to lipopolysaccharide-induced lung injury in the distal airways by interacting mainly with neutrophils.

Animals↗
PubMed2001

Heterozygosity for the factor V Leiden (G1691A) mutation predisposes renal transplant recipients to thrombotic complications and graft loss.

BACKGROUND: Heterozygosity for a mutation in the coagulation factor V gene (factor V Leiden; FVL) leads to resistance to activated protein C and represents the most common cause of inherited thrombophilia. FVL is associated with a high risk for thromboembolic events and might be a risk factor for venous thrombosis and early graft loss in renal transplant recipients. METHODS: We studied a cohort of 202 renal allograft recipients to assess the impact of the FVL mutation on thrombotic events and graft loss within 1 year after transplantation. We recorded the occurrence of deep venous thrombosis, pulmonary embolism, early graft perfusion defect, and graft loss. The occurrence of these events was then correlated with the presence or absence of heterozygosity for the FVL mutation. RESULTS: Heterozygosity for FVL was detected in 8 (4%) of 202 patients. The incidence of deep venous thrombosis or pulmonary embolism was higher in heterozygous compared with wild-type patients (25% vs. 5.7%, P=0.09). Furthermore, early graft perfusion defect (25% vs. 2.6%; P=0.03) and graft loss within 7 days after transplantation (2/8 vs. 1/194; P=0.004) were significantly more frequent among heterozygous carriers of FVL. All eight FVL carriers were negative for protein C or S deficiency and antiphospholipid and anticardiolipin antibodies, and were not carriers of the G20210A prothrombin mutation. CONCLUSIONS: Heterozygosity for the FVL mutation predisposes renal allograft recipients to venous thromboembolic complications, graft perfusion defects, and early transplant loss. Screening for the FVL mutation and appropriate peri- and postoperative anticoagulation after renal transplantation might prevent these thromboembolic complications.

Cohort Studies↗
PubMed2001

CC chemokine receptor 5 and renal-transplant survival.

BACKGROUND: About 1% of white populations are homozygous carriers of an allele of the gene for the CC chemokine receptor 5 (CCR5) with a 32 bp deletion (CCR5Delta32), which leads to an inactive receptor. During acute and chronic transplant rejection, ligands for CCR5 are upregulated, and the graft is infiltrated by CCR5-positive mononuclear cells. We therefore investigated the influence of CCR5Delta32 on renal-transplant survival. METHODS: Genomic DNA from peripheral-blood leucocytes of 1227 renal-transplant recipients was screened by PCR for the presence of CCR5Delta32. Demographic and clinical data were extracted from hospital records. Complete follow-up data were available for 576 recipients of first renal transplants. Graft survival was analysed by Fisher's exact test and Kaplan-Meier plots compared with a log-rank test. FINDINGS: PCR identified 21 patients homozygous for CCR5Delta32 (frequency 1.7%). One patient died with a functioning graft. Only one of the remaining patients lost transplant function during follow-up (median 7.2 years) compared with 78 of the 555 patients with a homozygous wild-type or heterozygous CCR5Delta32 genotype. Graft survival was significantly longer in the homozygous CCR5Delta32 group than in the control group (log-rank p=0.033; hazard ratio 0.367 [95% CI 0.157-0.859]). INTERPRETATION: Patients homozygous for CCR5Delta32 show longer survival of renal transplants than those with other genotypes, suggesting a pathophysiological role for CCR5 in transplant loss. This receptor may be a useful target for the prevention of transplant loss.

Adult↗
PubMed2001

CD44-mediated cyclooxygenase-2 expression and thromboxane A2 production in RAW 264.7 macrophages.

OBJECTIVE AND DESIGN: CD44 is the major cell surface receptor for hyaluronan (HA) on macrophages. Stimulation of macrophages via the HA-CD44 pathway leads to the enhanced expression of inflammatory gene products, including cytokines, chemokines, and adhesion molecules. We have examined whether activation of CD44 by crosslinking is capable of activating the cyclooxygenase (COX) and prostaglandin (PG)/thromboxane (TX) pathway in cultured macrophages. MATERIALS AND METHODS: CD44 was crosslinked on RAW 264.7 mouse macrophages using specific rat anti-mouse CD44 monoclonal antibodies and anti-rat IgG. Total RNA was extracted and subjected to RT-PCR analysis for genes of the PG/TX synthetic pathway. Supernatants were analyzed for PGE2 and TXB2 using specific ELISAs. RESULTS: Transcripts for COX-1, COX-2, TX synthase (TXS), and PGE2 synthase (PGES) were all constitutively expressed in the mouse macrophage cell line RAW 264.7. Crosslinking of CD44 markedly enhanced COX-2 and weakly increased TXS mRNA, whereas COX-1 and PGES mRNA did not change significantly in these cells. Crosslinking of CD44 selectively increased the production of TXB2 but not PGE2. CONCLUSIONS: These findings suggest that the activation of the CD44 pathway plays a unique role in PG synthesis. Activation of this pathway results in enhanced TXA2 but not PGE2 production. This leads to an imbalance of the TXA2/PGE2 profile which favors a proinflammatory and vasoconstrictory response.

Animals↗
PubMed2001

Hyaluronan-induced cyclooxygenase-2 expression promotes thromboxane A2 production by renal cells.

BACKGROUND: Matrix degradation products such as fragmented hyaluronan (HA) display important proinflammatory effects on renal tubular epithelial cells (TECs) and macrophages (MPhis). We hypothesized that HA could up-regulate cyclooxygenase type 2 (COX-2) in these cells and that the subsequent production of thromboxane A2 (TXA2) could play a role in inflammatory renal lesions. METHODS: We used an in vitro approach to examine the expression of COX-1 and COX-2 and the production of TXA2 in response to fragments of HA. COX-2 mRNA, protein, and the resulting TXA2 production were measured in CD44-positive, HA-responsive cells lines of TECs and MPhi. COX-2 mRNA was also measured in vivo in MRL-Faslpr mice and in mice with anti-glomerular basement membrane (anti-GBM) nephritis. RESULTS: In TECs and MPhis, HA increased the steady-state COX-2 mRNA and protein levels markedly, whereas COX-1 mRNA levels did not change. The HA-induced response was comparable to lipopolysaccharide stimulation. In comparison with MPhi, the response was much weaker in TECs. Likewise, the production of TXA2 in response to HA was markedly increased in MPhi, but less in TECs. In TECs and in MPhi, the HA-stimulated TXA2 synthesis was inhibited with the COX-2-selective inhibitors SC58125 (12.5 micromol/L) or celecoxib (0.25 to 5.00 micromol/L). COX-2 mRNA levels were increased in nephritic mice with MRL-Faslpr lupus nephritis and in mice with anti-GBM disease. CONCLUSIONS: HA is a proinflammatory factor that stimulates COX-2 expression and subsequent TXA2 production. Since HA accumulates markedly in renal injury, we speculate that this matrix molecule could therefore play a significant role in thromboxane-mediated immune events in the kidney.

Animals↗
PubMed2001

Factor V Leiden mutation: potential thrombogenic role in renal vein, dialysis graft and transplant vascular thrombosis.

Factor V is an important blood coagulation factor, the procoagulatory activity of which is inhibited by activated protein C. The factor V Leiden mutation is due to a single base-pair change (G1691A), which alters the initial cleavage site for activated protein C. The impaired degradation of factor V by activated protein C yields a hypercoagulable state that confers a lifelong increased risk of thrombosis in heterozygous and homozygous individuals. The factor V Leiden mutation represents the most common cause of inherited thrombophilia, and enhances the risk for venous thrombosis by approximately sevenfold. In normal Western populations, heterozygosity for the factor V Leiden mutation is present in 2-5%, whereas in patients with venous thrombosis and a family history of thrombotic disease this figure may reach 50-60%. The presence of the mutation markedly increases the risk for renal vein thrombosis, particularly in neonates. Heterozygosity for factor V Leiden mutation does not appear to be a major risk factor for dialysis access clotting. The presence of factor V Leiden mutation is most devastating in kidney transplant recipients. In these patients the mutation predisposes to renal transplant vein thrombosis and early graft loss. The risk for acute vascular rejection is also enhanced in transplant recipients who are heterozygous for the mutation. Routine screening for factor V Leiden mutation by polymerase chain reaction, and appropriate perioperative and postoperative anticoagulation after renal transplantation might be a valuable strategy to prevent thromboembolic complications in transplant recipients.

Factor V↗
PubMed2001

Suppression of ICAM-1 expression in renal proximal tubular cells by 1,25-dihydroxyvitamin D3.

BACKGROUND: 1,25-Dihydroxyvitamin D(3) is mainly synthesized by renal proximal tubular cells. More recently, it has been shown to affect cell growth and TGF-beta(1) synthesis in glomerular and tubular renal cells in vitro, and to prevent glomerulosclerosis in vivo in subtotally nephrectomized rats. The mechanisms involved have not been fully identified. We asked whether 1,25-vitamin D(3) might interact with additional immunoregulatory functions of renal cells by studying its effects on the expression of the cellular adhesion molecules ICAM-1 (CD54) and VCAM-1 (CD106) in human proximal tubular cells in vitro (HK-2 cells). METHODS: Expression of adhesion molecules was assessed in HK-2 cells cultured under basal conditions and after stimulation with TNF-alpha plus IFN-gamma, by flow cytometry, gene transcription (RT-PCR) and measurement of soluble ICAM-1 in culture supernatant by ELISA. RESULTS: Unstimulated HK-2 cells did not express VCAM-1 and only little ICAM-1. 1,25-Vitamin D(3) had no effect on the expression of adhesion molecules in unstimulated cells. TNF/IFN stimulation resulted in a 4-fold increase in ICAM-1 and VCAM-1 expression. The TNF/IFN-induced increase in ICAM-1 expression was reduced by 1,25-vitamin D(3) dose dependently (10(-7) M vs. solvent: -30%; 10(-9) M: -18%; 10(-11) M: -17%). 25(OH)-vitamin D(3) had no effect. ICAM-1 mRNA concentration was increased in TNF/IFN-stimulated cells. 1,25-Vitamin D(3) treatment prevented the increase of ICAM-1 mRNA by 27% after 24-72 h incubation (p = 0.03). The TNF/IFN-induced increase in soluble ICAM in culture supernatants was unchanged by 1,25-vitamin D(3). VCAM-1 expression was unchanged by incubation with 1,25-vitamin D(3) under basal conditions and after TNF/IFN stimulation. CONCLUSION: 1,25-Vitamin D(3) inhibits cytokine-induced ICAM-1 but not VCAM-1 expression in renal proximal tubular cells in vitro. The present data support the hypothesis that 1,25-vitamin D(3) is not only synthesized by renal tubular cells, but may also affect immunoregulatory functions in these cells.

Calcifediol↗
PubMed2000

The 825C/T polymorphism of the G-protein subunit beta3 does not influence blood pressure and renal function in kidney transplant recipients.

BACKGROUND: Recently, a polymorphism at position 825 (C-->T) of the cDNA that encodes the beta3 subunit of heterotrimeric G proteins (Gbeta3) was found to be associated with essential hypertension. The T allele leads to the formation of a truncated splice variant (Gbeta3-s) with enhanced activity, promoting hypertension. We examined whether the T allele had an influence on blood pressure (BP) and early renal function after renal transplantation. METHODS: We determined the Gbeta3 genotype and T allele frequencies in renal transplant patients and examined associations with BP, BP medications, and renal function in the first year after transplantation. RESULTS: In renal transplant recipients (n=216) the frequency of the T allele was marginally increased (0.34 vs 0.29) compared with normal healthy blood donors (n=163). Age, sex and body mass index were similar in patients with the CC, CT and TT genotype. BP, number of BP medications, and serum creatinine levels were also similar for the three genotypes within the first year after transplantation. Significantly more patients with the TT genotype (48%) had glomerulonephritis as the underlying renal disease, compared with the CT (29%) and CC (27%) genotypes. CONCLUSIONS: The T allele of Gbeta3 does not have a negative impact on BP and early renal function in recipients of a renal allograft. The T allele might play a role in the pathogenesis of chronic glomerulonephritides.

Adult↗
PubMed2000

Randomized trial of conversion from mycophenolate mofetil to azathioprine 6 months after renal allograft transplantation.

BACKGROUND: In the first year after renal allograft transplantation, triple therapy immunosuppression with cyclosporin (CsA), prednisone (P), and mycophenolate mofetil (MMF) is superior to a triple therapy treatment that includes azathioprine (AZA) instead of MMF. Whether long-term treatment with CsA-P-MMF is better than treatment with CsA-P-AZA is a matter of debate, as 3-year graft survival is similar in MMF- and AZA-treated patients. The purpose of the present study was to examine the short-term effect of changing MMF to AZA in low-risk renal allograft recipients 6 months after transplantation. METHOD: This was a randomized, open-label single-centre study, recruiting 48 low risk renal allograft recipients on CsA-P-MMF therapy 6 months after transplantation, comparing the outcome with continued MMF treatment (2 g b.i.d.) (group A, n=22) or switching MMF to AZA (1 mg/kg) treatment (group B, n=26). RESULTS: The outcome after a 6-months follow-up of patients in group A and group B was similar. Treatment failure rates (defined as clinically diagnosed acute rejection episodes) were 4.5% in group A and 3.8% in group B. There were no patient deaths and no graft failures during the 6-months observation period. Graft function was excellent and similar in both groups. CONCLUSION: Replacing MMF with AZA 6 months after transplantation in low-risk renal allograft recipients is safe and is not associated with altered graft function in the short term.

Acute Disease↗
PubMed1999

Molecular identification of a murine ubiquitin/60S ribosomal fusion protein and expression study in mouse kidney.

We have isolated and sequenced a 500-bp cDNA clone which is the murine homologue of a ubiquitin/60S ribosomal fusion protein. The cDNA and the deduced amino acid sequence are highly conserved. Northern blotting demonstrates constitutive expression in a mouse renal epithelial cell line and in mouse kidneys. Upon stimulation with interferon-gamma or phorbol esters, the expression is not changed, contrasting with the stimulation seen for polyubiquitin. Expression of the 16-kD ubiquitin/60S protein is also demonstrated in mouse epithelial cells.

Amino Acid Sequence↗
PubMed1999

Reduced kidney transplant rejection rate and pharmacoeconomic advantage of mycophenolate mofetil.

BACKGROUND: Several multinational controlled clinical trials have shown that triple therapy immunosuppressive regimens which include mycophenolate mofetil (MMF), cyclosporin A (CSA) and steroids (S) are superior compared with conventional regimens which include azathioprine (AZA), CSA and S, mainly because MMF reduces the rate of acute rejection episodes in the first 6 months after kidney transplantation. Post-marketing studies are useful to evaluate the general applicability and costs of MMF-based immunosuppressive regimens. METHODS: Based on the excellent results of the published controlled clinical trials, we have changed the standard triple therapy immunosuppressive protocol (AZA+CSA+S) to an MMF-based regimen (MMF+CSA+S) at our centre. To analyse the impact of this change in regimen, we have monitored 6-month patient and graft survival, rejection rate, serum creatinine and CSA levels, as well as the costs of the immunosuppressive and anti-rejection treatments, in 40 consecutive renal transplant recipients (MMF group) and have compared the data with 40 consecutive patients transplanted immediately prior to the change in regimen (AZA group). RESULTS: Recipient and donor characteristics were similar in the AZA and MMF groups. Patient survival (37/40; 92.5% in the AZA group vs 38/40; 95% in the MMF group), graft survival (36/40 vs 36/40; both 90%) and serum creatinine (137+/-56 vs 139+/-44 micromol/l) after 6 months were not significantly different. However, the rate of acute rejection episodes (defined as a rise in creatinine without other obvious cause and treated at least with pulse steroids) was significantly reduced with MMF from 60 to 20% (P=0.0005). The resulting cost for rejection treatment was lowered 8-fold (from sFr. 2113 to 259 averaged per patient) and the number of transplant biopsies was lowered > 3-fold in the MMF group. The cost for the immunosuppressive therapy was increased 1.5-fold with MMF (from sFr. 5906 to 9231 per patient for the first 6 months). CONCLUSIONS: The change from AZA to MMF resulted in a significant reduction in early rejection episodes, resulting in fewer diagnostic procedures and rehospitalizations. The optimal long-term regimen in terms of patient and pharmacoeconomic benefits remains to be defined.

Adult↗
PubMed1999

Regulation of hyaluronan-stimulated VCAM-1 expression in murine renal tubular epithelial cells.

BACKGROUND: Cytokines stimulate the expression of the adhesion molecule VCAM-1 in renal tubular epithelial cells. We have recently shown that VCAM-1 can also be upregulated by low molecular weight breakdown products of the matrix constituent hyaluronan (HA) (J Immunol 1998; 161: 3431-3437). The mechanisms of VCAM-I expression in response to HA remain to be defined. METHODS: Using a defined mouse cortical tubular (MCT) cell line we investigated the effect of protein kinase C (PKC) and tyrosine kinase (TK) inhibition on the HA-stimulated VCAM-1 expression by cell ELISA and RT PCR or Northern blotting. Furthermore, we examined the effect of PKC and TK inhibition on NF-kappaB. RESULTS: We found that the PKC inhibitor GF109203X (acting on conventional, novel and atypical isoforms) inhibited the HA-stimulated VCAM-1 expression in MCT cells dose-dependently up to 90%, whereas chelerythrine (acting on conventional and novel isoforms) had no effect. Downregulation of PKC with PMA did not prevent the HA-stimulated VCAM-1 expression, suggesting that Ca2+- and diacylglycerol-independent (atypical) isoforms of PKC are involved. The TK inhibitor genistein also inhibited the HA-stimulated VCAM-1 expression at the mRNA and protein level up to 70%. Interestingly, the HA-stimulated nuclear translocation of NF-kappaB could not be prevented with GF109203X and genistein. CONCLUSION: These data demonstrate that the HA-stimulated VCAM-1 expression in MCT cells involves PKC and TK pathways. The absence of an effect of PKC and TK inhibitors on the nuclear translocation of NF-kappaB suggests that additional transcription factors are involved for VCAM-1 expression.

Animals↗
PubMed1999

Enhanced hyaluronan synthesis in the MRL-Fas(lpr) kidney: role of cytokines.

BACKGROUND/AIM: Pathological accumulation of the extracellular matrix component hyaluronan (HA) occurs in the kidney cortex in immune-system mediated tissue injury. The purpose of the present study was to examine the pattern of HA deposition and the mechanisms of HA synthesis in the MRL-Fas(lpr) mouse model of lupus nephritis. METHODS: Kidneys from normal and autoimmune mice were examined for HA content by immunofluorescence staining. Steady state mRNA levels for key enzymes involved in HA synthesis - uridine diphosphate-glucose dehydrogenase (UDPGDH) and HA synthases (HAS) 1, 2 and 3 - were assessed by reverse-transcriptase polymerase chain reaction (RT-PCR). Using cultured mouse tubular epithelial cells, the regulation of the HA production in vitro in response to tumor necrosis factor alpha and interferon gamma was also examined. RESULTS: By immunofluorescence staining, large amounts of HA were detected in the cortical interstitium of MRL-Fas(lpr) mice with autoimmune renal injury, but not in congenic MRL-++ mice. By RT-PCR the presence of transcripts for several genes involved in the synthesis of HA in normal and autoimmune kidneys could be demonstrated, including mRNA for UDPGDH and HAS1 and HAS2, but not for HAS3. Except for HAS2, steady state mRNA levels for these enzymes did not correlate with disease activity. Analyzing a kidney tubular epithelial cell line in vitro, it was found that tumor necrosis factor alpha and interferon gamma, and particularly the combination of these two cytokines, markedly enhanced the synthesis of HA. The expression of HAS2 mRNA was also enhanced in response to cytokine treatment. CONCLUSIONS: HA deposition is prominent in MRL-Fas(lpr) mice with renal disease and could be mediated by local synthesis through HAS1 and HAS2. We hypothesize that the enhanced synthesis of HA could be promoted by proinflammatory cytokines in vivo. The functional significance of HA accumulation in autoimmune renal injury remains to be determined.

Animals↗
PubMed1999

Cytokines in the pathogenesis of systemic lupus erythematosus.

Cytokines, chemokines, and growth factors are overexpressed by renal parenchymal cells and by infiltrating mononuclear cells in human and experimental lupus nephritis. The importance of cytokines in the pathogenesis of lupus nephritis has been established using spontaneous mouse models of systemic lupus erythematosus (SLE). The actions of these cytokines are complex. There is a growing appreciation that the cytokine level and stage of kidney disease determines whether cytokine protects or promotes further tissue injury. This article identifies potential therapeutic targets and strategies that might halt progressive renal injury in patients with SLE.

Animals↗