Measurement of glomerular filtration rate using dynamic magnetic resonance imaging in patients with chronic kidney disease.

BACKGROUND: Determination of glomerular filtration rate (GFR) using plasma disappearance curves requires the injection of a filtration marker and repeated timed blood collections. Gadolinium-containing contrast media are excreted exclusively by glomerular filtration and could provide a novel approach to quantifying GFR using magnetic resonance (MR) imaging. The aim of this study was to demonstrate the feasibility of measuring GFR by the clearance of gadolinium-containing contrast medium in patients with chronic kidney disease (CKD). METHODS: Informed consent was obtained from stable CKD patients in stages 1, 2 or 3 (n=16; 5 women, 11 men; median age 54 years). GFR was measured after a bolus injection of gadobutrol (4 mL, approximately 0.05 mmol/kg) and calculated from the washout of the signal intensity obtained over the liver. The obtained MR-GFR was compared with simultaneously measured plasma clearance of inulin and gadobutrol. RESULTS: Technical failure occurred in 2 patients. The mean obtained MR-GFR was 71 ± 25 (SD) mL/min per 1.73 m² and agreed well with the mean inulin-GFR (70 ± 24 mL/min per 1.73 m²). Pearson's correlation coefficient was r=0.91. The mean of the paired differences was 1 ± 10 mL/min per 1.73 m² and not significantly different from zero. GFR obtained from gadobutrol plasma clearance also agreed well with inulin-GFR and MR-GFR (r=0.92 and r=0.75, respectively). CONCLUSIONS: We describe a novel method of determining GFR from MR imaging using a low dose of gadobutrol in patients with reduced GFR that enables the absolute quantification of GFR after routine contrast-enhanced MR imaging.

Responses to diuretic treatment in gene-targeted mice lacking serum- and glucocorticoid-inducible kinase 1.

BACKGROUND/AIMS: Serum- and glucocorticoid-inducible kinase 1 (SGK1) stimulates the epithelial sodium channel (ENaC), renal outer medullary K(+) channel 1, Na(+)/K(+)-ATPase and presumably the Na(+)-Cl(-) cotransporter (NCC). SGK1-deficient mice (sgk(-/-)) show a compensated salt-losing phenotype with secondary hyperaldosteronism. The present experiments explored the role of SGK1 in the response to diuretics. METHODS: sgk1(-/-) mice and their wild-type littermates (sgk1(+/+)) were treated with the ENaC blocker triamterene (200 mg/l), the Na(+)-K(+)-2Cl(-) cotransport inhibitor furosemide (125 mg/l), the NCC blocker hydrochlorothiazide (400 mg/l) and the mineralocorticoid receptor blocker canrenoate (800 mg/l) for 8 days. Renal SGK1 expression was studied using quantitative RT-PCR and immunofluorescence. RESULTS: Diuretic treatment increased SGK1 mRNA and protein expression in the kidney of wild-type sgk1(+/+) mice. The responses to furosemide, hydrochlorothiazide or canrenoate were not different between sgk1(+/+) and sgk1(-/-) mice, and were accompanied by moderate increases in plasma aldosterone and urea concentrations. However, treatment with triamterene in sgk1(-/-) mice (but not in sgk1(+/+) mice) led to severe, eventually lethal, body weight loss as well as increases in plasma aldosterone, urea and K(+) concentrations. CONCLUSIONS: SGK1 is required for diuretic tolerance to triamterene. The observations confirm the impaired kaliuretic potency of sgk1(-/-) mice and point to a role of SGK1 in renal Na(+) reabsorption by mechanisms other than ENaC.

Acute effects of haemodialysis on pro-/anti- apoptotic genes in peripheral blood leukocytes.

Several studies have implicated a remarkable dysfunctional apoptotic state and/or response in ESRD patients. Previously published studies are controversial with respect to acute effects of haemodialysis (HD) treatment on up- or downregulation of apoptotic genes. Twenty-eight chronic HD patients were haemodialysed for 4 hours with a 4008 dialyser using high-flux membranes. For subgroup analysis, patients were separated into a low (up to 0.5 mg/dl) and a high (0.5 to 5.0 mg/dl) CRP group. Blood was drawn prior to HD and 240 min after initiation of HD. Acute changes of transcript levels encoding pro- or anti-apoptotic genes were analyzed in RNA immediately isolated from blood leukocytes using quantitative real-time PCR. In the present study, we detected a significant elevation of the death receptor CD95/Fas (induction factor (IF) 1.55 +/- 0.16), the death receptor 5 (DR5) (IF 1.17 +/- 0.08), and caspase 8 (IF 1.37 +/- 0.14) gene expression during HD. mRNA levels of the respective ligands (CD95L, TRAIL), of the caspase 5 and anti-apoptotic Bcl-2 family members such as Bcl-2 and Bcl2l2 were slightly, but not significantly, increased after HD treatment. An additional anti-apoptotic molecule, BAG3, was found to be slightly, but significantly, induced after HD (IF 1.16 +/- 0.07). In addition to being an activator of immune cells, CD40L has been shown to be strongly induced after HD treatment (IF 1.70 +/- 0.20). Subgroup analysis revealed no significant differences between low vs. high CRP patient groups or diabetic vs. non-diabetic patients. These results indicate a marked influence of routine haemodialysis treatment on the transcription of pro- and anti-apoptotic molecules and the involvement of the extrinsic pathway for apoptosis through the activation of death receptors and the initiator caspase 8. Furthermore, following dialysis, lymphocytes seem to be activated by CD40L, which represents an early T-cell activation marker.

DOCA and TGF-beta induce early growth response gene-1 (Egr-1) expression.

Renal fibrosis is characterized by excessive accumulation of extracellular matrix proteins. Recent findings show that transforming growth factor-beta (TGF-beta) induces a rapid but transient expression of early growth response gene-1 (Egr-1) by skin fibroblasts. The present study aims to define the role of Egr-1 in mineralocorticoid-induced renal fibrosis. Therefore, we transiently transfected immortalized human renal fibroblasts (TK188) with recombinant Egr-1 and analysed the transcription of several pro-fibrotic genes (Coll1A1, Coll1A2, osteopontin, TIMP-1, and CTGF). We also examined Egr-1 expression and the regulation of pro-fibrotic genes in DOCA- (deoxycorticosterone acetate) and TGF-beta-treated renal fibroblasts. Finally, we compared Egr-1 gene expression in DOCA/high salt-induced fibrotic kidneys and untreated mice. Egr-1 transfection of TK188 fibroblasts induced the expression of TIMP-1 and osteopontin mRNA. Similar results were obtained after DOCA-activation of TK188 cells. Stimulation of TK188 with TGF-beta, but not with DOCA, resulted in elevated Coll1A1/Coll1A2 and CTGF levels. Co-stimulation with DOCA and TGF-beta was followed by enhanced Egr-1, Coll1A1, TIMP-1, and CTGF transcription. In conclusion, both DOCA and TGF-beta alone or in combination synergistically induced Egr-1 expression by human renal fibroblasts. DOCA induction of TIMP-1/osteopontin is Egr-1 dependent, whereas TGF-beta appears to induce Coll1A1 and CTGF by an Egr-1 independent pathway. In vivo analyses revealed significantly higher Egr-1 transcript levels in DOCA/high salt-induced fibrotic kidneys compared to untreated mice. Thus, we show for the first time that Egr-1 might participate in DOCA-induced renal fibrosis.

Effects of tetrahydrobiopterin on nitric oxide bioavailability and renal hemodynamics in healthy volunteers.

BACKGROUND: The endothelial nitric oxide (NO) system plays a central role in regulating vascular tone. Endothelial dysfunction has been closely linked to reduced activity in the NO system. Tetrahydrobiopterin (BH4) is an essential cofactor of all NO synthase isoforms. METHODS: We examined the effects of BH4 on the NO system assessed by measurement of serum cGMP levels and NO breakdown products (NOx) in 12 healthy volunteers. RESULTS: Application of a total of 19 mg/kg BH4 intravenously (i.v.) over 3 hours led to a dose-dependent increase in serum cGMP concentrations from a median 3.3 nM (interquartile range [IQR] 1.1-5.6) to 5.7 nM (IQR 2.4-13.3, p=0.008) and NOx from a median 49.3 microM (IQR 39.8-56.6) to 59.7 microM (39.6-85.5) (p=0.058). Systemic and renal hemodynamics measured by inulin and p-aminohippuric acid (PAH) clearance remained unchanged. Plasma renin activity was significantly increased (2.0 [IQR 1.0-2.8] to 2.3 ng AngI/mL per hour [IQR 1.7-4.0], p=0.045), whereas aldosterone, erythropoietin and B-type natriuretic peptide levels did not change. In a second study, oral BH4 given over 3 days (800 mg/day) similarly increased serum cGMP and ameliorated the depressive effects of the NO synthase inhibitor L-NAME (1.5 mg/kg i.v.) on the glomerular filtration rate. CONCLUSIONS: Application of BH4 in high doses is safe and enhances formation of cGMP, pointing to increased bioavailability of NO.

Variance of the SGK1 gene is associated with insulin secretion in different European populations: results from the TUEF, EUGENE2, and METSIM studies.

HYPOTHESIS: Serum- and Glucocorticoid-inducible Kinase 1 (SGK1) is involved in the regulation of insulin secretion and may represent a candidate gene for the development of type 2 diabetes mellitus in humans. METHODS: Three independent European populations were analyzed for the association of SGK1 gene (SGK) variations and insulin secretion traits. The German TUEF project provided the screening population (N = 725), and four tagging SNPs (rs1763527, rs1743966, rs1057293, rs9402571) were investigated. EUGENE2 (N = 827) served as a replication cohort for the detected associations. Finally, the detected associations were validated in the METSIM study, providing 3798 non-diabetic and 659 diabetic (type 2) individuals. RESULTS: Carriers of the minor G allele in rs9402571 had significantly higher C-peptide levels in the 2 h OGTT (+10.8%, p = 0.04; dominant model) and higher AUC(C-Peptide)/AUC(Glc) ratios (+7.5%, p = 0.04) compared to homozygous wild type TT carriers in the screening population. As interaction analysis for BMIxrs9402571 was significant (p = 0.04) for the endpoint insulin secretion, we stratified the TUEF cohort for BMI, using a cut off point of BMI = 25. The effect on insulin secretion only remained significant in lean TUEF participants (BMI< or =25). This finding was replicated in lean EUGENE2 rs9402571 minor allele carriers, who had a significantly higher AUC(Ins)/AUC(Glc) (TT: 226+/-7, XG: 246+/-9; p = 0.019). Accordingly, the METSIM trial revealed a lower prevalence of type 2 diabetes (OR: 0.85; 95%CI: 0.71-1.01; p = 0.065, dominant model) in rs9402571 minor allele carriers. CONCLUSIONS: The rs9402571 SGK genotype associates with increased insulin secretion in lean non-diabetic TUEF/EUGENE2 participants and with lower diabetes prevalence in METSIM. Our study in three independent European populations supports the conclusion that SGK variability affects diabetes risk.

Serum- and glucocorticoid-inducible kinase 1 in doxorubicin-induced nephrotic syndrome.

Doxorubicin-induced nephropathy leads to epithelial sodium channel (ENaC)-dependent volume retention and renal fibrosis. The aldosterone-sensitive serum- and glucocorticoid-inducible kinase SGK1 has been shown to participate in the stimulation of ENaC and to mediate renal fibrosis following mineralocorticoid and salt excess. The present study was performed to elucidate the role of SGK1 in the volume retention and fibrosis during nephrotic syndrome. To this end, doxorubicin (15 mug/g body wt) was injected intravenously into gene-targeted mice lacking SGK1 (sgk1(-/-)) and their wild-type littermates (sgk1(+/+)). Doxorubicin treatment resulted in heavy proteinuria (>100 mg protein/mg crea) in 15/44 of sgk1(+/+) and 15/44 of sgk1(-/-) mice leading to severe nephrotic syndrome with ascites, lipidemia, and hypoalbuminemia in both genotypes. Plasma aldosterone levels increased in nephrotic mice of both genotypes and was followed by increased SGK1 protein expression in sgk1(+/+) mice. Urinary sodium excretion reached signficantly lower values in sgk1(+/+) mice (15 +/- 5 mumol/mg crea) than in sgk1(-/-) mice (35 +/- 5 mumol/mg crea) and was associated with a significantly higher body weight gain in sgk1(+/+) compared with sgk1(-/-) mice (+6.6 +/- 0.7 vs. +4.1 +/- 0.8 g). During the course of nephrotic syndrome, serum urea concentrations increased significantly faster in sgk1(-/-) mice than in sgk1(+/+) mice leading to uremia and a reduced median survival in sgk1(-/-) mice (29 vs. 40 days in sgk1(+/+) mice). In conclusion, gene-targeted mice lacking SGK1 showed blunted volume retention, yet were not protected against renal fibrosis during experimental nephrotic syndrome.

Immunosuppressive treatment for focal segmental glomerulosclerosis in adults.

BACKGROUND: Corticosteroids remain the mainstay of treatment in idiopathic nephrotic syndrome, including focal and segmental glomerulosclerosis (FSGS). However, only about 20% of patients with FSGS experience a partial or complete remission of nephrotic syndrome despite treatment. OBJECTIVES: To assess the effects of different immunomodulatory and immunosuppressive regimes in adults with FSGS. SEARCH STRATEGY: We searched MEDLINE, EMBASE and CENTRAL and handsearched congress reports of the American Society of Nephrology and the European Dialysis and Transplantation Association. Date of search: 31 January 2007. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs which examined the effects of different doses, dose strategies and duration of treatment of steroids, alkylating agents, cyclosporin A and antimetabolites in the treatment of FSGS in adults, where included. DATA COLLECTION AND ANALYSIS: At least two authors independently assessed abstracts and/or full text articles to determine which studies satisfied the inclusion criteria. Information was entered onto a separate data sheet for each identified study. Data relevant to outcomes (complete or partial remission of nephrotic syndrome, doubling of serum creatinine, adverse effects) from identified studies were included. Results were expressed as risk ratios (RR) with 95% confidence intervals (CI). MAIN RESULTS: Four studies (108 participants) were included. Three studies investigated cyclosporin A (CSA) with or without prednisone versus prednisone or no treatment and one compared chlorambucil plus prednisone versus no treatment. Outcome data was only available for complete or partial remission and doubling of serum creatinine. There was a significant increase in the number of participants who obtained complete or partial remission with CSA plus low dose prednisone versus prednisone alone (one study, 49 participants: RR 8.85, 95% CI 1.22 to 63.92). Pooled analyses were not performed due to the heterogeneity of the data. AUTHORS' CONCLUSIONS: Adult patients treated with CSA at an initial dose of 3.5-5 mg/kg/d in two divided doses perhaps in combination with oral prednisolone 0.15 mg/kg/d are more likely to achieve a partial remission of the nephrotic syndrome compared with symptomatic treatment or prednisolone alone. However, there is a probability of deterioration of kidney function due to the nephrotoxic effect of CSA in the long term. For CSA, a larger controlled trial with longer follow-up should be performed to prove the benefit of this regimen not only on proteinuria but also on the preservation of kidney function. Present available data do not support the general use of alkylating substances for the treatment of FSGS in adults.

SGK1-dependent upregulation of connective tissue growth factor by angiotensin II.

Angiotensin II has previously been shown to trigger fibrosis, an effect involving connective tissue growth factor (CTGF). The signaling pathways linking angiotensin II to CTGF formation are, however, incompletely understood. A gene highly expressed in fibrosing tissue is the serum- and glucocorticoid-inducible kinase SGK1. The present study explored whether SGK1 is transcriptionally regulated by angiotensin II and participates in the angiotensin II-dependent regulation of CTGF expression. To this end, experiments have been performed in human kidney fibroblasts and mouse lung fibroblasts from gene-targeted mice lacking SGK1 (sgk1-/-) and their wild-type littermates (sgk1+/+). In human renal fibroblasts, SGK1 and CTGF protein expression were enhanced by angiotensin II (10 nM) within 4 h. In sgk1+/+ mouse fibroblasts, SGK1 transcript levels were significantly increased after 4 h of angiotensin II treatment. Angiotensin II stimulated both transcript and protein abundance of CTGF in fibroblasts from sgk1+/+ mice, effects significantly blunted in fibroblasts of sgk1-/- mice. In conclusion, angiotensin II stimulates the expression of SGK1, which is in turn required for the stimulating effect of angiotensin II on the expression of CTGF. Thus, SGK1 presumably contributes to the profibrotic effect of angiotensin II.

Lack of the serum and glucocorticoid-inducible kinase SGK1 attenuates the volume retention after treatment with the PPARgamma agonist pioglitazone.

PPARgamma-agonists enhance insulin sensitivity and improve glucose utilization in diabetic patients. Adverse effects of PPARgamma-agonists include volume retention and edema formation. Recent observations pointed to the ability of PPARgamma agonists to enhance transcription of the serum and glucocorticoid-inducible kinase SGK1, a kinase that is genomically upregulated by mineralocorticoids and stimulates various renal channels and transporters including the renal epithelial Na+ channel ENaC. SGK1 has been proposed to mediate the volume retention after treatment with PPARgamma agonists. To test this hypothesis, food containing the PPARgamma agonist pioglitazone (0.02%, i.e., approximately 25 mg/kg bw/day) was administered to gene-targeted mice lacking SGK1 (sgk1-/-, n=12) and their wild-type littermates (sgk1+/+), n=12). According to in situ hybridization, quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and immunofluorescence, treatment with pioglitazone significantly increased renal SGK1 mRNA and protein expression in sgk1+/+ mice. The treatment increased body weight significantly in both, sgk1+/+ mice (+2.2+/-0.3 g) and sgk-/- mice (+1.3+/-0.2 g), and decreased hematocrit significantly in sgk1+/+ mice (-6.5+/-1.0%) and sgk1-/- mice (-3.1+/-0.6%). Both effects were significantly (p<0.05) more pronounced in sgk1+/+ mice. According to Evans Blue distribution, pioglitazone increased plasma volume only in sgk1+/+ mice (from 50.9+/-3.9 to 63.7+/-2.5 microl/g bw) but not in sgk-/- mice (from 46.8+/-3.8 to 48.3+/-5.2 microl/g bw). Pioglitazone decreased aldosterone plasma levels and blood pressure and increased leptin plasma levels in both genotypes. We conclude that SGK1 contributes to but does not fully account for the volume retention during treatment with the PPARgamma agonist pioglitazone.

Major differences in gene expression in human coronary smooth muscle cells after nebivolol or metoprolol treatment.

OBJECTIVE: Vascular smooth muscle cells play a pivotal role in all stages of atherogenesis. Targeting their inflammatory and proliferative qualities might therefore inhibit the progression of atherosclerosis. This study aimed to characterize and compare the effects of the beta-receptor antagonists nebivolol and metoprolol on gene expression in human coronary artery smooth muscle cells (hcaSMC). METHODS AND RESULTS: hcaSMC were incubated with nebivolol or metoprolol (10(-5) mol/l) for 72 h. The downregulated genes are involved in inflammatory processes, oxidative stress and smooth muscle cell proliferation: i.e. downregulated were by nebivolol: interleukin-1alpha, cyclooxygenase-2, tumor-necrosis-factor (TNF)-alpha-induced protein 6, PDGF-A, growth-related oncogenes 2 and 3. Metoprolol increased the expression of interleukin-1alpha, cyclooxygenase-1, TNF-alpha-induced protein 3, heme oxygenase 1 and granulocyte/macrophage-colony-stimulating factor. In addition downregulated was monocyte chemoattractant protein 1 (MCP-1) mRNA by nebivolol. Nebivolol (10(-5) mol/l) reduced the amount of basal NF-kappaB after 48 and 52 h but not metoprolol. In the culture supernatants, MCP-1 concentrations were reduced by nebivolol. CONCLUSIONS: Nebivolol induced changes in the expression of inflammatory mediators in hcaSMC. These results add to data that suggest specific anti-inflammatory qualities of a beta-blocker of the third generation in comparison to metoprolol.

Role of the serum and glucocorticoid inducible kinase SGK1 in glucocorticoid stimulation of gastric acid secretion.

Glucocorticoids stimulate gastric acid secretion, an effect favoring the development of peptic ulcers. Putative mechanisms involved include the serum- and glucocorticoid-inducible kinase (SGK1), which stimulates a variety of epithelial channels and transporters. The present study explored the contribution of SGK1 to effects of glucocorticoids on gastric acid secretion. In isolated gastric glands from gene-targeted mice lacking functional SGK1 (sgk1 (-/-)) and their wild-type littermates (sgk1 (+/+)), H(+)-secretion (DeltapH/min) was determined utilizing 2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein (BCECF)-fluorescence, SGK1 transcript levels by in situ hybdridization, and expression of KCNQ1 channels by immunohistochemistry and real-time polymerase chain reaction. SGK1 transcript levels were enhanced by a 4-day treatment with 10 mug/g body weight (BW)/day dexamethasone (DEX). Before treatment, DeltapH/min was similar in sgk1 (-/-) and sgk1 (+/+)mice. DEX increased DeltapH/min approximately fourfold in sgk1 (+/+)mice and approximately twofold in sgk1 (-/-)mice, effects abolished in the presence of K(+)/H(+)ATPase-inhibitor omeprazole (50 microM). Increase in local K(+) concentrations to 35 mM (replacing Na(+)) enhanced DeltapH/min, which could not be further stimulated by DEX and was not significantly different between sgk1 (-/-) and sgk1 (+/+)mice. Carbachol (100 microM) and forskolin (5 microM) stimulated gastric acid secretion to a similar extent in sgk1 (-/-) and sgk1 (+/+)mice. In conclusion, SGK1 is not required for basal and cyclic AMP-stimulated gastric H(+) secretion but participates in the stimulation of gastric H(+) secretion by glucocorticoids. The effects of glucocorticoids and SGK1 are not additive to an increase in extracellular K(+) concentration and may thus involve stimulation of K(+) channels.

Serum erythropoietin concentrations and responses to anaemia in patients with or without chronic kidney disease.

BACKGROUND: Renal anaemia is caused by a relative erythropoietin (EPO) deficiency. Due to difficult interpretation of serum EPO concentrations adapted to anaemia and renal function, the diagnostic value of measuring serum EPO concentrations is limited. METHODS: We retrospectively analysed the relationship between haemoglobin and serum EPO concentrations routinely measured in in- and out-patients of our university hospital from 2001-04. Patients under EPO substitution or those with acute renal failure, polycystic kidney disease, renal carcinoma or polycythaemia due to pulmonary disease were excluded. The study population (n = 500) was then stratified according to the presence or absence of chronic kidney disease (CKD) and to the stage if CKD was present. EPO concentrations were expressed in percentiles corrected for the severity of anaemia and based on the EPO response in patients without CKD. RESULTS: In patients without CKD (n = 167) there was a strong parametric correlation between severity of anaemia and increase in EPO (r = -0.81). Linear regression of the log-transformed EPO values revealed the equation log EPO (mIU/ml) = -0.135 x Hb (g/dl) + 2.821 (r(2) = 0.65). With increasing stages of CKD the correlation between haemoglobin and EPO concentrations was gradually attenuated and was completely lost in CKD stage four and five. In anaemic patients with Hb < 11 g/dl, relative EPO deficiency defined as EPO concentrations below the 25th percentile was present in 38%, 67%, 93% and 100% of the patients with CKD stages 1-5, respectively. CONCLUSIONS: Expression of EPO concentrations in percentiles improves the diagnostic value of measuring EPO concentrations for diagnosing relative EPO deficiency and renal anaemia.

Hypomagnesemia and nephrocalcinosis in a patient with two heterozygous mutations in the CLDN16 gene.

We report the case of a 20-year-old male Caucasian patient with diagnosed nephrocalcinosis and a medical history of seizures and recurrent urinary tract infections. Laboratory investigations revealed clinical and biochemical abnormalities characteristic of familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC). Since FHHNC is caused by mutations in the CLDN16 gene encoding a renal tight junction protein, we sequenced the complete coding region of this gene and detected two heterozygous mutations, the known Leu151Phe (+453G-->T) mutation and a novel Cys120Arg (+358T-->C) mutation. Due to their location within the primary structure of Claudin-16, both mutations are suggested to interfere with renal paracellular magnesium conductance.

Dynamic magnetic resonance nephrography: is saturation recovery TrueFISP advantageous over saturation recovery TurboFLASH?

PURPOSE: In this volunteer study, 2 navigator-gated strongly T1-weighted saturation-recovery (SR) sequences, a turbo fast low angle shot (TurboFLASH) and a new true fast imaging in steady precession (TrueFISP) readout technique, were compared for suitability in dynamic magnetic resonance nephrography. MATERIALS AND METHODS: Ten healthy volunteers (mean age 26.1 +/- 3.6) were equally divided into 2 subgroups. After bolus-injection of 3.75 mL of gadobutrol (approximately 0.05 mmol/kg body weight), slightly obliqued coronal single-slice images of the kidneys were recorded every 4-5 seconds during free breathing using 1 of the 2 sequences. Time-intensity curves were determined from manually drawn regions-of-interest over the kidney parenchyma. Both sequences were subsequently evaluated with regard to linearity of signal, signal to noise ratio (SNR), and time-dependent behavior of signal intensity curves. RESULTS: : The TurboFLASH readout showed better linearity of the signal behavior as compared with the TrueFISP technique (TurboFLASH: no deviation from linearity down to T1 = 400 milliseconds; TrueFISP at T1 = 700 milliseconds: 12% deviation, at T1 = 400 milliseconds: 19%). The time-intensity curves of the TrueFISP sequence exhibited distinctly lower variability than the TurboFLASH approach. The SNR increased with TrueFISP by 3.4 +/- 0.5-fold for native renal parenchyma and by 3.3 +/- 0.9 for contrast-enhanced renal parenchyma. For split renal function evaluation, the linear regression to the signal increase in the first minutes after the first pass could be performed with higher reliability using the TrueFISP technique (increase of correlation coefficient by 17.1%). CONCLUSION: A SR navigator-gated TrueFISP sequence seems most favorable for dynamic magnetic resonance nephrography due to the high signal yield and low curve variability.

Influence of nebivolol and metoprolol on inflammatory mediators in human coronary endothelial or smooth muscle cells. Effects on neointima formation after balloon denudation in carotid arteries of rats treated with nebivolol.

OBJECTIVE AND BACKGROUND: Inflammation plays a critical role in all stages of atherogenesis. Proliferating vascular smooth muscle cells (SMC) and endothelial cells (EC) enhancing the inflammatory response, both contribute to the progression of atherosclerosis. Anti-proliferative, anti-inflammatory and anti-oxidative therapy seems to be a promising therapeutic strategy. The aim of this study was to assess the anti-proliferative and anti-inflammatory effect of the beta-blocker nebivolol in comparison to metoprolol in vitro and to find out whether nebivolol inhibits neointima formation in vivo. METHODS AND RESULTS: Real-time-RT-PCR revealed a decrease in VCAM-1, ICAM-1, PDGF-B, E-selectin and P-selectin mRNA expression in human coronary artery EC and SMC incubated with nebivolol for 72 hours while metoprolol did not have this effect. Nebivolol reduced MCP-1 and PDGF-BB protein in the culture supernatant of SMC and EC, respectively. Sprague-Dawley rats were treated with nebivolol for 0 or 35 days before and 28 days after carotid balloon injury. Immunohistological analyses showed that pre-treatment with nebivolol was associated with a decreased number of SMC layers and macrophages and an increased lumen area at the site of the arterial injury. The intima area was reduced by 43% after pre-treatment. CONCLUSION: We found that nebivolol reduced the expression of proinflammatory genes in endothelial cells and vascular smooth muscle cells in vitro whereas metoprolol did not. In vivo, nebivolol inhibited neointima formation by reducing SMC proliferation and macrophage accumulation.

Quantitative assessment of glomerular filtration rate with MR gadolinium slope clearance measurements: a phase I trial.

PURPOSE: To prospectively demonstrate the feasibility of quantifying the glomerular filtration rate (GFR) by assessing the renal clearance of gadolinium-based contrast medium from the extracellular fluid volume in healthy volunteers. MATERIALS AND METHODS: The study was approved by the ethics committee and the governmental drug administration department (registration number 4030139, EudraCT number 2004-002969-20, study protocol number 318/2004). Informed consent was obtained from 16 healthy volunteers (six female, 10 male; mean age, 24.5 years +/- 2.8 [standard deviation]). Thirteen volunteers (four women, nine men; mean age, 24.8 years +/- 2.7; range, 23-30 years) successfully contributed to the study. The GFR was assessed by recording the renal clearance of gadobutrol (3.75 mL, approximately 0.05 mmol per kilogram of body weight) at navigator-gated turbo fast low-angle shot magnetic resonance (MR) imaging. Time-signal intensity curves were constructed from manually drawn regions of interest in the liver, spleen, and renal cortex, and the GFR was calculated by using exponential fitting. Simultaneously obtained iopromide clearance measurements were the reference standard. Statistical evaluations included Bland-Altman plotting and analysis of the relative deviation from iopromide clearance. RESULTS: Evaluation of liver regions of interest revealed the lowest mean of paired differences from the iopromide clearance measurements (-5.9 mL/min per 1.73 m(2) +/- 14.6), with a mean GFR of 109.0 mL/min per 1.73 m(2) +/- 17.1 (134.1 mL/min per 1.73 m(2) +/- 35.4 for spleen, 100.7 mL/min per 1.73 m(2) +/- 25.1 for renal cortex) compared with a mean GFR of 103.1 mL/min per 1.73 m(2) +/- 9.4 measured by using iopromide clearance. The maximum deviation of MR-determined gadobutrol clearance values from iopromide clearance values was 29.2%. The mean disposition half-life of gadobutrol measured in the liver was 83.0 minutes +/- 14.2 (72.4 minutes +/- 20.2 in spleen, 92.6 minutes +/- 23.7 in renal cortex). CONCLUSION: The described MR imaging method enables absolute quantification of the GFR after routine contrast material-enhanced MR imaging.

Secondary syphilis after liver transplantation: case report and review of the literature.

Syphilitic disease is uncommon, but its incidence has increased worldwide in the last few years. An unusual manifestation of secondary syphilis after orthotopic liver transplantation is described which confirms that lues should be considered in patients with immune deficiency and abnormal liver function tests.

Efficacy and tolerability of the perindopril/indapamide combination therapy for hypertension: the PRIMUS study.

BACKGROUND: Tight blood pressure (BP) control is required to reduce cardiovascular morbidity and mortality. OBJECTIVE: To evaluate the efficacy and tolerability of the first line combination perindopril/indapamide in hypertension in daily practice. DESIGN AND METHODS: In this prospective, open-label, observational trial, 1892 general practitioners in Germany recruited patients with hypertension (n = 8023; mean age 59.6 years, 48.1% males, body mass index 27.6 kg/m2, systolic BP >or= 140 mmHg and/or diastolic BP >or= 90 mmHg) between October 2002 and December 2004. Patients received perindopril 2 mg/indapamide 0.625 mg for 12 weeks. BP measured in the general practice setting, safety, and tolerability were evaluated after 4 and 12 weeks. RESULTS: At baseline, most patients had moderate to severe hypertension (78%); initial BP was 164.6/95.8 mmHg. At inclusion, 38% of the patients were newly diagnosed hypertensives (mean BP 166.1/97.2 mmHg) and 58% of patients had uncontrolled BP despite preexisting antihypertensive treatment (163.5/94.9 mmHg). Previous treatment consisted of beta-blockers (49.5%), ACE inhibitors (36.4%), calcium-antagonists (29.3%), diuretics (28.8%), AT-I receptor antagonists (7.1%), and other treatments (8.1%). In the entire study cohort, treatment with perindopril/indapamide significantly decreased systolic BP (27.9 mmHg), diastolic BP (13.7 mmHg), and pulse pressure (14.2 mmHg), compared with baseline (p < 0.0001); 96% of patients responded to treatment and in 50% of patients BP was normalized (< 140/90 mmHg). Treatment dose was doubled in 9.5% of patients. Similar results were found in various subgroup analyses (newly diagnosed patients, the elderly, and patients with isolated systolic hypertension, additional cardiovascular risk factors, associated diseases, or target organ damage). The most frequent adverse events (< 1% of patients) were dry cough and nausea. CONCLUSIONS: The open-label, observational study PRIMUS, extends the existing evidence that the first line combination treatment of hypertension with perindopril/indapamide is effective, safe, and well tolerated in a representative cross-section of patients with newly diagnosed or pretreated but uncontrolled hypertension in daily practice.

Blunted DOCA/high salt induced albuminuria and renal tubulointerstitial damage in gene-targeted mice lacking SGK1.

Mineralocorticoids stimulate renal tubular Na(+) reabsorption, enhance salt appetite, increase blood pressure, and favor the development of renal fibrosis. The effects of mineralocorticoids on renal tubular Na(+) reabsorption and salt appetite involve the serum- and glucocorticoid-inducible kinase 1 (SGK1). The kinase is highly expressed in fibrosing tissue. The present experiments thus explored the involvement of SGK1 in renal fibrosis. To this end, SGK1-knockout mice (sgk1 (-/-)) and their wild-type littermates (sgk1 (+/+)) were implanted with desoxycorticosterone acetate (DOCA)-release pellets and offered 1% saline as drinking water for 12 weeks. The treatment led to significant increases in fluid and Na(+) intake and urinary output of fluid and Na(+) in sgk1 (+/+) mice, effects blunted in sgk1 (-/-) mice. Blood pressure increased within the first 7 weeks to a similar extent in both genotypes, but within the next 5 weeks, it increased further only in sgk1 (+/+) mice. Creatinine clearance did not change significantly but albuminuria increased dramatically in sgk1 (+/+) mice, an effect significantly blunted in sgk1 (-/-) mice. Histology after 12 weeks treatment revealed marked glomerular sclerosis and tubulointerstitial damage with interstitial fibrosis and inflammation in kidneys from sgk1 (+/+) mice, but not from sgk1 (-/-) mice. In conclusion, a lack of SGK1 protects against DOCA/high-salt-induced albuminuria and renal fibrosis.