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G Navis

Publications and source records attributed to G Navis.

At least 19 recordsLinked to original sources
PubMed2007

Effect of combining ACE inhibition with aldosterone blockade on proteinuria and renal damage in experimental nephrosis.

Aldosterone has pro-fibrotic properties and is a potential target for additional intervention in patients with chronic renal disease showing resistance to therapy during treatment with angiotensin-converting enzyme inhibitors (ACEi). Combining ACEi and aldosterone receptor blockade (aldoRB) in proteinuric renal disease reduces proteinuria, but effects on proteinuria-induced renal damage are unknown. We studied the effect of ACEi/aldoRB in adriamycin nephrosis (AN). Six weeks after injection of adriamycin in Wistar rats, randomized treatment with vehicle (VEH, n=8), aldoRB (n=12), ACEi (n=10), or a combination of ACEi/aldoRB (n=14) was given for 12 weeks. Healthy rats served as controls (n=6). Renal damage was quantified by markers of tubular injury (osteopontin (OPN) and kidney injury molecule-1 (Kim-1)), pre-fibrotic lesions (alpha-smooth muscle actin (SMA)), interstitial fibrosis (IF), and focal glomerulosclerosis (FGS). In AN animals, proteinuria was increased compared with controls. ACEi and ACEi/aldoRB significantly reduced proteinuria compared with VEH, whereas aldoRB monotherapy was without effect. Blood pressure was reduced in ACEi and ACEi/aldoRB compared with VEH and aldoRB. OPN and Kim-1 were increased in AN animals, but significantly reduced by ACEi/aldoRB. Treatment with ACEi and ACEi/aldoRB prevented an increase of SMA, IF, and FGS. In conclusion, ACEi/aldoRB effectively reduced proteinuria and markers of tubular injury and prevented renal damage in this rat model of chronic proteinuria-induced renal damage.

Actins↗
PubMed2006

Gender-specific correlations of plasminogen activator inhibitor-1 and tissue plasminogen activator levels with cardiovascular disease-related traits.

BACKGROUND: The purpose of this study was to examine the correlations between plasma levels of plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator (t-PA) and cardiovascular disease-related traits in a general population and whether these correlations differed between females and males. METHODS: Plasma PAI-1 and t-PA antigen levels and C-reactive protein (CRP), HDL-cholesterol, triglycerides, total cholesterol, systolic blood pressure, diastolic blood pressure, urinary albumin excretion, and glucose were measured in the population-based PREVEND study in Groningen, the Netherlands (n = 2527). RESULTS: Except for CRP and total cholesterol levels, all traits were significantly different between gender (P < 0.001). PAI-1 levels were correlated with all measured cardiovascular disease-related traits (P < 0.01) in both females and males. Except for urinary albumin excretion, similar results, albeit less significant, were found for t-PA levels. Age-adjusted correlations between PAI-1 and CRP, triglycerides, total cholesterol, systolic blood pressure, and diastolic blood pressure differed significantly between females and males (P < 0.01). Many of the gender differences were predominantly present between premenopausal females and males. CONCLUSION: PAI-1 and t-PA levels were correlated with cardiovascular disease-related traits in subjects obtained from the general population and several of these correlations differed across gender. The correlations found in the present study suggest the presence of coordinated patterns of cardiovascular risk factors and indicate which traits might influence PAI-1 and t-PA levels and thereby provide a framework and potential tool for therapeutic intervention to reduce thromboembolic events in the general population.

Adult↗
PubMed2006

The effect of a shift in sodium intake on renal hemodynamics is determined by body mass index in healthy young men.

A body mass index (BMI)>or=25 kg/m2 increases the risk for long-term renal damage, possibly by renal hemodynamic factors. As epidemiological studies suggest interaction of BMI and sodium intake, we studied the combined effects of sodium intake and BMI on renal hemodynamics. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured in 95 healthy men (median age 23 years (95% confidence interval: 22-24), BMI: 23.0+/-2.5 kg/m2) on low (50 mmol Na+, LS) and high (200 mmol Na+, HS) sodium intake. Mean GFR and ERPF significantly increased by the change to HS (both P<0.001). During HS but not LS, GFR and filtration fraction (FF) positively correlated with BMI (R=0.32 and R=0.28, respectively, both P<0.01). Consequently, BMI correlated with the sodium-induced changes in GFR (R=0.30; P<0.01) and FF (R=0,23; P<0.05). The effects of HS on GFR and FF were significantly different for BMI>or=25 versus <25 kg/m2, namely 7.8+/-12.3 versus 16.1+/-13.1 ml/min (P<0.05) and -0.1+/-2.2 and 1.1+/-2.3% (P<0.05). FF was significantly higher in BMI>or=25 versus <25 kg/m2, (22.6+/-2.9 versus 24.6+/-2.4%, P<0.05) only during HS. ERPF was not related to BMI. Urinary albumin excretion was increased by HS from 6.0 (5.4-6.7) to 7.6 (6.9-8.9). Results were essentially similar after excluding the only two subjects with BMI>30 kg/m2. BMI is a determinant of the renal hemodynamic response to HS in healthy men, and of GFR and FF during HS, but not during LS. Consequently, HS elicited a hyperfiltration pattern in subjects with a BMI>or=25 kg/m2 that was absent during LS. Future studies should elucidate whether LS or diuretics can ameliorate the long-term renal risks of weight excess.

Adult↗
PubMed2006

ACE inhibition has adverse renal effects during dietary sodium restriction in proteinuric and healthy rats.

Angiotensin-converting enzyme inhibitors (ACEi) provide renoprotection. A low sodium diet enhances their efficacy. However, the added effect of sodium restriction on proteinuria and blood pressure is not invariably associated with better preservation of renal morphology, suggesting that the combination of ACEi with a low sodium diet can elicit renal structural abnormalities. To test this hypothesis, the effects of ACEi in combination with a control (CS) or a low sodium (LS) diet were investigated in healthy rats and in adriamycin nephrotic rats. After 3 weeks of treatment, rats were sacrificed and kidneys examined for renal structural abnormalities. In healthy rats, ACEi reduced blood pressure: the fall in blood pressure was significantly greater in the ACEi/LS group. Renal morphology was normal in the ACEi/CS group but severe interstitial damage was found in the ACEi/LS group. This was associated with increased interstitial macrophage influx and up-regulation of osteopontin, alpha-smooth muscle actin, and collagen III expression. In addition, ACEi/LS induced an increase in the total medial area of afferent arterioles. In nephrotic rats, ACEi/LS reduced both blood pressure and proteinuria, whereas only blood pressure was reduced in the ACEi/CS group. Mild interstitial damage was present in the ACEi/CS group but, strikingly, pronounced tubulo-interstitial abnormalities occurred in the ACEi/LS group, similar to those seen in ACEi/LS healthy rats, with similar changes in afferent arteriolar walls. In conclusion, the combination of ACEi/LS elicits pronounced renal interstitial abnormalities in healthy and nephrotic rats, despite a significant reduction of proteinuria in the latter. Considering their occurrence in healthy rats, these renal adverse effects cannot be due to specific characteristics of adriamycin nephrosis. Further studies should elucidate the mechanisms underlying these observations and their impact on long-term renoprotection.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2006

The predictive value of renal vascular resistance for late renal allograft loss.

The renal artery resistance index (RI), assessed by Doppler ultrasonography, was recently identified as a new risk marker for late renal allograft loss. This finding requires confirmation since RI in that study was not measured at predetermined time points and ultrasonography is operator-dependent. We investigated the predictive value of renal vascular resistance (RVR), a less operator-dependent method as assessed by mean arterial pressure divided by renal blood flow, for the prediction of recipient mortality and death-censored graft loss. RVR was compared to commonly used risk markers such as creatinine clearance (CrCl), serum creatinine (SCreat) and proteinuria (UProt) in 793 first-time cadaveric renal transplant recipients at predetermined time points after transplantation using receiver operating characteristics (ROC) and Cox survival analyses. The present study showed that RVR is a prominent risk marker for recipient mortality and death-censored graft loss. However, the predictive value of RVR for recipient mortality owed mainly to the impact of mean arterial blood pressure. In contrast, RVR constituted more than the sum of its components for death-censored graft loss, but showed less predictive value than SCreat in univariate analysis. As the assessment of RVR is expensive and time-consuming, we believe that RVR holds no clinical merit for the follow-up of renal transplant recipients.

Adult↗
PubMed2004

Renoprotection by blockade of the renin-angiotensin-aldosterone system in diabetic and non-diabetic chronic kidney disease. Specific involvement of intra-renal angiotensin-converting enzyme activity in therapy resistance?

Data of numerous clinical trials show that lowering of blood pressure is prerequisite for reducing the rate of renal function loss in chronic renal disease. There is evidence supporting that blood pressure lowering obtained by intervention in the renin-angiotensin-aldosterone system (RAAS) has an additive renoprotective effect over reduction of blood pressure alone, both in diabetic and non-diabetic renal diseases. The main evidence for renoprotective action of RAAS blockade is provided by its consistent antiproteinuric action, which cannot completely be attributed to the reduction in blood pressure. Indeed, proteinuria reduction during therapy is the single most important factor predicting the renal prognosis, independent from the class of drugs used. Yet, still patients progress to end-stage renal disease. In this review, individual differences in therapy response and possibilities to overcome therapy resistance to RAAS blockade are discussed. Experimental data from studies in rats suggest a specific involvement of intrarenal factors, particularly of preexisting renal damage and renal angiotensin-converting enzyme (ACE) activity, in therapy resistance. Identification of such factors in individual renal patients provides mechanisms by which renoprotective strategies fail to overcome therapy resistance. This prompts for a dual approach to improve renoprotection, namely unravelling these specific intrarenal mechanisms on the one hand, and development of better strategies for early detection of renal risk on the other hand.

Angiotensin Receptor Antagonists↗
PubMed2003

Accelerated decline and prognostic impact of renal function after myocardial infarction and the benefits of ACE inhibition: the CATS randomized trial.

AIMS: Information regarding the cardiorenal axis in patients after a myocardial infarction (MI) is limited. We examined the change in renal function after a first MI, the protective effect of angiotensin converting enzyme (ACE) inhibition and the prognostic value of baseline renal function. METHODS AND RESULTS: The study population consisted of 298 patients with a first anterior wall MI who were randomized to the ACE inhibitor captopril or placebo after completion of streptokinase infusion. Renal function, by means of glomerular filtration rate (GFR), was calculated using the Cockroft-Gault equation (GFR(c)). In the placebo group, renal function (GFR(c)) declined by 5.5 min(-1)within 1 year, vs only 0.5 ml min(-1)in the ACE inhibitor group (P<0.05). This beneficial effect of captopril was most pronounced in patients with the most compromised renal function at baseline. The incidence of chronic heart failure (CHF) within 1 year increased significantly with decreasing GFR(c)(divided into tertiles: 24.0, 28.9, and 41.2%; P<0.01). The risk-ratio for GFR(c)<81 ml min(-1)vs >103 mL min(-1)was 1.86 (95% CI 1.11-3.13; P=0.019). CONCLUSIONS: Renal function markedly deteriorates after a first MI, but is significantly preserved by ACE inhibition. Furthermore, an impaired baseline renal function adds to the prognostic risk of developing CHF in patients after a first anterior MI.

Adult↗
PubMed2001

Chronic blockade of angiotensin II action prevents glomerulosclerosis, but induces graft vasculopathy in experimental kidney transplantation.

Long-term renin-angiotensin system blockade is beneficial in a variety of renal diseases. This study examines the long-term (34 weeks) effects of the angiotensin-converting enzyme inhibitor lisinopril and the angiotensin II receptor type I blocker L158,809 in the Fisher to Lewis rat model of chronic renal transplant failure. Treatment in allografted rats with lisinopril or L158,809 was initiated 10 days after transplantation, or at the time when proteinuria exceeded 50 mg/24 h. Untreated allografts and syngrafts served as controls. In contrast to syngrafts, untreated allografts developed proteinuria, hypercholesterolaemia, interstitial damage, and glomerulosclerosis. Lisinopril or L158,809 treatment in allografts starting at day 10 after transplantation completely prevented this, with the exception of interstitial damage, but this treatment also caused a reduction in blood pressure and renal function. Moreover, the intimal surface area of the renal arteries was dramatically increased in allografts treated with either lisinopril or L158,809 compared with untreated allografted rats. Treatment once proteinuria had developed was less effective in preventing glomerulosclerosis, but also caused less intimal expansion. Thus, chronic renin-angiotensin system blockade preserves glomerular morphology in the absence of proteinuria, but enhances intimal hyperplasia and reduces renal function in experimental transplantation. In view of these results, it should be questioned whether such treatment benefits renal transplant patients in the long term.

Angiotensin II↗
PubMed2001

Optimal antiproteinuric dose of losartan in nondiabetic patients with nephrotic range proteinuria.

Although the antiproteinuric response to antihypertensive treatment is the main predictor of renoprotective efficacy in long-term renal disease, to date, dose-finding studies of antihypertensives have been based only on blood pressure. We aimed to find the optimal antiproteinuric dose of the angiotensin II antagonist losartan. An open-label, dose-response study using subsequent 6-week treatment periods was performed in 10 nondiabetic patients with proteinuria of 5.8 +/- 0.8 g/d and a mean arterial pressure of 103 +/- 3.7 mm Hg without antihypertensive medication. All patients had normal to moderately impaired renal function. After the baseline period, five periods followed with a daily losartan dose of 50 mg, 100 mg, 150 mg, and 50 mg and a recovery without losartan. At the end of each period, proteinuria and mean arterial pressure were measured. The consecutive doses of losartan had a similar antihypertensive response (-11.3 +/- 2.8% by the 100-mg dose). The optimal antiproteinuric response was reached at 100 mg of losartan (-30 +/- 8%). The 50-mg dose (-13 +/- 7%) was less effective, and the 150-mg dose (-28 +/- 8%) was not more effective. A 100-mg dose of losartan is optimal for reduction of proteinuria in nondiabetic patients with nephrotic range proteinuria.

Antihypertensive Agents↗
PubMed2001

Role of genetic variability in the renin-angiotensin system in diabetic and nondiabetic renal disease.

Studies on genetic variability in the renin-angiotensin system (RAS) provide intriguing data that support its possible relevance to renal pathophysiology. However, from the discrepancies between different studies it is clear that RAS polymorphisms do not provide simple markers for renal prognosis or therapy response. Rather than attempting to force a conclusion from the available discrepancies, we should attempt to develop strategies from the current state of knowledge to attack this complex issue from different angles. Unraveling their functional impact in renal pathophysiology can provide a framework for understanding that can guide further studies with the eventual purpose of improving the prognosis of renal patients. Clinical association studies should be large and prospective, to obtain the necessary robustness, with proper attention paid to the role of contextual factors. Moreover, studies elucidating the physiologic mechanisms of the genetic determinants of the disease phenotype are of prime importance. Such information is vital, not only to make sense of observed associations, but all the more so if one wants to apply the insights on the role of genetic factors into better strategies for disease intervention.

Angiotensin Receptor Antagonists↗
PubMed2001

Time course of the antiproteinuric and renal haemodynamic responses to losartan in microalbuminuric IDDM.

BACKGROUND: Interference in the renin-angiotensin system with angiotensin-converting enzyme (ACE) inhibitors has proven to be effective in lowering albuminuria in patients with insulin-dependent diabetes mellitus (IDDM). We studied whether angiotensin II receptor antagonism reduces urinary albumin excretion (UAE) in IDDM patients, and the relationship between the antiproteinuric effect and changes in systemic and renal haemodynamics. METHODS: Nine IDDM patients with microalbuminuria (30-300 mg/24 h) were studied. Patients were studied after a 4 week placebo period, on days 3, 7 and 28 of treatment with losartan 50 mg once daily, and after a 4 week placebo-controlled recovery period. RESULTS: Mean arterial pressure (MAP) was only slightly lowered during losartan treatment. Effective renal plasma flow (ERPF) was significantly increased on the third day of treatment and remained stable throughout the treatment period. Glomerular filtration rate (GFR) did not change throughout the study. Filtration fraction (FF) was maximally lowered on the third day of treatment and remained stable during treatment. UAE was already significantly lowered after 2 days of treatment, during both the day and night, and remained stable throughout the treatment period. The time course of the changes in UAE paralleled that of the changes in MAP, ERPF and FF. CONCLUSIONS: The angiotensin receptor antagonist losartan effectively lowers UAE in microalbuminuric IDDM patients. The changes observed in renal haemodynamics and UAE are concordant in time and maximal within only a few days of treatment. These results support the importance of the specific effects of interference in the renin angiotensin system (RAS) in microalbuminuric IDDM on blood pressure and renal haemodynamics in reducing urinary protein leakage, rather than non-haemodynamic, structural changes of the glomerular basement membrane.

Albuminuria↗
PubMed2000

Renal and systemic effects of continued treatment with renin inhibitor remikiren in hypertensive patients with normal and impaired renal function.

BACKGROUND: Remikiren is an orally active renin inhibitor with established antihypertensive efficacy. As a single dose it induces renal vasodilatation, suggesting specific renal actions. Data on the renal effects of continued treatment by renin inhibition are not available, either in subjects with normal, or in subjects with impaired renal function. METHODS: The effect of 8 days of treatment with remikiren 600 mg o.i.d. on blood pressure, renal haemodynamics, and proteinuria was studied in 14 hypertensive patients with normal or impaired renal function.The study was conducted on an ambulatory in-hospital basis and was designed in a single-blind, longitudinal order. RESULTS: Remikiren induced a significant peak fall in mean arterial pressure of 11.2+/-0.8%, with corresponding trough values of -6+/-0.8%. This fall was somewhat more pronounced in the patients with renal function impairment (-13.3 vs -9.6%; P<0.01). Glomerular filtration rate remained stable, whereas effective renal plasma flow increased from 301+/-35 to 330+/-36 ml/min/1.73 m(2) (P<0.05). Filtration fraction and renal vascular resistance fell by 10+/-2% and 15+/-2% respectively (both P<0.01). Remikiren induced a cumulated sodium loss of -82+/-22 mmol and a positive potassium balance of 49+/-9 mmol (both P<0.01). During remikiren, proteinuria fell by 27% (range -18 to -38%; P<0.01) in the patients with overt proteinuria at onset (n=6). In the remainder of the patients albuminuria fell by 20% (range -1 to -61%, P<0.05). No side-effects were observed. CONCLUSIONS: Continued treatment with remikiren induced a sustained fall in blood pressure, renal vasodilatation, negative sodium balance, and a reduction in glomerular protein leakage. These data are consistent with a renoprotective potential of renin inhibition.

Adult↗
PubMed2000

Role of patient factors in therapy resistance to antiproteinuric intervention in nondiabetic and diabetic nephropathy.

Reduction of proteinuria is a prerequisite for successful long-term renoprotection. To investigate whether individual patient factors are determinants of antiproteinuric efficacy, we analyzed individual responses to different modes of antiproteinuric intervention in nondiabetic and diabetic patients, obtained in prior studies comparing the efficacy of various pharmacological regimens. The individual antiproteinuric response to angiotensin-converting enzyme (ACE) inhibition positively correlated to the response to angiotensin type I (AT1) receptor blockade in diabetic (r = 0.67, P < 0.01, N = 16) as well as nondiabetic patients (r = 0.75, P < 0.01, N = 12). This corresponded to the correlations for antihypertensive efficacy between ACE inhibition and AT1 receptor blockade in diabetic (r = 0.73, P < 0.001) as well as nondiabetic patients (r = 0.55, P < 0.05). Remarkably, the antiproteinuric response to ACE inhibition also correlated positively to the antiproteinuric response to indomethacin (r = 0.63, P < 0.05, N = 9). Thus, patients responding favorably to one class of antiproteinuric drugs also respond favorably to other classes of available drugs, supporting a main role for individual patient factors in responsiveness or resistance to antiproteinuric intervention. In the search for strategies to improve response in these high risk patients, combination-treatment (combining different drugs, and combining drugs with dietary measures like sodium and protein restriction), and the use of higher doses may provide more fruitful strategies to optimize renoprotection than shifting to other classes of the available drugs.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1999

Angiotensin-converting enzyme gene I/D polymorphism and renal disease.

In recent years a vast amount of data has been published on the association between the insertion/deletion (I/D) polymorphism of the gene coding for angiotensin-converting enzyme and renal disease. It has become clear that the polymorphism does not affect the prevalence of renal disease. However, data on the association with progression of renal disease and therapy response are still contradictory. Moreover, sufficient data on the physiological significance of this polymorphism are still lacking. This contribution provides an overview of the available studies and the potential pitfalls in interpreting the data. We also discuss the putative mechanisms for the association between the DD genotype and progression of renal disease and suggest directions for the future that might be employed to further clarify the role in renal pathophysiology.

Diabetes Mellitus, Type 1↗
PubMed1999

Impaired renal vascular response to a D1-like receptor agonist but not to an ACE inhibitor in conscious spontaneously hypertensive rats.

The natriuretic response to a dopamine 1-like receptor agonist is blunted in spontaneously hypertensive rats (SHRs). Whether the renal vasodilator response to D1-like receptor stimulation in SHRs is defective also is unclear. To determine whether the renal hemodynamic response to a D1-like receptor is impaired in SHR, we examined the effect of a continuous infusion of the D1-like receptor agonist fenoldopam (2 microg/kg/min) on systemic and renal hemodynamics in conscious SHRs and Wistar-Kyoto (WKY) rats. As an active control, we used an equivalent antihypertensive dosage of captopril (10 mg/kg). Fenoldopam significantly increased effective renal plasma flow (ERPF) in WKY rats (+22 +/- 5%; p < 0.01), whereas this response was absent in SHRs (+7 +/- 3%; NS). Mean arterial pressure (MAP) was significantly reduced in SHRs (-11 +/- 2%; p < 0.001), demonstrating a systemic vasodilator response to fenoldopam in SHRs. The reduction in renal vascular resistance (RVR) was more pronounced in WKY rats (-24 +/- 2%) than in SHRs (-13 +/- 4%; p < 0.05). Captopril significantly increased ERPF in SHRs (+16 +/- 3%; p < 0.001), demonstrating a preserved renal vasodilatory capacity in SHRs. The blunting of the renal vasodilatory response to fenoldopam in SHRs is present during a high as well as a low sodium intake. In conscious SHRs, the renal vasodilatory response to a D1-like receptor agonist is impaired, whereas the blood pressure response is more pronounced. The preserved renal vasodilatory response to captopril indicates that the defective vasodilatory response in SHRs is functional rather than due to altered structural properties of the renal vascular bed.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1999

Systemic factors are involved in the pathogenesis of proteinuria-induced glomerulosclerosis in adriamycin nephrotic rats.

This study aims to dissociate the respective roles of systemic nephrosis and of the intrarenal effects of proteinuria in the pathogenesis of focal segmental glomerulosclerosis (FGS) in adriamycin nephrosis. To this purpose, this study examined proteinuria and FGS in bilateral (BAP) and unilateral proteinuria (UAP) in two different rat strains. UAP was obtained by protecting one kidney from exposure to adriamycin by temporary clipping of one renal artery during adriamycin injection. At sacrifice (week 12), FGS was present in BAP and in exposed kidneys in UAP, but not in unexposed kidneys. FGS correlated significantly with proteinuria per kidney in BAP and UAP. Remarkably, for a given proteinuria per kidney, the sclerosis score was higher in BAP than in UAP, reflected by a higher ratio of FGS score per mg proteinuria per kidney (Wistar: 0.09 +/- 0.01 in BAP versus 0.05 +/- 0.01%/mg protein per d in UAP, P < 0.05; Lewis: 0.12 +/- 0.01 in BAP versus 0.07 +/- 0.01%/mg protein per d in UAP, P < 0.05), indicating that the local damaging effects of proteinuria are modified by other factors. Cholesterol correlated with total proteinuria in BAP and UAP. FGS score was positively correlated with cholesterol. The latter correlation was similar in BAP and UAP, indicating that cholesterol was a more uniform predictor for FGS than proteinuria per kidney. This was independent of strain-specific factors. On multilinear regression analysis, cholesterol turned out to be the most consistent predictor of FGS in proteinuric kidneys, with a stronger predictive value than proteinuria per kidney. It is concluded that although systemic sequelae of nephrosis do not induce renal damage in nonproteinuric kidneys, they modify the severity of proteinuria-induced FGS in proteinuric kidneys.

Animals↗