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Biomedical subjects

G Navis

Publications and source records attributed to G Navis.

At least 37 records · Page 2Linked to original sources
PubMed1999

Effect of proteinuria reduction on prevention of focal glomerulosclerosis by angiotensin-converting enzyme inhibition is modifiable.

BACKGROUND: Proteinuria is associated with a progressive loss of renal function; we recently found that both intrarenal effects of proteinuria and the state of systemic nephrosis play an independent role in proteinuria-induced renal damage. Reduction of proteinuria is an important mechanism underlying the renoprotective effect of angiotensin-converting enzyme inhibition (ACEi). Both the reduction of proteinuria and the attenuation of the systemic state of nephrosis may be involved in the renoprotection by ACEi. METHODS: This article entails a post hoc analysis of a previous study on the renoprotective effect of ACEi lisinopril in adriamycin nephrosis. It was attempted to modify therapeutic efficacy of ACEi by increasing lisinopril dose and by dietary sodium restriction, respectively. In this analysis, we aimed to delineate the contribution of proteinuria reduction and the reduction of other intermediate parameters such as hyperlipidemia and blood pressure on the protection against focal glomerulosclerosis (FGS). RESULTS: We found that in adriamycin nephrosis, ACEi significantly reduced proteinuria, lipids, and blood pressure and provided protection against FGS. Treatment modification by increasing the lisinopril dose resulted in a further reduction of FGS without significant effects on intermediate parameters (proteinuria, hyperlipidemia, and blood pressure), whereas surprisingly, treatment modification by sodium restriction resulted in a further attenuation of intermediate parameters, without additional protection against FGS. CONCLUSIONS: The renoprotective benefit of an obtained attenuation of intermediate parameters is modified by other factors. Further optimization of renoprotective therapy requires identification of such factors and explicit consideration of therapeutic efficacy on intermediate parameters as well as hard end points.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1998

Sample dilution: a methodological pitfall in the measurement of tissue but not serum ace-activity.

Many tissue ACE-assays suffer from underestimation of the ACE-activity at low sample dilutions. However, measurement of ACE-activity as the amount of hippuric acid produced by cleavage of the commonly used substrate hippuryl-histidyl-leucine might circumvent this problem. In this study, we investigated whether sample dilution affects the measurement of ACE-activity in rat tissue and serum. We found that serum ACE-activity was not affected by sample dilution. In homogenates of aorta, kidney, left ventricle, and lung, however, ACE-activity increased 1.6-2.8 times with increasing sample dilution until, ultimately, a plateau was reached at dilution factor 100, 50, 20, and 100, respectively. In addition, tissue homogenates inhibited the activity of exogenous ACE, whereas serum did not. These data suggest that the dilution effect probably results from interactions of inhibitory substances from the homogenates with ACE. The implications of these findings are that tissue ACE-activity measurements by any assay should be performed using sample dilution at the plateau. In many studies in the literature, specifications of sample dilution are lacking. Our findings demonstrate that caution is warranted in the interpretation of these studies.

Animals↗
PubMed1998

Norepinephrine-induced blood pressure rise and renal vasoconstriction are not attenuated by enalapril treatment in microalbuminuric IDDM.

BACKGROUND: In non-diabetic subjects, an attenuated systemic norepinephrine (NE) responsiveness may contribute to the mechanisms of action of angiotensin-converting enzyme (ACE) inhibitor treatment. We determined whether ACE inhibitor treatment influences systemic and renal haemodynamic responsiveness to exogenous NE, as well as urinary albumin excretion during NE, in microalbuminuric insulin-dependent diabetic (IDDM) patients, representing a patient category that benefits by strict blood pressure control. METHODS: In seven microalbuminuric IDDM patients, systemic and renal responsiveness to NE, infused at individually determined threshold [deltamean arterial pressure (MAP)=0 mmHg], 20% pressor (deltaMAP=4 mmHg) and pressor (deltaMAP=20 mmHg) doses, were compared before and after 8 weeks treatment with enalapril, 10 mg daily. Blood glucose was clamped at 5 mmol/l and insulin was infused at 30 mU/kg/h. RESULTS: Enalapril decreased MAP (P<0.05) and microalbuminuria (P<0.05), whereas effective renal plasma flow (ERPF) increased (P<0.01) and glomerular filtration rate remained unaltered. The filtration fraction tended to decline (P=0.09). The ACE inhibitor-induced fall in MAP disappeared at NE pressor dose, and the overall mean increase in MAP in response to NE was even higher with than without enalapril (P<0.05). After enalapril, the ERPF remained higher at all NE doses (P<0.05), but the magnitude of the NE-induced fall in ERPF was not altered by ACE inhibition treatment. Overnight urinary albumin excretion fell with ACE inhibition (P<0.05), but this effect was not seen during NE infusion. The angiotensin II/active renin ratio and serum aldosterone levels remained lower with enalapril at all NE doses (P<0.05). CONCLUSIONS: Enalapril does not attenuate systemic and renal vascular responsiveness to exogenous NE in microalbuminuric IDDM despite adequate inhibition of the renin-angiotensin-aldosterone system. These findings suggest that the effect of NE on vasoconstriction is not counteracted effectively by ACE inhibition treatment alone.

Adult↗
PubMed1998

The blunting of the antiproteinuric efficacy of ACE inhibition by high sodium intake can be restored by hydrochlorothiazide.

BACKGROUND: Dietary sodium restriction enhances the antiproteinuric and blood pressure lowering effect of ACE inhibition. In clinical practice, however, long-term compliance to a low-sodium diet may be difficult to obtain. We therefore investigated whether the blunting of the antiproteinuric and blood pressure lowering efficacy of ACE inhibition by high sodium intake can be restored by the addition of a diuretic. PATIENTS AND METHODS: Seven proteinuric patients with non-diabetic renal disease on chronic ACE inhibition were studied during three consecutive 4-week periods: low sodium (50 mmol/day), high sodium (200 mmol/day) and high sodium plus hydrochlorothiazide (50 mg o.i.d.). RESULTS: During low sodium intake proteinuria was 3.1 (0.7-5.2) g/day, during high sodium intake proteinuria increased to 4.5 (1.6-9.2) g/day (P < 0.05). Interestingly, addition of hydrochlorothiazide again reduced proteinuria to 2.8 (0.6-5.8) g/day (P < 0.05). Mean arterial blood pressure was 89 (84-96), 98 (91-104) and 89 (83-94) mmHg (P < 0.05) during the three periods, respectively. CONCLUSION: Addition of hydrochlorothiazide can overcome the blunting of the therapeutic efficacy of ACE inhibition on proteinuria and blood pressure by a high sodium intake.

Adult↗
PubMed1998

Risk factors for long-term renal survival after renal transplantation: a role for angiotensin-converting enzyme (insertion/deletion) polymorphism?

Chronic progressive renal function loss is a main cause of long-term graft loss after initially successful renal transplantation. Transplanted kidneys share some risk factors for renal function loss, such as hypertension or proteinuria, with diseased native kidneys. Recently, it has been shown that renal function loss is influenced by the angiotensin-converting enzyme (ACE) (insertion/deletion [I/D]) genotype in renal disease in diseased native kidneys. This study examines whether donor or recipient ACE (I/D) genotype is a risk factor for graft loss after renal transplantation. To avoid bias by acute events, graft survival was studied, with patients dying with a functioning graft censored, starting at 12 mo after transplantation in a cohort of 367 patients transplanted between 1987 and 1994 with at least 2 yr of follow-up. Mean follow-up was 58 mo. ACE (I/D) genotype was determined by PCR on stored donor and recipient lymphocytes. Neither donor nor recipient ACE (I/D) genotype was associated with graft survival. However, Cox proportional hazards analysis identified recipient, but not donor, ACE (I/D) genotype D-allele to be independently associated with a shorter time to graft loss in subgroups of patients at high risk for graft loss defined by a creatinine clearance <50 ml/min (n = 108, P = 0.017) or proteinuria > or =0.5 g/24 h at 12 mo (n = 97, P = 0.0051) after transplantation. In conclusion, recipient ACE (I/D) genotype was associated with time to graft loss in a specific high-risk subgroup of the study population. This suggests that the effect of ACE (I/D) genotype on graft survival only becomes apparent when other risk factors are simultaneously present.

Adult↗
PubMed1998

Exogenous norepinephrine induces an enhanced microproteinuric response in microalbuminuric insulin-dependent diabetes mellitus.

Exogenous norepinephrine (NE) increases intraglomerular pressure in animal experiments, but it is unknown whether NE induces a microproteinuric response in humans. Moreover, it has not been studied whether possible microproteinuric and renal hemodynamic changes induced by NE are altered in insulin-dependent diabetes mellitus (IDDM) complicated by microalbuminuria. Therefore, the microproteinuric and renal hemodynamic responses to exogenous NE infusions were measured in eight matched normoalbuminuric IDDM patients (group D1), microalbuminuric IDDM patients (group D2), and control subjects (group C). As anticipated, mean arterial pressure (MAP)-NE dose-response curves were significantly shifted leftward in groups D1 and D2 compared with group C (P < 0.05), indicating a higher systemic NE responsiveness in IDDM. On separate days, NE or placebo was infused at individually determined NE threshold doses (T; delta MAP = 0 mmHg), 20% pressor doses (20% P; delta MAP = 4 mmHg), and pressor doses (P; delta MAP = 20 mmHg), with measurement of urinary albumin (UalbV), IgG excretion (UIgGV), GFR (by 125I-iothalamate), and effective renal plasma flow (by 131I-hippurate). At NE pressor dose, UalbV and UIgGV rose in all groups (P < 0.05 to 0.01), whereas urinary beta 2-microglobulin was unchanged. The increases in UalbV and UIgGV were more pronounced in the microalbuminuric group than in the other groups (P < 0.05). An NE dose-dependent fall in effective renal plasma flow and rise in filtration fraction were found in all groups (P < 0.05 to 0.001 for all), whereas GFR did not change significantly. The renal hemodynamic dose-response relationship was similar in the groups. In conclusion, exogenous NE acutely promotes glomerular protein leakage, and it is plausible that intraglomerular NE effects contribute to this phenomenon. The microproteinuric response is enhanced in microalbuminuric IDDM despite unaltered renal hemodynamic responsiveness, which may reflect a specific NE response or a general effect of vasopressor stimuli to promote glomerular protein leakage in patients with a preexistent defect in glomerular permselectivity.

Adult↗
PubMed1998

Can continuous intraperitoneal infusion of 125I-iothalamate and 131I-hippuran be used for measurement of GFR in conscious rats?

We previously described a method to measure GFR in conscious spontaneously voiding rats. This method circumvents the need for anesthesia and for bladder instrumentation. It's main principle is the correction of renal 125I-iothalamate clearance for incomplete urine collection by the ratio of plasma and renal clearance of co-infused 131I-Hippuran. A disadvantage of this technique is the requirement of an intra-arterial catheter for infusion of the renal function tracers. We therefore tested whether intraperitoneal infusion of 125I-iothalamate and 131I-Hippuran can be used for such a GFR measurement in conscious spontaneously voiding rats. We found that during intraperitoneal administration, stable plasma levels of 131I-Hippuran could be obtained. However, urinary recovery of 131I-Hippuran was incomplete (66 +/- 32%), leading to a significant overestimation of GFR by 140 +/- 13% in comparison with the GFR measured by the intra-arterial technique. Thus intraperitoneal infusion of renal function tracers cannot replace intra-arterial infusion.

Animals↗
PubMed1997

A method for accurate measurement of GFR in conscious, spontaneously voiding rats.

Renal function measurement by clearance methods relies on accurately timed urine collection. In small experimental animals, renal function measurement is usually performed under anesthesia and/or with the application of bladder catheters to ensure accurate urine collection. To avoid both anesthesia and the need for bladder catheters we developed a method to measure glomerular filtration rate (GFR) in spontaneously voiding conscious rats. GFR was measured as the urinary clearance of constantly infused 125I-iothalamate. To correct for incomplete bladder emptying urinary clearance of 125I-iothalamate was multiplied by the ratio of plasma and urinary clearance of simultaneously infused 131I-hippuran, a correction method that has been previously validated in humans. Reproducibility of the technique was evaluated by analysis of the results of four consecutive clearance periods during the day (intra-assay variation) in a group of 17 rats and of two consecutive clearance periods on two or three separate days in a group of 20 rats (inter-assay variation), all with normal renal function. Application of the correction method reduced the intra-assay coefficient of variation (mean +/- SD) from 37.4 +/- 14.3 to 5.4 +/- 2.3% (P < 0.05). The mean inter-assay coefficient of variation fell slightly from 23.4 +/- 10.3 to 11.0 +/- 7.2% (P < 0.10). In rats with moderately impaired renal function (N = 8) the intra-assay variation fell from 27.9 +/- 20.7 to 2.7 +/- 1.6% (P < 0.05). Our data show that this correction method is a useful technique to assess renal function in conscious, spontaneously voiding rats.

Animals↗
PubMed1997

Is the antiproteinuric response to inhibition of the renin-angiotensin system less effective during the night?

BACKGROUND: In glomerular disease proteinuria usually has a circadian pattern with maximum excretion during the day. Blockade of the renin-angiotensin system (RAS) results in a 50% reduction of proteinuria as measured in 24-h urine collections. We questioned whether anti-proteinuric treatment by blockade of the RAS is as effective during the day as during the night. METHODS: We analysed data from two intervention studies on proteinuria in patients with non-diabetic renal disease. In the first study, six hospitalized patients (proteinuria 5.8 +/- 2.9 g/day) were treated with the renin-inhibitor remikiren 600 mg o.d. during 8 days. In the second study eight ambulant patients (proteinuria 7.5 +/- 2.7 g/day) were treated during 6 weeks with the ACE-inhibitor trandolapril 4 mg o.d. Urine was collected in a day- and in a night-time portion. RESULTS: Daytime proteinuria declined from 0.29 +/- 0.15 to 0.22 +/- 0.11 g/h (P < 0.05) during remikiren and from 0.33 +/- 0.14 to 0.16 +/- 0.08 g/h (P < 0.05) during trandolapril. Night-time proteinuria, however, was not significantly reduced from 0.23 +/- 0.11 to 0.19 +/- 0.11 g/h during remikiren and from 0.29 +/- 0.17 to 0.20 +/- 0.12 g/h during trandolapril. Both interventions effectively lowered blood pressure during the day as well as the night. CONCLUSION: In both studies relative nocturnal therapy resistance to the antiproteinuric effect of RAS blockade was found, despite 24-h efficacy of blood pressure effect. This may have clinical relevance because it contributes to rest-proteinuria and thus may affect long term renal function outcome. It may be worthwhile to explore alternative therapeutic regimens to improve the nocturnal antiproteinuric response.

Adult↗
PubMed1997

Renal hemodynamic effects of candesartan in normal and impaired renal function in humans.

The effects of angiotensin II type I receptor antagonist candesartan cilexitil, 8 mg once daily, were studied after single dose and after five days treatment in 17 hypertensive patients [median mean arterial pressure (MAP) 118 mm Hg, range 84 to 134] with renal function impairment of different severity [glomerular filtration rate (GFR) 60 ml/min, range 11 to 161]. The MAP fell by -8% (-14 to -5) and -11 (-16 to -5)% after single and multiple dose, respectively (both P < 0.02). Effective renal plasma flow (ERPF) increased by 13% (7 to 19) and 10% (3 to 14) after single and multiple dose, respectively (both P < 0.02), while the GFR did not change. Filtration fraction (FF) fell by -11% (-14 to -5) and -12% (-13 to -4) after single and multiple doses, respectively (both P < 0.02). After a single dose the % change in ERPF (r = 0.58) and FF (r = -0.52, both P < 0.05) positively correlated with pretreatment GFR, indicating a more pronounced response in patients with normal GFR. After five days of treatment these correlations were absent, indicating similar renal vasodilation in patients with normal and impaired renal function. Thus, multiple dose candesartan cilexitil had a favorable renal hemodynamic profile, irrespective of pretreatment renal function. Further studies are needed to establish whether this provides long-term renoprotection as well.

Angiotensin Receptor Antagonists↗
PubMed1996

Renal hemodynamics after lung transplantation. A prospective study.

Renal function impairment is common after solid organ transplantation, due to the nephrotoxicity of cyclosporine. Moreover, in patients with severe respiratory failure, renal function is often impaired. This renal function impairment may predispose patients to further renal function impairment after lung transplantation. Therefore, renal hemodynamics were measured in 44 patients before lung transplantation and 1, 6, 12, 18, 24, and 30 months after transplantation. After transplantation, a decline in renal function occurred, with a progressive fall in glomerular filtration rate (GFR) of 33 +/- 4% at 12 months and 42 +/- 9% at 30 months. Effective renal blood flow fell by 22 +/- 5% at 12 months and remained stable thereafter. Changes in effective renal plasma flow (ERPF) were less pronounced than those of effective renal blood flow, due to a fall in hematocrit after transplantation. Blood pressure and renal vascular resistance increased significantly, consistent with the effects of cyclosporine. Prior to transplantation, renal function impairment with intense renal vasoconstriction had been found in a subset of the patients. Remarkably, the decrease in renal function after transplantation was less pronounced in patients with renal function impairment prior to transplantation, as indicated by significant negative correlations between pretransplantation GFR and the percentage change in GFR after transplantation, and pretransplantation ERPF and the percentage change in ERPF after transplantation. This suggests that the net course of renal hemodynamics after lung transplantation is the result of the opposed effects of cyclosporine nephrotoxicity and the favorable effects of the normalization of respiratory status. In conclusion, after lung transplantation a decline in renal function occurs that is less pronounced in patients with renal function impairment and intense renal vasoconstriction prior to transplantation. Such a renal function impairment, therefore, should not be considered a contraindication to lung transplantation.

Adult↗
PubMed1996

Antiproteinuric effect predicts renal protection by angiotensin-converting enzyme inhibition in rats with established adriamycin nephrosis.

1. The mechanism of renal protection by angiotensin-converting enzyme inhibition is still the subject of debate. Inhibition of proteinuria might play a role. If so, a good antiproteinuric response to angiotensin-converting enzyme inhibition should predict subsequent protection against renal structural damage. This hypothesis has not been tested in models where treatment is started after the renal disease is well established, i.e. models that mimic the clinical situation. 2. We therefore investigated this hypothesis in 96 male Wistar rats with established adriamycin nephrosis. Reduction of proteinuria was achieved by lisinopril (0, 2, 5 and 10 mg day-1 kg-1) on two different sodium diets (0.3% and 0.05% NaCl). Therapy started 6 weeks after adriamycin (at stable proteinuria) and was continued for 6 weeks. 3. Lisinopril reduced blood pressure by 32 +/- 4% and proteinuria by an average of 72 +/- 7%, with stabilization after 2 weeks. Considerable interindividual differences in antiproteinuric response was found. Glomerulosclerosis score was reduced by 15 +/- 5%. All the effects of angiotensin-converting enzyme inhibitors were enhanced by sodium depletion, but sodium depletion in itself did not affect blood pressure (124 +/- 4 mmHg), proteinuria (664 +/- 68 mg/day) or glomerulosclerosis score (30 +/- 5%). Interestingly, the more proteinuria was reduced initially in an individual rat, the less sclerosis was found in the long term in that rat. 4. In conclusion, angiotensin-converting enzyme inhibition lowers proteinuria and prevents glomerulosclerosis in established adriamycin nephrosis. These effects are enhanced by sodium depletion. The individual short-term antiproteinuric effect predicts the protection against ultimate glomerular damage. This is consistent with the hypothesis that reduction of proteinuria is a mechanism by which angiotensin-converting enzyme inhibitors exert renoprotection.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1996

Renal 131I-hippurate clearance overestimates true renal blood flow in the instrumented conscious dog.

We evaluated renal 131I-hippurate clearance (ERPFhip) as a measure of renal blood flow (RBF) in chronically instrumented conscious dogs. When adjusted for renal hippurate extraction (Ehip, 0.77 +/- 0.01) and hematocrit (Hct, 39.7 +/- 1%), calculated RBFhip (656 +/- 37 ml/min) markedly exceeded renal blood flow measured with renal artery blood flow probes (RBFprobe, 433 +/- 27 ml/min). The discrepancy could not be explained by flow probe calibration, because in vivo comparison of flow probe values with renal venous outflow showed only a slight underestimation of renal blood flow (slope 0.93, 95% confidence interval 0.89-0.97). Redistribution of hippurate from erythrocytes into renal venous plasma during or shortly after blood sampling led to an underestimation of Ehip by 4 +/- 1% and thus could only explain a small part of the difference. Extrarenal hippurate clearance was excluded, because the amount of 131I-hippurate cleared from plasma equaled that appearing in the urine (303 +/- 17 and 307 +/- 17 ml/min). Applying these corrections, we found that RBFhip still exceeded RBFprobe by 37 +/- 3%. These data indicate that renal blood flow measured by the hippurate clearance technique markedly overestimates true renal blood flow. Because other errors were excluded, a combination of sampling of nonrenal blood and intrarenal hippurate extraction from erythrocytes might play a role.

Animals↗