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Gerjan Navis

Publications and source records attributed to Gerjan Navis.

At least 55 records · Page 3Linked to original sources
PubMed2004

The abnormal renal vasodilator response to D1-like receptor stimulation in conscious SHR can be normalized by AT1 blockade.

BACKGROUND: We previously showed that the renal vasodilator response to a D1-like receptor agonist is blunted in conscious SHR compared with WKY rats. The mechanism of this impaired dopaminergic responsiveness in SHR is unclear. An altered balance between the renin-angiotensin-aldosterone system (RAAS) and the dopaminergic system may be involved. To determine the interaction between the RAAS and the dopaminergic system in the blunted D1-like responsiveness in SHR, we studied the renal vasodilator response to the D1-like receptor agonist fenoldopam before and after 7 days of pretreatment with the AT1-receptor antagonist (AT1-A) L158,809 in conscious SHR and WKY rats. METHODS: Effective renal plasma flow (ERPF) was measured by the clearance of I-hippuran. Mean arterial pressure (MAP) was measured via an intraarterial catheter. RESULTS: Without pretreatment, MAP was reduced to comparable degrees by fenoldopam in WKY (-7 +/- 4%, ns) and SHR (-6 +/- 1%, P < 0.05). However, ERPF was significantly more increased (P < 0.006) by fenoldopam in WKY (+26 +/- 2%, P < 0.0001) than in SHR (+2 +/- 2%, ns). AT1-A treatment reduced MAP and increased ERPF and glomerular filtration rate significantly in both strains. Pretreatment with AT1-A significantly potentiated the fenoldopam-induced rise in ERPF in SHR, but not in WKY, without affecting the blood pressure responses in either strain. As a result, during pretreatment with an AT1-A, the rise in ERPF by fenoldopam was similar in both strains (SHR +25 +/- 2%, P < 0.0001; WKY +33 +/- 2%, P < 0.0001). CONCLUSIONS: These results suggest that the RAAS accounts for the blunted renal vasodilator response to a D1-like receptor agonist in SHR. A dysbalance between the dopaminergic system and the RAAS may be involved in the abnormal renal hemodynamic regulation in SHR.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2004

Body mass index is associated with altered renal hemodynamics in non-obese healthy subjects.

BACKGROUND: Weight excess is associated with increased renal risk. Data in overt obesity suggest a role for altered renal hemodynamics. Whether body mass index (BMI) is also relevant to renal function in non-obese subjects is unknown. METHODS: We studied the relation between BMI and renal hemodynamics in 102 healthy, non-obese (BMI <30 kg/m2) subjects [59 males, 43 females, mean age 39 (18-69) years] in a post-hoc analysis of subjects evaluated as prospective kidney donors or as healthy volunteers in renal hemodynamic studies. RESULTS: Mean (+/-SD) BMI was 24.0 +/- 2.8 kg/m2, mean arterial pressure (MAP) 93 +/- 11 mm Hg, glomerular filtration rate (GFR, iothalamate clearance) 111 +/- 19 mL/min/1.73 m2, effective renal plasma flow (ERPF, hippuran clearance) 458 +/- 108 mL/min/1.73 m2, FF (GFR/ERPF) 0.25 +/- 0.04. On univariate analysis, BMI correlated negatively with ERPF/1.73 m2 body surface area (BSA) (r=-0.46; P < 0.001), GFR/1.73 m2 BSA (r=-0.24, P= 0.013) and positively with FF (r= 0.45, P < 0.001), and age (r= 0.47, P < 0.001). On multivariate analysis both BMI and age were independent predictors of ERPF/1.73 m2 BSA (negative) and FF (positive, all P < 0.05). Age was the only predictor of GFR/1.73 m2 BSA (negative). Analyzed for renal function indexed for height (h), BMI correlated negatively with ERPF/h (r=-0.274, P= 0.005), but not with GFR/h (r= 0.13, P= 0.899). On multivariate analysis both BMI (positive) and age (negative) were independent predictors for GFR/h (both P < 0.001). Age was the only predictor for ERPF/h (negative). Predictors for FF (BMI and age, both positive) were by definition unaltered. CONCLUSION: The impact of BMI on renal function is not limited to overt obesity, as in subjects with BMI <30 kg/m2 a higher BMI is associated with higher FF, that is, a higher GFR relative to ERPF. This suggests an altered afferent/efferent balance and higher glomerular pressure (i.e., a potentially unfavorable renal hemodynamic profile) that may confer enhanced renal susceptibility when other factors, such as hypertension or diabetes are superimposed.

Adolescent↗
PubMed2004

Angiotensin administration stimulates renal 11 beta-hydroxysteroid dehydrogenase activity in healthy men.

BACKGROUND: We examined whether acute administration of angiotensin modulates the activity of 11 beta-hydroxysteroid dehydrogenase (11 beta HSD), the intracellular enzyme catalyzing the interconversion between the hormonally active cortisol and inactive cortisone. METHODS: Twenty-one male healthy subjects were examined after 1 week of a low- and high-salt diet (50 and 200 mmol/day, respectively). Separate infusions of angiotensin I (Ang I) and II (Ang II) were administered, both at rates of 4 and 8 ng/kg/min. The ratios of tetrahydrocortisol + allotetrahydrocortisol/tetrahydrocortisone (THF + allo-THF/THE) and of free cortisol/free cortisone (UFF/UFE) in urine were measured as indices of overall 11 beta HSD set point and activity of renal 11 beta HSD type 2, respectively. Glomerular filtration rate (GFR) was measured by constant infusion of (125)I-iothalamate. RESULTS: Ang I and Ang II infusion dose-dependently increased mean arterial blood pressure (MAP) and plasma aldosterone, and decreased plasma renin activity (PRA) and GFR at both diets. Ang I and Ang II infusion resulted in a dose-dependent decrease in the excretion of UFF, UFE, and of the UFF/UFE ratio at both diets, without changing the urinary (THF + allo-THF)/THE ratio. Salt restriction did not affect these 11 beta HSD variables, but was accompanied by a decrease in UFF and UFE excretion. CONCLUSION: This study suggests that acute angiotensin administration stimulates the activity of 11 beta HSD type 2 in human kidney. Angiotensin might therefore exert a dual effect on the mineralocorticoid receptor (i.e., an indirect agonistic effect by increasing aldosterone availability and a direct or indirect antagonistic effect by stimulation of renal 11 beta HSD type 2 activity).

11-beta-Hydroxysteroid Dehydrogenase Type 2↗
PubMed2003

The COOPERATE trial.

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Angiotensin Receptor Antagonists↗
PubMed2003

Inter-individual differences in anti-proteinuric response to ACEi in established adriamycin nephrotic rats are predicted by pretreatment renal damage.

ACE inhibition (ACEi) reduces proteinuria and provides reno-protection, but not all subjects benefit from ACEi. Individual differences in the reduction in proteinuria at the onset of treatment and in residual proteinuria during therapy predict differences in renal outcome. The present study investigated whether individual differences in the anti-proteinuric efficacy of ACEi are explained by differences in the severity of pretreatment renal structural damage and whether differences in the level of residual proteinuria during therapy are explained by the severity of renal structural damage at that time, in adriamycin nephrosis in the rat. Pretreatment renal structural damage was assessed in biopsies 6 weeks after exposure to adriamycin (2 mg/kg iv). Then ACEi (75 mg/l lisinopril, n = 23) or vehicle (n = 10) was administered; renal biopsies were repeated after stabilization of the anti-proteinuric response (week 8). Early renal damage (interstitial alpha-smooth muscle actin expression and macrophage accumulation) and established lesions [focal glomerulosclerosis (FGS) and interstitial fibrosis] were scored. During ACEi, proteinuria fell from 834 (487-851) mg/24 h pretreatment to 153 (66-265) mg/24 h at week 8 (p < 0.05); FGS stabilized from 27 (4-70) arbitrar units (AU) pretreatment to 26 (4-84) at week 12, whereas the vehicle did not affect proteinuria, resulting in progressive FGS: 18 (10-26) AU pretreatment versus 88 (46-130) at week 12 (p < 0.05). All parameters of pretreatment damage significantly predicted the anti-proteinuric response. Residual proteinuria during ACEi correlated significantly with renal structural damage parameters at that time. Pretreatment renal damage also predicted renal outcome during extended treatment. Thus, in this experimental setting, in rats with the same renal disorder and the same duration of disease, individual differences in pretreatment renal damage, albeit relatively modest, explain individual differences in renal responsiveness to ACEi. This implies that the limits of the efficacy of ACEi are set by prevalent renal damage. Further studies into the mechanisms of individual resistance to the anti-proteinuric action of ACEi are needed to develop additive intervention strategies.

Actins↗
PubMed2003

A central body fat distribution is related to renal function impairment, even in lean subjects.

BACKGROUND: Overweight and obesity are believed to be associated with renal damage. Whether this depends on fat distribution is not known. We hypothesize that in addition to overweight, fat distribution may be associated with renal function abnormalities. METHODS: We studied the relation between body weight and fat distribution and microalbuminuria and elevated or diminished filtration in 7,676 subjects without diabetes. Microalbuminuria is defined as urinary albumin excretion (UAE) of 30 to 300 mg/24 h. Elevated and diminished filtration are defined as filtration plus or minus 2 SDs of a nondiabetic lean group with a peripheral fat distribution and UAE of 0 to 15 mg/24 h, corrected for age and sex. The total population was divided into six groups according to body weight (overweight is defined as body mass index [BMI] > 25 and < or = 30 kg/m2; obesity, as BMI > 30 kg/m2) and fat distribution. RESULTS: In logistic regression analysis, obese subjects with central fat distribution had a greater risk for microalbuminuria (relative risk, 1.7; 95% confidence interval, 1.19 to 2.35). Obese subjects with either peripheral or central fat distribution had a greater risk for elevated filtration (relative risk, 3.2; 95% confidence interval, 1.19 to 8.47; relative risk, 2.6; 95% confidence interval, 1.59 to 4.28, respectively). Furthermore, subjects with central fat distribution, either lean, overweight, or obese, had a greater risk for diminished filtration (relative risk, 1.9; 95% confidence interval, 1.19 to 3.12; relative risk, 2.0; 95% confidence interval, 1.19 to 3.19; and relative risk, 2.7; 95% confidence interval, 1.46 to 4.85, respectively). Finally, by dividing waist-hip ratio (WHR) into quartiles, greater WHR was associated with a greater risk for diminished filtration, even when corrected for BMI. CONCLUSION: Not only overweight and obese subjects, but also lean subjects with central fat distribution are at risk for diminished filtration. Therefore, a central pattern of fat distribution, not overweight or obesity by itself, seems to be important for renal impairment.

Abdomen↗
PubMed2003

Renoprotective effects of VPI versus ACEI in normotensive nephrotic rats on different sodium intakes.

BACKGROUND: Control of blood pressure (BP) and optimal reduction of proteinuria (Uprot) are necessary for long-term renoprotection. Unfortunately, angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II (Ang II) antagonists are not effective during sodium repletion. Vasopeptidase inhibitors (VPI) cause dual inhibition of ACE and neutral endopeptidase, the latter resulting in decreased atrial natriuretic peptide (ANP) breakdown and thus enhanced natriuresis. Therefore, in contrast with ACEI, VPI may be effective during high sodium intake. METHODS: To test this hypothesis, the renoprotective actions of the new VPI gemopatrilat (GEM) were studied during low (0.05% NaCl) and high (3.0% NaCl) sodium diets in normotensive Wistar rats with established adriamycin nephrosis. The ACEI lisinopril (LIS) was used as control. Rats received either GEM (0.3 mg/g chow), an equihypotensive dose of LIS (75 mg/L drinking water), or vehicle (VEH) from week 6 (that is, established Uprot) until sacrifice. The effect of therapy was monitored by measuring systolic BP and Uprot (weekly) and structural renal damage at the end of study (week 16). RESULTS: During low sodium, GEM effectively reduced Uprot (-48 +/- 4%), but LIS was more effective (-80 +/- 2%), while Uprot slightly increased in VEH (+23 +/- 2%). The focal glomerulosclerosis (FGS) score after GEM (38 +/- 14) was lower than in the VEH group (79 +/- 27), although this was not significant. LIS (18 +/- 6) reduced FGS significantly. Remarkably, on high sodium, GEM was completely ineffective in reducing BP, Uprot and structural renal injury, just like LIS. CONCLUSIONS: The renoprotective actions of VPI depend on dietary sodium intake in normotensive nephrotic rats: therapeutic efficacy is fully blunted by a high sodium diet. During a low sodium diet, gemopatrilat was renoprotective, but less effective than lisinopril. Whether higher doses of the VPI could improve its renoprotective efficacy remains to be elucidated.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2003

High dietary sodium blunts affects of angiotensin-converting enzyme inhibition on vascular angiotensin I-to-angiotensin II conversion in rats.

High sodium intake blunts the efficacy of angiotensin (Ang)-converting enzyme (ACE) inhibition (ACEi), but the underlying mechanism is incompletely characterized. High sodium has been reported to increase vascular expression and vascular activity of ACE. To investigate whether high-dietary sodium-induced effects on vascular conversion of Ang I might be involved in the sodium-induced blunting of the response to ACEi, the authors studied the vasoconstrictor responses to Ang I and Ang II of isolated aortic rings from healthy rats on low dietary sodium (LS: 0.05% NaCl) and high dietary sodium (HS: 2.0% NaCl) after 3 weeks of ACEi (lisinopril 75 mg/L) or vehicle (CON). Blood pressure was similar in LS and HS in CON, but HS blunted the blood pressure response to ACEi. Functional conversion of Ang I was assessed as the difference in dose-response curves to Ang I and Ang II in parallel aortic rings. Sodium intake did not affect the dose-response curves to Ang I and Ang II in CON. In the ACEi groups, a significant difference was present between the curves for Ang I and Ang II on LS (deltaEC50, 6.7 nM; range, 2.2-13 nM; P < 0.01) but not on HS (deltaEC50: 1.3 nM; range, 0.0-4.1 nM, median [interquartile range], NS). Thus, HS blunts the ACEi-induced reduction of functional vascular Ang I conversion compared with LS. Whether the blunted functional vascular conversion is causally related to the blunted blood pressure response remains to be elucidated.

Angiotensin I↗
PubMed2003

Cardiovascular risk factors are differently associated with urinary albumin excretion in men and women.

Cardiovascular morbidity and mortality is not equally distributed among genders, men being more affected than women. It is not clear whether this is only related to a higher prevalence of the cardiovascular risk factors or to a similar prevalence of the risk factors as in women but a greater vascular susceptibility to these risk factors in men. This was tested by studying the association between various cardiovascular risk factors and urinary albumin excretion (UAE) in a large cohort of male and female subjects. While the prevalence of smoking and hypercholesterolemia was comparable between the genders, obesity was more common in women, and diabetes and hypertension were more frequent in men. The prevalence of microalbuminuria was about twofold higher in men. Interestingly, for a given level of any risk factor, UAE was higher in men than in women. On multivariate analysis with UAE as the dependent variable, an interaction with gender was found for the risk factors age, body mass index, and plasma glucose. Thus, for a higher age, body mass index, and glucose, the UAE is significantly increased in men when compared with women. It is concluded that gender differences exist in the association between cardiovascular risk factors and UAE. This is consistent with a larger vascular susceptibility to these risk factors in men as compared with women.

Adult↗
PubMed2003

Specific MAP-kinase blockade protects against renal damage in homozygous TGR(mRen2)27 rats.

Angiotensin II (AngII) plays an important role in renal damage by acting on hemodynamics, cell-growth, proliferation, and fibrosis, mainly by effects on the AngII type 1 (AT(1)) receptor. The AT(1) receptor activates several intracellular signaling molecules such as mitogen-activated protein kinases extracellular signal-regulated kinase (ERK) and p38, but their role in AngII-mediated renal damage is not well characterized. We therefore investigated whether pharmacologic blockade of ERK and p38 could prevent renal damage in high-renin homozygous transgenic rats (Ren2), with the effects of an AT(1) receptor antagonist (AT(1)-RA) as a reference. Seven-week-old homozygous Ren2 rats were treated with low-dose AT(1)-RA candesartan, ERK inhibitor tyrphostin, or p38 inhibitor SB239063 for 4 weeks. Untreated Ren2 and SD rats served as controls. Blood pressure was measured at 7 and 11 weeks. At 11 weeks, plasma renin activity (PRA) and serum aldosterone were determined, and the animals were killed. Kidney sections were scored for glomerular and interstitial smooth muscle actin and glomerular desmin expression as early markers for renal damage. Mesangial matrix expansion was determined as a marker for structural damage. PRA and aldosterone levels were elevated in untreated Ren2 rats in comparison to SD controls. AT(1)-RA further increased PRA but decreased aldosterone. All parameters of renal damage were elevated in untreated Ren2 rats. Blood pressure was not elevated at week 7 in Ren2 and not affected by either treatment. Mild signs of hypertensive damage were found in untreated Ren2 rats. All interventions significantly diminished damage to glomerular epithelium and interstitium. In addition, AT(1) receptor and p38 blockade reduced mesangial matrix expansion. In homozygous Ren2 rats, renal damage was ameliorated by a nonhypotensive dose of an AT(1)-RA and, similarly, by blockade of ERK or p38. This suggests that ERK and p38 are involved in AngII-mediated renal damage.

Actins↗
PubMed2003

Salt loading affects cortisol metabolism in normotensive subjects: relationships with salt sensitivity.

We studied cortisol metabolism together with insulin sensitivity [homeostatic model assessment (HOMA)] and renal hemodynamics in 19 salt-resistant (sr) and nine salt-sensitive (ss) normotensive subjects after a low- and high-salt diet. Results are described as high- vs. low-salt diet. Sum of urinary cortisol metabolite excretion (sum(metabolites)) increased in sr subjects (3.8 +/- 1.6 vs. 3.1 +/- 1.1 microg/min per square meter, P < 0.05) and decreased in ss subjects (2.3 +/- 1.0 vs. 2.9 +/- 1.1 microg/min per square meter, P < 0.05). Plasma 0830 h cortisol decreased in sr subjects but did not change significantly in ss subjects. In all subjects, the absolute blood pressure change correlated negatively with the percentage change in sum(metabolites) (P < 0.05) and positively with the percentage change in renal vascular resistance (P < 0.05). Sum(metabolites) during high-salt diet correlated negatively with the percentage changes in plasma 0830 h cortisol (P < 0.05) and renal vascular resistance (P = 0.05). HOMA did not change in either group, but the percentage change in HOMA correlated positively with the percentage change in plasma cortisol (P = 0.001) and negatively with the percentage change in sum(metabolites) (P < 0.01). Parameters of 11 beta-hydroxysteroid dehydrogenase activity were not different between groups and did not change. In conclusion, these data suggest that cortisol elimination is affected differently after salt loading in sr and ss subjects. Changes in circulating cortisol might contribute to individual sodium-induced alterations in insulin sensitivity.

17-Hydroxysteroid Dehydrogenases↗
PubMed2003

Role of proteinuria in the regulation of renal renin-angiotensin system components in unilateral proteinuric rats.

Renin-angiotensin system (RAS) overactivity has been implied in progressive renal function loss. We investigated whether changes in the renal expression of RAS components are specifically associated with the proteinuric kidney. Unilateral adriamycin-induced proteinuria was obtained by clamping the left renal artery before injection of adriamycin. In control animals, both left and right renal arteries were clamped. Twelve weeks later, mRNA expression of RAS components was determined in both kidneys. In the affected and non-affected kidney of the unilateral proteinuric rat, we demonstrate up-regulation of angiotensin- converting enzyme (ACE) mRNA (213%+22 and 188%+24 of controls, respectively), up-regulation of transforming growth factor beta (TGF-beta) mRNA (956%+229 and 418%+56) and down-regulation of angiotensin type 2 receptor (AT2-R) mRNA (24%+5 and 20%+5). The expression of angiotensin type 1 receptor (AT1-R) mRNA and inositol 1,4,5- trisphosphate receptor type I (IP3R-I) mRNA were unchanged. In conclusion, renal expression of ACE, AT2-R, and AT1-R mRNA is not mediated by protein leakage. Local intrarenal protein leakage did influence renal TGF-beta mRNA expression.

Animals↗
PubMed2003

Involvement of renal ACE activity in proteinuria-associated renal damage in untreated and treated adriamycin nephrotic rats.

Proteinuria is assumed to play a pathogenetic role in progressive renal damage. Angiotensin-converting enzyme (ACE) inhibition reduces proteinuria and provides renoprotection. This suggests that ACE activity might play a pathogenetic role in the development of proteinuria-induced renal structural damage. We investigated this hypothesis in untreated and treated established adriamycin nephrosis, a model of proteinuria-induced renal damage. In a time-course experiment, the development of renal structural damage in untreated adriamycin nephrotic rats was paralleled by a significant rise in renal ACE activity. Moreover, on cross-sectional analysis, a consistent positive correlation between renal, but not plasma, ACE activity and proteinuria, focal glomerulosclerosis and interstitial injury was present. Notably, these associations were present, not only in the untreated condition, but also during intervention with either ACE inhibition or AT(1)-receptor antagonism. Interestingly, we found that higher renal ACE activity is associated with more severe renal damage for a given amount of proteinuria, suggesting that renal ACE activity may be either a permissive or a promoting factor in the processes by which proteinuria eventually leads to renal structural damage. This relationship was abolished by renin-angiotensin system (RAS)-blockade, suggesting that RAS-mediated effects are involved in the relationship between renal ACE activity and proteinuria-induced renal damage. In conclusion, in untreated as well as treated adriamycin nephrotic rats, renal ACE activity is closely associated with renal outcome. This association appears to be independent of the specific mode of blockade of the RAS. Renal ACE activity is a consistent marker of individual differences in proteinuria-associated renal damage: further studies are needed to investigate a possible pathogenetic role in renal damage.

Angiotensin Receptor Antagonists↗
PubMed2002

Renal targeting of captopril selectively enhances the intrarenal over the systemic effects of ACE inhibition in rats.

1 In previous studies on the renal targeting of the ACE inhibitor captopril, we demonstrated that a 6 fold increased concentration of this drug could be obtained in the kidney after conjugation to the low-molecular-weight protein lysozyme. In this study, we investigated in unrestrained rats whether systemic administration of captopril-lysozyme also results in an enhanced effect on renal parameters, relative to the systemic effects. 2 Renal effects: intravenous infusion of captopril-lysozyme for 6 h resulted in a more pronounced increment of renal blood flow (31+/-2% vs 17+/-4% at 0.5 mg kg(-1) 6h(-1), P<0.01) and an approximately 5 fold enhanced natriuresis (167+/-17% vs 36+/-7% at 1 mg kg(-1) 6 h(-1), P<0.001) in comparison with equimolar amounts of captopril as a free drug. In correspondence with these findings, renal ACE inhibition was potentiated approximately 5 fold (-50+/-4% vs -22+/-3% at 1 mg kg(-1) 6 h(-1), P<0.001). 3 Systemic effects: conjugated captopril did not affect blood pressure in dosages up to 5 mg kg(-1) 6 h(-1). This effect coincided with a less pronounced inhibition of the pressor response to intravenously administered angiotensin I (-12+/-3% vs -66+/-5% at 1 mg kg(-1) 6 h(-1), P<0.001), and a markedly attenuated plasma ACE inhibition (-19+/-2% vs -37+/-3% at 1 mg kg(-1) 6 h(-1), P<0.001) compared to an equivalent dose of free captopril. 4 An experiment of continued intravenous administration of captopril-lysozyme for 7 days in nephrotic syndrome demonstrated that the conjugate is also active in renal disease: the antiproteinuric response was substantially augmented (-67+/-5% vs -15+/-7% at 4 mg kg(-1) 24 h(-1), P<0.001) compared to the free drug, in the absence of blood pressure reduction. 5 These data demonstrate that intravenous administration of a captopril-lysozyme conjugate leads to more selective renal ACE inhibition and enhanced renal effects as well as less systemic effects compared to captopril itself.

Angiotensin I↗
PubMed2002

Addition of AT1 blocker fails to overcome resistance to ACE inhibition in adriamycin nephrosis.

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors provide renoprotection, but there is considerable interindividual variability in therapeutic efficacy, with residual proteinuria and progressive renal function loss in many individuals. This requires additional strategies to optimize therapy response, particularly for individuals with a poor response to ACE inhibition. We studied whether co-treatment with an angiotensin II subtype 1 (AT1) receptor antagonist (AII-A) improves the individual antiproteinuric response of maximal ACE inhibition in established adriamycin nephrosis. METHODS: Rats were instituted on lisinopril (75 mg/L) six weeks after disease induction. After two weeks rats were re-stratified for residual proteinuria to continue this regimen, to a higher dose of lisinopril (150 mg/L) or to co-treatment with the AII-A L 158,809 for another four weeks. Groups on monotherapy AII-A and vehicle served as controls (all groups N=15). RESULTS: Lisinopril lowered proteinuria by 63% from 741 to 246 g/day (range of percentage change -90 to +2%). Neither increasing the dose of the ACE inhibitor nor addition of AII-A to ACE inhibition improved the antiproteinuric efficacy on a group or individual level: non-responders remained non-responders. All drug categories reduced hard end-points of focal glomerulosclerosis to a similar degree. CONCLUSIONS: ACE inhibition has variable renal protective efficacy in the adriamycin model. Neither increasing the dose of the ACE inhibitor beyond the optimal level nor co-treatment with AII-A overcome the individual therapy resistance. Thus, in established adriamycin nephrosis, blockade of the renin-angiotensin system at two different levels offers no additional benefit over ACE inhibition alone, either on the group or individual level.

Angiotensin Receptor Antagonists↗
PubMed2002

Dual renin-angiotensin system blockade at optimal doses for proteinuria.

BACKGROUND: The antiproteinuric effect of combining the angiotensin-converting enzyme (ACE) inhibitor lisinopril and the angiotensin II (Ang II) antagonist losartan was compared to that of the optimal antiproteinuric doses of monotherapy. METHODS: To this purpose, lisinopril and losartan were studied in 9 nondiabetic renal patients with median proteinuria 4.5 g/day (95% CI, 3.5, 6.4), creatinine clearance of 80 mL/min (95% CI, 66, 96), and mean arterial pressure (MAP) of 102 mm Hg (95% CI, 93, 112). First, in two protocols with six-week treatment periods per dose, the optimal antiproteinuric dose of each drug was established in each patient. Losartan and lisinopril were used in randomized order, each preceded by a baseline period without medication. The doses of losartan (mg/day) were 50, 100, 150, and again 50. The lisinopril doses were 10, 20, 40, and again 10. After the second protocol, patients were treated with a combination, using the optimal antiproteinuric doses established for the individual drugs. RESULTS: The antiproteinuric response by losartan was optimal at 100 mg (-46%; 95% CI, -60, -24%), being larger than at the 50 mg dose (-27%; 95% CI, -42, -4%, P < 0.05), but not different from the 150 mg dose (-46%; 95% CI, -58; -20%). Proteinuria decreased further at each up-titration step of lisinopril to -75% (95% CI, -85, -43%) at the 40 mg dose. Combination therapy reduced proteinuria more effectively (-85%; 95% CI, -96, -58) than monotherapy with losartan, and to a lesser extent than with lisinopril. Optimal blood pressure responses were obtained at similar doses. CONCLUSIONS: Dose-titration with a renin-angiotensin system blocker, followed by add-on therapy is highly effective in order to reduce proteinuria. The safety of this regimen needs to be addressed in future studies.

Adult↗