Determinants of urinary albumin excretion within the normal range in patients with type 2 diabetes: the Randomised Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study.

AIMS/HYPOTHESIS: In contrast to microalbuminuric type 2 diabetic patients, the factors correlated with urinary albumin excretion are less well known in normoalbuminuric patients. This may be important because even within the normoalbuminuric range, higher rates of albuminuria are known to be associated with higher renal and cardiovascular risk. METHODS: At the time of screening for the Randomised Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) Study, the urinary albumin/creatinine ratio (UACR) was 0.44 mg/mmol in 4,449 type 2 diabetic patients. The independent correlates of UACR were analysed. RESULTS: Independent correlates of UACR during baseline were (in descending order): night-time systolic BP (r(s) = 0.19); HbA(1c) (r(s) = 0.18); mean 24 h systolic BP (r(s) = 0.16); fasting blood glucose (r(s) = 0.16); night-time diastolic BP (r(s) = 0.12); office systolic BP, sitting (r(s) = 0.11), standing (r(s) = 0.10); estimated GFR (r(s) = 0.10); heart rate, sitting (r(s) = 0.10); haemoglobin (r(s) = -0.10); triacylglycerol (r(s) = 0.09); and uric acid (r(s) = -0.08; all p

Activation of p53 protein by telomeric (TTAGGG)n repeats.

Genome instability is a primary factor leading to the activation of the p53 tumor suppressor protein. Telomeric repeat (TR) sequences are also responsible for genome integrity. By capping the termini of the chromosomes, TRs prevent them undergoing nucleolytic degradation, ligation or chromosome fusion. Interestingly, telomere shortening was suggested to activate p53, which in turn may cause primary cells to senesce. In order to elucidate the nature of a possible cross talk between the two, we introduced into cells TRs of defined length and investigated their effect on p53 activation and subsequent cellular response. We found that the introduction of a TR into cells leads to stabilization of the p53 protein. This stabilization was specific to TRs and was not observed in response to exposure of cells to plasmids containing non-TR sequences. p53 stabilization requires the presence of an intact p53 oligomerization domain. TR-activated p53 exhibited enhanced transcriptional activity. Eventually, TRs induced p53-dependent growth suppression, measured as a reduction in colony formation.

[Renin-angiotensin system inhibition and cardiac and renal alteration induced by a high sodium diet in rat]. / Inhibition du système rénine-angiotensine et altérations cardiaque et rénale induites par une consommation excessive de sodium chez le rat.

BACKGROUND: The present study was designed to assess the influence of losartan on cardiac hypertrophy and albuminuria associated with early high sodium feeding in rats and to compare it to an angiotensin-converting enzyme inhibitor, enalapril, effect. METHODS: Male Sprague-Dawley rats received a regular diet (0.8% NaCl, NS, n=7), or high sodium diet (8% NaCl, HS, n=21) from weaning for 8 weeks. After 4 weeks of diet, two HS groups were treated or not for 4 weeks with losartan or enalapril (30 and 10 mg/kg(-1) x day(-1) respectively, n=7 in each). Food and water consumption, body weight, urinary volume and urinary excretion of sodium, potassium and albumin were measured at the end of treatment as well as arterial pressure (anesthetized rats), heart and kidney weight. RESULTS: Eight weeks after weaning, heart weight index and albuminuria were significantly higher in HS control group when compared to the control NS group without change of arterial pressure. Treatment with losartan or enalapril had no effect either on arterial pressure or cardio-renal alterations.

Comparative effect of captopril and nifedipine in normotensive patients with incipient diabetic nephropathy.

In these studies, the effect of a 6-wk treatment by placebo, the calcium-channel blocker nifedipine, or the converting-enzyme inhibitor captopril was assessed in normotensive patients with insulin-dependent diabetes and incipient nephropathy. In response to captopril and nifedipine, arterial pressure decreased slightly and to a similar extent. These drugs resulted in opposite effects on urinary excretion of albumin [i.e., increase in urinary albumin excretion (UAE) by 40% during nifedipine treatment and decrease by 40% during captopril treatment]. No change in UAE was observed in the placebo group. This observation of opposite changes in UAE in the presence of a similar fall in arterial pressure suggests that the effects of captopril and nifedipine on UAE result from some difference in their intrarenal action. The data do not present recommendations for the use or disuse of captopril or nifedipine in such a group of patients and do not allow extrapolation to hypertensive diabetic subjects well controlled by other conventional antihypertensive agents.

Measurement of cardiac output and its distribution in rats under various sodium intakes, using 15 and 10 micron spheres.

We estimated cardiac output and its distribution to organs using simultaneously injected 15 micrometers and 10 micrometers radioactive microspheres. This study was carried out in anaesthetised rats with high cardiac output induced by sodium loading and low cardiac output by sodium restriction. In neither group were the values of cardiac output and blood flow to kidneys, brain, heart and spleen affected by microsphere size. However, the ratio of blood flow estimated with 15 micrometer to that with 10 micrometer microspheres averaged 0.67: 0.60 for liver, 1.09: 1.10 for duodenum, 3.51: 3.52 for testes, and 1.19: 1.07 for adrenals in high and low sodium rats respectively. A significant escape of 10 micrometer microspheres from testicular, adrenal, and gastrointestinal vasculatures may explain such finding. With regard to the liver, this view was reinforced by the finding of comparable hepatic blood flow values with either bead size after clamping of the portal vein. Additional preferential losses of 10 micrometer microspheres from muscular vasculature seemed to contribute to the fractions of injected radioactivities recovered in lungs (that is 6 and 2% for 10 micrometer and 15 micrometer spheres respectively). These results suggest that in the rat blood flow data provided by 10 micrometer microspheres should be carefully analysed according to the organ(s) studied.

Chronic kinin blockade and effect of ramipril in renal adaptation to sodium restriction.

The contribution of endogenous kinins to impairment in renal adaptation to a 6-day period of dietary sodium withdrawal associated with treatment with ramipril (5 mg/kg per day) and losartan (30 mg/kg per day) was evaluated by use of concomitant chronic administration of the bradykinin B2-receptor antagonist Hoe 140 (150 or 300 micrograms/kg per day via subcutaneous osmotic pump). A similar level of higher cumulative sodium excretion was observed in ramipril- and losartan-treated rats compared with untreated animals, and the effect of ramipril was not affected by Hoe 140. Similarly, the fall in arterial pressure and the renal vasodilatation associated with ramipril and losartan were not modified by Hoe 140. Glomerular filtration rate (785 +/- 73 microL/min per g KW in untreated sodium-depleted rats) decreased to a larger extent in ramipril-treated rats compared with losartan-treated rats (371 +/- 78 and 550 +/- 55 microL/min per g KW, respectively). Hoe 140 markedly prevented the alteration in glomerular filtration rate associated with ramipril, thus resulting in a final glomerular filtration rate (543 +/- 41 microL/min per g KW) similar to that observed with losartan. These findings demonstrate that despite a lack of influence on arterial pressure and sodium balance, accumulation of kinins markedly contributes to deterioration of the glomerular filtration rate induced by ramipril in sodium-depleted rats.

Is microalbuminuria a marker of early intrarenal vascular dysfunction in essential hypertension?

The relation between basal intrarenal hemodynamics and the renal response to acute inhibition of angiotensin-converting enzyme by captopril and albuminuria was assessed in 106 lean patients with essential hypertension without detectable proteinuria. It was observed that the microalbuminuric group (24.5% of the total population) was characterized by a higher systemic arterial pressure, a lower level of high-density lipoprotein cholesterol, and similar mean values of age, duration of hypertension, glomerular filtration rate, renal plasma flow, filtration fraction, and plasma renin activity when compared with normoalbuminuric subjects. In response to captopril, a significant renal vasodilatation without a change in glomerular filtration rate or a fall in filtration fraction was observed in normoalbuminuric patients only. In contrast, the renal vasodilator response was abolished in microalbuminuric subjects, together with blunting of the rise in plasma renin activity associated with captopril. This occurred despite similar indexes of activity of the endogenous renin-angiotensin system. It is suggested that microalbuminuria may be a marker of early functional or fixed intrarenal vascular dysfunction in never-treated lean patients with essential hypertension.

Contrasting effect of antihypertensive treatment on the renal response to L-arginine.

We assessed the renal hemodynamic response to L-arginine infusion (30 g within 60 minutes) in normotensive subjects, patients with never-treated essential hypertension, and hypertensive patients controlled by long-term (more than 2 years) treatment with or without an angiotensin-converting enzyme inhibitor. The renal vasodilator response to L-arginine observed in normotensive subjects (15 +/- 4% increase in effective renal plasma flow) was abolished in untreated hypertensive patients and restored only in the group treated by angiotensin-converting enzyme inhibition. In the whole population a positive correlation between the change in effective renal plasma flow and the change in urinary cGMP was obtained. It is suggested that abnormalities of the renal nitric oxide pathway not corrected by increased availability of L-arginine and reversible only on long-term treatment by angiotensin-converting enzyme inhibition may underlie the abnormal renal resistance observed in essential hypertension.

The antihypertensive effect of captopril. Evidence for an influence of kinins.

The acute effect of the orally-active converting enzyme inhibitor, captopril, was compared to that of saralasin in 13 patients with various forms of hypertension on ad libitum sodium intake. A significant difference between the effects of the two drugs on mean arterial pressure (MAP) was found (-11 +/- 3 mm Hg with saralasin, -24 +/- 4.5 mm Hg after captopril). This difference was not correlated with control plasma renin activity (PRA). To determine the influence of the endogenous kallikrein-kinin system in the antihypertensive action of captopril, the effect of aprotinin (Apro), an inhibitor of kinin generation, on the MAP level achieved by captopril was assessed in five normal subjects and 15 patients with hypertension on ad libitum sodium intake. In normal subjects, captopril did not alter MAP, nor did Apro have any effect. In six patients with essential hypertension and normal PRA, MAP decreased by 5.5 +/- 2 mm Hg following captopril, and Apro did not modify this level. In nine patients with renovascular hypertension (RVH), MAP fell by 22 +/ 3 mm Hg after captopril administration, and Apro infusion induced a rise in MAP of 13 +/- 1.7 mm Hg. A positive correlation between log control PRA and the effect of aprotinin was obtained ( r = 0.63, p less than 0.005). Apro had no effect in two patients with RVH who experiences a large drop in MAP during salasin. These results suggest that endogenous kinins as well as other substances, the generation of which is inhibited by aprotinin, may participate to the antihypertensive effect of captopril in patients with angiotensin-dependent hypertension. The lack of an aprotinin effect on the MAP level achieved during saralasin infusion suggests that the influence of the kallikrein-kinin system is related to the effect of captopril rather than the fall in arterial pressure resulting from angiotensin blockade.

Combined renal effects of overweight and hypertension.

The existence of a direct relationship between body mass and arterial pressure is well recognized; however, the effect of obesity on known target organs of hypertension is not clearly understood. We undertook the present studies to assess the influence of obesity on renal function and urinary albumin excretion in 40 normotensive subjects and 80 nevertreated hypertensive patients matched for age, sex, arterial pressure level, and known duration of hypertension in whom an oral glucose tolerance test was within normal limits. Glomerular filtration rate and effective renal plasma flow (expressed as absolute values or values normalized for height) were increased in overweight compared with lean subjects whether normotensive or hypertensive. Glomerular filtration rate was positively correlated with protein intake (as assessed from urinary excretion of urea) and fasting serum insulin level. Urinary excretion of albumin but not IgG and beta 2 microglobulin was higher in hypertensive patients compared with normotensive subjects. The overweight condition clearly enhanced the influence of arterial pressure on albuminuria; in fact, a steeper regression line between albumin excretion rate and arterial pressure was found in overweight compared with lean subjects. These results indicate that the overweight condition is associated with renal hyperfiltration and hyperperfusion, irrespective of the presence of hypertension, and that obesity magnifies the effect of hypertension on albuminuria, thus raising the possibility of an increased susceptibility of obese hypertensive patients to the development of renal damage.

Prevention of the cardiovascular and renal effects of angiotensin II by endothelin blockade.

Angiotensin II (Ang II) stimulates the release and gene expression of endothelin-1 in isolated vascular smooth muscle cells. In 47 Sprague-Dawley rats, we assessed the influence of concomitant treatment by the mixed ET(A)/ET(B) endothelin receptor antagonist bosentan (30 mg/kg per day, gavage) on the effect of a 10-day infusion of Ang II (200 ng/kg per minute, SC, osmotic pump) on arterial pressure, renal hemodynamics (microsphere method), albuminuria, cardiac weight, and carotid structure. Ang II increased systolic arterial pressure (SAP) by 49+/-7 mm Hg. Although bosentan alone did not affect SAP, the development of Ang II-induced hypertension was entirely prevented by the endothelin antagonist. In addition, the reduction in renal blood flow induced by Ang II (4.9+/-0.3 versus 7.4+/-0.2 mL x min-1 x g-1 in control rats) was prevented by concomitant administration of bosentan (8.8+/-0.8 mL x min-1 x g-1). The marked increase in albuminuria observed in rats infused with Ang II (2524+/-961 versus 91+/-6 microg/24 h in control rats) was prevented by bosentan. Similarly, bosentan abolished the increase in heart weight index (from 2.96+/-0.03 to 3.41+/-0.08 mg/g body weight) and carotid media thickness (from 73+/-14 to 108+/-6 microm) induced by Ang II infusion. Of interest, the dipsogenic action of Ang II was not influenced by bosentan. In conclusion, endogenous endothelin contributes to the cardiovascular and renal effects of Ang II.

Renal changes associated with cyclosporine in recent type I diabetes mellitus.

The effects of cyclosporine A treatment on arterial pressure and renal function were assessed in 11 young patients with type I diabetes of short duration. Cyclosporine was started at 7.5 mg/kg/day, progressively decreased to 6.3 mg/kg/day at 6 months, and then continued at a lower dose (4.1 mg/kg/day) for an additional 3 months in patients in whom remission of insulin dependency was obtained (n = 6). After 3 months of cyclosporine, a slight but significant increase in arterial pressure (+5.2 +/- 1.5 mm Hg), a rise in renal vascular resistance (approximately 20%), a decrease in glomerular filtration rate (approximately 25%), and a fall in filtration fraction were observed. Such changes were sustained after 6 and eventually 9 months of therapy. The decrease in glomerular filtration rate observed during cyclosporine treatment contrasted with the lack of change in simultaneously estimated creatinine clearance; in fact, the creatinine clearance/glomerular filtration ratio increased from 1.07 +/- 0.05% to 1.33 +/- 0.09% within 3 months of cyclosporine therapy, thus suggesting an enhanced tubular secretion of creatinine. Plasma renin activity and urinary excretion of kallikrein decreased significantly (approximately 50%), whereas plasma aldosterone concentration remained unaltered and plasma concentration of potassium increased during cyclosporine therapy. These changes were observed in the presence of a constant urinary excretion of sodium and potassium and a constant body weight. All parameters returned to pretreatment values within 3 months after cessation of cyclosporine. These results indicate that cyclosporine given for 6-9 months at a moderate dose causes a deleterious but reversible effect on arterial pressure and renal function in young diabetic patients.

Preglomerular sudanophilia in L-NAME hypertensive rats: involvement of endothelin.

To characterize alterations of renal vessels occurring during systemic hypertension elicited in rats by 5, 10, and 25 days of treatment by the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME)(20 mg/kg daily), preglomerular vasculatures, consisting of arcuate arteries and their branches, interlobular arteries, and afferent arterioles, were isolated by HCl maceration. Blockade of nitric oxide synthase significantly increased tail-cuff systolic blood pressure by 21 +/- 2% and 42 +/- 3% after 5 and 25 days, respectively. Medias of hypertensive arcuate arterial branches and interlobular arteries but not of afferent arterioles had focal deposits of Sudan black-positive lipid droplets. At 25 days, vessel wall thickness increased by 72 +/- 6% along the sudanophilic areas. Immunostaining of sudanophilic lesions with a panel of antibodies unveiled medial cell proliferation, macrophage invasion, immunoreactive vascular cell adhesion molecule-1, and low-density lipoprotein. The frequency of sudanophilic lesions increased with time to affect 26 +/- 2% and 36 +/- 3% of arcuate arterial branches and interlobular arteries, respectively, at 25 days. Hypertensive L-NAME-treated rats developed glomerular injury probed by albuminuria and glomerular immunostaining for alpha-smooth muscle actin. Administration of the nonselective endothelin antagonist bosentan (30 mg/kg daily) blunted the development of sudanophilic lesions during L-NAME treatment without affecting arterial hypertension or degree of glomerular injury. Therefore, L-NAME hypertension leads to rapid development of focal, inflammatory, proliferative, and sudanophilic lesions along preglomerular vessels, suggesting atherosclerosis-like processes. Furthermore, endothelin is a likely mediator in the development of these lesions.

Sodium and angiotensin in hypertension induced by long-term nitric oxide blockade.

The influence of dietary sodium restriction and angiotensin II blockade on hypertension induced by a 25-day period of administration of the inhibitor of nitric oxide synthesis NG-nitro-L-arginine-methyl ester (10 mg/kg twice daily by gavage) was assessed in Wistar rats fed a normal or low sodium diet. In addition, the angiotensin II receptor blocker losartan (30 mg/kg once daily by gavage) was administered before and during NG-nitro-L-arginine-methyl ester in rats fed the normal sodium diet. At the end of the studies, conscious systolic arterial pressure increased similarly in NG-nitro-L-arginine-methyl ester-treated groups maintained on normal or low sodium intake. Moreover, a 25% reduction in cardiac output due to a decrease in stroke volume was observed in both groups. A slight but significant cardiac hypertrophic response was observed in hypertensive rats irrespective of sodium intake. At the completion of studies, plasma renin activity was similar to corresponding controls in the hypertensive groups on normal or low sodium intake. Losartan totally prevented the development of hypertension as well as the decrease in stroke volume and cardiac hypertrophy associated with NG-nitro-L-arginine-methyl ester treatment in rats on normal sodium intake. In conclusion, hypertension resulting from long-term blockade of nitric oxide synthesis was not affected by dietary sodium restriction. A crucial role for the renin-angiotensin system was demonstrated in this new model of hypertension.

Renal characteristics and effect of angiotensin suppression in oral contraceptive users.

-The determinants of the increase in arterial blood pressure associated with the use of estrogen-progestogen oral contraceptives (OC) remain poorly known. The purpose of this study was to assess the renal characteristics and the role of the renin-angiotensin system in women with OC-associated hypertension. Urinary clearances of technetium-labeled diethylene triaminopentaacetic acid (glomerular filtration rate) and 131I-ortho iodohippurate (effective renal plasma flow) were estimated before and after acute administration of captopril in 38 women who became hypertensive while taking OC, 38 non-OC users with essential hypertension matched for age, body mass index, and level of blood pressure, and 38 normotensive women (19 with and 19 without OC). Plasma renin activity was higher in OC hypertensives when compared with those with essential hypertension, but captopril-induced changes in blood pressure and renal hemodynamics and function were similar in both groups. In addition, 24-hours urinary albumin excretion was increased in OC users when compared with nonusers with similar arterial blood pressure. In 13 hypertensive women followed up for 6 months after OC withdrawal, a decrease in plasma renin activity, blood pressure, and glomerular filtration rate but no significant change in urinary albumin excretion and captopril-induced changes in blood pressure and renal hemodynamics were observed. These results indicate that the use of OC is associated with an increased albuminuria and no evidence of a prominent role for the renin-angiotensin system in the maintenance of high blood pressure and renal hemodynamics when compared with non-OC users with essential hypertension.

Chronic bradykinin infusion and receptor blockade in angiotensin II hypertension in rats.

The influence of endogenous bradykinin(BK) on the control of arterial pressure and the development of cardiac hypertrophy was assessed in chronically angiotensin II(Ang II)-infused rats (200 ng. kg-1. min-1) through the effects of concomitant infusion of 3 doses of BK (15 ng. kg-1. d-1, 100 ng. kg-1. d-1 and 100 ng. kg-1. min-1 ie, 144 000 ng. kg-1. d-1) or BK-blockade by Hoe140 (300 microg. kg-1. d-1) for 10 days. In Ang II-infused rats, tail-cuff pressure increased from 124+/-3 to 174+/-6 mm Hg (P<0.001). The pressor effect of Ang II was not affected by simultaneous infusion of BK or Hoe140. At the end of the experiments, cardiac mass was higher in rats infused with Ang II alone (3.56+/-0.10 versus 2.89+/-0.05 mg/g in untreated controls, P<0.01) and the development of cardiac hypertrophy was not modified by administration of the 3 doses of BK or Hoe140. In addition, the fall in cardiac output associated with Ang II was prevented only by the moderate and high doses of BK, mainly through an increase in stroke volume and a decrease in total peripheral resistance. In the same way, the renal vasoconstrictor effect of Ang II was abolished by the medium and high dose of BK. Hoe140 did not affect cardiac output or renal blood flow in this model. No influence of BK or Hoe140 on the increase in albuminuria induced by Ang II was detected. In conclusion, exogenous BK may oppose the effect of Ang II on vascular tone, but it cannot prevent hypertension and target-organ damage associated with this experimental model of hypertension, even at a very high dose.

Renal function in hypertension.

Hypertension certainly accelerates the age-related changes in renal structure and function, mainly in the glomerulus. Both sodium handling and the renin-angiotensin system are involved in the aging process. Among the available classes of antihypertensive agents, the eventual deterioration of renal function induced by angiotensin-converting enzyme inhibitors in bilateral stenosis and stenosis of a single functioning kidney suggests that changes in glomerular pressure may participate in the changes of renal function. In essential hypertension and other conditions, it is possible that at a certain stage an increase in intraglomerular capillary pressure plays a role in the acceleration of the loss in renal function. As a consequence, it is proposed that in treating hypertension we should aim at reducing systemic blood pressure together with an attempt to reduce intraglomerular pressure using agents that act predominantly on post-glomerular resistance in order to have renal protection.

Renal adaptation to sodium deprivation. Effect of captopril in the rat.

Dietary sodium restriction is associated with a rapid decrease in urinary sodium excretion and achievement of a new sodium balance within three to five days. In addition, renal vasoconstriction and progressive activation of intrarenal systems with vasoconstrictor (renin-angiotensin) or vasodilating (kallikrein-kinin and prostaglandins) properties are observed. The relationship between sodium homeostasis and the renin-angiotensin system was assessed through the use of captopril in the rat. Treatment with captopril, before and during a six-day period after suppression of dietary sodium, was associated with sodium wasting (urinary sodium always exceeded sodium intake during the observation period); in addition, the normal increase in urinary aldosterone was blunted by about 80 percent. When captopril treatment was given for six days to rats maintained on long-term sodium restriction (at least four weeks) urinary sodium increased, although transiently; at the end of the study, renal vasodilatation together with a redistribution of glomerular blood flow to nonsuperficial glomeruli was observed. These studies indicate that captopril administration markedly blunts the renal and systemic adaptations to a reduced sodium intake in the rat. They suggest that the renin-angiotensin system is probably indispensable in preventing sodium loss when dietary sodium is suppressed.

Nephrotic-range proteinuria in patients with renovascular disease.

PURPOSE: Proteinuria is usually considered a manifestation of glomerular disease. We sought to describe the characteristics of patients with nephrotic-range proteinuria resulting from renovascular disease and to compare them with those of patients who had glomerulonephritis. SUBJECTS AND METHODS: We identified 14 patients with nephrotic-range proteinuria and renovascular disease and compared them with 14 patients who had nephrotic-range proteinuria and biopsy-proven glomerulonephritis, matched for sex, age, and glomerular filtration rate. RESULTS: Patients with renovascular disease were more likely to have known atherosclerotic vascular disease [13 of 14 (93%) vs 3 of 14 (21%), P < 0.0001) and were usually smokers [12 of 14 (85%) vs 3 of 14 (21%), P < 0.0001]. They also had a greater mean (+/- SD) difference between the lengths of their kidneys (29 +/- 10 vs 5 +/- 5 mm, P < 0.001); greater systolic blood pressure (203 +/- 22 vs 174 +/- 25 mm Hg, P < 0.005), plasma renin activity (17 +/- 19 vs 2 +/- 2 ng/mL/h, P = 0.005), and plasma aldosterone concentration (40 +/- 23 vs 11 +/- 10 ng/dL, P = 0.0001); and lower serum potassium levels (3.3 +/- 0.5 vs 3.8 +/- 0.5, P <0.05). Effective renal plasma flow was lower (139 +/- 68 vs 307 +/- 185 mL/min/1.73 m3) and filtration fraction was markedly greater (0.28 +/- 0.04 vs 0.15 +/- 0.07, P = 0.0001) in the patients with renovascular disease. After the oral administration of captopril, blood pressure, effective renal plasma flow, and glomerular filtration rate decreased only among patients with renovascular disease. Of the 14 patients with renovascular disease, 13 had evidence of renal artery thrombosis seen at angiography; 2 patients required dialysis, and 3 others died during follow-up. CONCLUSION: Our findings suggest that the patients with nephrotic-range proteinuria resulting from renovascular disease have distinct characteristics and a poor prognosis.

Systemic and renal effect of nicotine in non-smokers: influence of vitamin C.

OBJECTIVES: To investigate whether the administration of the anti-oxidant vitamin C could prevent the systemic and renal effects of nicotine in healthy non-smoker volunteers. METHODS: The acute effects of oral, 4 mg, nicotine gum (n = 10), intravenous vitamin C (12 mmol, n = 8) or both (n=9) on mean arterial pressure (MAP), heart rate, glomerular filtration rate (GFR), effective renal plasma flow (ERPF) and urinary cyclic guanosine monophosphate (cGMP) were assessed in non-smokers. RESULTS: In subjects receiving nicotine, MAP (+8 +/- 4 mmHg, P<0.0001) and HR (+13 +/- 8 beats/min, P < 0.001) increased whereas ERPF (-65 +/- 69 ml/min per 1.73 m2, P < 0.01), GFR (-14.5 +/- 16.8 ml/min per 1.73 m2, P < 0.01) and cGMP (-180 +/- 173 pmol/min, P < 0.01) decreased as compared to baseline values. The concomitant administration of nicotine and vitamin C caused similar haemodynamic changes; however, cGMP remained unchanged. In subjects receiving only vitamin C, there were no significant changes in MAP, heart rate, ERPF, GFR and cGMP. CONCLUSIONS: The present findings indicate that vitamin C was unable to prevent the renal vasoconstriction, but it prevented the fall in cGMP provoked by nicotine in non-smokers. This suggests that nicotine induces a degradation of nitric oxide mediated by oxygen-derived free radicals which may be prevented by vitamin C administration. The nicotine-induced renal vasoconstriction may be related to other mechanism(s).