Arterial stiffness may predict renal and cardiovascular prognosis in autosomal-dominant polycystic kidney disease.

Background and aims Autosomal-dominant polycystic kidney disease (ADPKD) is one of the most common causes of end-stage renal disease (ESRD). The most important cause of death among ADPKD patients is cardiovascular (CV). The aim of this study was to examine the prognostic significance of arterial stiffness on CV and renal outcomes in ADPKD. Methods A total of 55 patients with ADPKD were examined. Pulse wave velocity was determined and stiffness index (SIDVP) was calculated. Combined primary endpoints (CV and renal) were major CV events (myocardial infarction, stroke, and CV intervention) as CV endpoints, and attaining of ESRD or start of renal replacement therapy as renal endpoints. Secondary endpoints were CV or renal endpoints separately. Results The mean age of those 55 ADPKD patients was 45 ± 12 years, 21 patients were male. The average value of the SIDVP was 11.11 ± 2.22 m/s. The patients were divided into two groups by the cutoff value of 11 m/s of SIDVP and then outcomes were analyzed. In the higher arterial stiffness group (SIDVP > 11 m/s), occurrence of combined primary endpoint (CV and renal) was significantly higher than in the group with more elastic arteries (p = 0.033). A statistically significant difference was found in the renal endpoints (p = 0.018), but not in the CV endpoints (p = 0.952) between the two groups. Conclusions Increased arterial stiffness predicts the onset of ESRD in ADPDK. Assessment of SIDVP appears to be a useful method for estimating the renal and CV prognosis in ADPKD.

L-carnitine supplementation and adipokines in patients with end-stage renal disease on regular hemodialysis.

Chronic hemodialysis (HD) patients frequently encounter carnitine depletion, elevated adipose tissue-derived hormones/cytokines, that may contribute to accelerated arteriosclerosis. 10 non-diabetic HD patients were studied over 28 weeks. In the 12 weeks treatment period 1 g L-carnitine was given iv after each HD session. Measurements of plasma free- and acylcarnitines, insulin, leptin, adiponectin, resistin and ghrelin were performed at baseline, at weeks 2, 4, 8, 12 (treatment period) and at weeks 24-28 (post-treatment period). L-carnitine supplementation resulted in progressive increase of free- and acylcarnitine levels. Plasma levels of insulin, resistin, leptin and ghrelin remained at the already elevated baseline values. L-carnitine therapy induced a significant increase in plasma adiponectin from 20.2 ± 12.7 µg/ml (baseline) to 32.7 ± 20.2 µg/ml in week 2 (p<0.05) and 35.4 ± 19.6 µg/ml in week 12 (p < 0.03), which remained unchanged in the post-carnitine period. Plasma insulin levels correlated positively with leptin (r = 0.525, p<0.0001) and resistin (r = 0.284, p<0.005); adiponectin levels correlated inversely with leptin (r = -0.255, p<0.02) and resistin (r = -0.213, p<0.04) irrespective of carnitine status. Plasma levels of adipokines and related hormones are greatly elevated in patients on regular HD. L-carnitine administration further augmented the plasma levels of protective adiponectin, therefore it may have a role in preventing cardiovascular complications of uremia.

[Endothelial dysfunction]. / Endotheldysfunctio.

The endothelium is a major regulator of vascular tone, releasing vasoconstrictive (endothelin, cyclooxigenase-dependent factors, including prostanoids and oxygen free radicals) and vasodilating (endothelium--derived nitric oxid, endothelium--derived hyperpolarizing factor) mediators. These biologically active substances control not only the vascular tone but the vascular structure and permeability, coagulation and fibrinolysis, as well inflammatory response of the vascular wall. In endothelial dysfunction the balance in the endothelial production of vasodilating and vasoconstricting substances is altered resulting an apparent decrease in endothelium-dependent relaxations. Endothelial dysfunction is an important event in the pathogenesis of the early phase of atherosclerosis and hypertension. The testing and monitoring of endothelial dysfunction include tests of endothelium-dependent vasomotion, as well as circulating markers of endothelial damage. Further methods are needed to build up a panel of tests which measure the extent of endothelial dysfunction (= subclinical atherosclerosis), predict the subsequent risk and response to therapy.

[Comparative study of the reno-protective effect of short- and long-acting antihypertensive agents in IgA nephropathy]. / A rövid és a hosszú hatású antihypertensiv szerek renoprotective hatásának összehasonlító vizsgálata IgA nephropathiás betegekben.

The progression of IgA-NP is influenced unfavourably by development and existence of hypertension. The treatment of hypertension (HTN) has an important role in these patients. Both short- and long-acting formulations of angiotensin convertase enzim inhibitors (ACEi) and calcium channel blockers (CCB) lower blood-pressure, however long-acting preparations may provide better control and may have more renoprotective effect. Verifying this hypothesis, 22 IgA-NP patients were followed for 7.25 +/- 2.36 years. The patients were on short-acting ACEi (captopril, n = 9) or dihydropyridine type CCB (nifedipin, n = 2) or both (captopril + nifedipine n = 11), after at least 3 years the medication was changed to long-acting ACEI (enalapril, n = 4; cilazapril, n = 1), or non dihydropyridine type CCB (diltiazem hydrochlorid, n = 1) or both (n = 16). Just before changing the medication these patients underwent 24 hour ambulatory blood pressure monitoring and at the same time the level of proteinuria and the creatine clearance were measured. Values of serum-creatinine were measured in every 3-4 months within a 3 years period before and after the exchange of antihypertensive drugs. The regression of 1/creatinine was a = -5.28.10(-5) +/- 1.16.10(-4) before and a = 1.03.10(-4) +/- 2.05.10(-4) after the change of medication. Using paired t-test there was a significant difference between the regressions of 1/creatine (p < 0.005). Systolic blood pressure (SBP) (128 +/- 81 Hgmm vs. 126.09 +/- 11.67 Hgmm) was not different, however, diastolic blood pressure (DBP) (84.15 +/- 7.94 Hgmm vs. 79.78 +/- 7.17 Hgmm), diastolic percent time elevation index (HTI) (43.58 +/- 23.57% vs. 25.61 +/- 20.1%) and 24-hour diastolic hyperbaric impact (114.71 +/- 81.9 vs. 51.51 +/- 51.4, p < 0.05) was lower with long-acting antihypertensive agents, as was the proteinuria (1.18 +/- 0.94 g/die vs. 0.69 +/- 1.08 g/die, p < 0.05). Diurnal variation and systolic percent time elevation index were not different. We conclude that long-acting ACEi and non dihydropyridine type CCB formulations result in better outcomes in IgA nephropathy patients compared to short-acting drugs, probably because of better and smoother blood pressure control, lowering of proteinuria and better compliance of the patients.

Ambulatory blood pressure monitoring and progression in patients with IgA nephropathy.

BACKGROUND: Hypertension is a recognized marker of poor prognosis in IgA nephropathy. METHODS: The present study investigated the prevalence of white-coat hypertension, the diurnal rhythm of blood pressure (BP), the effectiveness of antihypertensive drug therapy, and the effect of the above on the progression of the kidney disease in IgA nephropathy. One hundred twenty-six IgA nephropathy patients were selected consecutively for 24-h ambulatory blood pressure monitoring (ABPM). Fifty-five patients were normotensive and 71 were treated hypertensives. Their antihypertensive drugs were angiotensin-converting enzyme inhibitors (ACEI) alone or in combination with calcium-channel blockers (CCB). RESULTS: The mean night-time BP of normotensives (108+/-9/67+/-6 mmHg) was significantly lower than their day-time BP (125+/-8/82+/-7 mmHg, P<0.05). There was no significant difference between the mean day-time and night-time BP in hypertensive patients (125+/-9/82+/-7 mmHg vs 128+/-10/85+/-9 mmHg). The circadian variation of BP was preserved ('dippers') in 82% of the normotensive and 7% of the hypertensive patients (P<0.001). There were 10 'white-coat hypertensives' among the patients classified as normotensives with ABPM (mean office blood pressure 149+/-7/96+/-8 mmHg, 24-h blood pressure 127+/-6/83+/-5 mmHg, P<0.05) and 14 among treated hypertensives (mean office BP 152+/-8/98+/-6 mmHg, 24-h BP 130+/-4/85+/-8 mmHg, P<0.05). There was no difference in mean day-time BP among normotensive and treated hypertensive patients (125+/-8/81+/-5 mmHg vs 128+/-10/85+/-9 mmHg). Hypertensives had significantly higher night-time BP (125+/-9/85+/-9 mmHg) than normotensives (108+/-9/67+/-6 mmHg, P<0.001). There was no difference in serum creatinine levels among the different groups at the time of the ABPM. However, thirty-six+/-4.1 months after the ABPM, hypertensive patients (n=52) had higher serum creatinine levels (124+/-32 micromol/l) than at the time of the ABPM (101+/-28 micromol/l). The serum creatinine of normotensive patients (n=43) did not change during the follow-up period. 'Non-dipper' normotensives (n=10) had significantly higher serum creatinine levels at the end of the follow-up period than at its beginning (106+/-17 micromol/l vs 89+/-18 micromol/l, P<0.05). There was no increase in serum creatinine of 'dipper' normotensives. The mean serum creatinine of 'white-coat hypertensives' was significantly higher at the end of the study period than at its beginning. CONCLUSIONS: There is no diurnal blood pressure variation in most of the hypertensive IgA nephropathy patients. ACEI and CCB treatment have better effect on day-time than night-time hypertension. The lack of the circadian rhythm and 'white-coat hypertension' seems to accelerate the progression of IgA nephropathy.

Structural vascular changes in hypertension: role of angiotensin II, dietary sodium supplementation, blood pressure, and time.

The dose and time dependence of angiotensin II (Ang II) induced hypertension and structural vascular changes and the effect of dietary sodium supplementation on these relationships were investigated. Male Sprague-Dawley rats were treated with 50, 100, or 200 ng . kg-1 . min-1 Ang II subcutaneously for 4 or 12 weeks on normal sodium diet (0.7% NaCl) or with 50 ng . kg-1 . min-1 Ang II SC for 12 weeks on high sodium diet (2% NaCl). Additional rats were sham-operated and fed normal sodium (control rats) or high sodium diet. Plasma Ang II level of rats receiving 100 ng . kg-1 . min-1 Ang II for 4 weeks was 26+/-5 pg/mL (mean+/-SEM, n=7) compared with 11+/-2 pg/mL (n=15) in control rats (P<0.03). Lumen and external diameters of small (50 to 100 microm OD) and intermediate-size (100 to 150 microm OD) resistance arteries were measured in maximally dilated, pump-perfused (55 to 60 mm Hg), in situ fixed mesenteric vascular beds of rats, and wall-to-lumen ratios (W/L) were calculated. Large mesenteric arteries of rats treated with 100 ng . kg-1 . min-1 Ang II for 12 weeks were examined to distinguish hypertrophy from hyperplasia of vascular muscle. Tail systolic blood pressure (BP) and W/L of resistance arteries of Ang II treated rats increased in a dose-dependent manner. Treatment with 50 ng . kg-1 . min-1 Ang II for 12 weeks had no significant effect on BP but produced the same increase in W/L (+10%, n=8, P<0.06) as 100 ng . kg-1 . min-1 Ang II for 4 weeks (+9%, n=18, P<0.05) (time dependence). A 2% NaCl diet for 12 weeks had no significant effect on either BP or W/L, but in combination with 50 ng . kg-1 . min-1 Ang II, it increased systolic BP by 31 mm Hg (P<0.01) and W/L of small resistance arteries by 28% (P<0.01) (synergism). In rats treated with 100 ng . kg-1 . min-1 Ang II for 12 weeks, arterial smooth muscle cell thickness was increased without a change in the number of cell layers (hypertrophy). There was a dissociation between the average BP load (the area under the weekly systolic BP curve) of Ang II treated rats and the W/L of their mesenteric resistance arteries. Ang II induced hypertension and structural vascular changes are dose- and time-dependent and synergistically enhanced by dietary sodium supplementation. Dissociation between BP and vascular structure in Ang II treated rats suggests that a direct trophic effect of Ang II may contribute to the development of structural vascular changes.

Effect of neonatal sympathectomy on the development of structural vascular changes in angiotensin II-treated rats.

BACKGROUND: In a previous study, we found that neonatal sympathectomy prevented the development of angiotensin II (ANG II)-induced hypertension but not the development of structural changes in small mesenteric arteries. OBJECTIVES: To investigate further the dissociation between hypertension and structural vascular changes in sympathectomized ANG II-treated rats by extending morphometric measurements to include all segments of the mesenteric arterial tree. METHODS: Neonatally sympathectomized and sham-sympathectomized male Sprague-Dawley rats, aged 34 months, were administered 200 ng/kg per min ANG II subcutaneously for 4 weeks. Sham-operated sympathectomized and sham-sympathectomized rats were controls. At the end of the treatment period the mesenteric circulation of rats was perfusion-fixed for morphometric measurements. RESULTS: Tail systolic blood pressure in ANG II-treated sham-sympathectomized rats increased by 47 mmHg (P < 0.001); the increase of systolic blood pressure (11 mmHg) in ANG II-treated sympathectomized rats did not attain statistical significance. Sympathectomy alone increased the lumen and reduced the wall : lumen ratio of first- and second-order branches of the superior mesenteric artery (hypotrophic outward remodeling). ANG II treatment increased the dimensions, wall thickness, and wall area of first- and second-order arteries (hypertrophic outward remodeling) and the wall : lumen ratio of small resistance arteries in sham-sympathectomized rats. Neonatal sympathectomy attenuated the development of structural changes in large arteries but had no effect on the development of structural changes in small arteries of ANG II-treated rats. CONCLUSION: Hypertension and sympathetic innervation appear to be contributing to the development of structural changes in large arteries of ANG II-treated rats because sympathectomy attenuated these changes. Structural changes in small arteries, on the other hand, appear to be due to a direct trophic effect of ANG II.

Synergistic vascular effects of dietary sodium supplementation and angiotensin II administration.

The hypertensinogenic action of dietary sodium supplementation was investigated in angiotensin II (ANG II)-treated rats. We hypothesized that high-sodium diet would potentiate ANG II-induced vasoconstriction and hypertension, including the development of structural vascular changes, through synergistic action with ANG II in stimulating sympathetic activity and vascular growth. Mesenteric vasoconstrictor responses to ANG II, norepinephrine (NE), arginine vasopressin (AVP), and periarterial nerve stimulation were measured in Sprague-Dawley rats after 7-10 days of the following treatments: 200 ng.kg-1.min-1 ip ANG II (n = 12), 4% NaCl diet (n = 11), ANG II + 4% NaCl diet (n = 7), and 0.7% NaCl diet (controls) (n = 15). Additional rats received 50 ng.kg-1.min-1 sc ANG II (n = 8), 2% NaCl diet (n = 9), ANG II + 2% NaCl diet (n = 6), or 0.7% NaCl diet (controls) (n = 10) for 12 wk. Systolic blood pressure (SBP) values were measured weekly for 4 wk and then every other week for 8 wk. Then, the wall-to-lumen ratio (W/L) of mesenteric resistance arteries (< 150 microns OD) was measured after in situ perfusion-fixation. After 7-10 days of treatment, there were no significant changes in SBP in any of the groups. High-sodium diet increased vasoconstrictor responses to ANG II (P < 0.01) and nerve stimulation (P < 0.02), but not to NE or AVP, and in combination with ANG II treatment further potentiated vasoconstrictor responses to ANG II (synergism). After 12 wk of treatment, ANG II increased W/L of small resistance arteries by 11% (P < 0.05) without a significant rise in SBP. ANG II and 2% NaCl diet in combination raised SBP by 36 mmHg (P < 0.01) and increased small artery W/L by 28% (P < 0.001) compared with values obtained in control rats. To test the specificity of the interaction between ANG II and high-sodium diet, all the experiments were repeated during phenylephrine (PE, 10 micrograms.kg-1.min-1 sc) treatment of rats. PE by itself or in combination with high-sodium diet had no effect on the measured parameters. Thus short-term administration of high-sodium diet appears to potentiate vasoconstrictor responses to ANG II by facilitating sympathetic neurotransmission, and long-term administration of high-sodium diet raises SBP by potentiating the trophic vascular effects of ANG II. The interaction appears to be specific to ANG II and is occurring on the vascular level.

Effect of neonatal sympathectomy on development of angiotensin II-induced hypertension.

We tested, in the early stage of angiotensin II (ANG II)-induced hypertension, whether sympathectomy prevented the autopotentiation of vasoconstrictor responses by ANG II and, in the chronic, established phase of hypertension, whether the antihypertensive effect of sympathectomy, if any, was related to the prevention of structural vascular changes. Neonatally and sham-sympathectomized male Sprague-Dawley rats received 100 or 200 ng x kg(-1) x min(-1) ANG II intraperitoneally for 7-10 days or 200 ng x kg(-1) x min(-1) ANG II subcutaneously for 4 wk. Sham-treated sympathectomized and sham-sympathectomized rats were controls. Vasoconstrictor responses to ANG II, norepinephrine (NE), arginine vasopressin, and periarterial nerve stimulation were measured in the mesentery of rats, and thereafter, in the chronically treated rats, mesenteric resistance arteries were fixed in situ for morphometric measurements. In ANG II-treated sham-sympathectomized rats: 1) tail systolic blood pressure was unchanged after 7-10 days and increased by 23 mmHg at 4 wk (P < 0.001); 2) vasoconstrictor responses were selectively increased to ANG II (autopotentiation; P = 0.026) and nerve stimulation (P = 0.031) at 7-10 days and nonselectively increased to all stimuli at 4 wk (P < 0.05 to P < 0.01); and 3) after 4 wk, the wall-to-lumen ratio of resistance arteries was increased (P < 0.02). In ANG II-treated sympathectomized rats, there were no changes in systolic blood pressure or vasoconstrictor responses at either 7-10 days or 4 wk, but structural vascular changes developed to the same extent as in sham-sympathectomized ANG II-treated rats. Autopotentiation of vasoconstrictor responses appears to be due to an interaction between ANG II and the sympathetic nervous system, because it is prevented by sympathectomy. The dissociation of function and structure in the chronic stage of ANG II administration to sympathectomized rats suggests that structural vascular changes by themselves are insufficient to cause hypertension, but increased vascular reactivity or vasoconstrictor input is also needed.