Fibrinogen, mortality and incident cardiovascular complications in end-stage renal failure.

OBJECTIVE: Fibrinogen is an established predictor of cardiovascular events in the general population but the relationship between fibrinogen, mortality and incident cardiovascular complications has been very little investigated in patients with end-stage renal disease (ESRD). DESIGN AND SUBJECTS: We investigated the relationship between fibrinogen and all cause mortality and cardiovascular outcomes in a prospective cohort study in 192 patients on chronic haemodialysis treatment (follow-up: 34 +/- 16 months). RESULTS: Fibrinogen was significantly higher in patients who died during the follow-up than in those who survived. Similarly, fibrinogen was higher in patients who had fatal or nonfatal cardiovascular events than in event free patients. On multivariate Cox regression analysis fibrinogen was an independent predictor of survival [hazard ratio (1 g x L(-1) increase in plasma fibrinogen): 1.19, 95% confidence interval (CI): 1.05-1.35, P = 0.006] and a highly significant (P = 0.0008), independent predictor of fatal and nonfatal cardiovascular events [hazard ratio (1 g x L(-1) increase in plasma fibrinogen): 1.25, 95% CI: 1.10-1.43] in a model including traditional risk factors and serum C-reactive protein (CRP) and plasma homocysteine. CONCLUSIONS: Fibrinogen is as an independent risk factor for overall and cardiovascular mortality in patients with ESRD. Intervention studies are required to see whether reducing plasma fibrinogen may help to curb the exceedingly high cardiovascular risk of the uremic population.

Fibrinogen, inflammation and concentric left ventricular hypertrophy in chronic renal failure.

BACKGROUND: We investigated the relationship between fibrinogen and echocardiographic measurements of left ventricular (LV) geometry and LV function in a group of 192 patients with end stage renal disease (ESRD). RESULTS: Patients in the third fibrinogen tertile had higher mean wall thickness (MWT), relative wall thickness (RWT) and left ventricular mass index (LVMI) and lower LV end diastolic diameter and LV ejection fraction than those in the other tertiles. On multivariate analysis fibrinogen resulted to be an independent correlate of MWT (P = 0.001) and RWT (P = 0.0001) and the first factor in rank explaining the variance in LV ejection fraction (P = 0.0001). Left ventricular concentric hypertrophy was more prevalent (P = 0.001) in patients in the third fibrinogen tertile (n = 35, 54%) than in those in the second (n = 24, 37%) and first (n = 13, 21%) tertiles. In a multiple logistic regression model patients in the third tertile of fibrinogen had a risk for left ventricular concentric hypertrophy that was 3.56 (95% CI: 1.56-8.14) fold higher than in those in the first tertile (P = 0.003). CONCLUSIONS: Elevated fibrinogen is independently associated with LV concentric hypertrophy and systolic dysfunction in ESRD patients. These relationships may contribute to the negative prognostic impact of elevated fibrinogen levels in ESRD.

Circulating natriuretic peptide concentrations in patients with end-stage renal disease: role of brain natriuretic peptide as a biomarker for ventricular remodeling.

OBJECTIVES: To determine levels of natriuretic peptides (NPs) in patients with end-stage renal disease (ESRD) and to examine the relationship of these cardiovascular peptides to left ventricular hypertrophy (LVH) and to cardiac mortality. PATIENTS AND METHODS: One hundred twelve dialysis patients without clinical evidence of congestive heart failure underwent plasma measurement of NP concentrations and echocardiographic investigation for left ventricular mass index (LVMI). RESULTS: Plasma atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) concentrations correlated positively with LVMI and inversely with left ventricular ejection fraction, whereas C-type NP and Dendroaspis NP levels did not correlate with LVMI. In dialysis patients with LVH (LVMI >125 g/m2), plasma ANP and BNP concentrations were increased compared with those in dialysis patients without LVH (both P<001). In a subset of 15 dialysis patients without LVH or other concomitant diseases, plasma BNP concentrations were not significantly increased compared with those in 35 controls (mean +/- SD, 20.1+/-13.4 vs 13.5+/-9.6 pg/mL; P=.06), demonstrating that the BNP concentration was not increased by renal dysfunction alone. Furthermore, the BNP level was significantly higher in the 16 patients who died from cardiovascular causes compared with survivors (mean +/- SD, 129+/-13 vs 57+/-7 pg/mL; P<.003) and was significantly associated with greater risk of cardiovascular death in Cox regression analysis (P<.001), as was the ANP level (P=.002). CONCLUSIONS: Elevation of the plasma BNP concentration is more specifically related to LVH compared with the other NP levels in patients with ESRD independent of congestive heart failure. Thus, BNP serves as an important plasma biomarker for ventricular hypertrophy in dialysis patients with ESRD.

Long-term CAPD patients are volume expanded and display more severe left ventricular hypertrophy than haemodialysis patients.

BACKGROUND: Whether hypertension and left ventricular hypertrophy (LVH) are more prevalent in CAPD than in haemodialysis (HD) patients is still under discussion. METHODS: To examine this problem we compared a group of 51 CAPD patients, with a group of 201 HD patients. The evaluation included the measurement of atrial natriuretic peptide (atrial natriuretic factor (ANF)), taken as indicator of volume status, and echocardiographic measurements. RESULTS: CAPD patients were older, had been treated for a shorter time, and had lower serum albumin and phosphate than HD patients. Plasma ANF was higher (P<0.01) in CAPD (median 33.8 pmol/l (interquartile range 18.2-63.0)) than in HD patients (22.7 pmol/l (14.9-38.7)). Similarly, the left atrial volume was substantially higher (P<0.0001) in CAPD patients (49+/-22 ml) than in HD patients (37+/-17 ml), while the left ventricular end-diastolic diameter was similar in the two groups (CAPD 51+/-7 mm; HD 50+/-7 mm). Furthermore, left ventricular hypertrophy was more severe (P<0.0001) in CAPD (157+/-37 g/m(2)) than in HD patients (133+/-39 g/m(2)). The proportion of CAPD patients requiring antihypertensive drugs was markedly higher than that of HD patients (65 vs 38% P<0.001). Multivariate modelling showed that volume expansion and pressure load as well as serum albumin were independent predictors of left ventricular mass. CONCLUSIONS: Left ventricular hypertrophy is more severe in long-term CAPD patients than in HD patients. This finding is associated with evidence of more pronounced volume expansion, hypertension, and hypoalbuminaemia. Volume and pressure load along with factors associated with hypoalbuminaemia may aggravate LVH in uraemic patients on CAPD.

Urinary adrenomedullin is related to ET-1 and salt intake in patients with mild essential hypertension. Salt Sensitivity Group of Italian Society of Hypertension.

Adrenomedullin (ADM) infusion increases salt excretion in the rat. However, there is no evidence that this substance is related to changes in salt intake in humans. In this study we sought whether the urinary excretion rate of this autacoid is related to salt intake and by the expected changes in arterial pressure in patients with mild essential hypertension. The influence of salt intake on the renal excretion of ADM was investigated in 55 hypertensive patients in a double blind, randomized and crossover study comparing a 2-week 50 mmol/day salt intake period with a 150 mmol/day salt intake period. Twenty-four-hour ADM and endothelin-1 (ET-1) excretion rate were measured by radioimmunoassay on preextracted urinary samples (intraassay confidence variable <8%). The antibodies used in these assays had minimal ADM-ET-1 cross-reactivity (<1%). Twenty-four-hour microalbuminuria was measured by nephelometry. On univariate analysis changes in urinary ADM were significantly related to those in salt excretion (r = 0.33, P = .01) as well as to changes in urinary ET-1 (r = 0.56, P = .0001). Furthermore, changes in urinary albumin excretion were related to those in urinary ET-1 (r = 0.26, P = .05), but were independent of those in urinary ADM (P = .19). In a multiple regression model including age, sex, body mass index, and changes in systolic pressure, plasma renin activity and plasma aldosterone and urine volume, salt excretion resulted as the stronger independent predictor of urinary ADM (r = 0.33, P = .01). However, changes in urinary salt lost prediction power (P = .11) for urinary ADM when urinary ET-1 was introduced into the model. In this model (multiple r = 0.31) urinary ET-1 resulted to be the only independent predictor of urinary ADM (beta = 0.56, P = .0001). This study is the first to show that the renal excretion of ADM is related to changes in salt intake and that it is tightly linked to that of ET-1. The data support the notion that these autacoids play a role in the regulation of sodium metabolism in patients with mild hypertension. The intercorrelations between ET-1, ADM, and microalbuminuria are compatible with the hypothesis that ET-1 is involved in a salt-induced increase in glomerular pressure and suggest that ADM may act as a counterregulatory factor in this situation.

Diagnostic potential of cardiac natriuretic peptides in dialysis patients.

BACKGROUND: In the general population, the plasma concentrations of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are useful to predict left ventricular hypertrophy (LVH) and LV systolic dysfunction. Whether these cardiac hormones have a similar diagnostic potential in dialysis patients is unknown. METHODS: We studied the diagnostic value of ANP and BNP for alterations in LV mass and function in a cohort of 246 dialysis patients without clinical evidence of heart failure. RESULTS: Both ANP and BNP were independently related to left ventricular mass (P < 0.0001) as well as to ejection fraction (P < 0.0001). In an analysis based on a prospectively defined threshold (95th percentile of the normal range), BNP had a significantly higher (P < 0.01) sensitivity (88%) than ANP (51%) for the diagnosis of LVH, but the positive predictive value of the two peptides was very similar (92 and 87%, respectively, P = NS). However, the negative predictive value of BNP for excluding LVH was 22% higher than that of ANP (53 vs. 31%, P = 0.05). Both natriuretic peptides had a high sensitivity for the detection of LV dysfunction (87 and 94%), but their positive predictive value was low (25 and 15%). Importantly, both ANP and BNP proved to be very useful for excluding this alteration (negative predictive value 97 and 96%, respectively). An analysis based on the "best cut-offs" of each peptide as identified on the basis of the ROC curves augmented the positive and negative prediction values of BNP for the diagnosis of LVH to 95 and 61%, respectively. This approach also raised the BNP-positive prediction value for the identification of LV dysfunction to 31% but did not modify the diagnostic potential of ANP (either for LVH or for LV dysfunction). CONCLUSIONS: Measuring the plasma concentration of cardiac natriuretic hormones, particularly BNP, may be useful for the identification of dialysis patients with LVH or for excluding systolic dysfunction.

Gender-dependent differences in plasma leptin in essential hypertension.

Leptin, the gene product of the ob gene, is influenced by gender and insulin sensitivity. Because in human hypertension there are important endocrine-hemodynamic gender-dependent differences, we compared plasma leptin in 39 essential hypertensives (EH) and in 27 normotensive healthy subjects (HS) matched for gender, age, and fat mass. Fat mass was measured by bioelectrical impedance analysis (BIA), plasma leptin by a sensitive radioimmunoassay RIA (intraassay CV < 6%), and insulin sensitivity by the HOMA-R index. Both in essential hypertensives and in normotensive subjects plasma leptin was consistently higher in females than in males and was strictly related to fat mass. Gender differences in plasma leptin were not explained by differences in fat mass. Separate analysis of data by gender showed that leptin was significantly higher (P < .05) in hypertensive men (median, 5.4 ng/mL; interquartile range, 4.1-9.5) than in normotensive men (4.6 ng/mL, 2.6-7.4) whereas it was identical in hypertensive and normotensive women. In essential hypertensives, in a multiple regression model only fat mass, gender, and the HOMA-R index were independently linked to plasma leptin. Similarly, fat mass and gender were independent predictors of plasma leptin in normotensive subjects. In the combined group of hypertensive and normotensive men, heart rate as well as systolic and diastolic pressure were univariate predictors of leptin. However, in a multivariable model only heart rate was independently related to leptin, and neither systolic nor diastolic pressure contributed significantly to explain the variability in plasma leptin. No relationship was found between leptin and heart rate or systolic or diastolic pressure in women. These results support the notion that leptin may participate in the gender-dependent variability of human hypertension.

Renal endothelin-1 is linked to changes in urinary salt and volume in essential hypertension. Salt Sensitivity Group of the Italian Society of Hypertension.

METHODS: We investigated the influence of salt intake on urinary and plasma endothelin-1 (ET-1) in 55 patients who entered a two-week double-blind, randomised, crossover study comparing a 50 mMol/day salt intake and 150 mMol/day. Twenty-four-hour ET-1 excretion and plasma ET-1 were measured by RIA on pre-extracted samples. RESULTS: In the whole cohort (n=55), changes in urinary ET-1 were related to salt excretion (r=0.28, P=0.04) and urinary volume (r=0.47, P=0.0001). In a multivariable model, changes in PRA, plasma aldosterone, blood pressure and heart rate did not add any predictive power to salt excretion with regard to urinary ET-1 variations. The relationship between urinary volume and urinary ET-1 was stronger than that of urinary sodium with ET-1 excretion because sodium was excluded from the multivariable model when urinary volume was introduced. Changes in urinary ET-1 were unrelated to mean blood pressure changes (P=0.66). Changes in plasma ET-1 were unaffected by changes in salt intake (P=0.58) but were strongly related to those in PRA (r= -0.45, P=0.01) and plasma aldosterone (r= -0.53, P=0.002). CONCLUSIONS: The renal excretion of ET-1 is influenced by changes in salt intake and appears largely independent of the blood pressure response to salt. Changes in urinary volume which accompany variations in salt excretion play an important role in this response. Since urinary ET-1 reflects its renal synthesis, our data support the notion that renal ET-1 plays a role in the regulation of sodium balance in patients with mild hypertension.

Smoking, blood pressure and serum albumin are major determinants of carotid atherosclerosis in dialysis patients. CREED Investigators. Cardiovascular Risk Extended Evaluation in Dialysis patients.

AIM: To investigate the relationship between carotid atherosclerosis and some major cardiovascular risk factors in uremic patients on chronic dialysis. METHODS: A cross-sectional study was carried out in 119 unselected dialysis patients (89 on hemodialysis and 30 on chronic ambulatory peritoneal dialysis, CAPD). Fasting blood sampling for serum lipids, albumin, hemoglobin, and echo-colour-Doppler evaluation of common carotid arteries were performed in all patients (during the non-dialysis day in hemodialysis patients). In hemodialysis patients BP was measured before and after dialysis; in CAPD patients home BP values were recorded during the month before the study day. RESULTS: Ninety-five patients had at least one plaque and 57 had at least four plaques. Thirty-eight had mild and eleven severe carotid stenosis. In multiple regression models, the mean internal diameter of carotid arteries was explained (R=0.52, P=0.0001) by systolic pressure (r=0.39), serum cholesterol (r=-0.28), age (r=0.27) and smoking (r=0.24) while the degree of carotid stenosis was predicted (R=0.39, P=0.0001) by age (r=0.36) and smoking (r=0.25). The number of atherosclerotic plaques was explained (R=0.51, P=0.0001) by age (r=0.36), smoking (r=0.25) and pulse pressure (r=0.20), serum albumin just failing to reach statistical significance (P = 0.06). However, serum albumin was a significant and independent predictor of the number of atherosclerotic plaques (r=-0.26) in hemodialysis patients (n=89). Sex, diabetes, Kt/V, duration of dialysis treatment, hemoglobin, serum calcium and phosphate did not add any predictive power to the models. CONCLUSIONS: In dialysis patients arterial pressure and smoking are associated with carotid atherosclerosis. Serum albumin appears to serve as an independent predictor of carotid atherosclerosis.

Plasma adrenomedullin during acute changes in intravascular volume in hemodialysis patients.

BACKGROUND: Adrenomedullin, is a potent vasorelaxant that is highly expressed in the adrenal medulla, kidney, heart and lung. Since there is indirect evidence that hypervolemia enhances the release of this peptide, we measured plasma adrenomedullin in 9 uremic patients on chronic dialysis treatment and in 10 healthy subjects matched for age and gender. METHODS: Measurements were performed in baseline conditions, after isotonic fluid subtraction (by isolated ultrafiltration) and during a 70 degrees tilt. Tilt was performed in volume-depleted state, that is, after isolated ultrafiltration (UF). In the control experiment patients underwent sham UF (UF = 0) followed by a period of supine resting identical to the one they had spent in tilted position in the active experiment. Adrenomedullin was measured on pre-extracted plasma samples (Sep-Pak C-18 cartridges) by a specific RIA for human adrenomedullin 1-52. RESULTS: The average plasma adrenomedullin was 2.6 times higher (P < 0.01) in uremic patients (103 +/- 8 pg/ml) than in healthy subjects (39 +/- 7 pg/ml). After fluid subtraction (-2.6 +/- 0.2 liter) adrenomedullin fell to 79. +/- 8 pg/ml (P = 0.02) but remained well above the upper limit of the 95% CI in normal subjects (52 pg/ml). There was no relationship between adrenomedullin and ANF changes. In the control experiment sham UF did not modify plasma adrenomedullin. Tilt did not significantly change plasma adrenomedullin either in dialysis patients or healthy subjects. CONCLUSIONS: Plasma adrenomedullin is markedly raised in uremic patients on dialysis, which confirms that the kidney has a major role in the clearance of this peptide. However, the fall in plasma adrenomedullin after isolated UF indicates that the plasma concentration of this peptide is influenced by the body fluid volume status. Whether or not adrenomedullin participates in the counter-regulatory response to fluid subtraction in uremic patients remains to be explored by specific antagonists of this substance.

The influence of volume depletion and central hypovolemia on the plasma concentration of parathyroid hormone in dialysis patients.

Because changes in extracellular volume during dialysis cause reflex neurohonnonal changes that may influence parathyroid hormone (PTH) release independently of calcium, the influence of isotonic volume depletion (by isolated ultrafiltration) and central hypovolemia (70 degrees tilt) on serum PTH1-84 was studied in 16 hemodialysis patients. Tilting was performed in volume depleted state, i.e., immediately after hemodialysis. In the control study, patients underwent sham ultrafiltration (UF = 0) and after dialysis maintained the supine position for the same length of time they remained in the tilt position in the active experiment. Isolated ultrafiltration (-2.3 +/- SEM 0.3 L) caused a 21% fall in mean arterial pressure (from 101 +/- 6 to 80 +/- 6 mmHg, P < 0.01), a fall that was accompanied by a marked increase in plasma catecholamine levels (norepinephrine P < 0.001, epinephrine P < 0.025), in plasma renin activity (P < 0.001) and in plasma arginine vasopressin (P < O.001). Atrial natriuretic factor showed a slight reduction, whereas the plasma endothelin-1 level did not change. Serum Ca showed the expected, hemoconcentration-dependent rise (from 4.1 +/- 0.1 to 4.4 +/- 0.1 meq/L, P < 0.01). Interestingly, UF caused a marked rise in plasma PTH1-84 concentration (from 252 +/- 62 to 335 +/- 72 pg/ml, P < 0.01). UF-induced changes in serum PTH1-84 were related to norepinephrine changes (r = 0.57) as well as to plasma renin activity (r = 0.50). After hemodialysis, tilting induced a pronounced rise in serum PTH1-84 (from 102 +/- 29 to 200 +/- 55 pg/ml), and these changes were slightly related to plasma epinephrine (r = 0.49) but independent of other parameters. In the control experiment, neither sham UF nor recumbency modified serum PTH. In hemodialysis patients, serum PTH is sensitive to changes in extracellular and central blood volume of magnitude sufficient to decrease arterial pressure. Avoiding marked volume stimuli might help to refine the interpretation of the Ca/PTH curves during hemodialysis in these patients.

Measures of tubular function in normoalbuminuric insulin-dependent diabetic patients and their relationship with sodium lithium countertransport activity.

The aim of this study was to assess the relationship between markers of tubular function, markers of glycaemic control and erythrocyte sodium-lithium countertransport activity (SLC) in 40 normotensive, normoalbuminuric insulin-dependent diabetic (IDDM) subjects and 11 normal control subjects. Nine IDDM subjects had SLC > 0.40 mmol lithium h-1 litre RBC-1. Glomerular filtration rate (GFR) and the excretion rate of retinol-binding protein (RBP), N-acetyl-beta-D-glucosaminidase (beta-NAG) and glucose were significantly higher in IDDM subjects compared to control subjects (Mann-Whitney test, p = 0.02, < 0.001, < 0.001 and < 0.001, respectively), whilst the two groups had similar SLC and TmPO4 levels. There was no significant relationship between SLC and the other variables in IDDM subjects, even when comparing IDDM subjects with normal and high SLC. beta-NAG excretion rate was correlated to urinary glucose (rs 0.47, p = 0.001) and, weakly, to the other markers of glycaemic control (fasting blood glucose rs = 0.31, p = 0.03, fructosamine rs 0.28, p = 0.04, HbA1 rs 0.27, p = 0.04). RBP excretion rate was correlated to the excretion rate of beta-NAG (rs 0.38; p = 0.007) and albumin (rs 0.45; p = 0.002); the excretion rates of beta-NAG and albumin were significantly associated (rs 0.37, p = 0.009). Diabetes duration did not correlate to any of the aforementioned variables. In this study, beta-NAG and RBP overnight excretion rates were higher in normoalbuminuric IDDM subjects compared to control subjects but no relationship was present between SLC and tubular function in IDDM patients without complications. Excretion rates of different proteins appear to be interrelated and, in IDDM, beta-NAG excretion is associated with glycaemic control.

Urinary and plasma endothelin 1 in essential hypertension and in hypertension secondary to renoparenchymal disease.

An alteration in renal metabolism of endothelin may contribute to hypertension in the SHR and it has been shown that the excretion rate of endothelin is reduced in patients with essential hypertension. We measured plasma and urinary endothelin 1 (ET-1) in 20 untreated essential hypertensives with normal renal function, in eight normotensive healthy subjects, and in 13 hypertensive patients with primary renoparenchymal disease. Plasma ET-1 was higher (P < 0.01) in essential hypertensives (median 1.69, interquartile range 1.2-3.3 pg/ml) than in normal subjects (0.84, 0.37-1.10 pg/ml) but significantly less (P < 0.01) than in hypertensives with renoparenchymal disease (3.57, 1.45-9.52 pg/ml). ET-1 levels slightly correlated with diastolic pressure in essential hypertensives (r = 0.43, P < 0.05) and tended to be correlated with systolic pressure in hypertensives with renal disease (r = 0.47, P = 0.08). ET-1 excretion in essential hypertensives (137, 99-154 ng/24 h) and in normal subjects (120, 62-150 ng/24 h) was significantly lower than in renal hypertensives (191, 123-241 ng/24 h). The ET clearance/GFR ratio (ClET/GFR) was markedly reduced (30%, 21-67%) in essential hypertensives and substantially raised in renal hypertensives (164%, 86-314%) in comparison with normal subjects (83%, 35-94%). Since the ClET/GFR ratio should be 100% if all filtered ET-1 is excreted, the data indicate that ET-1 is synthesized at a reduced rate and/or broken down at an enhanced rate by the kidney in essential hypertension and confirm that there is a high ET-1 generation rate in remnant nephrons in hypertension secondary to renal disease.

Influence of extracellular volume expansion on circulating PTH1-84 in subjects with mild essential hypertension.

The effect of acute volume expansion by saline (1 L/40 min) on serum parathyroid hormone (PTH) concentration was studied in 28 subjects with mild essential hypertension. At the zenith volume expansion there was a significant increase in systolic pressure (7 +/- 2 mm Hg, P < .01) while diastolic pressure and heart rate showed minor (NS) variations. The rise in systolic pressure was accompanied by a significant (P = .02) decrease in plasma ionized calcium (from 1.12 +/- 0.03 to 1.08 +/- 0.03 mmol/L) and by a marked PTH increase (from 36 +/- 3 to 60 +/- 4 pg/mL, P < .01). The arterial pressure variations were independent of changes in serum PTH. In a second experiment (n = 11), aimed at preventing the changes in calcium concentration brought about by hemodilution, we infused the same volume of saline with the addition of 1.25 mmol of elemental calcium. In this study PTH showed a small, nonsignificant, decrease while systolic pressure changes were similar to those of the first study (ie, an isolated 9 +/- 4 mm Hg increase in systolic pressure). In a third experiment (n = 7), aimed at studying the effect of raised plasma PTH concentration in isocalcemic conditions, PTH1-38 was continuously infused (1 ng/kg/min) during the volume expansion phase performed with the same solution as used in the second experiment. The hemodynamic changes were again identical to those of the other studies (an isolated 9 +/- 3 mm Hg increase in systolic pressure).(ABSTRACT TRUNCATED AT 250 WORDS)

The influence of salt intake on plasma calcitonin gene-related peptide in subjects with mild essential hypertension.

BACKGROUND: Calcitonin gene-related peptide is a pleiotropic neuropeptide with potent vasodilatory properties, which interferes with renin release and might participate in cardiovascular homeostasis. DESIGN AND METHODS: We studied the influence of salt intake on the plasma concentration of calcitonin gene-related peptide, parathyroid hormone and on the renin-aldosterone system in 15 patients with mild hypertension. Each participant was studied after 1 week of high salt intake (200 mmol/day) and after 1 week of low salt intake (50 mmol/day). The order of the two diet periods was randomized and crossover. Plasma calcitonin gene-related peptide concentration was measured by radioimmunoassay after pre-extraction by reverse chromatography. Seven patients were classified as salt-sensitive and eight as salt-resistant. RESULTS: In the whole group the low salt intake caused a significant decrease in arterial pressure and the expected increase in plasma renin activity and in plasma aldosterone concentration. Such changes were accompanied by a significant increase in plasma calcitonin gene-related peptide. In salt-resistant patients in the sodium-replete state calcitonin gene-related peptide levels tended to be reduced in comparison with salt-sensitive patients. Sodium depletion, however, caused a more pronounced rise in plasma calcitonin gene-related peptide in salt-resistant hypertensives, who attained levels close to those in salt-sensitive hypertensives. Interestingly, in salt-resistant hypertensives changes in plasma calcitonin gene-related peptide were closely related to plasma renin activity (r = 0.71, P = 0.003), whereas no such correlation was found in salt-sensitive patients. Parathyroid hormone was not influenced by changes in salt intake. CONCLUSIONS: In subjects with mild hypertension calcitonin gene-related peptide is sensitive to changes in salt intake in the physiological range. Such a response seems to be linked to the individual arterial pressure response to salt, because salt-resistant patients showed reduced calcitonin gene-related peptide levels in the sodium-replete state and a more pronounced calcitonin gene-related peptide increase, closely related to plasma renin activity, during sodium deprivation.

Influence of cardiovascular damage and residual renal function on plasma endothelin in chronic renal failure.

To study the influence of cardiovascular damage on plasma endothelin in chronic renal failure, we have measured the plasma concentration of this peptide in 32 uremic patients (7 undialyzed uremics, 8 CAPD patients and 16 hemodialysis patients) and in 9 healthy subjects. Sixteen patients had severe cardiovascular damage while the other 16 had no cardiovascular involvement. Endothelin was markedly raised (p < 0.01) in the uremic group as a whole (13.9 +/- 2.6 pmol/l) in comparison with the group of healthy subjects (8.6 +/- 1.6 pmol/l). Hemodialysis patients displayed endothelin levels much higher (p < 0.01) than CAPD patients and undialyzed uremics. Endothelin was directely related with BUN (r = 0.37) and with serum creatinine (r = 0.52) in dialysis patients. Similar correlations were also found in undialyzed uremics. Plasma endothelin was almost identical in patients with severe cardiovascular damage (15.5 +/- 1.6 pmol/l) and in those without cardiovascular involvement (15.9 +/- 2.6 pmol/l). There was no relationship between arterial pressure and plasma endothelin. Residual renal function is an important determinant of circulating endothelin even at very advanced stages of renal insufficiency. It appears unlikely that atherosclerosis plays a major role in the pathogenesis of high plasma concentration of this peptide in uremic patients.

The influence of autonomic failure on plasma ANF concentration in uremic patients on chronic hemodialysis.

We compared plasma ANF concentration in 5 diabetic-uremics with combined sympathetic-parasympathetic dysfunction with that in 9 uremic patients without autonomic impairment. Symptomatic dialysis hypotension was a major clinical problem in all diabetic-uremics. In the volume-expanded state, ANF was almost twice as high (p less than 0.025) in diabetic-uremics than in control uremics (152 +/- 29 vs 84 +/- 10 pg/ml) in the face of similar right atrial pressure (14 +/- 3 vs 12 +/- 1 cm H2O). After isolated ultrafiltration, ANF fell significantly in both groups remaining slightly (NS) higher in diabetic-uremics. The slope of the relationship between ANF and right atrial pressure was significantly (p less than 0.01) steeper in diabetic-uremics than in control uremics. The data indicate that autonomic failure amplifies the effect of atrial stretching on plasma ANF in diabetic-uremics on chronic hemodialysis treatment.

Hyperfiltration and calcium metabolism in essential hypertension.

To test the hypothesis that hyperfiltration in essential hypertension is linked to alterations in calcium metabolism, we studied the relationship between urinary calcium excretion and glomerular filtration rate (GFR, creatinine clearance) in 38 untreated essential hypertensives on a free diet. We also studied the influence of changes in calcium intake on GFR in 30 essential hypertensives (15 with well-defined hypercalciuria and 15 with normal urinary calcium excretion) and in 11 normotensive healthy subjects. In the patients on a free diet, urinary calcium excretion was directly and independently related to GFR (r = 0.56, P less than .001), while serum calcium showed an opposite trend (r = -0.27, P = .12). In patients on fixed calcium diets, GFR was significantly higher (P = .008) at low calcium intake (115 +/- 31 mL/min/1.73 m2) than at high calcium intake (98 +/- 22 mL/min/1.73 m2). Further analysis showed that the hyperfiltering effect of low calcium almost exclusively occurred in hypercalciuric patients and in hypertensive women. In hypercalciuric hypertensives there was a highly significant inverse correlation between GFR and serum calcium (r = -0.51, P = .004) and a similar correlation between GFR and plasma renin activity (r = -0.70, P = .003) in the high calcium phase of the study. Changes in calcium intake had no influence on GFR in normal subjects (Low Ca 103 +/- 22 mL/min/1.73 M2, High Ca 110 +/- 23 mL/min/1.73 m2). The data indicate that alterations in calcium metabolism interfere to an important extent with mechanism(s) regulating GFR in essential hypertension.