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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.

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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.

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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.

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The D allele of the angiotensin-converting enzyme (ACE) gene has been linked with diabetic nephropathy and IgA glomerulonephritis and with faster renal disease progression. The association of this allele with nephroangiosclerosis has been scarcely investigated. We have tested this association in 45 hypertensive patients (all whites) with well defined nephroangiosclerosis (diagnosis established on the basis of renal biopsy in all cases) and moderate to severe renal failure. As studies of genetic association of small size often produce conflicting results, besides a control group of 343 Italian patients with essential hypertension and normal renal function, we elected to use also a very large control group of race-matched subjects taken from a meta-analysis of 27,565 whites. The proportion of patients with the D allele (64%) was higher in patients with nephroangiosclerosis than that in Italian hypertensives (54%) and in whites (54%). DD and DI genotypes were more prevalent in patients than in control groups. The dominant model (DD and DI v II: nephroangiosclerosis v Italian controls: chi2 = 6.19, P = .012; nephroangiosclerosis v whites chi2 = 6.86, P = .009) fitted the data better than the codominant and the recessive model (P < or = .022). The D allele is associated with nephroangiosclerosis with a dominant effect in the sample of patients studied. Although intervention studies are needed to see whether these findings imply a causal association, our data suggest that this allele may at least act as disease marker in nephroangiosclerosis.

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BACKGROUND: The reproducibility of the arterial pressure response to change in salt intake in essential hypertensives has been little investigated. OBJECTIVE: To study the reproducibility of the response to salt in 14 untreated patients with mild essential hypertension. METHODS: After a run-in phase (1 month), each patient ingested, in random order and with cross-over, 1 week of high salt intake (170 mmol/day) and 1 week of low salt intake (40 mmol/day). The identical experimental protocol was then repeated after an average interval of 3.4 months. Arterial pressure was measured (clinic arterial pressure and 24 h ambulatory monitoring) on the seventh day of each diet period. The reproducibility of the arterial pressure response was assessed in terms the intraclass correlation coefficient and the K statistics. RESULTS: There was a good compliance with the dietary prescription because the urinary Na excretion was on average very close to the prescribed intake both during the first and during the second salt intake period. Both clinic and 24 h arterial pressure fell significantly (P < 0.01) and to the same extent in the low-salt phases of the study. Clinic arterial pressure was consistently higher than 24 h ambulatory arterial pressure but the average changes induced by salt depletion were similar. The variability of 24 h ambulatory arterial pressure at constant salt intake was lower than that of clinic arterial pressure. However, the arterial pressure response to salt showed the same variability with the two methods. The reproducibility of the dichotomous classification of patients into salt-sensitive and -resistant was low both in terms of 24 h ambulatory and in terms of clinic blood pressure. CONCLUSION: Although on rechallenging the average arterial pressure response to salt remains unchanged in essential hypertensives, the individual responses are variable and the reproducibility of the dichotomous classification is unsatisfactory. The problem of dichotomizing patients into salt-sensitive and -resistant ones is only in very little part resolved by more precise arterial pressure estimates.

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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)

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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.

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We have studied the metabolic response to changes in calcium in 15 hypercalciuric essential hypertensives, in 8 normotensive hypercalciuric stone formers and in 11 normotensive healthy subjects matched for age and sex. At variance with hypercalciuric stone formers, at low calcium intake hypercalciuric hypertensives did not appropriately reduce urinary calcium excretion and developed mild hypocalcemia. Furthermore, the PTH response to calcium deprivation was not appropriately enhanced in these patients. The data indicate that different mechanisms prevail in these two forms of hypercalciuria: the renal in essential hypertension and the intestinal in urolithiasis.

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We carried out a retrospective survey to assess prevalence and type of diabetes in three Italian Renal Units located respectively in the North (Tradate, Varese), in the Middle (Latina) and in the South (Reggio Calabria) of Italy. The prevalence of diabetes among patients accepted for RRT was 10.5% (60/659). 40 patients (66.7%) were non-insulin dependent and only 6 patients were insulin-dependent. A similar pattern was observed among the 289 patients referred to the Renal Unit of Reggio Calabria during 1972-1987 for evaluation of Chronic Renal Failure. Our data suggest that among the Italian diabetic patients treated by dialysis and transplantation insulin-dependent diabetes is uncommon. This finding could be explained by the low incidence of insulin-dependent diabetes in Italy.

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The authors carried out a retrospective survey assessing the total proportion of diabetic patients and relative proportion of patients with Type I and Type II diabetes among patients receiving renal replacement therapy and those evaluated for chronic renal failure in a southern Italian renal unit during the period 1972-1986. The proportion of diabetics among patients accepted for renal replacement therapy was 10% (34/336); of the 34 diabetic patients, only one was clearly affected by Type I diabetes, 26 had Type II diabetes, and the classification was uncertain in four patients. Similar relative proportions of Types I and II diabetes were observed among patients referred during the same period for evaluation of chronic renal failure.

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