Almerico Novarini

Urinary volume, water and recurrences in idiopathic calcium nephrolithiasis: a 5-year randomized prospective study.

PURPOSE We define the role of urine volume as a stone risk factor in idiopathic calcium stone disease and test the actual preventive effectiveness of a high water intake. MATERIALS AND METHODS We studied 101 controls and 199 patients from the first idiopathic calcium stone episode. After a baseline study period the stone formers were divided by randomization into 2 groups (1 and 2) and they were followed prospectively for 5 years. Followup in group 1 only involved a high intake of water without any dietetic change, while followup in group 2 did not involve any treatment. Each year clinical, laboratory and radiological evaluation was obtained to determine urinary stone risk profile (including relative supersaturations of calcium oxalate, brushite and uric acid by Equil 2), recurrence rate and mean time to relapse. RESULTS The original urine volume was lower in male and female stone formers compared to controls (men with calcium oxalate stones 1,057 +/- 238 ml./24 hours versus normal men 1,401 +/- 562 ml./24 hours, p < 0.0001 and women calcium oxalate stones 990 +/- 230 ml./24 hours versus normal women 1,239 +/- 440 ml./24 hours, p < 0.001). During followup recurrences were noted within 5 years in 12 of 99 group 1 patients and in 27 of 100 group 2 patients (p = 0.008). The average interval for recurrences was 38.7 +/- 13.2 months in group 1 and 25.1 +/- 16.4 months in group 2 (p = 0.016). The relative supersaturations for calcium oxalate, brushite and uric acid were much greater in baseline urine of the stone patients in both groups compared to controls. During followup, baseline values decreased sharply only in group 1. Finally the baseline urine in patients with recurrences was characterized by a higher calcium excretion compared to urine of the patients without recurrences in both groups. CONCLUSIONS We conclude that urine volume is a real stone risk factor in nephrolithiasis and that a large intake of water is the initial therapy for prevention of stone recurrences. In cases of hypercalciuria it is suitable to prescribe adjuvant specific diets or drug therapy.

Nifedipine and Methylprednisolone in Facilitating Ureteral Stone Passage: A Randomized, Double-Blind, Placebo-Controlled Study

Expulsive medical therapy of ureteral stones is not well established. To test the efficacy of a calcium antagonist (nifedipine) associated with a corticosteroid (methylprednisolone) in facilitating ureteral stone passage, we studied 86 patients with a unilateral ureteral radiopaque stone not larger than 15 mm. in maximum diameter, confirmed in each case by drop excretory urography. Patients were randomly treated for a maximum of 45 days under double-blind conditions with 16 mg. methylprednisolone plus 40 mg. nifedipine daily (group 1-13 women and 30 men, mean age 45 +/- 14 years, standard deviation) and with 16 mg. methylprednisolone plus placebo daily (group 2-18 women and 25 men, mean age 43 +/- 14 years). All patients also received 2 l. of low mineral content water daily. The average maximum diameter of the stones was 6.7 +/- 3.0 mm. in group 1 and 6.8 +/- 2.9 mm. in group 2 (not significant). Partial ureteral obstruction was present in approximately half of the patients in both groups. Four patients in group 1 and 6 in group 2 dropped out of the study. In group 1, 34 patients had successful results (stone passage without surgical manipulation) and 5 failed (success rate 87%), compared to 24 and 13, respectively, in group 2 (success rate 65%). This difference was significant (p = 0.021, Fishers exact test). No difference was present in the maximum stone diameter among the successful cases in groups 1 and 2 (6.4 +/- 2.8 and 5.3 +/- 2.2 mm., respectively, not significant). In both groups the maximum diameter of the stone was larger in the failed than in the successful cases (group 1-10.4 +/- 3.0 versus 6.4 +/- 2.8 mm., p = 0.005, and group 2-9.3 +/- 2.5 versus 5.3 +/- 2.2 mm., p = 0.0001). In group 1 the mean interval for stone passage in the successful cases was 11.2 +/- 7.5 days, compared to 16.4 +/- 11.0 days in group 2 (p = 0.036, Students t test). We conclude that nifedipine associated with methylprednisolone is effective in facilitating ureteral stone passage.

Randomized prospective study of a nonthiazide diuretic, indapamide, in preventing calcium stone recurrences

We examined the biochemical changes and the efficacy of indapamide in the prevention of calcium stone recurrences. Seventy-five patients with calcium nephrolithiasis and hypercalciuria were randomly assigned to three different therapies: diet and fluid (group A), diet and fluid plus indapamide 2.5 mg/day (group B). and diet and fluid plus indapamide 2.5 mg/day plus allopurinol 300 mg/day (group C). Before treatment and after 6, 12, 24, and 36 months of therapy, we evaluated blood pressure, serum and urine risk parameters (including relative supersaturations of calcium oxalate. calcium phosphate and uric acid), stone rate, and the proportion of calculi-free patients. During the 3 years of treatment, urinary calcium greatly decreased in groups B and C. dropping to 50% of the pretreatment values: urinary oxalate also significantly declined in group B (- 24%) and group C (-27%). Relative supersaturations of calcium oxalate and calcium phosphate decreased to the same extent in groups B and C (about one-half of the pretreatment value), and relative supersaturation of uric acid was particularly reduced in group C (-65% of the pretreatment value). The stone rate improved in all three groups (p > 0.005). but using actuarial analysis in the evaluation of calculi-free patients, indapamide, and indapamide plus allopurinol groups were found to have a significantly more favorable effect than diet and fluid treatment (p > 0.02), without any difference between the two drug groups. Because indapamide has fewer side effects than thiazide diuretics, we conclude that indapamide could be an interesting alternative to thiazides in the prevention of calcium stones in hypercalciuric patients.

Hot Occupation and Nephrolithiasis

We investigated the prevalence of stone disease and urinary stone risk factors in machinists chronically exposed to a hot environment and massive sweating, without interference of nephrotoxic metals or other lithogenic compounds. The study was performed at a glass plant and exposure to heat stress was estimated by the Wet Bulb Globe Temperature climatic index. The prevalence of nephrolithiasis on the entire population of the machinists was 8.5% (20 of 236), while the prevalence on the controls working in normal temperature was 2.4% (4 of 165) (p = 0.03). A high incidence (38.8%) of uric acid stones was present in the workers exposed to heat stress. Among the urinary stone risk indexes determined for 3 days during the 8-hour work shift on a randomly selected sample of 21 workers exposed and 21 workers not exposed to heat stress without any evidence of stone disease significant differences were found in uric acid concentration (722 +/- 195 versus 482 +/- 184 mg./l., p < 0.001), specific gravity (1,026 +/- 4 versus 1,021 +/- 6, p < 0.005) and pH (5.31 +/- 0.28 versus 5.64 +/- 0.54, p < 0.02), respectively. Thus, high uric acid relative supersaturation was present during occupation in hot temperatures (8.67 +/- 3.49) compared to occupation in normal temperatures (4.15 +/- 2.7) (p < 0.001). This study confirms that chronic dehydration represents a real lithogenic risk factor, mainly for uric acid stones, and adequate fluid intake is recommended during hot occupations.

Urine Volume: Stone Risk Factor and Preventive Measure

Background: A high fluid intake is the oldest existing treatment for kidney stones, and, up until a few decades ago, it was the only preventive measure at the physician’s disposal for stone recurrences. Methods: Using the data available in literature and partly unpublished personal research, we examine the role of urine volume as a stone risk factor, its impact on calcium crystallization mechanisms and its real importance as a means of prevention. Results: To sum up, the most important findings are: (1) a low urine volume must be considered as a real risk factor, both as regards the onset of renal calculi and stone relapses; (2) an increase in urine volume induced by a high water intake produces favourable effects on the crystallization of calcium oxalate and does not reduce the activity of natural inhibitors; (3) a sufficiently high intake of water and probably other fluids such as coffee, tea, beer and wine has a preventive effect on nephrolithiasis and its recurrence, and (4) the role of fruit juice is still to be defined. Conclusions: A high intake of fluids, especially water, is still the most powerful and certainly the most economical means of prevention of nephrolithiasis, and it is often not used to advantage by stone formers.

Vertebral Mineral Content in Diet-Dependent and Diet-Independent Hypercalciuria

The vertebral mineral content was measured using dual photon absorptiometry in 41 calcium stone patients with idiopathic hypercalciuria. These patients had been previously divided into 2 groups (diet-dependent and diet-independent hypercalciuria) during a low sodium and low calcium diet. In some of the patients (11 with diet-dependent and 11 with diet-independent hypercalciuria) the vertebral mineral content was evaluated in relation to serum ionized calcium, intact parathyroid hormone, alkaline phosphatase and osteocalcin determined after a low sodium and low calcium diet. The vertebral mineral content, expressed as Z-VMD, was normal in diet-dependent and lower in diet-independent hypercalciuric stone patients (-0.30 +/- 1.19 versus -0.26 +/- 1.18, p less than 0.02). In 7 of 21 patients (33.3%) the vertebral mineral content was less than 2 standard deviations of the normal value, indicating a true involvement in bone metabolism. Serum intact parathyroid hormone and osteocalcin levels were not different from the controls in both groups, while alkaline phosphatase activity and ionized calcium were higher in diet-independent hypercalciuric patients. Serum ionized calcium was negatively correlated with bone vertebral density. The results suggest that an increased bone turnover may be a primary event in causing hypercalciuria in calcium stone patients unable to decrease urinary calcium to less than the calcium intake.

Body Weight, Diet and Water Intake in Preventing Stone Disease

Nutrition plays a major role in the pathogenesis of the most widespread forms of nephrolithiasis, i.e. calcium (calcium oxalate and phosphate) and uric acid stone disease. For this reason, dietary measures are the first level of intervention in primary prevention, as well as in secondary prevention of recurrences. An unbalanced diet or particular sensitivity to various foods in stone formers can lead to urinary alterations such as hypercalciuria, hyperoxaluria, hyperuricosuria, hypocitraturia and an excessively acid urinary pH. Over the course of time, these conditions contribute to the formation or recurrence of kidney stones, due to the effect they exert on the lithogenous salt profile. The fundamental aspects of the nutritional approach to the treatment of idiopathic nephrolithiasis are body weight, diet and water intake. This paper will present data resulting from our own investigations and the most significant evidence in literature.

Effects of Salt Sensitivity on Neural Cardiovascular Regulation in Essential Hypertension

Salt-sensitive hypertensive subjects, as defined by conventional categorical classification, exhibit alterations of autonomic cardiovascular control. The aim of our study was to explore whether, in hypertensive subjects, the degree of autonomic dysfunction and the level of salt sensitivity are correlated even when the latter is only mildly elevated and displays under-threshold values. Salt sensitivity of 34 essential hypertensive subjects was assessed on a continuous basis by the salt sensitivity index after low- and high-sodium diet. Beat-by-beat finger blood pressure was recorded after each diet period. Autonomic cardiovascular control was evaluated by spectral analysis of blood pressure and pulse interval and by assessment of spontaneous baroreflex sensitivity (sequence technique). Salt sensitivity and baroreflex sensitivity showed a negative relationship during low and high sodium intake, starting from low values of the salt sensitivity index. All spectral indexes of pulse interval, except the ratio between low- and high-frequency powers, were inversely related to salt sensitivity index after high sodium intake. In subjects with lower salt sensitivity, baroreflex sensitivity and pulse interval power in the high-frequency band were higher after high sodium intake than after low sodium intake. In contrast, subjects with a higher salt sensitivity index showed lower values of baroreflex sensitivity and pulse interval power in the high-frequency band, uninfluenced by salt intake. Our results provide the first demonstration of an impairment of parasympathetic cardiac control in parallel with the increase in the degree of salt sensitivity, also in subjects who were not ranked as salt-sensitive by the conventional categorical classification.

Endothelin-A Blockade Attenuates Systemic and Renal Hemodynamic Effects of L-NAME in Humans

Eight Na-repleted volunteers underwent 3 separate 90-minute infusions of either N(G)-nitro-L-arginine methyl ester (L-NAME) 3.0 mg. kg(-1). min(-1) or endothelin-A receptor (ET-A) blocker BQ-123 (BQ) 0.125 nmol. kg(-1). min(-1) or both. Mean arterial pressure (MAP), glomerular filtration rate (GFR), renal blood flow (RBF), renal vascular resistances (RVR), and sodium excretion rate (UNaV) were measured at baseline (b) and from 0 to 45 minutes (period 1) and 45 to 90 minutes (period 2) of infusion. BQ alone had no effect. GFR declined by 4.9% (P<0.001 versus b) in period 1, to 9.9% (P<0. 001) in period 2 with L-NAME, and by 3.3% (P<0.01) to 6.6% (P<0.001) with L-NAME plus BQ (P=NS between L-NAME and L-NAME plus BQ). UNaV fell equally with L-NAME or L-NAME plus BQ. MAP rose significantly in period 2 with L-NAME (6.9%; P<0.001) but not with coinfused BQ (2. 1%; P=NA versus b, P=0.005 versus L-NAME alone). RBF declined by 12. 2% (P<0.001) to 18.3% (P<0.001) with L-NAME and by 4.6% (P<0.005) to 8.2% (P<0.001) with L-NAME plus BQ. These changes were smaller with L-NAME plus BQ (P<0.05 in period 1 and P<0.02 in period 2). Blunted changes were also seen for RVR (P<0.005 in period 1 and P<0.001 in period 2 between L-NAME alone and L-NAME plus BQ). These findings show that systemic and renal vasoconstriction due to L-NAME are attenuated by BQ, which suggests that an interaction between endogenous nitric oxide production and ET-A activity participates in the maintenance of baseline systemic and renal vascular tone in humans.

Endothelial dysfunction and cardiovascular risk profile in long-term withdrawing alcoholics.

Background Rates of cardiovascular morbidity and mortality are greater in heavy alcoholics than in either teetotallers or light-to-moderate drinkers. Objective On the assumption that factors leading to atherosclerotic damage remain operative even after long-term alcohol withdrawal, we studied the possible mechanisms of raised cardiovascular risk in former heavy alcoholics. Methods Forty-two apparently disease-free, normotensive alcoholics detoxified for 37.1 ± 31.9 (SD) months, median 24, participated in the study. They were compared with 39 lifetime alcohol-abstaining control subjects, carefully matched for age, sex, body mass index, smoking and dietary habits, physical activity, lipids and fasting glucose. Endothelial function (flow-mediated dilation of brachial artery, high-resolution ultrasound technique), blood pressure, and some parameters of endothelial activation, oxidative stress, vascular inflammation and insulin sensitivity were measured. Results The maximal percentage of flow-mediated dilatation was reduced in detoxified alcoholics (10.1 ± 4.6 versus 14.9 ± 7.4, P < 0.001) who also showed significantly higher blood pressure (systolic 127.5 ± 12.9 versus 118.2 ± 10.7 mmHg, P < 0.001; diastolic 79.4 ± 7.1 versus 74.6 ± 6.4 mmHg, P < 0.01; mean 95.4 ± 8.2 versus 89.1 ± 7.3 mmHg, P < 0.001), uric acid (5.0 ± 1.1 versus 4.4 ± 0.8 mg/dl, P < 0.05), high-sensitivity C-reactive protein (2.1 ± 2.0 versus 1.0 ± 0.9 mg/l, P < 0.01), endothelin-1 (0.38 ± 0.11 versus 0.17 ± 0.10 pg/ml, P < 0.001) and fasting insulin (10.4 ± 4.5 versus 5.6 ± 1.6 μU/ml, P < 0.001) with abnormal homeostasis model assessment index of insulin resistance (2.3 ± 1.1 versus 1.2 ± 0.4, P < 0.001). Conclusion Previous heavy alcoholism, in spite of long-term withdrawal, is associated with endothelial dysfunction and a wide cluster of haemodynamic, vascular and metabolic abnormalities that indicate an unfavourable cardiovascular and metabolic risk profile even in apparently disease-free former alcoholics.