Loris Borghi

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.

Effects of a low-salt diet on idiopathic hypercalciuria in calcium-oxalate stone formers: a 3-mo randomized controlled trial

BACKGROUND A direct relation exists between sodium and calcium excretion, but randomized studies evaluating the sustained effect of a low-salt diet on idiopathic hypercalciuria, one of the main risk factors for calcium-oxalate stone formation, are still lacking. OBJECTIVE Our goal was to evaluate the effect of a low-salt diet on urinary calcium excretion in patients affected by idiopathic calcium nephrolithiasis. DESIGN Patients affected by idiopathic calcium stone disease and hypercalciuria (>300 mg Ca/d in men and >250 mg Ca/d in women) were randomly assigned to receive either water therapy alone (control diet) or water therapy and a low-salt diet (low-sodium diet) for 3 mo. Twenty-four-hour urine samples were obtained twice from all patients: one sample at baseline on a free diet and one sample after 3 mo of treatment. RESULTS A total of 210 patients were randomly assigned to receive a control diet (n = 102) or a low-sodium diet (n = 108); 13 patients (2 on the control diet, 11 on the low-sodium diet) withdrew from the trial. At the follow-up visit, patients on the low-sodium diet had lower urinary sodium (mean +/- SD: 68 +/- 43 mmol/d at 3 mo compared with 228 +/- 57 mmol/d at baseline; P < 0.001). Concomitant with this change, they showed lower urinary calcium (271 +/- 86 mg/d at 3 mo compared with 361 +/- 129 mg/d on the control diet, P < 0.001) and lower oxalate excretion (28 +/- 8 mg/d at 3 mo compared with 32 +/- 10 mg/d on the control diet, P = 0.001). Urinary calcium was within the normal range in 61.9% of the patients on the low-salt diet and in 34.0% of those on the control diet (difference: +27.9%; 95% CI: +14.4%, +41.3%; P < 0.001). CONCLUSION A low-salt diet can reduce calcium excretion in hypercalciuric stone formers. This trial was registered at clinicaltrials.gov as NCT01005082.

Pathophysiology, clinics, diagnosis and treatment of heart involvement in carbon monoxide poisoning

The toxicity of carbon monoxide has been recognized for long throughout history and is unquestionably the leading cause of unintentional poisoning deaths in the Western countries. The severity of poisoning is dependent upon environmental and human factor. The leading pathophysiological mechanism resides in the ability of carbon monoxide to bind to hemoglobin molecules with high affinity, displacing oxygen and generating carboxyhemoglobin, which is virtually ineffective to deliver oxygen to the tissues. The organs with the highest demand for oxygen such as the brain and the heart are more vulnerable to injury. Myocardial involvement is commonplace in moderate to severe carbon monoxide poisoning and is associated with a substantially higher risk of mortality. Besides hypoxic damage, carbon monoxide produces myocardium injuries with cardiospecific mechanisms, mostly attributable to direct damage at cellular or subcellular level. The clinical spectrum of heart involvement is broad and encompasses cardiomyopathy, angina attack, myocardial infarction, arrhythmias and heart failure up to myocardial stunning, cardiogenic shock and sudden death. Patients with underlying cardiac disease, especially coronary heart disease, are at greater risk of infarction and arrhythmias. Single photon emission computed tomography (SPECT) is the technique of choice for diagnosing cardiac involvement, whereas the recent introduction of the highly sensitive troponin immunoassays seems promising for the early triage of patients. No specific treatment other than oxygen delivery can be advocated for cardiac toxicity at present, and 100% oxygen therapy should be continued until the patient is asymptomatic and carboxyhemoglobin levels decrease below 5-10%.

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.

Polymorphisms at the regulatory regions of the CASR gene influence stone risk in primary hyperparathyroidism

BACKGROUND AND OBJECTIVE Single nucleotide polymorphisms (SNPs) of the calcium-sensing receptor (CASR) gene at the regulatory region were associated with idiopathic calcium nephrolithiasis. To confirm their association with nephrolithiasis, we tested patients with primary hyperparathyroidism (PHPT). DESIGN A genotype-phenotype association study. METHODS In all, 332 PHPT patients and 453 healthy controls were genotyped for the rs7652589 (G>A) and rs1501899 (G>A) SNPs sited in the noncoding regulatory region of the CASR gene. Allele, haplotype, and diplotype distribution were compared between PHPT patients and controls, and in stone forming and stone-free PHPT patients. RESULTS The allele frequency at rs7652589 and rs1501899 SNPs was similar in PHPT patients and controls. The A minor alleles at these two SNPs were more frequent in stone forming (n=157) than in stone-free (n=175) PHPT patients (rs7652589: 36.9 vs 27.1%, P=0.007; rs1501899: 37.1 vs 26.4%, P=0.003). Accordingly, homozygous or heterozygous PHPT patients for the AA haplotype (n=174, AA/AA or AA/GG diplotype) had an increased stone risk (odds ratio 1.83, 95% confidence interval 1.2-2.9, P=0.008). Furthermore, these PHPT patients had higher serum concentrations of ionized calcium and parathyroid hormone (1.50 ± 0.015 mmol/l and 183 ± 12.2 pg/ml) than patients with the GG/GG diplotype (n=145, 1.47 ± 0.011 mmol/l (P=0.04) and 150 ± 11.4 pg/ml (P=0.049)). Using a logistic regression model, the increase in stone risk in PHPT patients was predicted by AA/AA or AA/GG diplotype, the highest tertile of serum ionized calcium values and the lowest tertile of age. CONCLUSIONS Polymorphisms located in the regulatory region of the CASR gene may increase susceptibility of the PHPT patients to kidney stone production.