The effects of magnesium (Mg) and citrate on the metastable limit of calcium oxalate (CaOx) solubility (synonym: tolerable oxalate TO) were examined in artificial urine and in postprandial urine of male patients with idiopathic calcium urolithiasis (ICU). In artificial urine increasing pH, Mg and citrate elevate TO, decrease CaOx supersaturation only marginally, but elevate considerably free citrate; the effect of Mg alone was small in comparison with citrate alone, and the effects of both substances appeared additive. In ICU patients, matched for sex, age and CaOx supersaturation to non-stone-forming controls, TO was decreased (mean values 0.33 vs. 0.52 mM/l in controls, P < 0.05). Additional significant (P < 0.05) differences were found between ICU and controls: the former exhibited increased CaOx crystal growth, decreased crystal agglomeration time, a more acidic urinary pH, increased concentrations of free calcium and free Mg, and decreased free oxalate and free citrate. After ingestion of a urine-acidifying test meal, or this meal supplemented with either neutral Mg citrate or Mg-alkali citrate, by three groups of male ICU patients, matched for age and CaOx supersaturation, only the last-named preparation evoked an increase in TO and a decrease in crystal diameter, while the normally occurring pH decline from fasting urine was virtually abolished, and the ratios urinary Mg/citrate and calcium/citrate tended towards low values. In contrast, Mg citrate increased crystal agglomeration time, while changes in the other parameters were only insignificant. The crystals formed in urine were CaOx di- and monohydrate (by electron microscopy), and energy dispersive X-ray analysis showed calcium peaks exclusively. However, chemical analysis of crystals verified the presence not only of oxalate and calcium, but also of Mg, phosphate, citrate, and urate; moreover, these crystal constituents seemed to be influenced by Mg citrate and Mg-alkali citrate in different ways. It was concluded that (1) Mg and citrate are effectors of TO in artificial and natural urine; (2) in ICU, low TO and other disturbed CaOx crystallization parameters appear related to the prevailing low urinary pH and low free citrate; (3) Mg-alkali citrate inhibits CaOx crystallization, probably via actions of the citrate, but not the Mg. Because of the eminent role of Mg in human health and ICU, further studies on crystallization after oral intake of Mg in the form of citrate are warranted.

In idiopathic recurrent calcium urolithiasis (RCU) the state of insulin and carbohydrate metabolism, and relationships to minerals such as phosphate, are insufficiently understood. Therefore, in two groups of males with RCU (n = 30) and healthy controls (n = 8) the response to an oral carbohydrate- and calcium-rich test meal was studied with respect to glucose, insulin, and C-peptide in peripheral venous blood (taken before and up to 180 min post-load), and phosphate and glucose in fasting and post-load urine. In one RCU group (n = 16) the meal was supplemented with ascorbic acid (ASC; 5 mg/kg body weight). The mean age (RCU 29, RCU + ASC 30, controls 27 years) and mean body mass index [RCU 24.4, RCU + ASC 25.0, controls 24.0 kg/m2] were similar. Insulin resistance (synonymous sensitivity of peripheral organs to insulin) was calculated from insulin serum concentration, as was also integrated insulin, C-peptide, and glucose. Untreated stone patients (RCU) developed hyperinsulinaemia between 60 and 120 min post-load, increased integrated insulin, and insulin resistance (P < or = 0.05 vs controls), whereas the rise of C-peptide and glycaemia (absolute and integrated values) was only of borderline significance. Fasting phosphaturia was low in both RCU subgroups vs controls; however, phosphaturia in untreated RCU rose in response to the meal, contrasting sharply with a decrease in controls. ASC supplementation of the meal (in the RCU + ASC subgroup) normalized insulin, failed to normalize post-load phosphaturia, but reduced post-load glucosuria and urinary pH significantly (mean pH values 5.55 vs 5.93 in untreated RCU, controls 5.50). Postprandial urinary oxalate, calcium, protein, and supersaturation products were not changed. The postprandial changes in phosphaturia and insulin sensitivity were inversely correlated (n = 38, r = -0.44, P = 0.007). It was concluded that in younger RCU males: (1) postprandial hyperinsulinaemia, the failure to reduce phosphaturia and - within limits - glucosuria, appropriately, as well as poor urine acidification are important features of the metabolism; (2) these phenomena are probably caused by insulin resistance of organs, the kidney included; and (3) the addition of a supraphysiological dose of ASC to a meal, the subsequent abolition of hyperinsulinaemia, and the restoration of normal urine acidification suggest that this antioxidant is capable of counteracting some pre-existing basic abnormality of cell metabolism in RCU.

BackgroundIn IRCU it is uncertain whether variation of urinary protein, especially non-albumin protein (NAlb-P), is due to the presence of stones or reflects alteration of oxidative metabolism.AimsTo validate in a tripartite cross-sectional study of 187 ambulatory male patients, undergoing a standardized laboratory programme, whether stones impact on N-Alb-P or the state of oxidative metabolism interferes with IRCU pathophysiology.MethodsIn part 1 the strata low and high of fasting urinary excretion rate per 2 h of N-Alb-P, malonedialdehyde, hypoxanthine, xanthine, pH and other urine components were compared, and association with renal stones in situ evaluated; in part 2 the co-variation of oxidatively modulated environment, fasting urinary pH, calcium (Ca) salt crystallization risk and the number of patients with stones in situ was examined; in part 3, the nucleation of Ca oxalate and Ca phosphate was tested in undiluted postprandial urine of patients and related to the state of oxidative metabolism.ResultsIn part 1, N-Alb-P excretion > 4.3 mg was associated with increase of blood pressure, excretion of total protein, hypoxanthine (a marker of tissue hypoxia), malonedialdehyde (a marker of lipid peroxidation), sodium, magnesium, citrate, uric acid, volume, pH, and increase of renal fractional excretion of both NAlb-P and uric acid; when stones were present, urinary pH was elevated but other parameters were unaffected. Significant predictors of N-Alb-P excretion were malonedialdehyde, fractional N-Alb-P and hypoxanthine. In part 2, urine pH > 6.14 was associated with unchanged blood pressure and plasma vasopressin, increase of blood pH, urinary volume, malonedialde hyde, fractional excretion of N-Alb-P, uric acid, Ca phosphate, but not Ca oxalate, supersaturation; this spectrum was accompanied by decrease of concentration of urinary total and free magnesium, total and complexed citrate, plasma uric acid (in humans the major circulating antioxidant) and insulin; the number of stone-bearing patients was increased. Significant predictors of urine pH were body mass index, plasma insulin and uric acid (negative), and urinary xanthine (positive). In part 3 low plasma uric acid, not high urinary malonedialdehyde or high ratio malonedialdehyde/uric acid was significantly associated with diminished Ca but not oxalate tolerance, with the first nucleating crystal type being mostly Ca phosphate (hydroxyapatite), in the rest Ca oxalate dihydrate; uricemia correlated marginally positively (p = 0.055) with Ca tolerance of urine, stronger with blood pressure and insulin, and negatively with urinary xanthine, fractional N-Alb-P, volume, sodium.ConclusionsIn IRCU 1) not renal stones in situ, but disturbed oxidative metabolism apparently modulates nephron functionality, ending up in higher renal NAlb-P release, urinary volume, sodium and pH of fasting urine; 2) etiologically unknown decline of uricemia may represent antioxidant deficiency and cause a risk of hydroxyapatite crystallization and stone formation in a weakly acidic or a...

Previous work in younger males with recurrent idiopathic calcium urolithiasis (RCU) demonstrated inappropriately high postprandial phosphaturia, hyperinsulinemia and insulin resistance, but normal glycemia. To investigate further whether these abnormalities occur also in RCU patients with a mean age corresponding to the life period with peak formation of calcium-containing stones, two trials were carried out in 155 males of comparable age and body mass index. All participants underwent a standardized laboratory examination, including collection of urine and blood before and following a test meal rich in carbohydrate and calcium but low in phosphorus. In trial 1, comprising control subjects (n = 12, mean age 42 years) and RCU patients (n = 24, mean age 41 years), phosphate (Pi) excretion and fractional Pi excretion in postprandial urine of controls did not change compared with the values in fasting urine, but were significantly increased in RCU, despite the fact that there was almost equal suppression of serum parathyroid hormone (PTH) and increase in serum calcitonin. Postprandially, RCU patients were hyperinsulinemic but still normoglycemic versus controls. In trial 2, carried out in unclassified (in terms of calciuria) RCU patients (n = 119, mean age 40 years) only, the post-load Pi-uria was similar in magnitude to Pi-uria of RCU patients in trial 1; increased postprandial Pi-uria was a phenomenon also of normocalciuria but was slightly more pronounced in hypercalciuria, while changes in calcium phosphate (brushite) and calcium oxalate supersaturation of urine were unrelated to calciuria. In RCU patients, but not controls, there was a tendency toward higher urinary glucose in post-load as compared with fasting urine. When urinary Pi and fractional Pi excretion in trial 2 were considered as dependent variables in multivariate regression analysis, they appeared unrelated to age, but positively associated with postprandial glycemia as the best predictor, followed by insulinemia, insulin resistance, to a lesser degree fasting serum PTH and the metabolic activity of stone disease, negatively associated with blood total lipids and very low density lipoprotein (VLDL) cholesterol. It was concluded that RCU males (1) show low Pi-uria during fasting but impaired renal Pi conservation in response to a mixed meal, a situation carrying the risk of Pi deficiency over the long term; (2) represent a population developing hyperPi-uria despite suppressed PTH; (3) exhibit insulin resistance but are still able to maintain normoglycemia at the expense of hyperinsulinemia. It is suggested that calcium-containing renal stones are related to impaired Pi and glucose translocation across cell membranes, and that the role of lipids in this setting deserves further investigation.