Recurrent Calcium Urolithiasis Research Articles

How useful is an oral calcium load test for diagnosing recurrent calcium stone formers?

Hypercalciuria is the main risk factor for recurrent calcium urolithiasis. The goal of our study is to determinate how useful an oral calcium load test is for stone formers to classify different forms of hypercalciuria in pathogenetic categories defined as renal or absorptive according to the current knowledge. Between June 2013 and February 2016, a prospective study was carried out on 117 documented recurrent hypercalciuric stone formers undergoing an oral calcium load test modified from the original description by Pak. After 2days of calcium-restricted diet, urine and blood were analyzed at baseline and 120min after receiving orally 1g of calcium. Total and ionized calcium, parathyroid hormone from serum and urine calcium and creatinine were assessed in order to divide patients in three groups as previously described: resorptive, absorptive, and renal hypercalciuria. This allowed the identification of 19, 39, 34 and 33 patients with normocalcemic primary hyperparathyroidism (NPHPT), renal hypercalciuria aka renal calcium leak (RCL), absorptive hypercalciuria (AH) and unidentified cause, respectively. Patients with NPHPT (who required parathyroidectomy) experienced a lower PTH decrease (41.41 ± 12.82 vs. 54.06 ± 13.84% p < 0.01), higher beta-crosslaps, as well as lower TmP/GFR and distal third radius bone mineral density. RCL resulted in increased fasting urine calcium-to-creatinine ratio (Uca/Cr), i.e., > 0.37mmol/mmol), without hyperparathyroidism. AH was diagnosed by the presence of ΔUCa/Cr > 0.60mmol/mmol between baseline and 120min without any other anomaly. For all remaining patients, results were inconclusive due to the lack of sufficient increase in serum calcium or because the cause of lithogenesis could not be clearly identified. The oral calcium load test is useful in nearly 80% of patients by identifying the different forms of hypercalciuria causing urolithiasis and by guiding treatment, including parathyroid surgery.

CALCIPHYLAXIS AND SODIUM THIOSULPHATE: A GLIMMER OF HOPE IN DESPERATE SITUATION

Calciphylaxis is an uncommon and often under diagnosed condition affecting patients undergoing chronic dialysis. Its pathogenesis is poorly understood. The abnormalities of calcium, phosphate and parathyroid hormone homeostasis leading to vascular calcification and ischaemic skin necrosis are thought to be the central problem. Meticulous wound care and aggressive metabolic control remain the cornerstone of the treatment; however, the overall benefit of these treatment options remains low and mortality and morbidity remain very high. Sodium thiosulphate is an inorganic salt, which is used for treating acute cyanide poisoning, recurrent calcium urolithiasis and nephrocalcinosis. Recently, it has also been reported to be useful in treating severe cases of calciphylaxis with promising results. A resistant case of calciphylaxis in a patient on long-term haemodialysis was treated with sodium thiosulphate (50 ml solution with 50% sodium thiosulphate) three times a week during the end of each dialysis session. The skin lesions started to heal after two weeks and completely resolved after five months of treatment. Sodium thiosulphate can be a safe and effective treatment option for resistant and severe cases of calciphylaxis.

Idiopathic recurrent calcium urolithiasis (IRCU): pathophysiology evaluated in light of oxidative metabolism, without and with variation of several biomarkers in fasting urine and plasma - a comparison of stone-free and -bearing male patients, emphasizing mineral, acid-base, blood pressure and protein status*

BackgroundIRCU is traditionally considered as lifestyle disease (associations with, among others, overweight, obesity, hypertension, type-2 diabetes), arising from excess, in 24 h urine, of calcium (Ca) salts (calcium oxalate (CaOx), calcium phosphate (CaPi)), supersaturation of, and crystallization in, tubular fluid and urine, causing crystal-induced epithelial cell damage, proteinuria, crystal aggregation and uroliths.MethodsAnother picture emerges from the present uncontrolled study of 154 male adult IRCU patients (75 stone-bearing (SB) and 79 age-matched stone-free (SF)), in whom stone-forming and other parameters in fasting urine and plasma were contrasted with five biomarkers (see footnote) of oxidative metabolism (OM), without and with variation of markers.Results1) In SB vs. SF unstratified OM biomarkers were statistically unchanged, but the majority of patients was overweight; despite, in SB vs. SF urine pH, total and non-albumin protein concentration were elevated, fractional urinary uric acid excretion and blood bicarbonate decreased, whereas urine volume, sodium, supersaturation with CaOx and CaPi (as hydroxyapatite) were unchanged; 2) upon variation of OM markers (strata below and above median) numerous stone parameters differed significant!)', among others urine volume, total protein, Ca/Pi ratio, pH, sodium, potassium, plasma Ca/Pi ratio and parathyroid hormone, blood pressure, renal excretion of non-albumin protein and other substances; 3) a significant shift from SF to SB patients occurred with increase of urine pH, decrease of blood bicarbonate, and increase of diastolic blood pressure, whereas increase of plasma uric acid impacted only marginally; 4) in both SF and SB patients a strong curvilinear relationship links a rise of urine Ca/Pi to urine Ca/Pi divided by plasma Ca/Pi, but in SB urine Ca/Pi failed to correlate significantly with urine hydroxyapatite supersaturation; 5) also in SB, plasma Ca/Pi and urinary nitrate were negatively correlated, whereas in SF plasma Ca/Pi ratio, PTH and body mass index correlated positively; 6) multivariate regression analysis revealed that PTH, body mass index and nitrate together could explain 22 (p = 0.002) and only 7 (p = 0.06) per cent of variation of plasma Ca/Pi in SF and SB, respectivelyConclusionsIn IRCU a) numerous constituents of fasting urine, plasma, blood and blood pressure change in response to variation of OM biomarkers, suggesting involvement of OM imbalance as factor in functional deterioration of tissue; b) in the majority of patients a positive exponential relationship links urine Ca/Pi to urine Ca/Pi divided by plasma Ca/Pi, presumably to accumulate Ca outside tubular lumen, thereby minimizing intratubular and urinary Ca salt crystallization; c) alteration of interactions of low urine nitrate, PTH and Ca/Pi in plasma may be of importance in formation of new Ca stone and co-regulation of dynamics of blood vasculature; d) overweight, combined with OM-modified renal interstitial environment appears to facilitate these processes, carrying the risk that CaPi mineral develops within or/and close to blood vessel tissue, and spreads towards urothelium.For future research focussing on IRCU pathogenesis studies are recommended on the role of affluent lifestyle mediated renal ischemia, mild hypertensive nephropathy, rise of uric acid precursor oxypurines and uricemia, clarifying also why loss of significance of interrelationships of OM biomarkers with traditional Ca stone risk factors is characteristic for SB patients.OM biomarkersPlasma uric acid - Discussed as scavenger of reactive oxygen species, but also as donator (via the xanthine oxido-reductase reaction)Urinary malonedialdehydc - Accepted as indicator of peroxidation of lipids within biological cell membranesUrinaiy nitrate - Accepted as indicator of vasodilation-mediating nitric oxide production by blood vessel endotheliumUrinary malonedialdehyde/Plasma uric acid - Tentative markers of oxidant/antioxidant imbalanceUrinary nitrate/Plasma uric acid - Tentative markers of oxidant/antioxidant imbalance

Experimental Induction of Calcium Oxalate Nephrolithiasis in Mice

The availability of various transgenic and knockout mice provides an excellent opportunity to better understand the pathophysiology of calcium oxalate stone disease. However, attempts to produce calcium oxalate nephrolithiasis in mice have not been successful. We hypothesized that calcium oxalate nephrolithiasis in mice requires increasing urine calcium and oxalate excretion, and experimentally induced hyperoxaluria alone is not sufficient. To provide evidence we induced hyperoxaluria by administering hyperoxaluria inducing agents in normocalciuric and hypercalciuric mice, and investigating various aspects of nephrolithiasis. We administered ethylene glycol, glyoxylate or hydroxyl proline via diet in male and female normocalciuric B6 mice, and in hypercalciuric sodium phosphate co-transporter type 2 a -/- mice for 4 weeks. We collected 24-hour urine samples on days 0, 3, 7, 14, 21 and 28, and analyzed them for pH, creatinine, lactate dehydrogenase calcium and oxalate. Kidneys were examined using light microscopy. Urine was examined for crystals using light and scanning electron microscopy. Hypercalciuric mice on hydroxyl proline did not tolerate treatment and were sacrificed before 28 days. All mice on ethylene glycol, glyoxylate or hydroxyl proline became hyperoxaluric and showed calcium oxalate crystalluria. No female, normocalciuric or hypercalciuric mice showed renal calcium oxalate crystal deposits. Calcium oxalate nephrolithiasis developed in all mice on glyoxylate and in some on ethylene glycol. In all mice the kidneys showed epithelial injury. Male mice particularly on glyoxylate had more renal injury and inflammatory cell migration into the interstitium around the crystal deposits. Results confirm that hyperoxaluria induction alone is not sufficient to create calcium oxalate nephrolithiasis in mice. Hypercalciuria is also required. Kidneys in male mice are more prone to injury than those in female mice and are susceptible to calcium oxalate crystal deposition. Perhaps epithelial injury promotes crystal retention. Thus, calcium oxalate nephrolithiasis in mice is gender dependent, and requires hypercalciuria and hyperoxaluria.

Association between calcium-sensing receptor gene polymorphisms and recurrent calcium kidney stone disease: A comprehensive gene analysis

Comprehensive sequencing of the coding exons of the calcium-sensing receptor gene (CASR) was performed in a group of Iranian recurrent calcium kidney stone-formers and the results were compared with a control group. Serum and urine parameters were evaluated in 99 males aged between 30 and 55 years old with idiopathic recurrent calcium urolithiasis and in 107 men as a control group. Products of polymerase chain reaction were sequenced using forward primer until a mutation was found in that exon. Then, other cases were analysed by single-strand conformation polymorphism. Four polymorphisms were detected in CASR exons, all in the coding region of exon 7. These polymorphisms and their minor allele frequency were P748P (100%), A986S (1%), R990G (3%) and E1011Q (98%). There was a significantly higher count of 986S (p = 0.006), 990G (p = 0.006) and E1011 (p = 0.02) alleles in patients. The odds ratio (95% confidence interval) was 2.55 (1.31-4.96) in those at risk of stone disease for the 986S allele and 8.06 (1.80-35.9) for the 990G allele. Men with the RR genotype at R990G showed a significantly higher serum ionized calcium than the RG or GG group (p = 0.03). A significantly lower serum total calcium was found in subjects with the QQ than the EQ genotype with respect to the 1011 locus (p = 0.005). Furthermore, the 1011Q allele was marginally associated with hypercalciuria (p = 0.05). The 986S, 990G and 1011Q alleles were associated with a recurrent calcium kidney stone-forming state. 986S and 1011Q alleles, but not 986S, were associated with hypercalcaemia.

New insights into the pathogenesis of bone loss in recurrent calcium stone formers

Background/aims: Urolithiasis is one of the leading social and economical problems of modern society. It is estimated that 10% of males and 4 % of females between 30 and 50 years of age have urinary tract stone disease. Recurrence rate of urolithiasis is 75% at 15 years with no treatment. Calcium is the major calculus component since 75-80% of renal stones are composed of calcium oxalate, while idiopathic metabolic hypercalciuria is one of the most frequent causes of recurrent calcium urolithiasis. Numerous studies showed that urolithiasis patients have higher rate of bone resorption and lower bone mineral content as well as bone mineral density, which is more evident in idiopathic calcium stone formers. However, mechanisms of action and factors involved in bone loss in these patients are still unknown. Increased production of cytokines such as IL-1, IL-6, TNF as well as osteopontin (OPN), osteoprotegerin (OPG) and RANKL (receptor activator of NF-kappaB ligand) may enhance bone resorption and therefore lower bone mass in patients with idiopathic calcium urolithiasis. Aim of this study is to assess changes of cytokines involved in bone turnover and increased bone resorption, as that might play role in bone loss in recurrent calcium stone formers. Methods: 49 recurrent calcium stone formers were involved in the study and compared to healthy age and sex matched controls. Anthropometrical measurements and metabolic evaluation were performed. Bone mineral density (BMD ; g/cm2) was assessed by dual-energy x-ray absorptiometry (« Lunar Prodigy» ). BMD measurements were performed at the lumbar spine, femoral neck, forearm and total body. Results are presented as bone mineral content (BMC ; g) and bone area (BA ; cm2). Ca2+, Mg2+, P, creatinine, Na+, K+, Cl-, proteins, uric acid, alkaline phosphatase, osteocalcin, calcitonin, PTH, 25-OH D vitamin and 1, 25-OH D vitamin were assessed by standard biochemical serum analysis. IL-1, IL-6, TNF-α , OPG, RANKL and OPN serum levels were determined by quantitive enzyme-linked immunosorbent assay (ELISA) according to manufacture’ s protocol (Quantikine, R&D Systems, Inc., Minneapolis, USA). Results: The frequency of low BMD between male and female recurrent calcium stone formers was 36.4% to 45.8%, respectiveley. Different calcium excretion levels influenced the frequency of low BMD and ranged from 31.6% in normocalciuric patients to 50% in patients with hypercalciuria, respectiveley. The frequency of increased bone turnover markers showed differences between recurent stone formers with and without low BMD as well as between male and female participants. PTH was increased in 54.5% female participants with low BMD and in 25%

Idiopathic recurrent calcium urolithiasis (IRCU): variation of fasting urinary protein is a window to pathophysiology or simple consequence of renal stones in situ?

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 alkaline inhibitor-deficient and NAlb-P-rich milieu; 3) several observations, linking oxidative and systemic metabolism, are compatible with Ca stone initiation beyond tubules.

Is idiopathic recurrent calcium urolithiasis in males a cellular disease? Laboratory findings in plasma, urine and erythrocytes, emphasizing the absence and presence of stones, oxidative and mineral metabolism: an observational study

The site of origin of idiopathic recurrent calcium urolithiasis (IRCU)--a disorder characterized by stones composed of calcium oxalate (CaOx) and/or calcium phosphate (CaPi)--is uncertain, because in urine such risk factors for stones as disturbed Ox, Ca and Pi are not regularly observed. To evaluate whether imbalance of antioxidants and oxidants might be present in IRCU patients that is then followed by abnormal urine, plasma and intracellular mineral homeostasis, and stones. Males were investigated in the laboratory under standardized conditions, and three trials were organized. Trial 1 was cross-sectional, comparing IRCU patients with (n = 111) and without stones in situ (n = 126), focussing on abnormalities of oxypurines and minerals in urine and plasma, and metabolic activity (MA) of the disease. Trial 2 was partly controlled (n = 14 healthy subjects; n = 53 IRCU patients), comparing the plasma levels of total antioxidant status (TAS) and uric acid, the major antioxidant in humans, using the subsets Low (n = 26) and High (n = 27) TAS among IRCU patients in terms of plasma levels of uric acid, ascorbic acid, albumin, alpha-tocopherol and minerals, urinary minerals, CaOx and CaPi (hydroxyapatite) supersaturation. Trial 3, comprising stone-free IRCU patients (n = 8) and healthy controls (n = 8), compared minerals and mineral ratios in plasma and red blood cells (RBCs). Established analytical methodologies were used throughout. In trial 1, uricemia, hypoxanthinuria and proteinuria were elevated, fractional urinary clearance (FE) of uric acid was decreased in stone-bearing patients, and MA correlated positively with uricemia and urinary total protein excretion. In trial 2, TAS was significantly decreased in IRCU patients vs. healthy controls; low TAS coincided with low plasma uric acid and albumin, unchanged ascorbic acid, alpha-tocopherol and parathyroid hormone, but increased FE-uric acid and Pi excretion; the latter correlated negatively with TAS. In trial 3, plasma minerals were significantly decreased in IRCU patients vs. controls, and Ca/Pi, (Ca/Pi)/Mg and (Ca/Pi)/Na molar ratios increased; the latter ratio was also increased in RBCs, and correlated highly positively with the same ratio in plasma. In IRCU 1) renal stones in situ in combination with high fasting uricemia, high hypoxanthinuria and protein-uria, and high MA suggest that a systemic metabolic anomaly underlies stone formation; 2) antioxidant deficit is frequent, unrelated to the presence or absence of stones but apparently related to poor renal uric acid recycling, low uricemia and albuminemia, exaggerated urinary Pi excretion, and low MA; 3) the combination of low plasma TAS, disordered Ca/Pi and other mineral ratios in urine, plasma and RBCs, but unchanged urinary Ca salt supersaturation is compatible with the view that CaPi solid and Ca microlith formation start inside oxidatively damaged cells.

Is calcium oxalate nucleation in postprandial urine of males with idiopathic recurrent calcium urolithiasis related to calcium phosphate nucleation and the intensity of stone formation? Studies allowing insight into a possible role of urinary free citrate and protein.

In idiopathic recurrent urolithiasis (IRCU) calcium oxalate and calcium phosphate are components of stones. It is not sufficiently known whether in urine the nucleation (liquid-solid transition) of each salt requires a different environment, if so which environment, and whether there is an impact on stone formation. Nucleation was induced by in vitro addition of oxalate or calcium to post-test meal load whole urine of male stone patients (n=48), showing normal daily and baseline fasting oxaluria. The maximally tolerated (until visible precipitates occur) concentration of oxalate (T-Ox) or calcium (T-Ca) was determined; additionally evaluated were other variables in urine, including total, complexed and free citrate (F-Cit), protein (albumin, non-albumin protein) and the clinical intensity (synonymous metabolic activity; MA) of IRCU. In the first of three trials the accumulation of substances in stone-forming urine was verified (trial-V); in the second (clinical trial 1) two strata of T-Ox (Low, High) were compared; in the third (clinical trial 2) IRCU patients (n=27) and a control group (n=13) were included to clarify whether in stone-forming urine the first crystal formed was calcium oxalate or calcium phosphate, and to identify the state of F-Cit. T-Ox was studied at the original pH (average < 6.0), T-Ca at prefixed pH 6.0; the precipitates were subjected to electron microscopy and element analysis. Trial-V: Among the urinary substances accumulating at the indicated pHs were calcium, oxalate and phosphate, and the crystal-urine ratios were compatible with the nucleation of calcium oxalate, calcium-poor and calcium-rich calcium phosphate; citrate, protein and potassium also accumulated. Clinical trial 1: the two strata exhibited an inverse change of T-Ox and T-Ca, the ratio T-Ox/T-Ca and MA. The initial (before induction of Ox or Ca excess) supersaturation of calcium oxalate and brushite were unchanged, with the difference of proteinuria being borderline. Several correlations were significant (p < or = 0.05): urine pH with citrate and volume, protein with volume and MA, T-Ox with T-Ca and MA. Clinical trial 2: in patients with reduced urine volume and moderate urine calcium excess, the first precipitate appeared to be calcium oxalate, followed by amorphous calcium phosphate. Conversely, when the calcium excess was extreme, calcium-rich hydroxyapatite developed, followed by calcium oxalate; F-Cit, not total and complexed citrate, was decreased in IRCU vs. male controls; F-Cit rose pH-dependently, and the ratio F-Cit at original pH vs. F-Cit at pH 6.0 correlated inversely with the nucleation index T-Ox/T-Ca; MA correlated inversely with the ratio F-Cit at pH 6.0, respectively, original pH, but directly with the urinary albumin/non-albumin protein ratio. In summary 1) to study calcium oxalate and calcium phosphate nucleation in whole urine of IRCU patients is feasible; 2) at this crystallization stage the two substances, dominant in calcium stones, appear intimately linked, 3) in stone-forming urine, calcium phosphate may be ubiquitously present, likely as particles < 0.22 microm; 4) together with co-precipitation of calcium oxalate and calcium phosphate, low F-Cit and alteration of proteinuria may act in concert and accelerate stones.

Bone Mineral Density Loss in Patients with Urolithiasis: A Follow-Up Study

Background Recurrent calcium urolithiasis is often associated with disorders of calcium metabolism. The purpose of this investigation was to assess bone mineral content (BMC) and bone mineral density (BMD) over a period of 1 year in patients with urolithiasis and to determine the factors that could have influenced the changes in bone density during that period. Methods The patient group comprised 34 men aged 41.2 ± 7.9 years with recurrent urolithiasis. A wide spectrum of biochemical measurements was performed. Bone mineral density (g/cm 2), bone mineral content (BMC), and bone area (BA) were measured twice during a period of 1 year at the lumbar spine (L2–L4), femoral neck, Ward triangle, and trochanter, using dual energy absorptiometry. Patient results were compared to those obtained from 30 healthy male controls of a comparable age group. Results Nine patients were hypercalciuric, while the majority of the remaining metabolic parameters were within the reference values. Bone mineral content and bone areas at all regions were lower in patients comparing to controls, but not significantly. The greatest annual reduction of BMD was noticed at Ward triangle (−5.70% in patients and −2.36% in controls), followed by femoral neck (−4.06% patients, −2.03% controls) and trochanter (−3.06% patients, −1.39% controls). There was no significant decrease of the BMD of the spine. Analyzing the influence of age, body mass index (BMI), metabolic parameters, and dietary calcium intake on the annual reduction of bone density, we found that age, hyperuricosuria, and calcium intake were significantly associated with bone loss in that time period. Conclusions Bone mass reduction in patients with urolithiasis over a 1-year period did not differ significantly from that in controls and was principally related to age, hyperuricosuria, and calcium dietary restriction but not to increased calcium excretion.

Oxypurines, Protein, Glucose and the Functional State of Blood Vasculature Are Markers of Renal Calcium Stone-forming Processes? Observations in Men with Idiopathic Recurrent Calcium Urolithiasis

In idiopathic calcium urolithiasis the relationships between oxypurines, accompanying proteins and glucose in urine and plasma, and the associated metabolic activity (MA) are unknown. To establish whether MA is related to these parameters and to calcium oxalate crystallization, or whether it reflects a reaction of metabolism to systemic insults was the major goal of the work. One hundred fifty one males were studied in three trials: trial 1 (n=130 patients) and trial 2 (n=24 patients) were cross-sectional; trial 3 included 11 patients and 14 controls). Mean age was 46 years (trials 1 and 2) and 29 years (trial 3). In trial 1 the stratification was based on the median urinary oxypurine excretion, in trial 2 on the median plasma oxypurine concentration (below or above: Low and High subgroups). No dietary restrictions were imposed, but standardized ambulatory laboratory testing was carried out. MA was quantitated by a score. Established analytical methods were used, except for oxypurine measurement which was done by high performance liquid chromatography. Patients with kidney stones tended to be overweight (body mass index >25 kg/(m)2) and to have fasting hyperglycemia. In trial 1 severe oxypurinuria, and especially severe xanthinuria, was associated with an increase in urinary pH, creatinine clearance, proteins, uric acid, malonedialdehyde (indicator of lipid peroxidation), systolic blood pressure, and with a decrease in plasma uric acid (synonymous with a decrease of antioxidant capacity). Tubular reabsorption of proteins and stone-forming substances was diminished but MA remained unchanged despite slightly increased calcium oxalate crystal growth. In trial 2 high adenosine and xanthine coincided with elevated systolic and diastolic blood pressure, high uric acid with high urinary malonedialdehyde, high summed oxypurines minus uric acid with an increase of diastolic blood pressure, glycemia and MA; urinary nitrate (indicator of systemic vasodilation) was unchanged. In trial 3 patients' oxypurinemia and proteinuria were normal, but body mass index, glycemia and insulinemia were increased. Urinary total protein, albumin and non-albumin proteins were positively predicted (multivariate regression analysis) by urinary xanthine, glucose and pH (trial 1); MA was positively (trial 3) or negatively (trial 2) predicted by urinary total protein. In calcium urolithiasis, a disorder of affluence, 1) oxypurinuria and proteinuria and oxypurinemia and MA appear causally linked, presumably via oxidant/antioxidant imbalance-induced renal tissue damage; 2) urinary proteins may act as inhibitors or promoters of stone-forming processes; 3) a stone-initiating role of impaired vasodilatation is conjectural; 4) overweight, obesity, mild glucosuria and hyperdynamic blood circulation are regular signs.

Stone Recurrence after Lithotripsy in Patients with Recurrent Idiopathic Calcium Urolithiasis: Efficacy of Treatment with Fiuggi Water

A multicentric study was carried out on 384 patients (231 males, mean age 28.3 years; 153 females, mean age 40.8 years) previously treated with extracorporeal shock wave lithotripsy for recurrent idiopathic calcium urolithiasis. Patients were selected and submitted to different types of high fluid intake treatment (oligomineral water with a calcium content of 15 mg/l vs. tap water with a calcium content ranging between 55 and 130 mg/l) to evaluate stone recurrence and to identify any potential risk factors. During follow–up (range 14–34 months, mean 19 months) 44 (23%) of the 192 patients treated with tap water presented recurrence versus 32 (17%) of the 192 patients treated with Fiuggi mineral water, the difference in incidence between the two groups being 6%. Of the possible predictors of recurrence, evaluated at the beginning of follow–up and analyzed in a multivariate statistical study, the 24–hour diuresis and calciuria were seen to be directly related to the recurrence.

Comparison of comprehensive and limited metabolic evaluations in the treatment of patients with recurrent calcium urolithiasis

Comparison of comprehensive and limited metabolic evaluations in the treatment of patients with recurrent calcium urolithiasis

Citrate in the management of urolithiasis.

Citrate therapy for recurrent calcium urolithiasis has become common over the last decade. The hypotheses that chronic stone formers must have biochemical defects that increase recurrence risks have instigated medical therapy directed at these defects. The utilization of stone clinics, detailed metabolic evaluations, and meticulous follow-up of recurrent stone formers has led to a greater understanding and knowledge of treatment options. Citrate therapy has been used like aspirin in the medical community perhaps without a clear understanding of its mechanism of action and indications. This article provides a synopsis of citrate use in the medical and surgical treatment of urolithiasis.

Comparison of comprehensive and limited metabolic evaluations in the treatment of patients with recurrent calcium urolithiasis: Yagisawa T, Chandhoke PS, Fan J J Urol 161: 1449–1452 May 1999

Comparison of comprehensive and limited metabolic evaluations in the treatment of patients with recurrent calcium urolithiasis: Yagisawa T, Chandhoke PS, Fan J J Urol 161: 1449–1452 May 1999

Acute effects of calcium sodium citrate supplementation of a test meal on mineral homeostasis, oxalate, and calcium oxalate crystallization in the urine of healthy humans — Preliminary results in patients with idiopathic calcium urolithiasis +

Calcium, in the form of regular food supplementation, can improve bone metabolism, but it can also increase the risk for renal calcium stones, and may aggravate pre-existing calcium urolithiasis. To study the first of these two aspects, ten healthy volunteers were given a conventional test meal (breakfast; calcium content 28 mg) with or without two dosages of calcium (as calcium-sodium citrate, CSC 1, 680 mg; CSC 2 1,360 mg), taken after an overnight 12 h fast. To study the latter aspect, patients with idiopathic recurrent calcium urolithiasis (ICU) received a balanced test meal of fixed composition, containing 1,000 mg calcium either as CSC (Meal + CSC3; n = 6) or as calcium gluconate (Mcal; n = 8). In normals, CSC induced a dose-dependent increasing intestinal absorption of calcium, and a decrease in oxalate absorption; in serum, CSC increased calcitonin and suppressed parathyroid hormone, but left unchanged the markers of bone turnover, serum osteocalcin and bone alkaline phosphatase. In urine, CSC decreased bone resorption markers (collagen crosslinks) and phosphaturia increased citrate, created signs of metabolic alkalosis, and inhibited several parameters of CaOx crystallization. In ICU, the CSC3 load failed to promote the crystallization of CaOx and calcium phosphate. It was concluded that CSC supplementation of a meal: (1) is well tolerated by healthy subjects and ICU patients, renders calcium highly available to bone, and prevents post-prandial oxaluria from rising; and, (2) is followed by the inhibition of crystallization of renal stone forming calcium-containing substances. Long-term studies aimed at evaluating the usefulness of CSC in preserving healthy bone, and in the metaphylaxis of renal stones would appear justified.

Postprandial hyperinsulinaemia, insulin resistance and inappropriately high phosphaturia are features of younger males with idiopathic calcium urolithiasis: attenuation by ascorbic acid supplementation of a test meal.

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.

Magnesium status in idiopathic calcium urolithiasis--an orientational study in younger males.

With the aim of revealing a possible magnesium (Mg) deficiency in the aetiology of idiopathic recurrent calcium urolithiasis we studied the Mg content of red blood cells, serum total, protein-bound, ionised and complexed fractions of Mg, and urinary Mg after an overnight fast. The two study groups comprised 12 male recurrent calcium urolithiasis patients and 12 healthy male controls (mean age 31 and 29 years, respectively). In recurrent calcium urolithiasis, serum albumin and Mg of erythrocytes were significantly decreased, as was serum total and protein-bound Mg, whereas serum ultrafiltrable, ionised and complexed Mg were statistically indistinguishable from values in controls. Urinary Mg (per unit creatinine) in recurrent calcium urolithiasis (mean 0.188 vs 0.209 in controls; p = 0.386) was not statistically different, whereas urinary total protein, glucose, and pH were significantly increased. The renal clearances of Mg and glucose were positively correlated (r = 0.56; p < 0.01), with a steeper slope in recurrent calcium urolithiasis than controls. Further fractionation of serum and urinary Mg into ions and complexes in recurrent calcium urolithiasis subjects with identical creatinine clearance revealed no statistical difference between 1) Mg ions and complexes filtered by renal glomeruli; 2) Mg ions and complexes excreted in urine; 3) fractional Mg excretion. Median urine supersaturation with respect to calcium oxalate was insignificantly lower (1.5 vs 2.2), with respect to hydroxyapatite insignificantly higher (3.3 vs 1.8), than in controls. It is concluded that relatively young recurrent calcium urolithiasis patients exhibit a deficiency of Mg in erythrocytes and serum total Mg, but no alteration of renal Mg handling. Thus, in recurrent calcium urolithiasis, a role of Mg deficiency in urine as a factor initiating stone formation may be ruled out, whereas a possible link between cellular Mg deficiency and the impairment of renal tubular functions involved in reabsorption of glucose and proteins, and in urine acidification, deserves further studies.

Value of repeated analyses of 24-hoururine in recurrent calcium urolithiasis

Objectives. The value of repeated analyses of 24-hour urine collectionsfor daily excretion of calcium, uric acid, citrate, phosphorus, and creatinine and for volume and pH performed to detect and classify metabolic disorders in a selected group of calcium stone formers with striking recurrence rates was assessed in a retrospective study. Methods. A total of 441 urinalyses made over a mean period of 80.4 months of samples obtained from 49 patients were reviewed. Fifty-nine percent of patients were initially found to have metabolic disorders (absorptive hypercalciuria types I and II, hyperuricuria, hypocitraturia) and therefore received specific drug therapy (allopurinol, thiazide, alkali citrate, orthophosphate) for a mean of 45.7 months (group I). The remaining patients were classified as metabolically inactive and were given general metaphylactic instructions (group II) Results. In 73% of patients recurrent stones developed, with no statistically significantdifference between the two groups (79% vs 65%). In 55% of group I patients, urinalyses continued to yield abnormal findings during follow-up; however, subsequent abnormal findings were also seen in 40% of the metabolically inactive group II patients. Overall, metabolic disorders were observed at some point in 75% of patients. Only 27% remained recurrence free, and 62% thereof also had pathologic urinary findings. Conclusions. It does not appear that drug treatment in recurrent calcium urolithiasisbased on urinary findings is superior to simple general metaphylactic recommendations, nor that repeated analyses of 24-hour urine collections furnish additional information on the risk of recurrent stone formation or on the presence of risk factors leading to recurrence in the long-term course of disease.

Value of repeated analyses of 24-hour urine in recurrent calcium urolithiasis.

The value of repeated analyses of 24-hour urine collections for daily excretion of calcium, uric acid, citrate, phosphorus, and creatinine and for volume and pH performed to detect and classify metabolic disorders in a selected group of calcium stone formers with striking recurrence rates was assessed in a retrospective study. A total of 441 urinalyses made over a mean period of 80.4 months of samples obtained from 49 patients were reviewed. Fifty-nine percent of patients were initially found to have metabolic disorders (absorptive hypercalciuria types I and II, hyperuricuria, hypocitraturia) and therefore received specific drug therapy (allopurinol, thiazide, alkali citrate, orthophosphate) for a mean of 45.7 months (group I). The remaining patients were classified as metabolically inactive and were given general metaphylactic instructions (group II). In 73% of patients recurrent stones developed, with no statistically significant difference between the two groups (79% vs 65%). In 55% of group I patients, urinalyses continued to yield abnormal findings during follow-up; however, subsequent abnormal findings were also seen in 40% of the metabolically inactive group II patients. Overall, metabolic disorders were observed at some point in 75% of patients. Only 27% remained recurrence free, and 62% thereof also had pathologic urinary findings. It does not appear that drug treatment in recurrent calcium urolithiasis based on urinary findings is superior to simple general metaphylactic recommendations, nor that repeated analyses of 24-hour urine collections furnish additional information on the risk of recurrent stone formation or on the presence of risk factors leading to recurrence in the long-term course of disease.