International Alliance of Urolithiasis (IAU) guidelines on the metabolic evaluation and medical management of urolithiasis.

The aim of this study was to construct the fourth in a series of guidelines on the treatment of urolithiasis by the International Alliance of Urolithiasis (IAU) that by providing a clinical framework for the metabolic evaluation, prevention, and follow-up of patients with urolithiasis based on the best available published literature. All recommendations were summarized following a systematic review and assessment of the literature in the PubMed database from January 1976 to June 2022. Each generated recommendation was graded using a modified GRADE methodology. Guideline recommendations were developed that addressed the following topics: initial evaluation, metabolic testing, dietary measures, medical management, and follow-up of recurrent stone formers. It was emphasized by the Panel that prevention of new stone formation is as important as the surgical removal of the stones. Although general preventive measures may be effective in reducing stone recurrence rates in some patients, specific medical and dietary management should be well considered and eventually applied in an individualized manner based on the outcomes of metabolic work-up, stone analysis and some certain patient related factors. A detailed follow-up of each case is essential depending on the metabolic activity of each individual patient.

Urinary metabolic profile and stone composition in kidney stone formers with and without heart disease.

OBJECTIVE: Kidney stone disease seems to be associated with an increased risk of incident cardiovascular outcomes; the aim of this study is to identify differences in 24-h urine excretory profiles and stone composition among stone formers with and without cardiovascular disease (CVD). METHODS: Data from patients attending the Department of Renal Medicine's metabolic stone clinic from 1995 to 2012 were reviewed. The sample was divided according to the presence or absence of CVD (myocardial infarction, angina, coronary revascularization, or surgery for calcified heart valves). Univariable and multivariable regression models, adjusted for age, sex, BMI, hypertension, diabetes, eGFR, plasma bicarbonate and potential renal acid load of foods were used to investigate differences across groups. RESULTS: 1826 patients had available data for 24-h urine analysis. Among these, 108 (5.9%) had a history of CVD. Those with CVD were older, have higher prevalence of hypertension and diabetes and lower eGFR. Univariable analysis showed that patients with CVD had significantly lower 24-h urinary excretions for citrate (2.4 vs 2.6 mmol/24 h, p = 0.04), magnesium (3.9 vs 4.2 mmol/24 h, p = 0.03) and urinary pH (6.1 vs 6.2, p = 0.02). After adjustment for confounders, differences in urinary citrate and magnesium excretions remained significant. No differences in the probability of stone formation or stone compositions were found. CONCLUSIONS: Stone formers with CVD have lower renal alkali excretion, possibly suggesting higher acid retention in stone formers with cardiovascular comorbidities. Randomized clinical trials including medications and a controlled diet design are needed to confirm the results presented here.

LITHOSCREEN: a comprehensive screening program and database for the assessment and treatment management of patients with kidney stones.

The aim of the LITHOSCREEN project was to construct a comprehensive screening program and database for recording and assessing the various risk factors for stone-formation in patients with urolithiasis. It is intended for use in Stone Clinics and is now being made available free of charge to researchers in the field who wish to maintain a comprehensive record of their patients' medical histories, demographic backgrounds, lifestyle activities, metabolic abnormalities, biochemical risk of forming stones of various types, diet histories, stone analysis and long-term treatment records. From the recorded data for each patient, the program automatically calculates numerous functions important in the understanding of the clinical and chemical risk factors for stone-formation, including the renal handling of the ions involved, various metabolic functions, the biochemical risk of forming kidney stones (PSF), the Tiselius Indices of the supersaturation of urine with respect to calcium oxalate and calcium phosphate, the projected effects of changing the composition of each patient's urinary composition on the risk of stone recurrence, and a program for analysing the diet of patients. It automatically produces one-page Summaries of each patient's biochemical and dietary records with abnormal values highlighted according to a "traffic-light" colour-coding system and generates charts designed to improve patient compliance with treatment in the form of colour-coded "Target Diagrams" showing (a) the patient's 24-h urine composition, (b) the patient's biochemical risk of forming stones of different types and (c) the composition of the patient's diet. The Summary pages and "Target Diagrams" are suitable for inclusion in the patient's Case Notes. LITHOSCREEN also produces charts projecting the effect of changing the composition of urine on the patient's biochemical risk of forming further stones. These graphs provide clues as to which urinary risk factors to target to reduce the patient's risk of stone recurrence.

Urine and stone analysis for the investigation of the renal stone former: a consensus conference.

The Consensus Group deliberated on a number of questions concerning urine and stone analysis over a period of months, and then met to develop consensus. The Group concluded that analyses of urine and stones should be routine in the diagnosis and treatment of urinary stone diseases. At present, the 24-h urine is the most useful type of urine collection, and accepted methods for analysis are described. Patient education is also important for obtaining a proper urine sample. Graphical methods for reporting urine analysis results can be helpful both for the physician and for educating the patient as to proper dietary changes that could be beneficial. Proper analysis of stones is also essential for diagnosis and management of patients. The Consensus Group also agreed that research has shown that evaluation of urinary crystals could be very valuable, but the Group also recognizes that existing methods for assessment of crystalluria do not allow this to be part of stone treatment in many places.

Changes in urinary risk profile after short-term low sodium and low calcium diet in recurrent Swiss kidney stone formers.

BACKGROUND: Kidney stone disease is common in industrialized countries. Recently, it has attracted growing attention, because of its significant association with adverse renal outcomes, including end stage renal disease. Calcium-containing kidney stones are frequent with high recurrence rates. While hypercalciuria is a well-known risk factor, restricted intake of animal protein and sodium, combined with normal dietary calcium, has been shown to be more effective in stone prevention compared with a low-calcium diet. Notably, the average sodium intake in Switzerland is twice as high as the WHO recommendation, while the intake of milk and dairy products is low. METHODS: We retrospectively analyzed Swiss recurrent kidney stone formers (rKSF) to test the impact of a low-sodium in combination with a low-calcium diet on the urinary risk profile. In patients with recurrent calcium oxalate containing stones, we investigated both, the consequence of a low-sodium diet on urinary volume and calcium excretion, and the influence of a low-sodium low-calcium diet on urinary oxalate excretion. RESULTS: Of the 169 patients with CaOx stones, 49 presented with hypercalciuria at baseline. The diet resulted in a highly significant reduction in 24-h urinary sodium and calcium excretion: from 201 ± 89 at baseline to 128 ± 88 mmol/d for sodium (p < 0.0001), and from 5.67 ± 3.01 to 4.06 ± 2.46 mmol/d (p < 0.0001) for calcium, respectively. Urine volume remained unchanged. Notably, no increase in oxalate excretion occurred on the restricted diet (0.39 ± 0.26 vs 0.39 ± 0.19 mmol/d, p = 0.277). Calculated Psf (probability of stone formation) values were only predictive for the risk of calcium phosphate stones. CONCLUSION: A diet low in sodium and calcium in recurrent calcium oxalate stone formers resulted in a significant reduction of urinary calcium excretion, but no change in urine volume. In this population with apparently low intake of dairy products, calcium restriction does not necessarily result in increased urinary oxalate excretion. However, based on previous studies, we recommend a normal dietary calcium intake to avoid a potential increase in urinary oxalate excretion and unfavorable effects on bone metabolism in hypercalciuric KSFs.

Vitamin D deficiency is prevalent among idiopathic stone formers, but does correction pose any risk?

While vitamin D (vitD) deficiency is thought to contribute to poor health in a variety of ways and should be corrected, there is still concern about giving vitD supplements to patients with a history of nephrolithiasis. The aim is to study the prevalence of vitD deficiency and the effect on stone risk of cholecalciferol (vitD3) supplementation in a cohort of idiopathic stone formers (ISF). We screened for vitD deficiency and urinary measures of stone risk, comparing vitD deficient (serum 25-OH vitD ≤30 nmol/L; ≤12 ng/mL) with vitD insufficient (31-75 nmol/L; 13-30 ng/mL) or vitD replete (>75 nmol/L; >30 ng/mL); we investigated the effect of giving vitD3 (20,000 IU orally, weekly for 4 months) to 37 of the vitD deficients. Thirty-one percent (142/456) were vitD deficient, 57% (259/456) vitD insufficient, and the rest (12%) vitD replete (55/456). Comparison among the groups showed that baseline 24-h urinary measures related to stone risk expressed as concentration ratios over urine creatinine (Cr), such as U. Calcium/Cr, U. Oxalate/Cr, U. Citrate/Cr, and U. Uric acid/Cr were not significantly different. VitD3 supplementation did significantly increase serum 25-OH vitD levels and U. Phosphate/Cr ratios, as well as reduce serum parathyroid hormone (PTH) concentrations. Following vitD3 supplementation, there was an overall rise in 24-h urine calcium excretion, but it failed to reach statistical significance (p = 0.06). U. Calcium/Cr increased in 22 out of 37 patients (average increase +0.07 mmol/mmol), decreased in 14 (average decrease -0.13 mmol/mmol), and remained unchanged in 1; 6 out of 26 initially normocalciuric ISF developed hypercalciuria; and 6 out of 9 patients who became vitD replete were hypercalciuric after supplementation. It is appropriate to monitor urinary Ca excretion in vitD-supplemented stone formers, because it may reveal underlying hypercalciuria in some treated patients.

Do "inhibitors of crystallisation" play any role in the prevention of kidney stones? A critique.

A critical examination of data in the literature and in as yet unpublished laboratory records on the possible role of so-called inhibitors of crystallisation in preventing the formation of calcium-containing kidney stones leads to the following conclusions. So-called inhibitors of spontaneous "self-nucleation" are unlikely to play any role in the initiation of the crystallisation of CaOx or CaP in urine because excessive urinary supersaturation of urine with respect to these salts dominates the onset of "self-nucleation" within the normal time frame of the transit of tubular fluid through the nephron (3-4 min). Inhibitors of the crystal growth of CaOx crystals may or may not play a significant role in the prevention of CaOx stone-formation since once again excessive supersaturation of urine can overwhelm any potential effect of the inhibitors on the growth process. However, they may play a role as inhibitors of crystal growth at lower levels of metastable supersaturation when the balance between supersaturation and inhibitors is more equal. Inhibitors of CaOx crystal aggregation may play a significant role in the prevention of stones, since they do not appear to be strongly affected by excessive supersaturation, either in vitro or in vivo. Inhibitors of CaOx crystal binding to renal tubular epithelium may exist but further studies are necessary to elucidate their importance in reducing the risk of initiating stones in the renal tubules. Inhibitors of CaOx crystal binding to Randall's Plaques and Randall's Plugs may exist but further studies are necessary to elucidate their importance in reducing the risk of initiating stones on renal papillae. There may be an alternative explanation other than a deficiency in the excretion of inhibitors for the observations that there is a difference between CaOx crystal size and degree of aggregation in the fresh, warm urines of normal subjects compared those in urine from patients with recurrent CaOx stones. This difference may depend more on the site of "self-nucleation" of CaOx crystals in the renal tubule rather than on a deficiency in the excretion of so-called inhibitors of crystallisation by patients with CaOx stones. The claim that administration of potassium citrate, potassium magnesium citrate or magnesium hydroxide reduces the rate of stone recurrence may be due to the effect of these forms of medication on the supersaturation of urine with respect to CaOx and CaP rather than to any increase in "inhibitory activity" attributed to these forms of treatment. In summary, there is a competition between supersaturation and so-called inhibitors of crystallisation which ultimately determines the pattern of crystalluria in stone-formers and normals. If the supersaturation of urine with respect to CaOx reaches or exceeds the 3-4 min formation product of that salt, then it dominates the crystallisation process both in terms of "self-nucleation" and crystal growth but appears to have little or no effect on the degree of aggregation of the crystals produced. At supersaturation levels of urine with respect to CaOx well below the 3-4 min formation product of that salt, the influence of inhibitors increases and some may affect not only the degree of aggregation but also the crystal growth of any pre-formed crystals of CaOx at these lower levels of metastability.

Kidney stones.

Kidney stones are mineral deposits in the renal calyces and pelvis that are found free or attached to the renal papillae. They contain crystalline and organic components and are formed when the urine becomes supersaturated with respect to a mineral. Calcium oxalate is the main constituent of most stones, many of which form on a foundation of calcium phosphate called Randall's plaques, which are present on the renal papillary surface. Stone formation is highly prevalent, with rates of up to 14.8% and increasing, and a recurrence rate of up to 50% within the first 5 years of the initial stone episode. Obesity, diabetes, hypertension and metabolic syndrome are considered risk factors for stone formation, which, in turn, can lead to hypertension, chronic kidney disease and end-stage renal disease. Management of symptomatic kidney stones has evolved from open surgical lithotomy to minimally invasive endourological treatments leading to a reduction in patient morbidity, improved stone-free rates and better quality of life. Prevention of recurrence requires behavioural and nutritional interventions, as well as pharmacological treatments that are specific for the type of stone. There is a great need for recurrence prevention that requires a better understanding of the mechanisms involved in stone formation to facilitate the development of more-effective drugs.

Methods for diagnosing the risk factors of stone formation.

OBJECTIVE: To compare various systems for assessing the risk of recurrent stones, based on the composition of urine. METHODS: The relative supersaturation (RSS) of urine, the Tiselius Indices, the Robertson Risk Factor Algorithms (RRFA) and the BONN-Risk Index were compared in terms of the numbers of variables required to be measured, the ease of use of the system and the value of the information obtained. RESULTS: The RSS methods require up to 14 analyses in every urine sample but measure the RSS of all the main constituents of kidney stones. The Tiselius Indices and the RRFA require only seven analyses. The Tiselius Indices yield information on the crystallisation potentials (CP) of calcium oxalate and calcium phosphate; the RRFA also provide information on the CP of uric acid. Both methods provide details on the particular urinary abnormalities that lead to the abnormal CP of that urine. The BONN-Risk Index requires two measurements in each urine sample but only provides information on the CP of calcium oxalate. Additional measurements in urine have to be made to identify the cause of any abnormality. CONCLUSIONS: The methods that are based on measuring RSS are work-intensive and unsuitable for the routine screening of patients. The Tiselius Indices and the RRFA are equally good at predicting the risk of a patient forming further stones. The BONN-Risk Index provides no additional information about the causative factors for any abnormality detected.

Stone formation in the Middle Eastern Gulf States: A review.

OBJECTIVES: To review the possible causes of the high incidence of urolithiasis in the oil-rich Gulf States. METHODS: Data were extracted from published reports on the incidence of urolithiasis, affluence and diet in the Gulf States, various Western countries and China. RESULTS: There are strong relationships: (a) between the life-expectancy of stones in men and the Gross National Income (GNI) per capita of these countries; and (b) between the daily consumption of animal protein and GNI per capita. Together these data suggest that the occurrence of stones is proportional to the intake of animal protein, although they also indicate that there are additional factors that further increase the risk of urolithiasis in the populations of the Gulf. The consumption of oxalate in the Gulf is three times higher and that of calcium a half of what it is in Western countries. Thus, the average oxalate/calcium ratio in the intestines of the Gulf populations is five to six times higher than that in Western populations, leading to enteric hyperoxaluria and an increased risk of calcium-oxalate stone formation. The risk is further accentuated by the lower urine volumes, due to the hot, dry climate of the region, and lower excretions of citrate, from the highly acidic urine resulting from the high intake of animal protein. There is a high incidence of uric acid-containing stones from the acidic urine and the hyperuricosuria caused by the high intake of purine. CONCLUSIONS: The high incidence of urolithiasis in the Gulf is due to an adverse combination of dietary and environmental factors.

Net intestinal transport of oxalate reflects passive absorption and SLC26A6-mediated secretion.

Mice lacking the oxalate transporter SLC26A6 develop hyperoxalemia, hyperoxaluria, and calcium-oxalate stones as a result of a defect in intestinal oxalate secretion, but what accounts for the absorptive oxalate flux remains unknown. We measured transepithelial absorption of [(14)C]oxalate simultaneously with the flux of [(3)H]mannitol, a marker of the paracellular pathway, across intestine from wild-type and Slc26a6-null mice. We used the anion transport inhibitor DIDS to investigate other members of the SLC26 family that may mediate transcellular oxalate absorption. Absorptive flux of oxalate in duodenum was similar to mannitol, insensitive to DIDS, and nonsaturable, indicating that it is predominantly passive and paracellular. In contrast, in wild-type mice, secretory flux of oxalate in duodenum exceeded that of mannitol, was sensitive to DIDS, and saturable, indicating transcellular secretion of oxalate. In Slc26a6-null mice, secretory flux of oxalate was similar to mannitol, and no net flux of oxalate occurred. Absorptive fluxes of both oxalate and mannitol varied in parallel in different segments of small and large intestine. In epithelial cell lines, modulation of the charge selectivity of the claudin-based pore pathway did not affect oxalate permeability, but knockdown of the tight-junction protein ZO-1 enhanced permeability to oxalate and mannitol in parallel. Moreover, formation of soluble complexes with cations did not affect oxalate absorption. In conclusion, absorptive oxalate flux occurs through the paracellular "leak" pathway, and net absorption of dietary oxalate depends on the relative balance between absorption and SLC26A6-dependent transcellular secretion.

Comparison of biochemistry and diet in patients with enterocystoplasty who do and do not form stones.

OBJECTIVE: To evaluate patients with a history of urinary stones in intestinal reservoirs and compare them with similar patients who have never formed stones. PATIENTS AND METHODS: One consequence of storing urine in an intestinal reservoir is urolithiasis, and there are several theories on its cause, all based on limited evidence. There are many factors predisposing to stone formation, and dietary and biochemical factors might be useful to distinguish those who form stones from those who do not. In a prospective study (with ethical committee approval) we identified 15 patients (six male and six female, mean age 29 years) who had formed stones after an enterocystoplasty (group 1), and another 10 (three male and seven female, mean age 44 years) with no history of urolithiasis after enterocystoplasty (group 2). The respective mean (range) follow-up was 14.6 (8-24) and 15.2 (6-23) years. They were investigated using our stone-screening protocol described previously and the results compared between the groups using an unpaired Student's t-test, with statistically significance indicated at P < 0.05. RESULTS: There was a statistically significant difference in almost all the variables assessed. The mean 24-h urine output was 41% higher (P = 0.009) and the mean citrate excretion 173% higher (P = 0.002) in group 2. The mean (range) urinary pH was 6.46 (6.0-7.0) and 6.93 (6.3-7.8) in groups 2 and 1, respectively (P = 0.005). Of the stone-forming elements, only the excretion of calcium was significant (2.78 vs 5.2 mmol/day, P < 0.001). The biochemical risk of stone formation was significantly higher for both calcium oxalate and calcium phosphate stones in group 1 than group 2 (P < 0.001 in both). From the dietary diaries there was a 24% higher fluid intake in group 2 (P = 0.04). The difference between group 2 and group 1 for the intake of magnesium (18.2 vs 12.38 mmol/day) and phosphate (49 vs 37.8 mmol/day) was statistically significant (P = 0.04 and 0.02, respectively). CONCLUSIONS: Apparently the use of bowel in the urinary tract does not alone increase the risk of urolithiasis. Patients in group 1 were more prone due to the constituents of urine and possibly their dietary habits. This implies that with adequate fluid intake and eating a healthy balanced diet, the risk of urolithiasis can be reduced in patients with enterocystoplasty, as with idiopathic stone formers.

Heat-shock protein 25 ameliorates calcium oxalate crystal-mediated oxidative stress in renal epithelial cells.

OBJECTIVE: To investigate whether the antioxidant protection attributed to small heat-shock proteins (sHSPs) affects calcium oxalate stone formation, a pro-oxidant disease. MATERIALS AND METHODS: Canine distal tubular epithelial cells (Madin-Darby canine kidney, MDCK cells) were grown as confluent monolayers. Treatment regimens included control and HS-treated cells (37 degrees C and 42 degrees C for 1 h) with or without calcium oxalate monohydrate (COM) or free oxalate treatment (28 microg/cm2) 16 h later. In digitonin-permeabilized cells, O2- was measured by lucigenin-enhanced chemiluminescence over a 5-min period, to measure mitochondrial O2- production. Protein expression was assessed by sodium dodecyl sulphate-polyacrylamide gel electrophoresis Western blot analysis using specific antibodies. RESULTS: COM significantly increased O2- production in MDCK cells. HS treatment, which up-regulated HSP25 expression, significantly decreased this O2- production (P < 0.05) but had no effect in control cells. In COM-treated cells (20 h) there was a marked and significant down-regulation of both HSP 25, HSP 70 and heme oxygenase-1 expression compared to cells treated with HS alone (P < 0.05). Free oxalate had no effect on HSP 25 expression. CONCLUSIONS: The results suggest that the COM-induced increase in mitochondrial O2- production in MDCK cells is ameliorated by HSP 25 up-regulation via HS. Specific COM inhibition of HSP 25, HSP 70 and heme oxygenase-1 up-regulation suggests that COM-induced reactive oxygen species damage is unable to benefit from HSP-associated physiological resistance.

The increased risk of urinary stone disease in betel quid chewers.

The chewing of betel quid is a common practice in many countries of the world, particularly in Southeast Asia. The quid consists of a preparation of areca nut, betel leaf and calcium hydroxide "lime" paste ("chuna"). For the first time, we present a study that links its use to urinary stone disease. Eight patients (seven male and one female) who presented to our Stone Unit with recurrent urinary stones were included in the study. All were from the Indian subcontinent and were found to regularly chew betel. The patients underwent metabolic screening including blood, random urine and 24-h urine tests, quantitative chemical analysis of their calculi (where possible) and each completed a 7-day Diet Diary on his/her free, home diet. The study demonstrated a high incidence of hypercalciuria, a tendency to pass an alkaline urine and low urinary citrate excretion among the patients. Together these urinary risk factors increase the probability of developing both calcium phosphate-containing and calcium oxalate-containing stones. In support of this hypothesis, the patients were found to form stones consisting mainly of calcium phosphate but mixed with calcium oxalate. It is concluded that the use of calcium hydroxide "chuna" in the betel quid is the major contributor to the cause of urinary stones in its users. Moreover, the development of urinary lithiasis in such patients may be a precursor to milk-alkali syndrome in those individuals whose chewing habit is more extensive than in the patients in this study and who do not seek to decrease their habit over the long term.

Crystal and microparticle effects on MDCK cell superoxide production: oxalate-specific mitochondrial membrane potential changes.

We have previously shown that crystals of calcium oxalate (COM) elicit a superoxide (O2-) response from mitochondria. We have now investigated: (i) if other microparticles can elicit the same response, (ii) if processing of crystals is involved, and (iii) at what level of mitochondrial function oxalate acts. O2- was measured in digitonin-permeabilized MDCK cells by lucigenin (10 microM) chemiluminescence. [(14)C]-COM dissociation was examined with or without EDTA and employing alternative chelators. Whereas mitochondrial O2- in COM-treated cells was three- to fourfold enhanced compared to controls, other particulates (uric acid, zymosan, and latex beads) either did not increase O2- or were much less effective (hydroxyapatite +50%, p < 0.01), with all at 28 microg/cm(2). Free oxalate (750 microM), at the level released from COM with EDTA (1 mM), increased O2- (+50%, p < 0.01). Omitting EDTA abrogated this signal, which was restored completely by EGTA and partially by ascorbate, but not by desferrioxamine or citrate. Omission of phosphate abrogated O2-, implicating phosphate-dependent mitochondrial dicarboxylate transport. COM caused a time-related increase in the mitochondrial membrane potential (deltapsi(m)) measured using TMRM fluorescence and confocal microscopy. Application of COM to Fura 2-loaded cells induced rapid, large-amplitude cytosolic Ca(2+) transients, which were inhibited by thapsigargin, indicating that COM induces release of Ca(2+) from internal stores. Thus, COM-induced mitochondrial O2- requires the release of free oxalate and contributes to a synergistic response. Intracellular dissociation of COM and the mitochondrial dicarboxylate transporter are important in O2- production, which is probably regulated by deltapsi(m).