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Primary hyperoxaluria (PH) type 1 and type 2 are autosomal recessive defects of oxalate metabolism resulting from glyoxylate accumulation which occurs by two distinct pathways. PH1 is associated to glycolic aciduria; PH2 to L-glyceric aciduria. Because hyperoxaluria leads to nephrolithiasis or nephrocalcinosis in both, they can be differentiated only through detection of the associated acidurias. However, glycolate and L-glycerate assays are not widely available and, in the setting of ESRF, diagnosis is hampered by a number of misleading events. At any stage of the disease diagnosis is crucial because there are differences between the two forms in clinical behaviour, long-term prognosis, and treatment. In this paper we outline diagnostic criteria for identification of PH2 in two patients, one with maintained renal function and one with ESRF on CPD, based on the use of a novel HPLC assay of L-glycerate in different body fluids. With the routine application of this procedure PH2 has been identified in two of 23 patients fulfilling criteria for diagnosis of PH. This suggests that the type 2 variant of PH may occur more frequently than so far suspected, and should be tested for even in the setting of ESRF. [ABSTRACT FROM PUBLISHER]

Systemic oxalosis is a constant feature in patients with primary hyperoxaluria type 1 (PH1) and chronic renal failure (CRF) and is not prevented by regular dialysis (RDT), because removal cannot keep up with retention and overproduction of oxalate. These patients are candidates to kidney and/or liver transplantation, which should be ideally planned prior to the development of oxalosis. However, methods to detect the presence and extent of oxalosis are invasive and poorly reproducible, and only indirect approaches are feasible. Because supersaturation of body fluids is an essential condition for oxalotic deposits to form, we have assessed serum calcium oxalate saturation (β) in 12 patients with PH1 and 26 with PH1-unrelated renal diseases and varying degrees of CRF. Nineteen healthy individuals were taken as controls. β was closely dependent on oxalate serum levels. Serum oxalate and β were increased in patients with CRF as compared to controls, and were inversely related to GFR, assessed as creatinine clearance. However, at any level of GFR, both were always greater in PH1 patients. From the slopes of the regression of β over CICr, saturation was predicted to be obtained at CICr ranging 24–34 and 8–11 ml/min/1.73 m in PH1 and non-PH1 patients respectively. Based on the dependence of β on oxalate, saturation was associated with serum oxalate between 44 and 46 µmol/l, irrespective of either the prevailing GFR or the underlying disease. These simple procedures represent a valuable non-invasive tool to define the risk of systemic oxalosis and may assist in timing of transplantation. [ABSTRACT FROM PUBLISHER]

- Oxalate excretion was measured in healthy subjects and idiopathic calcium stone-formers on dietary regimens which differed in the type and amount of protein allowed; 24-h urine collections were obtained from 41 practising vegetarians and 40 normal persons on a free, mixed, 'mediterranean' diet. Twenty idiopathic calcium stone-formers were also studied while on two low calcium, low oxalate diets which differed in that animal protein was high in one and restricted in the other. Vegetarians had higher urinary oxalate levels than controls and although the calcium levels were markedly lower, urinary saturation with calcium/oxalate was significantly higher. This mild hypercalciuria was interpreted as being secondary to both a higher intake and increased fractional intestinal absorption of oxalate. Changing calcium stone-formers from a high to a low animal protein intake produced a significant decrease in calcium excretion but there was no variation in urinary oxalate. As a result, the decrease in calcium oxalate saturation was only marginal and not significant. It was concluded that dietary animal protein has a minimal effect on oxalate excretion. Mild hyperoxaluria of idiopathic calcium stone disease is likely to be intestinal in origin. Calcium stone-formers should be advised to avoid an excess of animal protein but the risks of a vegetable-rich diet should also be borne in mind. [ABSTRACT FROM AUTHOR]

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., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: One limitation of the use of 24-hour collection is impracticality. We analysed the performance of spot urine measurements to estimate 24-hour excretion in patients with kidney stones., Methods: A total of 74 adult patients from two centres performed a 24-hour urine collection. A sample of the last micturition was sent for spot urine analysis. Twenty patients were asked to collect two additional spot urine samples, one before dinner and the other after dinner. Urinary concentrations of creatinine, calcium, oxalate, uric acid, citrate and magnesium were measured in the 24-hour and each of the spot urine samples. Four approaches were used to estimate 24-hour urinary excretion, multiplying the ratio of the spot urinary analyte to creatinine concentration by (i) measured 24-hour urinary creatinine excretion (Prediction 1), (ii) estimated 24-hour urinary creatinine excretion (Prediction 2), (iii) assumed 1-g 24-hour urinary creatinine excretion (Prediction 3) or (iv) assumed 1.5-g 24-hour urinary creatinine excretion (Prediction 4). For each parameter we computed Lin's concordance correlation coefficients (CCCs), Bland-Altman plots and 95% limits of agreement., Results: The performance of estimates obtained with Prediction 1 and Prediction 2 was similar, except for citrate and uric acid, for which Prediction 2 performed worse. Both approaches performed moderately well: citrate CCC {0.82 [95% confidence interval (CI) 0.75-0.90]}, oxalate [0.66 (95% CI 0.55-0.78)], magnesium [0.66 (95% CI 0.54-0.77)], calcium [0.63 (95% CI 0.50-0.75)] and uric acid [0.52 (95% CI 0.36-0.68)]. The performance of Predictions 3 and 4 was worse., Conclusions: Although spot urine samples may hold promise for clinical and population-based research, at present they have limited utility in clinical practice. Measuring or estimating 24-hour creatinine, rather than assuming a given creatinine excretion, will be necessary in future studies of spot urine samples., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Estimation of state of saturation with stone-forming salt represents a reliable tool to assess the overall risk. The available methods are based on computer-assisted ab initio calculations. Our earlier method URSUS was subsequently substituted by Lithorisk®, a software including visualization of risk profiles. Unfortunately, Lithorisk does not adapt to new versions of Windows® and Macintosh® Apple, neither runs on smartphones or tablets. We propose a novel version of the software which can be directly used online on any device equipped by different operating systems. Upon online connection and after registration, the software is ready for unlimited accesses, in either Italian, English or French. After digiting input variables (urea and creatinine also included) in a fixed dashboard, state of saturation is promptly given. In addition to state of saturation (ß) with calcium oxalate, brushite and uric acid, ß struvite and cystine are available. Both input variables and ß results are graphically depicted as green or red horizontal bars to indicate recommended values. The software was implemented with equations allowing to omit sulphate and ammonium excretion for users with difficult access to these measurements. This simplified version, tested for ßCaOx and ßBsh on 100 urine samples showed close correlation with the full version. The software gives a list of total and free concentrations and soluble complex species distribution. Results can be printed or saved as PDF. So, we propose an easily accessible software to estimate state of saturation usable on any operating system and personal device.

Background : Metabolic and physicochemical evaluation is recommended to manage the condition of patients with nephrolithiasis. The estimation of the saturation state (β values) is often included in the diagnostic work-up, and it is preferably performed through calculations. The free concentrations of constituent ions are estimated by considering the main ionic soluble complexes. It is contended that this approach is liable to an overestimation of β values because some complexes may be overlooked. A recent report found that β values could be significantly lowered upon the addition of new and so far neglected complexes, [Ca(PO 4 )Cit] 4- and [Ca 2 H 2 (PO 4 ) 2 ]. The aim of this work was to assess whether these complexes can be relevant to explaining the chemistry of urine. Methods: The Ca-phosphate-citrate aqueous system was investigated by potentiometric titrations. The stability constants of the parent binary complexes [Cacit] - and [CaPO 4 ] - , and the coordination tendency of PO 4 3- toward [Ca(cit)] - to form the ternary complex, were estimated. β CaOx and β CaHPO4 were then calculated on 5 natural urines by chemical models, including or not including the [CaPO 4 ] - and [Ca(PO 4 )cit] 4- species. Results: Species distribution diagrams show that the [Ca(PO 4 )cit] 4- species was only noticeable at pH > 8.5 and below 10% of the total calcium. β values estimated on natural urine were slightly lowered by the formation of [CaPO 4 ] - species, whereas [Ca(PO 4 )cit] 4- results were irrelevant. Conclusions: While [CaPO 4 ] - species have an impact on saturation levels at higher pHs, the existence of ternary complex and of the dimer is rejected.

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.

Introduction: In this paper, we investigated whether cholecalciferol supplementation may increase the risk of stone recurrence in patients with calcium nephrolithiasis and Vitamin D deficiency., Methods: Thirty-three stone formers (56 ± 17 years old, 12 males) with 25(OH)D < 20 ng/mL were considered. Calcium excretion and urine supersaturation with calcium oxalate (ßCaOx) and brushite (ßbsh) were evaluated, both before and after cholecalciferol supplementation. Values of ß > 1 mean supersaturation. Cholecalciferol was prescribed as oral bolus of 100,000-200,000 IU, followed by weekly (5000-10,000 IU) or monthly (25,000-50,000 IU) doses. Calcium intake varied between 800 and 1000 mg/day. In urine, total nitrogen (TNE) was taken as an index of protein intake, sodium as a marker of dietary intake, and net acid excretion (NAE) as an index of acid-base balance., Results: TNE, sodium, and NAE did not change during the study (p = ns). Compared to baseline values, after cholecalciferol, both serum calcium and phosphate did not vary (p = ns); 25(OH)D increased from 11.8 ± 5.5 to 40.2 ± 12.2 ng/mL (p < 0.01); 1.25(OH) 2 D increased from 41.6 ± 17.6 to 54 ± 16 pg/mL (p < 0.01); PTH decreased from 75 ± 27.2 to 56.7 ± 21.1 pg/mL (p < 0.01); urinary calcium increased from 2.7 ± 1.5 to 3.6 ± 1.6 mg/Kg b.w. (p < 0.01); ßbsh increased from 0.9 ± 0.7 to 1.3 ± 1.3 (p = 0.02); whereas ßCaOx varied but not significantly. Before cholecalciferol supplementation, 6/33 patients were hypercalciuric (i.e., urine Ca ≥ 4 mg/Kg b.w.) and increased to 13/33 after cholecalciferol supplementation (pX 2  = 0.03)., Conclusions: Cholecalciferol supplementation may increase calcium excretion, or reveal an underlying condition of absorptive hypercalciuria. This may increase both urine supersaturation with calcium salts and stone-forming risk.

Objective: This study evaluated the role of body mass index (BMI) and dietary potential renal acid load (PRAL) with urinary saturation for calcium oxalate (US-CaOx), calcium phosphate (US-CaP) and uric acid (US-UA) in renal stone formers., Materials and Methods: A retrospective analysis was conducted of laboratory data collected on 442 renal stone-forming patients. Demographic information, BMI and 24 h urinary samples were collected from patients on their regular diets. PRAL was calculated as the Load of Acid to Kidney Evaluation (LAKE) score through a short questionnaire., Results: Urinary risk factors, but also inhibitors of calcium stone formation such as magnesium, tended to increase in relation to BMI (p = .000). Urinary pH (p = .002) and ammonium/sulfate ratio (p = .000) were negatively related to BMI. This resulted in a positive correlation between BMI and US-UA (p = .000), whereas US-CaOx and US-CaP were not influenced by BMI. LAKE score was positively correlated with US-CaOx (p = .022) and US-CaP (p = .000) as a consequence of the inverse relationship between LAKE score and citrate (p = .000). Multiple linear regression analysis identified BMI (p = .009) and male gender (p = .002) as independent predictors of US-UA, and LAKE score (p = .004) and age (p = .001) as independent predictors of US-CaP., Conclusions: BMI, which depends on excessive intake of energy from food, is not related to an increased biochemical risk of calcium stone formation, which is more dependent on the renal acid load of the diet. In contrast, obesity is associated with an increased risk of uric acid stone formation due to insulin resistance, impaired ammoniagenesis and low urinary pH.

Background: Nephrolithiasis is a common condition with several studies documenting an increased prevalence over the past four decades. EAU and AUA guidelines recommend 24-hour urine metabolic evaluation in high-risk stone formers. Aim of this study is to retrospectively evaluate the first three years of experience with LithoTest® (Biohealth Italia Srl, Turin, Italy) through the analysis of demographic, clinical and biochemical data collected from a large cohort of patients with kidney stones., Methods: We retrospectively analyzed data from the LithoCenter database, including data from outpatient consultations, between January 2007 and December 2009 from all over Italy. LithoTest® was performed through a 24-hour urine collection and included measurements of urine volume and pH, 24-hour excretion of creatinine as well as main cations and anions, including calcium, magnesium sodium potassium, ammonium, uric acid, oxalate, citrate, phosphate, inorganic sulphate and chloride. Urine state of saturation for calcium oxalate (βCaOx), calcium hydrogen phosphate or brushite (βbsh) and uric acid (βUA) were also calculated by means of the computer program LithoRisk. Brand's test for cystinuria was also carried out. Statistical analysis was performed using the S-PSS software v. 22.0., Results: The number of patients with data available for analysis was 435, of whom 236 were male (54%) and 199 female (46%). Complete 24-hour urine measurements were available for all 435 patients. Compared to men, women had significantly lower values for creatinine, urate, oxalate, phosphate, sodium, potassium, magnesium and chloride excretion, whereas 24-hour pH and citrate excretion were higher. No significant differences were found for the other examined variables. βCaOx and βUA were significantly higher in men than women, whereas no significant difference was found for βbsh. There was a direct relationship between calcium and sodium urine excretion. Excessive sodium excretion was recorded in 191 patients (44%) and low urine volumes in 201 (46.2%). Hyperoxaluria was observed in 118 patients (27.3%), hypercalciuria in 115 (26.6%), hyperuricosuria in 153 (35.4%), hypomagnesuria in 96 (22.2%), and hypocitraturia in 134 patients (31%). Hyperexcretion of sodium, hypocitraturia and hyperoxaluria were most frequent in males. βCaOx was significantly higher in the setting of hypercalciuria, hypocitraturia, hyperoxaluria and urine pH below 5.5., Conclusions: Our findings in a large cohort of high-risk stone-forming patients show significant differences in urinary metabolic profiles between men and women. Carrying on the collection and analysis of data by LithoTest® from 2009 to 2015 and matching urinary and dietary data could eventually improve our understanding on the metabolic profile of stone-formers in Italy.

Background: Primary hyperoxaluria (PH) is a rare autosomal recessive disease commonly arising in childhood and presenting with nephrolithiasis, nephrocalcinosis and/or chronic renal failure. Three genes are currently known as responsible: alanine-glyoxylate aminotransferase (AGXT, PH type 1), glyoxylate reductase/hydroxypyruvate reductase (GRHPR, PH type 2), and 4-hydroxy-2-oxoglutarate aldolase (HOGA1, PH type 3). In our Centre, at the end of 2014 molecular diagnosis of PH1 had been performed in 80 patients, while one patient received a PH2 diagnosis., Materials and Methods: Fifteen patients referred to our Centre and suspected to have PH on clinical grounds were negative for pathogenic variants in the entire coding sequence and exon-intron boundaries of the AGXT gene. Therefore, we extended the analysis to the AGXT promoter region and the GRHPR and HOGA1 genes., Results: Two patients were heterozygous for two novel AGXT-promoter variants (c.-647C > T, c.-424C > T) that were probably non pathogenic. One patient was homozygous for a novel HOGA1 variant of intron 2 (c.341-81delT), whose pathogenicity predicted by in silico splicing tools was not confirmed by a minigene splicing assay in COS-7 and HEK293T cells., Conclusion: New genetic subtypes of PH can be hypothesized in our patients, that may be caused by mutations in other gene encoding proteins of glyoxylate metabolism. Alternatively, some kind of mutations (e.g., deletions/duplications, deep intronic splicing regulatory variants) could be missed in a few cases, similarly to other genetic diseases.

Nephrolithiasis (NL) is one of the most prevalent nontransmissible diseases in western countries. It is being associated with other frequent diseases, including osteoporosis, cardiovascular disease, hypertension, diabetes mellitus, through a putative common link with metabolic syndrome and insulin resistance or altered mineral metabolism. This review will focus on classification, physicochemical basis, risk factors, laboratory and imaging investigations, medical management.Classification as to stone composition includes calcium, uric acid (UA), cystine (Cys), infected, 2-8 dihydroxyadenine and rare NL. According to pathophysiology, NL is classified as primary, secondary to systemic diseases or drugs, caused by renal or metabolic hereditary disorders.A stone can only form in supersaturated environment, and this is sufficient in UA, Cys and infected NL, but not in Ca-NL, which results from the imbalance between supersaturation and inhibition. All types are characterized by derangements of peculiar risk factors. Laboratory investigations aim at identifying type of NL, underlying risk factors and state of saturation, and pathophysiology. This justifies a rationale therapy able to dissolve some types of stones and/or produce reduction in recurrence rate in others.Medical management includes alkali and allopurinol for UA nephrolithiasis (UA-NL), thiols and alkali in Cys-NL, dietary and pharmacological intervention for Ca-NL. Thiazides and alkaline citrate salts are the most widely used drugs in Ca-NL, where they proved efficient to prevent new stones. Other drugs have only been used in particular subsets.Proper medical management and modern urological approaches have already notably improved clinical outcomes. Future studies will further clarify mechanisms of NL with expected new and targeted therapeutic options.