Effect of Carnosine on the Activity of Matrix Metalloproteinase-2 and Oxidative Stress in the Kidneys in Experimental Urate Nephrolithiasis.

The effect of carnosine on MMP-2 activity and oxidative stress in the kidneys in experimental urate nephrolithiasis was studied. Urate nephrolithiasis was modeled in Wistar rats by intragastric administration of a mixture of oxonic and uric acids. Carnosine was administered intragastrically through a tube in a dose of 15 mg/kg. In rats treated with carnosine, the concentration of MMP-2 in the urine decreased by 3.7 times, and the excretion of MMP-2 with urine decreased by 4.3 times. In the homogenate of the kidneys from rats treated with carnosine, the concentration of TBA-reactive substances decreased by 5 times and the concentration of MMP-2 decreased by 12.7%. After treatment with carnosine, the number of histologically confirmed cases of urate nephrolithiasis decreased by 2 times, while the mean size of urate deposits decreased by 2.7 times. Thus, carnosine inhibits MMP-2 and reduces the intensity of oxidative stress in the kidneys, which prevents the development of urate nephrolithiasis.

The microbiome of kidney stones and urine of patients with nephrolithiasis.

The incidence of nephrolithiasis is rising worldwide. Although it is a multifactorial disease, lifestyle plays a major role in its etiology. Another considerable factor could be an aberrant microbiome. In our observational single-center study, we aimed to investigate the composition of bacteria in kidney stones and urine focusing on patients with features of metabolic syndrome. Catheterized urine and kidney stones were collected prospectively from 100 consecutive patients undergoing endoscopic nephrolithotomy between 2020 and 2021 at our clinic. Microbiome composition was analyzed via 16S rRNA gene amplicon sequencing. Detection of bacteria was successful in 24% of the analyzed kidney stones. These patients had a prolonged length of stay compared to patients without verifiable bacteria in their stones (2.9 vs 1.5 days). Patients with features of metabolic syndrome were characterized by kidney stones colonized with classical gastrointestinal bacteria and displayed a significant enrichment of Enterococcaceae and Enterobacteriaceae. Stones of patients without features of metabolic syndrome characterized by Ureaplasma and Staphylococcaceae. Patients with bacteria in their kidney stones exhibit a longer length of stay, possibly due to more complex care. Patients presenting with features of metabolic syndrome displayed a distinct stone microbiome compared to metabolically fit patients. Understanding the role of bacteria in stone formation could enable targeted therapy, prevention of post-operative complications and new therapeutic strategies.

Premature Senescence and Telomere Shortening Induced by Oxidative Stress From Oxalate, Calcium Oxalate Monohydrate, and Urine From Patients With Calcium Oxalate Nephrolithiasis.

Oxidative stress, a well-known cause of stress-induced premature senescence (SIPS), is increased in patients with calcium oxalate (CaOx) kidney stones (KS). Oxalate and calcium oxalate monohydrate (COM) induce oxidative stress in renal tubular cells, but to our knowledge, their effect on SIPS has not yet been examined. Here, we examined whether oxalate, COM, or urine from patients with CaOx KS could induce SIPS and telomere shortening in human kidney (HK)-2 cells, a proximal tubular renal cell line. Urine from age- and sex-matched individuals without stones was used as a control. In sublethal amounts, H2O2, oxalate, COM, and urine from those with KS evoked oxidative stress in HK-2 cells, indicated by increased protein carbonyl content and decreased total antioxidant capacity, but urine from those without stones did not. The proportion of senescent HK-2 cells, as indicated by SA-ßgal staining, increased after treatment with H2O2, oxalate, COM, and urine from those with KS. Expression of p16 was higher in HK-2 cells treated with H2O2, oxalate, COM, and urine from those with KS than it was in cells treated with urine from those without stones and untreated controls. p16 was upregulated in the SA-ßgal positive cells. Relative telomere length was shorter in HK-2 cells treated with H2O2, oxalate, COM, and urine from those with KS than that in cells treated with urine from those without stones and untreated controls. Transcript expression of shelterin components (TRF1, TRF2 and POT1) was decreased in HK-2 cells treated with H2O2, oxalate, COM, and urine from those with KS, in which case the expression was highest. Urine from those without KS did not significantly alter TRF1, TRF2, and POT1 mRNA expression in HK-2 cells relative to untreated controls. In conclusion, oxalate, COM, and urine from patients with CaOx KS induced SIPS and telomere shortening in renal tubular cells. SIPS induced by a lithogenic milieu may result from upregulation of p16 and downregulation of shelterin components, specifically POT1, and might contribute, at least in part, to the development of CaOx KS.

Impact on urinary oxalate levels with use of ezetimibe.

Background: Calcium oxalate stones are the most common cause of nephrolithiasis in the United States. Smaller studies of <15 patients investigating ezetimibe, a selective cholesterol absorption inhibitor, have suggested increased urine oxalate levels with use of the drug. We attempt to better define this relationship of ezetimibe on urinary oxalate using a larger patient sample analysing multiple urine collections on and off treatment. Materials and Methods: We retrospectively reviewed all consecutive patients from 01/2018 through 04/2019 evaluated for nephrolithiasis with use of ezetimibe documented in their medical record at Mayo Clinic Florida. Primary outcomes included increase in urinary oxalate with use of ezetimibe and reduction in urinary oxalate with discontinuation of medication. Results: Of 57 reviewed patients, 30 (53%) met inclusion criteria yielding 117 24-h urine measurements either on ezetimibe (72 measurements) or off ezetimibe (41 measurements). The mean urinary oxalate level off ezetimibe was 39.86 mg versus 40.45 mg with ezetimibe. After adjusting for age and sex, the estimated difference was 1.239 mg (95% CI, -4.856 to 7.335 mg; p = 0.93). A subset of six patients with urinary oxalate values both on and off ezetimibe showed a difference in 24-h urinary oxalate levels ranged from -16.40 to 14.95 mg (mean difference = 0.93 mg; median difference = 3.84 mg). Conclusion: Use of ezetimibe does not provide clear evidence of a difference in urinary oxalate levels.

Effect of dietary treatment and fluid intake on the prevention of recurrent calcium stones and changes in urine composition: A meta-analysis and systematic review.

To perform a systematic review and meta-analysis of randomized controlled trials (RCTs) for investigating the effect of dietary treatment and fluid intake on the prevention of recurrent calcium stones and changes in urine composition. PubMed, Web of Science, Embase, EBSCO, and Cochrane Library databases (updated November 2020) were searched for studies with the following keywords: diet, fluid, recurrent, prevention, randomized controlled trials, and nephrolithiasis. The search strategy and study selection process was conducted by following the PRISMA statement. Six RCTs were identified for satisfying the inclusion criteria and enrolled in this meta-analysis. Our result showed that low protein with or without high fiber diet intervention does not decrease the recurrence of stone upon comparing with control groups (RR = 2.32, 95% CI = 0.42-12.85; P = 0.34) with significant heterogeneity among the studies (I2 = 81%, P = 0.02). But normal-calcium, low protein, low-salt diet had recurrences did reduced the recurrence compared to normal-calcium diet. And the fluid intake has a positive effect on prevention of recurrent stone formation (RR = 0.39, 95% CI = 0.19-0.80; P = 0.01) with insignificant heterogeneity among the studies (I2 = 9%, P = 0.30). The different components of urine at baseline were reported in four studies. Upon reviewing the low protein with or without high fiber dietary therapy groups, it was found that there were no obvious changes in the 24-hour urine sodium, calcium, citrate, urea, and sulfate. In conclusion, our study shows that the only low protein with or without fiber does not affect recurrence, but low Na, normal Ca diet has a marked effect on reducing recurrence of calcium stone. And fluid intake shows a significant reduction in the recurrence of calcium stone.

Modulation of Tubular pH by Acetazolamide in a Ca2+ Transport Deficient Mice Facilitates Calcium Nephrolithiasis.

Proximal tubular (PT) acidosis, which alkalinizes the urinary filtrate, together with Ca2+ supersaturation in PT can induce luminal calcium phosphate (CaP) crystal formation. While such CaP crystals are known to act as a nidus for CaP/calcium oxalate (CaOx) mixed stone formation, the regulation of PT luminal Ca2+ concentration ([Ca2+]) under elevated pH and/or high [Ca2+] conditions are unknown. Since we found that transient receptor potential canonical 3 (TRPC3) knockout (KO; -/-) mice could produce mild hypercalciuria with CaP urine crystals, we alkalinized the tubular pH in TRPC3-/- mice by oral acetazolamide (0.08%) to develop mixed urinary crystals akin to clinical signs of calcium nephrolithiasis (CaNL). Our ratiometric (λ340/380) intracellular [Ca2+] measurements reveal that such alkalization not only upsurges Ca2+ influx into PT cells, but the mode of Ca2+ entry switches from receptor-operated to store-operated pathway. Electrophysiological experiments show enhanced bicarbonate related current activity in treated PT cells which may determine the stone-forming phenotypes (CaP or CaP/CaOx). Moreover, such alkalization promotes reactive oxygen species generation, and upregulation of calcification, inflammation, fibrosis, and apoptosis in PT cells, which were exacerbated in absence of TRPC3. Altogether, the pH-induced alteration of the Ca2+ signaling signature in PT cells from TRPC3 ablated mice exacerbated the pathophysiology of mixed urinary stone formation, which may aid in uncovering the downstream mechanism of CaNL.

Glycine suppresses kidney calcium oxalate crystal depositions via regulating urinary excretions of oxalate and citrate.

An abnormal urine composition is a key reason for kidney stone formation, but little is known about the roles of small metabolites in the urine during kidney stone formation. Here, we found urine glycine in patients with kidney calcium oxalate (CaOx) stone was significantly lower than that in healthy people via 1 H NMR spectra detection, and investigated the role and underlying mechanism of glycine in the regulation of CaOx stone formation. Our results showed that glycine could significantly attenuate ethylene glycol-induced CaOx crystal depositions in rat kidney via decreasing urine oxalate and increasing urine citrate. Mechanism studies revealed that glycine could decrease urine oxalate through downregulating Slc26a6 expression, whereas increase urine citrate via inhibiting Nadc1 expression. Moreover, glycine decreased the protein expression of both Slc26a6 and Nadc1 via increasing the expression of miRNA-411-3p, which directly bound to the 3'-untranslated regions of Slc26a6 and Nadc1 messenger RNAs, in vitro and in vivo. Together, our results revealed a novel role of glycine in the regulation of kidney CaOx crystal formation and provided a potential target for the treatment of kidney CaOx stone.

Antiurolithic effects of medicinal plants: results of in vivo studies in rat models of calcium oxalate nephrolithiasis-a systematic review.

Urolithiasis is one of the oldest diseases affecting humans, while plants are one of our oldest companions providing food, shelter, and medicine. In spite of substantial progress in understanding the pathophysiological mechanisms, treatment options are still limited, often expensive for common people in most parts of the world. As a result, there is a great interest in herbal remedies for the treatment of urinary stone disease as an alternative or adjunct therapy. Numerous in vivo and in vitro studies have been carried out to understand the efficacy of herbs in reducing stone formation. We adopted PRISMA guidelines and systematically reviewed PubMed/Medline for the literature, reporting results of various herbal products on in vivo models of nephrolithiasis/urolithiasis. The Medical Subject Heading Terms (Mesh term) "Urolithiasis" was used with Boolean operator "AND" and other related Mesh Unique terms to search all the available records (July 2019). A total of 163 original articles on in vivo experiments were retrieved from PubMed indexed with the (MeshTerm) "Urolithiasis" AND "Complementary Therapies/Alternative Medicine, "Urolithiasis" AND "Plant Extracts" and "Urolithiasis" AND "Traditional Medicine". Most of the studies used ethylene glycol (EG) to induce hyperoxaluria and nephrolithiasis in rats. A variety of extraction methods including aqueous, alcoholic, hydro-alcoholic of various plant parts ranging from root bark to fruits and seeds, or a combination thereof, were utilized. All the investigations did not study all aspects of nephrolithiasis making it difficult to compare the efficacy of various treatments. Changes in the lithogenic factors and a reduction in calcium oxalate (CaOx) crystal deposition in the kidneys were, however, considered favorable outcomes of the various treatments. Less than 10% of the studies examined antioxidant and diuretic activities of the herbal treatments and concluded that their antiurolithic activities were a result of antioxidant, anti-inflammatory, and/or diuretic effects of the treatments.

Surface analysis of ureteral stent before and after implantation in the bodies of child patients.

The aim of this work was to determine which part of a double-J ureteral stent (DJ stents) showed the highest tendency to crystal, calculi, and biofilm deposition after ureterorenoscopic-lithotripsy procedure (URS-L) to treat calcium oxalate stones. Additionally, the mechanical strength and the stiffness of DJ stents were evaluated before and after exposure to urine. Obtained results indicated that the proximal (renal pelvis) and distal (urinary bladder) part is the most susceptible for post-URS-L fragments and urea salt deposition. Both, the outer and inner surfaces of the DJ ureteral stents were completely covered even after 7 days of implantation. Encrustation of DJ stents during a 31-day period results in reducing the Young's modulus by 27-30%, which confirms the loss of DJ stent elasticity and increased probability of cracks or interruption. Performed analysis pointed to the need to use an antibacterial coating in the above-mentioned part of the ureteral stent to prolong its usage time and to prevent urinary tract infection.

Proton-pump inhibitors associated with decreased urinary citrate excretion.

INTRODUCTION: Proton-pump inhibitors (PPIs) may increase the risk of kidney stone formation, but the mechanism has not been elucidated. There is a paucity of literature evaluating the effects of PPIs on urinary metabolites and urine pH. METHODS: We performed a retrospective review of nephrolithiasis patients treated at our institution and compared patients who were taking PPIs to those who were not at the time of their 24-h urine collections. Hierarchical multivariate linear regression was used to evaluate the independent relationship between PPI use and urinary mineral composition. RESULTS: We identified 301 consecutive patients, 88 (29%) of whom were taking PPIs at the time of their 24-h urine collections. Patients taking PPIs were older and more likely to have medical comorbidities associated with metabolic syndrome such as hypertension, diabetes, and dyslipidemia (p < 0.01). Controlling for these factors, patients taking PPIs were found to have 12% lower 24-h urine citrate excretion (ß = - 0.12, ΔF = 4.24, p = 0.04). There were no other differences in urinary mineral composition between the groups. CONCLUSION: Our findings suggest that patients who take PPIs regularly may be at risk for decreased urinary citrate excretion. The consequent decrease in urinary citrate may become clinically significant for patients with other predisposing factors for hypocitraturia.

Comparison of Two Dietary Supplements for Treatment of Uric Acid Renal Lithiasis: Citrate vs. Citrate + Theobromine.

BACKGROUND: Uric acid (UA) renal lithiasis has a high rate of recurrence and a prevalence ranging from 10% and 15%, depending on the population. The most important etiological factor is persistence of urinary pH below 5.5 and one of the most common treatments is alkalization with citrate. Recent studies demonstrated that theobromine, which is abundant in chocolate and cocoa, is a potent inhibitor of UA crystallization. AIM: The aim was to compare the efficacy of citrate versus citrate + theobromine as treatment for UA lithiasis. METHODS: This randomized cross-over trial investigated the efficacy of two treatments in 47 patients with UA renal lithiasis. Urine volume, pH, UA excretion, theobromine excretion, and risk of UA crystallization (RUAC) at baseline and at the end of each intervention period were measured. RESULTS: Each treatment significantly reduced the risk of UA crystallization compared to basal values. The RUAC after citrate + theobromine was lower than the RUAC after citrate, although this difference was not statistically significant. CONCLUSION: The combined consumption of citrate and theobromine may be a promising strategy for the prevention of UA kidney stones.

Urinary Lithogenic Risk Profile in ADPKD Patients Treated with Tolvaptan.

BACKGROUND AND OBJECTIVES: Nephrolithiasis is a common health problem in autosomal dominant polycystic kidney disease (ADPKD) and significantly contributes to patient morbidity. Recently, Tolvaptan has been introduced for the treatment of ADPKD, but whether it is associated with alterations of the urinary lithogenic risk profile remains unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted an analysis of participants enrolled in the Bern ADPKD registry, a prospective observational cohort study. Twenty-four-hour urine analyses were performed at baseline and then at yearly follow-ups. Relative supersaturation ratios for calcium oxalate, brushite, and uric acid were calculated with the program EQUIL2. Unadjusted and multivariable mixed-effects linear regression models, adjusted for age, sex, body mass index, eGFR, net acid excretion, and height-adjusted total kidney volume, were used to assess the association of Tolvaptan with urinary parameters relevant for kidney stone formation. The maximum individual follow-up time was 3 years, median follow-up time 1.9 years, and cumulative follow-up time 169 years. RESULTS: In total, 125 participants (38 with and 87 without Tolvaptan treatment) were included in the analysis. In multivariable analysis, Tolvaptan treatment was associated [adjusted estimate of the difference between Tolvaptan and no Tolvaptan; 95% confidence interval (CI)] with lower urine relative supersaturation ratios for calcium oxalate (-0.56; 95% CI, -0.82 to -0.3; P<0.001), brushite (-0.33; 95% CI, -0.54 to -0.11; P=0.004), and uric acid (-0.62; 95% CI, -0.88 to -0.37; P<0.001), and with higher urine citrate in mmol/mmol creatinine per day (0.25; 95% CI, 0.05 to 0.46; P=0.02) and calcium in mmol/mmol creatinine per day (0.31; 95% CI, 0.09 to 0.53; P=0.006) excretion. In addition, Tolvaptan treatment was associated with lower net acid excretion in mEq/mmol creatinine per day (-0.54; 95% CI, -0.90 to -0.17; P=0.004) and higher net gastrointestinal alkali absorption in mEq/mmol creatinine per day (0.57; 95% CI, 0.26 to 0.88; P<0.001). CONCLUSIONS: Tolvaptan treatment is associated with a significantly improved urinary lithogenic risk profile in patients with ADPKD.

Clinical validation of urinary indole-reacted calcium oxalate crystallization index (iCOCI) test for diagnosing calcium oxalate urolithiasis.

An indole-reacted calcium oxalate crystallization index (iCOCI) test was developed to quantify the total competence of urine to precipitate calcium oxalate (CaOx) crystals. We conducted the prospective cohort study in accordance with the STARD guideline to evaluate the accuracy of urinary iCOCI test (index test) for diagnosing urolithiasis. A total of 281 participants were recruited for the study. Levels of urinary iCOCI were determined in the pre-diagnostic 24-h urine samples. Positive urinary iCOCI (≥ 0.6 COM eqv., g/L) was accounted for 51% (144/281), and the rest of 49% (137/281) were negative. Non-contrast CT imaging (reference standard) was subsequently performed for the definite diagnosis of urolithiasis to divide the participants into two groups, non-stone subjects (NSS, n = 122) and stone-forming subjects (SFS, n = 159). It should be noted that only subjects who currently had urinary stone at the time of study were classified as SFS. Urinary iCOCI levels in the SFS were significantly higher than the NSS. ROC analysis revealed an area under curve (AUC) of 0.893 (95% CI: 0.855-0.932) in separating NSS from all SFS. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy, positive likelihood ratio (LH+) and negative likelihood ratio (LH-) of urinary iCOCI test for diagnosis of all urolithiasis were 87%, 80%, 84%, 84%, 83%, 4.44 and 0.16, respectively. Of 159 SFS, 38 were confirmed to have CaOx stones. Among these 38 CaOx SFS, only 2 had negative urinary iCOCI test. The AUC of urinary iCOCI test for separating CaOx SFS from NSS was markedly high (0.946, 95% CI: 0.914-0.978). Sensitivity, specificity, PPV, NPV, accuracy, LH+ and LH- of urinary iCOCI test for diagnosing CaOx urolithiasis were 95%, 86%, 68%, 98%, 88%, 6.80 and 0.06, respectively. Conclusion, we clinically validated that an innovative non-invasive urinary iCOCI test was highly accurate to diagnose urolithiasis, especially CaOx stone. With its high sensitivity and NPV, urinary iCOCI test is clinically intended to use as a screening test for CaOx urolithiasis. LH- of 0.06 indicates that negative result of urinary iCOCI test is highly accurate to rule out the CaOx stone formation. It is noted that urinary iCOCI level is expressed as arbitrary unit, and it is not directly related to the actual physiological level of urinary oxalate.

Hypomagnesuria is Associated With Nephrolithiasis in Patients With Asymptomatic Primary Hyperparathyroidism.

CONTEXT: The pathogenesis of nephrolithiasis in primary hyperparathyroidism (PHPT) remains to be elucidated. The latest guidelines suggest parathyroidectomy in patients with asymptomatic PHPT with hypercalciuria (> 400 mg/d) and increased stone risk profile. OBJECTIVE: The objective of this work is to evaluate the association of urinary stone risk factors and nephrolithiasis in patients with asymptomatic sporadic PHPT and its clinical relevance. DESIGN: A total of 157 consecutive patients with sporadic asymptomatic PHPT were evaluated by measurement of serum and 24-hour urinary parameters and kidney ultrasound. RESULTS: Urinary parameters were tested in the univariate analysis as continuous and categorical variables. Only hypercalciuria and hypomagnesuria were significantly associated with nephrolithiasis in the univariate and multivariate analysis adjusted for age, sex, body mass index, estimated glomerular filtration rate, parathyroid hormone, 25-hydroxyvitamin D, serum calcium, and urine volume (odds ratio, OR 2.14 [1.10-4.56]; P = .04; OR 3.06 [1.26-7.43]; P = .013, respectively). Hypomagnesuria remained associated with nephrolithiasis in the multivariate analysis (OR 6.09 [1.57-23.5], P = .009) even when the analysis was limited to patients without concomitant hypercalciuria. The urinary calcium/magnesium (Ca/Mg) ratio was also associated with nephrolithiasis (univariate OR 1.62 [1.27-2.08]; P = .001 and multivariate analysis OR 1.74 [1.25-2.42], P = .001). Hypomagnesuria and urinary Ca/Mg ratio had a better, but rather low, positive predictive value compared with hypercalciuria. CONCLUSIONS: Hypomagnesuria and urinary Ca/Mg ratio are each associated with silent nephrolithiasis and have potential clinical utility as risk factors, besides hypercalciuria, for kidney stones in asymptomatic PHPT patients. The other urinary indices that have been commonly thought to be associated with kidney stones in PHPT are not supported by our results.

The Impact of Alternative Alkalinizing Agents on 24-Hour Urine Parameters.

OBJECTIVES: To determine if alternative alkalinizing agents lead to similar changes in 24-hour urine pH and citrate compared to potassium citrate (KCIT). Many stone formers cannot tolerate KCIT due to side effects or cost. In these patients, we have prescribed potassium bicarbonate or sodium bicarbonate as alternative alkali (AA), though their efficacy is unclear. METHODS: We performed a retrospective cohort study of adult stone formers seen from 2000 to 2018 with 24-hour urine analyses. Two analyses were performed. The first evaluated the alkalinizing and citraturic effects in patients with baseline low urine pH or hypocitraturia off of any alkalinizing medications, who were subsequently treated with either KCIT or AA. The second analysis compared the pH and citrate in patients changing from KCIT to an AA. Reasons for switching were abstracted by chart review and cost savings percentages were calculated using GoodRx medication prices. RESULTS: When starting alkali therapy, the median increase in pH from baseline was 0.64 for KCIT and 0.51 for AA (P = .077), and the median increase in citrate from baseline was 231 mg for KCIT and 171 mg for AA (P = .109). When switching alkali therapy, median pH and citrate did not significantly change. Hyperkalemia (24%), GI upset (19%), and cost (17%) were the most common reasons cited for switching to an AA. AA represented a savings of 86%-92% compared to KCIT. CONCLUSION: Alternative alkali appear to offer comparable improvements in 24-hour urine parameters and significant cost-savings compared to KCIT.

Hyperparathyroidism in patients over 75: Clinical characteristics and outcome. Is conservative treatment a safe alternative?

OBJECTIVE: With the current aging of the world's population, primary hyperparathyroidism (PHPT) is increasingly detected in the elderly. Yet data on the presentation and outcome of PHPT in this group are scarce. The objective was to describe a cohort of patients aged 75 years or more with PHPT observed in our endocrine clinic. STUDY DESIGN: A retrospective analysis of medical records in an endocrine clinic at a tertiary hospital. We evaluated 182 patients with PHPT, aged 75 years or more at their last follow-up, all diagnosed at age 65 or more. Laboratory data were compared at diagnosis and last follow-up. RESULTS: Mean age at diagnosis was 73 ± 4 years, last follow-up was at 83 ± 4 years, and mean follow-up was 11.3 ± 5.5 years. Osteoporosis, fractures, and nephrolithiasis were diagnosed in 114(63 %), 84(46 %), and 43(24 %) patients, respectively. Overall, 150 patients had an indication for surgery; of them, the 29 who underwent parathyroidectomy were younger than the non-operated patients and had higher rates of hypercalciuria. During the follow-up of the 141 patients who did not undergo operation, serum and urinary calcium levels significantly had decreased, and vitamin D level had increased at last visit (10.4 ± 0.5 mg/dl, 161 ± 70 mg/24 h, 69 ± 17 nmol/l, p < 0.01 respectively) compared with levels at diagnosis (10.6 ± 0.2 mg/dl, 223 ± 95 mg/24 h, 53 ± 15 nmol/l, respectively, p = 0.001). Overall, 38 of the 182 patients (20 %) died during follow-up; these patients were significantly older at diagnosis (76 ± 5 vs. 72 ± 4 years) but there were no differences in laboratory variables. CONCLUSIONS: While most patients had a formal indication for surgery, few underwent parathyroidectomy. Serum and urinary calcium significantly decreased during follow-up in patients who did not undergo surgery. Our data are reassuring and support at least the consideration of conservative treatment for these patients.

Association Between Daily Water Intake and 24-hour Urine Volume Among Adolescents With Kidney Stones.

OBJECTIVE: To determine the association between daily water intake and 24-hour urine volume among adolescents with nephrolithiasis in order to estimate a "fluid prescription," the additional water intake needed to increase urine volume to a target goal. METHODS: We conducted a secondary analysis of an ecological momentary assessment study that prospectively measured daily water intake of 25 adolescents with nephrolithiasis over 7 days. We identified 24-hour urine volumes obtained for clinical care within 12 months of water intake assessment. A linear regression model was fit to estimate the magnitude of the association between daily water intake and 24-hour urine volume, adjusting for age, sex, race, and daily temperature. RESULTS: Twenty-two participants completed fifty-seven 24-hour urine collections within 12 months of the study period. Median daily water intake was 1.4 L (IQR 0.67-1.94). Median 24-hour urine volume was 2.01 L (IQR 1.20-2.73). A 1 L increase in daily water intake was associated with a 710 mL increase in 24-hour urine output (95%CI 0.55-0.87). Using the model output, the equation was generated to estimate the additional fluid intake needed fluid prescription (FP) to produce the desired increase in urine output (dUOP): FP = dUOP/0.71. CONCLUSION: The FP equation (FP = dUOP)/0.71), which reflects the relationship between water intake and urine volume, could be used to help adolescents with nephrolithiasis achieve urine output goals to decrease stone recurrence.

Measurement of preprandial and postprandial urine calcium to creatinine ratios in male Miniature Schnauzers with and without urolithiasis.

BACKGROUND: We aimed to identify a simple test for excessive calciuresis and predict calcium oxalate (CaOx) disease in Miniature Schnauzers. We investigated the impact of postprandial time on the urine calcium to creatinine ratio (UCa/Cr) in male dogs of this breed, with the goal of improving the utility of the UCa/Cr. HYPOTHESES: (1) Significant differences will exist in preprandial and postprandial UCa/Cr between CaOx urolith-forming and control Schnauzers. (2) The UCa/Cr will increase significantly from the first morning baseline at ≥1 postprandial time point(s) in both control and CaOx urolith-forming dogs. (3) Biochemical abnormalities and other variables may be associated with urolith status. ANIMALS: Twenty-four male Miniature Schnauzer dogs, consisting of 9 with (urolith formers) and 15 without (controls) CaOx uroliths. METHODS: Urine was collected before and 1, 2, 4, and 8 hours after feeding a standardized diet. Receiver operator characteristic curve analysis was performed to identify the UCa/Cr cutoff that most accurately differentiates dogs based on urolith status. RESULTS: Urolith formers had significantly higher mean UCa/Cr over the course of 8 hours. The postprandial change in UCa/Cr was not significant at any time point between or within groups. The cutoff UCa/Cr value of 0.06 had a specificity of 93% (95% confidence interval [CI], 80%-100%) and a sensitivity of 56% (95% CI, 21%-86%) for identifying CaOx urolithiasis. CONCLUSIONS AND CLINICAL IMPORTANCE: Urolith-forming male Miniature Schnauzers have excessive calciuresis, and the postprandial sampling time up to 8 hours is not critical. This simple urine measurement has potential as a marker of CaOx disease.

Prevalence of low molecular weight proteinuria and Dent disease 1 CLCN5 mutations in proteinuric cohorts.

BACKGROUND: Dent disease type 1 (DD1) is a rare X-linked disorder caused mainly by CLCN5 mutations. Patients may present with nephrotic-range proteinuria leading to erroneous diagnosis of focal segmental glomerulosclerosis (FSGS) and unnecessary immunosuppressive treatments. METHODS: The following cohorts were screened for CLCN5 mutations: Chronic Kidney Disease in Children (CKiD; n = 112); Multicenter FSGS-Clinical Trial (FSGS-CT) (n = 96), and Novel Therapies for Resistant FSGS Trial (FONT) (n = 30). Urinary α1-microglobulin (α1M), albumin (A), total protein (TP), and creatinine (Cr) were assessed from CKiD subjects (n = 104); DD1 patients (n = 14); and DD1 carriers (DC; n = 8). TP/Cr, α1M/Cr, α1M/TP, and A/TP from the CKiD cohort were compared with DD1 and DC. RESULTS: No CLCN5 mutations were detected. TP/Cr was lower in DC and CKiD with tubulointerstitial disease than in DD1 and CKiD with glomerular disease (p < 0.002). α1M/Cr was higher in DD1 than in CKiD and DC (p < 0.001). A/TP was lower in DD1, DC, and CKiD with tubulointerstitial disease and higher in CKiD with glomerular disease (p < 0.001). Thresholds for A/TP of ≤ 0.21 and α1M/Cr of ≥ 120 mg/g (> 13.6 mg/mmol) creatinine were good screens for Dent disease. CONCLUSIONS: CLCN5 mutations were not seen in screened CKiD/FSGS cohorts. In our study, a cutoff of TP/Cr > 600 mg/g (> 68 mg/mmol) and A/TP of < 0.3 had a high sensitivity and specificity to distinguish DD1 from both CKiD glomerular and tubulointerstitial cohorts. α1M/Cr ≥ 120 mg/g (> 13.6 mg/mmol) had the highest sensitivity and specificity when differentiating DD1 and studied CKiD populations.

Linking 24-h urines to clinical phenotypes: what alternatives does the future bring?

PURPOSE OF REVIEW: The 24-h urine test is recommended as part of the metabolic evaluation for patients with nephrolithiasis to guide preventive interventions. However, this test may be challenging to interpret and has limits in its predictive ability. In this review, we summarize and discuss the most recent research on the opportunities and challenges for utilizing urinary biomarkers for kidney stone prevention. RECENT FINDINGS: Contemporary studies utilizing the 24-h urine test have improved our understanding of how to better administer testing and interpret test results. Beyond the standard panel of 24-h urine parameters, recent applications of proteomics and metabolomics have identified protein and metabolic profiles of stone formers. These profiles can be assayed in future studies as potential biomarkers for risk stratification and prediction. Broad collaborative efforts to create large datasets and biobanks from kidney stone formers will be invaluable for kidney stone research. SUMMARY: Recent advances in our understanding of kidney stone risk have opened opportunities to improve metabolic testing for kidney stone formers. These strategies do not appear to be mutually exclusive of 24-h urine testing but instead complementary in their approach. Finally, large clinical datasets hold promise to be leveraged to identify new avenues for stone prevention.