Metformin ameliorates calcium oxalate crystallization and stone formation by activating the Nrf2/HO-1 signaling pathway: Two birds with one stone.

Deposition of calcium oxalate (CaOx) crystals and oxidative stress-induced injury of renal tubular epithelial cell are the primary pathogenic factors of nephrolithiasis. In this study we investigated the beneficial effects of metformin hydrochloride (MH) against nephrolithiasis and explored the underlying molecular mechanism. Our results demonstrated that MH inhibited the formation of CaOx crystals and promoted the transformation of thermodynamically stable CaOx monohydrate (COM) to more unstable CaOx dihydrate (COD). MH treatment effectively ameliorated oxalate-induced oxidative injury and mitochondrial damage in renal tubular cells and reduced CaOx crystal deposition in rat kidneys. MH also attenuated oxidative stress by lowering MDA level and enhancing SOD activity in HK-2 and NRK-52E cells and in a rat model of nephrolithiasis. In both HK-2 and NRK-52E cells, COM exposure significantlylowered the expressions of HO-1 and Nrf2, which was rescued by MH treatment even in the presence of Nrf2 and HO-1 inhibitors. In rats with nephrolithiasis, MH treatment significantly rescued the down-regulation of the mRNA and protein expression of Nrf2 and HO-1 in the kidneys. These results demonstrate that MH can alleviate CaOx crystal deposition and kidney tissue injury in rats with nephrolithiasis by suppressing oxidative stress and activating the Nrf2/HO-1 signaling pathway, suggesting the potential value of MH in the treatment of nephrolithiasis.

Alkalinizing Agents: A Review of Prescription, Over-the-Counter, and Medical Food Supplements.

Introduction: Kidney stones affect 1 in every 11 people in the United States each year. There is a significant high recurrence rate without a stone prevention protocol. Alkali citrate is beneficial in decreasing stone recurrence, but because of the cost and gastrointestinal side effects there is a low adherence rate. This study aims to serve as a review of some of the most commonly used alkalizing over-the-counter supplements that are advertised to prevent and treat kidney stones. Methods: Data were gathered by a comprehensive online literature search and company inquiries for kidney stone prevention supplements. An additional informal poll of the authors selected supplements that are most commonly taken by their patients. A total of eight supplements were evaluated for cost, alkali equivalent provided, dosing, and regulatory information. Results: Eight of the most commonly used supplements were reviewed with a focus on alkalizing agents. Information reviewed revealed dosing recommendations resulting in decreased citrate alkali equivalents per day compared with prescription-strength potassium citrate. Cost, peer-reviewed study results, and regulatory data were reviewed, tabulated, and analyzed. Cost per alkali equivalent was substantially decreased for each supplement compared with the prescribed drug. All supplements were found to be readily available online. Conclusion: Over-the-counter alkalizing agents are available to patients and may be an appropriate alternative to cost-prohibitive potassium citrate when treating urolithiasis patients. Additional testing will be necessary in the future to determine the efficacy of these supplements in the treatment and prevention of urinary stone disease.

Use of medical expulsive therapy in children: An assessment of nationwide practice patterns and outcomes.

INTRODUCTION: Early data support the use of medical expulsive therapy (MET) in children. However, little is known regarding use or outcomes associated with MET outside of pediatric-specific practices. Using a national administrative dataset, we sought to characterize utilization patterns of MET as well as assess outcomes associated with MET exposure. STUDY DESIGN: We interrogated the MarketScan Commercial Claims and Encounters database to identify children under the age of 18 presenting to the emergency department (ED) with any diagnosis of upper urinary tract calculi (UUTC, including renal and ureteral calculi). MET exposure was defined as having a prescription filled for a MET agent within 1 week of the ED encounter. Characteristics of children receiving MET were defined and outcomes compared between children with and without MET exposure. RESULTS: Of 1325 children included in the study, 13.2% received MET, including 15.4% of children with a diagnosis of "calculus of the ureter." MET use increased significantly throughout the study period (p = 0.004), although only 30.4% of children considered potential MET candidates received MET in the final year of the study (2013). Among all patients, receipt of MET was associated with male gender, presence of comorbidity, provider-type (urologist), and year of diagnosis, although among those with a specific diagnosis of "calculus of the ureter," only year of diagnosis remained a significant factor. Rates of unplanned physician visits and surgical interventions were similar between groups. Children receiving MET were more likely to receive follow-up imaging, although only 46% of children with ureteral calculi had appropriate follow-up imaging within 90 days, regardless of MET exposure. Odds ratios of factors and outcomes associated with MET exposure are shown in the Table. DISCUSSION: Although early data support safety and efficacy MET in children, nationwide use in children is low among potential candidates for MET. For children with ureteral calculi, only year of diagnosis was a significant factor associated with MET use. No difference in unplanned physician visits or surgical interventions was noted. Most notable, however, was the low rate of follow-up imaging within 90 days for children presenting acutely with UUTC. CONCLUSIONS: Use of MET for children with ureteral calculi is increasing, although still fewer than a third of children considered potential candidates receive this treatment. Follow-up imaging is not obtained for many children with ureteral calculi. Future work is needed to standardize management and follow-up protocols for children with acute renal colic.

Medical expulsive therapy versus early endoscopic stone removal for acute renal colic: an instrumental variable analysis.

PURPOSE: The use of medical expulsive therapy to hasten stone passage potentially decreases expenditures around episodes of renal colic. However, these efficiency gains may be mitigated if patients treated with medical expulsive therapy have frequent health care encounters due to pain while waiting for the stones to pass. MATERIALS AND METHODS: Using claims data (2002 to 2006) we identified adult men with acute renal colic. We compared 6-week payments as well as frequency of hospitalization and emergency department revisits associated with an initial course of medical expulsive therapy with those for early endoscopic stone removal. To account for unmeasured confounding we performed an instrumental variable analysis, exploiting variation in recommended treatments based on the day of the week that a patient's first emergency department visit occurred. RESULTS: Overall 1,835 and 4,397 men underwent medical expulsive therapy or early endoscopic stone removal, respectively. Although minimal differences existed between men with respect to the day of the week of emergency department presentation, weekend encounters were strongly associated with receiving medical expulsive therapy (p <0.001). Two-stage least squares regression revealed 6-week payments to be tenfold lower for men on medical expulsive therapy who were candidates for either treatment (p <0.001). While there was no difference in frequency of hospitalization, these men were more likely to have a repeat emergency department visit compared to those who underwent endoscopic stone removal (68.8% vs 39.6%, respectively, p = 0.025). CONCLUSIONS: Findings on medical expulsive therapy are mixed, with lower 6-week payments but more frequent repeat emergency department visits. These data inform patients who are candidates for medical expulsive therapy or endoscopic stone removal when making decisions about their care.

Renal calculi: emergency department diagnosis and treatment.

The acute treatment of kidney stones (urolithiasis) addresses pain management and focuses on the effects of the morbidity associated with an obstructed renal system. Minimal fluid intake, resulting in decreased urine production and a high concentration of stone-forming salts, is a leading factor in renal calculi development. Radio-opaque calcareous stones account for 70% to 75% of renal calculi. Microscopic hematuria in the presence of acute flank pain is suggestive of renal colic, but the absence of red blood cells does not exclude urolithiasis. Furthermore, many inflammatory and infectious conditions cause hematuria, demonstrating the low specificity of urinalysis testing. The diagnostic modality of choice is a noncontrast computed tomography (CT); ultrasonography s preferred in pregnant patients and children. Combining opioids with non-steroidal anti-inflammatory drugs (NSAIDs) is the optimal evidence-based regimen to treat severe symptoms. Rapid intravenous (IV) hydration has not shown a benefit. Potentially life-threatening diagnoses including abdominal aortic aneurysm, ovarian torsion, and appendicitis may mimic renal colic and must be ruled out.

In vivo 31P-MRS assessment of muscle-pH, cytolsolic-[Mg2+] and phosphorylation potential after supplementing hypokaliuric renal stone patients with potassium and magnesium salts.

Renal stone patients in rural northeast Thailand have a low potassium and magnesium status and low urinary excretion of citrate. We measured the changes of urinary citrate excretion and assessed in vivo skeletal muscle metabolism for intracellular-pH, cytosolic-[Mg(2+)] and phosphorylation potential (using the phosphorus magnetic resonance spectroscopy (31)P-MRS) after oral supplementation to hypokaliuric renal stone patients with oral potassium and magnesium salts. The patients comprised four groups: Group 1 (n = 10) control, Group 2 (n = 3), Group 3 (n = 5) and Group 4 (n = 6) supplemented for a month with potassium citrate, potassium citrate plus amino acid chelated magnesium, and potassium-magnesium citrate, respectively. Though urinary citrate excretion was increased in all three supplemented groups, the increases in intracellular-pH, cytosolic-[Mg(2+)] and phosphocreatine (PCr)/beta-ATP were prominent only in Group 3. The increase in PCr/beta-ATP was also observed in Group 4.

Management of calcium oxalate stones.

This article discusses the incidence and prevalence of calcium oxalate renal stones. Etiology and risk factors for all renal stone formation are reviewed. The evaluation, diagnostic procedures, and management for new and recurrent stone formation are detailed. Management includes long-term pharmacologic and nonpharmacologic measures for successful prevention or reduction in the frequency of recurrent stones. Specific patient education factors, patient and family psychological aspects, and referral resources are discussed.

Propensity for spontaneous nucleation of calcium oxalate. Quantitative assessment by urinary FPR-APR discriminant score.

The stone-forming urinary environment may be conducive to spontaneous nucleation of calcium salts, since it is generally characterized by a reduced limit of metastability (FPR or minimum supersaturation required for initiation of spontaneous nucleation) and an increased saturation (APR) of calcium oxalate and brushite (CaHPO4.2H2O). A discriminant analysis of the relationship between FPR and APR yielded a FPR-APR discriminant score, which gave a quantitative measure of the propensity for spontaneous nucleation. Positive scores, indicative of the "likelihood" of spontaneous nucleation, were found in the majority of patients with hypercalciuria in whom stones formed. Negative scores, representative of the "unlikelihood" of nucleation, were found in the majority of control subjects. Treatment with thiazide or sodium cellulose phosphate significantly reduced the discriminant score for both calcium oxalate and brushite, a finding which suggested that the propensity for spontaneous nucleation of calcium salts was retarded. Allopurinol lowered the score for calcium oxalate but not for brushite. Moreover, the FPR-APR discriminant score for calcium oxalate was positively correlated with the stone formation rate. It is concluded that FPR-APR discriminant scores are useful in the identification of stone-forming potential in urine, and in the assessment of response to therapy.