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.

The ability of a limited metabolic assessment to identify pediatric stone formers with metabolic abnormalities.

INTRODUCTION: American Urological Association guidelines recommend a urinary metabolic evaluation after the first stone event in all pediatric stone patients. Prior studies identified hypercalciuria and urine hypovolemia as the most common abnormalities in children with urolithiasis. Recent data suggest that hypocitraturia is most prevalent. It was hypothesized that a limited evaluation would detect the majority of clinically significant metabolic abnormalities in pediatric stone formers. MATERIAL AND METHODS: A retrospective analysis of all children (<18 years of age) with renal/ureteral calculi evaluated at the study institution from 2005 to 2015 was performed. Children with ≥ one 24-h urinary metabolic profile after a clinical visit for renal/ureteral calculi were included. Those with bladder stones and those with undercollection or overcollection or missing urinary creatinine were excluded. Demographics and data from the first urinary metabolic profile and stone analyses were collected. The sensitivity, specificity, and positive and negative predictive value (NPV) of a limited urinary metabolic evaluation consisting of four parameters (24-h calcium, citrate, and oxalate and low urinary volume) were compared to a complete urinary metabolic profile. The number and type of metabolic abnormalities that would have been missed with this limited evaluation weredetermined. RESULTS: Of 410 patients, 21 were excluded for age ≥18 years, 13 for bladder stones, 248 for overcollections, 38 for undercollections, and 10 for missing creatinine. This left 80 patients for inclusion: median age 11.4 years, 60% female, and 96.3% white. Of the entire cohort, 69.6% had hypocitraturia, 52.5% had low urine volume, and 22.5% had hypercalciuria. Sensitivity was 87.5%. Specificity could not be calculated because no patients had a normal complete metabolic evaluation. The NPV was zero, and the positive predictive value was 100%, but these are artifacts resulting from the absence of patients with a normal complete metabolic evaluation. Of the 80 patients, 10 had at least one abnormality missed by a limited metabolic evaluation (Table 1). The missed abnormalities were high pH (n = 6), abnormal 24-h phosphorus (low in 1 patient and high in 1 patient), low 24-h magnesium (n = 3), low 24-h potassium (n = 3), and high 24-h sodium (n = 4). DISCUSSION: A limited urinary metabolic evaluation would have detected the vast majority of clinically significant metabolic abnormalities in the study sample. Approximately two-thirds of the study patients submitted inadequate 24-h urine specimens. CONCLUSIONS: A simplified approach to metabolic evaluation in first-time stone formers with a stone analysis available was proposed. This streamlined approach could simplify the metabolic evaluation and reduce health care costs.

Assessment of Urinary Inhibitor or Promoter Activity in Uric Acid Nephrolithiasis.

PURPOSE: We assessed decreased inhibitor activity or increased promoter activity in the urine of idiopathic uric acid stone formers compared to nonstone formers independent of urinary pH. MATERIALS AND METHODS: A total of 30 idiopathic uric acid stone formers, and 9 obese and 12 lean nonstone formers collected 24-hour urine while on a metabolic diet. Three urine aliquots per subject were used to assess spontaneous nucleation (de novo crystal formation), crystal growth using a 0.1 mg/ml anhydrous uric acid seed and steady-state uric acid solubility (the maximum amount of uric acid dissolvable in urine) using a 5 mg/ml uric acid seed. All experiments were performed for 6 hours at a constant pH of 5.0. Uric acid concentration was measured in filtered aliquots at 0, 3 and 6 hours. RESULTS: At baseline 24-hour urinary pH was significantly lower and uric acid saturation was significantly higher in idiopathic uric acid stone formers. No significant spontaneous nucleation developed and similar uric acid steady-state solubility was reached in the 3 groups. Idiopathic uric acid stone formers and lean nonstone formers showed a similar decrease in uric acid concentration during crystal growth. Obese nonstone formers started with a higher uric acid concentration and consequently demonstrated a greater decrease in the uric acid concentration for crystal growth. CONCLUSIONS: This study suggests that there is no significant difference between idiopathic uric acid stone formers and nonstone formers in promoter or inhibitor activity in whole urine against uric acid stone formation when urine pH is maintained constant. The findings suggest that uric acid stone formation is dictated by high urinary saturation with respect to uric acid, which is driven primarily by low urine pH.

Effect of percutaneous nephrolithotripsy on renal function: assessment with quantitative SPECT of (99m)Tc-DMSA renal scintigraphy.

PURPOSE: To measure the effect of PCNL on global and regional renal function using quantitative single-photon emission CT (SPECT) measurement of Tc-dimercaptosuccinic acid (DMSA) uptake by the kidneys (QDMSA). PATIENTS AND METHODS: A series of 47 male and 41 female patients with a mean age of 47 +/- 16 years were studied by sequential QDMSA examinations before and 1.5 to 24 months after PCNL. Among the 67 patients (76%) in whom PCNL was performed using upper- or lower-pole access, the function of the affected and nonaffected poles of the treated kidney was calculated separately. RESULTS: There was no statistically significant difference in the uptake by the treated kidneys before versus after PCNL (11.9% +/- 5% v 11.6% +/- 5%; t = 0.9; P = 0.368). The total functional volume of the treated kidney was slightly decreased, from 235 cc +/- 62 cc to 224 cc +/- 59 cc (t = 2.7; P = 0.011). The percent of the injected isotope dose per cubic centimeter of tissue of the treated kidney was not affected (0.051 +/- 0.02 v 0.053 +/- 0.02; t = 0.86; P = 0.296). Regional assessment revealed a statistically significant decrease in the functional volume at the PCNL port of entry (91 cc +/- 30 cc v 82 cc +/- 27 cc; t = 2.64; P = 0.013). Regarding the percent of the injected dose per cubic centimeter of renal tissue, no statistically significant difference was found between the area of the kidney that underwent PCNL and the untreated area of the same kidney (0.049 +/- 0.02 v 0.05 +/- 0.02; t = 0.693; P = 0.494). The function of the contralateral kidneys remained unchanged (13.4% +/- 5.2% v 13.6% +/- 4.8%; t = 0.68; P = 0.5). CONCLUSIONS: Despite the statistically significant decrease in the functional volume of the surgically treated region, neither total percent uptake nor percent of injected dose were reduced significantly. Further studies with long-term follow-up of treated kidneys are required.

Assessment of oxalate absorption from almonds and black beans with and without the use of an extrinsic label.

PURPOSE: Oxalate bioavailability is an important determinant of whether the consumption of a particular food is a high risk in individuals predisposed to kidney stones. We estimated and compared oxalate absorption from a high oxalate containing legume (black beans) and a high oxalate containing nut (almonds). We also compared an isotope method using extrinsically labeled oxalate and an oxalate load method to assess oxalate absorption. MATERIALS AND METHODS: Six male and 5 female subjects participated in the 4 oxalate load tests, namely almonds, almonds with 20 mg C2-oxalic acid, black beans and black beans with 20 mg C2-oxalic acid. Each treatment provided a total of 120 mg oxalate, after which timed urine samples were collected for the analysis of oxalate, calcium and creatinine. RESULTS: Average oxalate absorption from the 2 almond treatments (5.9%) using the oxalate load method was significantly higher than that from the 2 black bean treatments (1.8%) during the 24-hour post-oxalate load collection period. In contrast, C2-oxalic acid absorption from the almond (7.9%) and black bean (8.6%) treatments did not significantly differ. CONCLUSIONS: The higher oxalate absorption from almonds than from black beans suggests that the relative amount of soluble and insoluble oxalate in food has an important role in the determination of oxalate absorption. Since extrinsically provided C2-oxalate and oxalate naturally occurring in the high oxalate test foods appeared to be differentially absorbed, the data do not support the use of extrinsically labeled oxalate to assess food oxalate absorption.

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.

Renal stone risk assessment during Space Shuttle flights.

PURPOSE: The metabolic and environmental factors influencing renal stone formation before, during, and after Space Shuttle flights were assessed. We established the contributing roles of dietary factors in relationship to the urinary risk factors associated with renal stone formation. MATERIALS AND METHODS: 24-hr. urine samples were collected prior to, during space flight, and following landing. Urinary and dietary factors associated with renal stone formation were analyzed and the relative urinary supersaturation of calcium oxalate, calcium phosphate (brushite), sodium urate, struvite and uric acid were calculated. RESULTS: Urinary composition changed during flight to favor the crystallization of calcium-forming salts. Factors that contributed to increased potential for stone formation during space flight were significant reductions in urinary pH and increases in urinary calcium. Urinary output and citrate, a potent inhibitor of calcium-containing stones, were slightly reduced during space flight. Dietary intakes were significantly reduced for a number of variables, including fluid, energy, protein, potassium, phosphorus and magnesium. CONCLUSIONS: This is the first in-flight characterization of the renal stone forming potential in astronauts. With the examination of urinary components and nutritional factors, it was possible to determine the factors that contributed to increased risk or protected from risk. In spite of the protective components, the negative contributions to renal stone risk predominated and resulted in a urinary environment that favored the supersaturation of stone-forming salts. Dietary and pharmacologic therapies need to be assessed to minimize the potential for renal stone formation in astronauts during/after space flight.

[Nephrolithiasis--rational etiological assessment]. / Nephrolithiasis--Sinnvolle ätiologische Abklärungen.

Although underlying metabolic abnormalities do not differ fundamentally in patients with either first or recurrent nephrolithiasis and 35% of patients with a first event may have to face a recurrence 5 years later, extended metabolic investigations in patients with a first renal calculus should be restricted to particular, exceptional cases. However, in patients with a first calculus basic investigations with respect to specific causes for a concrement such as primary hyperparathyroidism, incomplete renal-tubular acidosis, recurrent urinary tract infection and cystinuria are mandatory. This includes, in addition to a laboratory investigation of blood and urine after a 2-hour-fasting period, analysis of the stone and a urography. The extended metabolic investigation in patients with recurrences or a first occurrence in a patients with a risk constellation includes evaluation of the most important lithogenic (calcium, oxalate, phosphate, uric acid) and inhibiting components (citrate) in the 24-hour urine, in patients with cystine calculi quantitation of cystine. A metabolic investigation should never be undertaken in the hospital or under standardized diet, but always under accustomed, unrestricted nutrition. At least 2 urine samples should be investigated from each patient, preferably not prior to 3-4 months after the event when homeostasis of the patient is restored analogously to the onset of concrement development.

Outpatient metabolic evaluation of patients with recurrent kidney stones.

We have designed an outpatient, comprehensive metabolic evaluation program for patients with recurrent kidney stone disease. This protocol can be expected to detect and identify specific biochemical abnormalities contributing to kidney stone formation in about 95% of these patients. Individualized therapy can then be started based on the particular metabolic defect discovered in each patient. This diagnostic and treatment program will stop new kidney stone formation in these high-risk patients virtually completely. For each stone-related hospitalization eliminated, the average savings are at least $2,700. The total potential savings in our small community alone are over $460,000! Our metabolic stone evaluation protocol is the only one with which we are familiar that was designed and implemented exclusively at the community hospital level. It is readily adaptable to other medical facilities.