Effect of potassium depletion on urinary stone risk factors in Wistar rats

Various studies have suggested that potassium depletion leads to acidosis and hypocitraturia. In Northeastern Thailand, for example, mild hypokalemia and mild hyperoxaluria are observed in most stone formers. However, there are limited reports about the direct link between potassium depletion and the formation of urinary stones, most of which are calcium oxalate stones. Therefore, we studied the direct effect of potassium depletion on the risk factors for calcium oxalate stone formation. Seventy-two rats were fed a control diet or a potassium-deficient diet for 1, 2, or 3 weeks (n = 12 per group). Twenty-four-hour urine collection was done for the measurement of potassium, calcium, oxalate, glycolate, citrate, phosphorus, and magnesium. Lactate dehydrogenase activity was also measured in order to assess renal tubular damage, and kidneys were harvested for histological examination. Furthermore, urinary supersaturation of calcium oxalate was calculated. With potassium depletion, the urinary concentrations of potassium, citrate, magnesium, and phosphorus decreased rapidly. There was no detectable renal damage, renal calcium deposition, and no significant increase of urinary oxalate or calcium. However, the urinary supersaturation index of calcium oxalate increased significantly in rats with potassium depletion. These findings indicate that potassium deficiency may increase the risk of stone formation through enhanced supersaturation.     

Effects of potassium-magnesium citrate supplementation on cytosolic ATP citrate lyase and mitochondrial aconitase activity in leukocytes: A window on renal citrate metabolism

BACKGROUND: An increase in urinary citrate excretion is associated with a decrease in activity of renal cortical cytosolic ATP citrate lyase (ACL) and mitochondrial aconitase (m-aconitase). Because potassium-magnesium citrate causes an increase in urinary citrate excretion, we decided to assess its effects on ACL and m-aconitase in the leukocytes of renal stone patients. METHODS: Twenty male renal stone patients were supplemented with potassium-magnesium citrate twice daily (i.e. 42 mEq potassium, 21 mEq magnesium, and 63 mEq citrate per day) for a period of 1 month. Two 24-h urine and one 15-mL heparinized blood samples were collected from each patient before and after supplementation. Urine samples were analyzed for relevant biochemical compositions. Leukocytes were separated from blood samples by centrifugation and assayed for ACL and m-aconitase activity. RESULTS: Supplementation with potassium-magnesium citrate significantly increased urinary pH (P < 0.005) and excretions of potassium (P < 0.001), magnesium (P < 0.001) and citrate (P < 0.0001). The activity of both ACL and m-aconitase were significantly decreased (P < 0.004 and P < 0.02 respectively). The decrease in ACL activity was inversely correlated with an increase in urinary excretion of both potassium (r = -0.620, P < 0.0001) and citrate (r = -0.451, P < 0.004). A similar inverse correlation was observed between m-aconitase activity and urinary excretion of citrate (r = -0.322, P < 0.043). CONCLUSION: Changes in enzyme activity, related to citrate metabolism in leukocytes, might reflect the status of renal tubular cells.     

Renal function in pediatric patients with β-thalassemia major

In patients with β-thalassemia major, the most important cause of mortality and morbidity is organ failure due to deposits of iron.. In this study, the nature of the kidney injury and possible pathogenetic factors were investigated. Seventy children with β-thalassemia major and 14 age and sex-matched healthy children were involved in the study. Blood and timed urine samples were obtained for hematological and biochemical tests. The mean values of blood urea nitrogen (BUN), serum creatinine, creatinine clearance, serum sodium, urine osmolality, fractional excretion of sodium, potassium, and uric acid were not statistically different between the groups. Serum levels of potassium, phosphorus, and uric acid and the urine volume, high urinary protein to creatinine (U_P/Cr), urinary N-acetyl-β-d-glucosaminidase to creatinine (U_NAG/Cr), and urinary malondialdehyde to creatinine, (U_MDA/Cr) and the tubular phosphate reabsorption (TRP) values were statistically different between two groups (P<0.05). Increased serum levels of potassium, phosphorus, and uric acid in the patient group were attributed to the rapid erythrocyte turnover. The presence of high U_P/Cr, U_NAG/Cr and U_MDA/Cr ratios shows that in these patients with proximal renal tubular damage may be secondary to oxidative lipid peroxidation mediated by the iron overload. Received: 30 September 1999 / Revised: 19 May 2000 / Accepted: 22 May 2000     

Effect of extracorporeal shock wave lithotripsy on renal function-an experience with the new type piezoelectric lithotripter, Therasonic

Seventeen patients with renal stones and 17 patients with ureteral stones were treated using the newly developed piezoelectric shock wave lithotripter, THERASONIC. To determine the effect of shock wave on renal function, urinary N-acetyl-beta-D-glucosaminidase (NAG) activity, urinary beta 2 microglobulin (BMG) concentration, serum BMG concentration and creatinine clearance (Ccr) were measured. Urinary NAG activity and urinary BMG concentration in renal stone patients were significantly elevated immediately after the treatment and returned to the pretreatment value within 24 hours. Neither serum BMG nor Ccr showed significant change in any of the patients. Therefore, we conclude that the renal tubular damage, which is transient and subtle, is the effect of shock wave lithotripsy using THERASONIC machine.     

Lithogenic activity and clinical relevance of lipids extracted from urines and stones of nephrolithiasis patients

We investigated contents and classes of urinary and stone matrix lipids, and evaluated their clinical relevance in nephrolithiasis patients. Lithogenic role of major lipid classes was explored. Urine (24 h) and stone samples were collected from 47 patients with nephrolithiasis. Control urines were obtained from 29 healthy subjects. Urinary 8-hydroxy-deoxyguanosine (8-OHdG), malondialdehyde (MDA), N-acetyl-β-glucosaminidase (NAG) activity and total proteins were measured. Total lipids were extracted from centrifuged urines (10,000 rpm, 30 min) and stones by chloroform/methanol method. Major classes of lipids were identified using multi-one-dimensional thin-layer chromatography (MOD-TLC). Influence of each lipid class purified from stone matrices on stone formation was evaluated using crystallization and crystal aggregation assays. Urinary NAG activity and 8-OHdG were significantly elevated in nephrolithiasis patients. Total lipids in centrifuged urines of the patients were not significantly different from that of controls. In nephrolithiasis, urinary excretion of total lipids was linearly correlated to urinary MDA, 8-OHdG, NAG activity and total proteins. Lipid contents in stone matrices varied among stone types. Uric acid stone contained lower amount of total lipids than calcium oxalate and magnesium ammonium phosphate stones. MOD-TLC lipid chromatograms of healthy urines, nephrolithiasis urines and stone matrices were obviously different. Triacylglyceride was abundant in urines, but scarcely found in stone matrices. Stone matrices were rich in glycolipids and high-polar lipids (phospholipids/gangliosides). Partially purified glycolipids significantly induced crystal aggregation while cholesterol was a significant inducer of both crystal formation and agglomeration. In conclusion, total lipids in centrifuged urines did not differ between nephrolithiasis and healthy subjects. Our finding suggests that the significant sources of lipids in patients’ urine may be large lipids-containing particles, which are removed in centrifuged urines. However, urinary lipid excretion in nephrolithiasis patients was associated with the extent of oxidative stress and renal tubular injury. Triacylglyceride was abundant in urines, but rarely incorporated into stones. Glycolipids were principal lipid constituents in stone matrices and functioned as crystal aggregator. Cholesterol purified from stone matrices bared crystal nucleating and aggregating activities.     

Magnesium status of patients with renal stones and its effect on urinary citrate excretion

OBJECTIVES: To assess the magnesium status and its effect on urinary citrate excretion in patients with renal stones, as they have a low muscular magnesium content. PATIENTS, SUBJECTS AND METHODS: Using a magnesium-tolerance test (0.1 mmol/L MgSO4/kg body weight, delivered intravenously), the magnesium status was assessed in 17 patients with renal stones from rural North-east Thailand, and in three groups of normal subjects from different environments (i.e. 17 from rural Central Thailand, 16 from urban and 14 from rural North-east Thailand). Participants with magnesium deficiency (magnesium retention > 50%) were supplemented with 300 mg chelated magnesium daily for 1 month and reassessed. Their urinary citrate excretion was also measured before and after supplementation. RESULTS: Nine of the patients with renal stones were magnesium deficient, as were six normal subjects from the same area, whereas only one and two of the rural Central and urban North-east Thais had magnesium deficiency. The magnesium status of the 13 deficient subjects significantly improved (P = 0.003) after supplementation with chelated magnesium. The supplement also caused a significant increase in mean (sd) urinary citrate excretion, from 237.7 (173.1) to 361.3 (284.1) mg/day (P= 0.012). CONCLUSIONS: These results indicate that magnesium deficiency is common among patients with renal stones in rural North-east Thailand, and that the probable cause is environmental. The increase in urinary citrate excretion after magnesium supplementation suggests that magnesium is important in renal stone formation, through its effect on citrate metabolism.     

Urinary excretion of citrate, glycosaminoglycans, magnesium and zinc in relation to age and sex in normal subjects and in patients who form calcium stones.

One hundred and ninety-seven healthy subjects and 104 patients with idiopathic calcium stone disease had their urinary excretion of citrate, glycosaminoglycans, magnesium, and zinc measured and the results correlated with sex and age. In normal subjects the daily excretion of citrate, magnesium, and zinc increased with age to a maximum during the fifth decade and remained relatively constant until the eighth decade when they decreased. The daily excretion of magnesium and zinc were higher in men than in women, which was attributed to the higher body weights of the men. The urinary excretion of citrate, magnesium, and zinc related to creatinine remained relatively constant with age in adult life; analyses of magnesium and zinc excretion rates divided by urine creatinine did not distinguish men from women. There was no significant difference between men and women for citrate excretion in 24 hour urine, but the citrate:creatinine ratio was significantly higher in women than men. The higher citrate excretion in women may explain the lower incidence of calcium stones in women. The highest glycosaminoglycan excretion rates were seen during the first two decades which is why children and teenagers are less prone to develop calcium stones in spite of high urinary calcium concentrations. Urinary citrate and magnesium excretion were lower, and glycosaminoglycan and zinc excretion were higher, in stone formers than in controls. It seems that a decreased excretion of citrate and magnesium together with an increased excretion of calcium, may contribute to the formation of calcium stones. The role of urinary glycosaminoglycans and zinc in the formation of calcium stones remains uncertain.     

Prevention of recurrent calcium stone formation with potassium citrate therapy in patients with distal renal tubular acidosis

Distal renal tubular acidosis is a common cause of intractable calcium nephrolithiasis. We examined the effect of oral potassium citrate therapy in 9 patients with incomplete distal renal tubular acidosis diagnosed on the basis of an abnormal response to an oral ammonium chloride load. Patients were studied during a control phase and after 3 months of potassium citrate treatment (60 to 80 mEq. daily). Potassium citrate caused a significant increase in urinary pH and urinary citrate, and a decrease in urinary calcium. The urinary relative saturation ratio of calcium oxalate significantly decreased during treatment, while that of brushite did not change. Potassium citrate also was shown to inhibit new stone formation. During a mean treatment period of 34 months none of the 9 patients had new stones, although 39.3 plus or minus 79.7 (standard deviation) stones per patient formed during the 3 years preceding treatment. The results support the potential clinical advantage of potassium citrate therapy in patients with distal renal tubular acidosis and recurrent calcium nephrolithiasis.     

Urinary 8-hydroxydeoxyguanosine is elevated in patients with nephrolithiasis

8-hydroxydeoxyguanosine (8-OHdG) is an oxidatively modified guanosine, which has been widely used as an oxidative DNA damage marker in various diseases. The present study aimed to determine urinary 8-OHdG in nephrolithiasis patients and evaluate its clinical significance. Thirty-six nephrolithiasis patients and 30 healthy subjects were recruited. Urine volume, creatinine, malondialdehyde, β-N-acetylglucosaminidase (NAG) activity and proteins were measured in 24 h urine samples. Urinary 8-OHdG was determined by competitive enzyme-linked immunosorbent assay. Mineral composition of stones was analyzed using Fourier-transformed infrared spectroscopy. Nephrolithiasis patients excreted urinary 8-OHdG significantly higher than healthy controls. Urinary 8-OHdG levels compared among patients with calcium oxalate, struvite and uric acid stones were insignificantly different. The urinary NAG activity correlated positively with urinary 8-OHdG. Multiple linear regression showed that urinary NAG activity was an independent predictor of urinary 8-OHdG level. Receiver operating characteristic analysis revealed that the urinary 8-OHdG test was adequate for diagnosing nephrolithiasis. At 10 μg/g creatinine cutoff, the 8-OHdG test imparted high specificity (96.67%) and a positive predictive value (91.67%). In conclusion, this is the first report of elevated urinary 8-OHdG excretion in nephrolithiasis patients indicating increased oxidative DNA damage. Increased renal tubular damage was independently associated with elevated urinary 8-OHdG. Elevated urinary 8-OHdG levels adjunct with metabolic profile may be useful for identifying people at risk of stone development.     

Risk factors for developing renal stones in inflammatory bowel disease

OBJECTIVE: To correlate renal calculi and other clinical factors with urinary biochemical analytes in patients with inflammatory bowel disease, and to investigate the relative importance of hyperoxaluria (associated with fat malabsorption) or reduced stone inhibitors in the development of calculi in these patients. PATIENTS, SUBJECTS AND METHODS: Samples were obtained from 25 patients with Crohn's disease (CD), 15 with ulcerative colitis (UC) and 17 normal subjects (controls). Evidence for the presence of renal calculi was obtained from plain films, ultrasonography or intravenous urography. Urine oxalate and citrate were analysed using commercial enzymatic assays; magnesium was measured using atomic absorption and other analytes assayed using standard methods on automated analysers. RESULTS: Renal calculi were found in two patients with CD and in none with UC. Hyperoxaluria was present in 36% of patients with CD but was absent in those with UC. Analysis of covariance showed an association between low urinary citrate/creatinine ratio and renal stones (P=0.02), and between a combined urinary citrate and magnesium deficit relative to calcium, as expressed in the CMC index ((citratexmagnesium)/calcium), and renal stones (P=0.017). Changes in urinary calcium, oxalate, urate, magnesium or the calcium oxalate index were not associated with the presence of stones. There was no independent relationship between any clinical factor and the presence of stones. CONCLUSION: Lower urinary concentrations of magnesium and citrate (stone inhibitors), relative to calcium (stone promoter; the CMC index) may be more important in lithogenesis in inflammatory bowel disease than is hyperoxaluria. In patients with a functioning colon, a low CMC index may predict likely stone-formers; this requires a prospective evaluation. Avoiding low urinary levels of magnesium and citrate may aid in preventing and treating renal calculi.