Proteomic analysis of kidney in rats chronically exposed to monosodium glutamate.

BACKGROUND: Chronic monosodium glutamate (MSG) intake causes kidney dysfunction and renal oxidative stress in the animal model. To gain insight into the renal changes induced by MSG, proteomic analysis of the kidneys was performed. METHODS: Six week old male Wistar rats were given drinking water with or without MSG (2 mg/g body weight, n = 10 per group) for 9 months. Kidneys were removed, frozen, and stored at -75°C. After protein extraction, 2-D gel electrophoresis was performed and renal proteome profiles were examined with Colloidal Coomassie Brilliant Blue staining. Statistically significant protein spots (ANOVA, p<0.05) with 1.2-fold difference were excised and analyzed by LC-MS. Proteomic data were confirmed by immunohistochemistry and Western blot analyses. RESULTS: The differential image analysis showed 157 changed spots, of which 71 spots were higher and 86 spots were lower in the MSG-treated group compared with those in the control group. Eight statistically significant and differentially expressed proteins were identified: glutathione S-transferase class-pi, heat shock cognate 71 kDa, phosphoserine phosphatase, phosphoglycerate kinase, cytosolic glycerol-3-phosphate dehydrogenase, 2-amino-3-carboxymuconate-6-semialdehyde decarboxylase, α-ketoglutarate dehydrogenase and succinyl-CoA ligase. CONCLUSION: The identified proteins are mainly related to oxidative stress and metabolism. They provide a valuable clue to explore the mechanism of renal handling and toxicity on chronic MSG intake.

Personalized tacrolimus doses determined by CYP3A5 genotype for induction and maintenance phases of kidney transplantation.

BACKGROUND: Cytochrome P450 (CYP) 3A4 and 3A5 are major isoforms involved in the metabolism of tacrolimus, with the CYP3A5 gene being more polymorphic. It is hypothesized that individual variation in the metabolism of tacrolimus drug may result from genetic polymorphism of CYP3A5. It has been reported that the clearance of tacrolimus in patients with the CYP3A5*1 allele was ~2.5-fold greater than that in those with the CYP3A5*3/*3 genotype. Recent data have also shown that polymorphism in exon 26 (C3435T) of the multidrug resistance gene (MDR1) was correlated with the expression level and function of P-glycoprotein in the lower duodenum, making the relationship between polymorphism of MDR1 and the effective dose of tacrolimus a source of controversy. OBJECTIVES: This study investigated the influence of genetic polymorphisms of CYP3A5 and MDR1 on the dose requirements for the induction and maintenance phases of tacrolimus therapy in kidney transplant recipients. METHODS: Sixty-eight kidney transplant recipients were enrolled, and their clinical and laboratory data were retrospectively reviewed after 6 months of tacrolimus administration. Genotypes of CYP3A5*1 and CYP3A5*3 and exon 26 of MDR1 (C3435T) were determined by the single-nucleotide polymorphism genotyping method. RESULTS: The frequencies of CYP3A5*3/*3, CYP3A5*1/*3, and CYP3A5*1/*1 were 44.1%, 35.3%, and 20.6%, respectively. The mean dose of tacrolimus required for the induction phase was significantly greater in the CYP3A5*1/*1 group (0.142 [0.050] mg/kg/d) than that required in the CYP3A5*1/*3 group (0.097 [0.040] mg/kg/d; P = 0.072) and in the CYP3A5*3/*3 group (0.077 [0.020] mg/kg/d; P = 0.005). The maintenance dose of tacrolimus required in the CYP3A5*1/*1 group (0.12 [0.03] mg/kg/d) was 1.3-fold higher than that in the CYP3A5*1/*3 group (0.09 [0.03] mg/kg/d; P = 0.018) and 2.4-fold higher than in the CYP3A5*3/*3 group (0.05 [0.02] mg/kg/d; P < 0.0001). No statistically significant relationship was observed between the doses of tacrolimus required for the induction and maintenance phases and MDR1 polymorphism. CONCLUSION: Determination of the CYP3A5 genotype would be helpful in the design of adequate immunosuppressive treatment and in lowering toxicity by predicting the doses of tacrolimus required for the induction and maintenance phases in individual kidney transplant recipients.

Monosodium glutamate (MSG) consumption is associated with urolithiasis and urinary tract obstruction in rats.

BACKGROUND: The peritoneal injection of monosodium glutamate (MSG) can induce kidney injury in adult rats but the effects of long-term oral intake have not been determined. METHODS: We investigated the kidney histology and function in adult male Wistar rats that were fed ad libitum with a standard rat chow pellet and water with or without the addition of 2 mg/g body weight MSG/day in drinking water (n=10 per group). Both MSG-treated and control animals were sacrificed after 9 months when renal function parameters, blood and urine electrolytes, and tissue histopathology were determined. RESULTS: MSG-treated rats were more prone to kidney stone formation, as represented by the alkaline urine and significantly higher activity product of calcium phosphate. Accordingly, 3/10 MSG-treated rats developed kidney stones over 9 months versus none of the control animals. Further, 2/10 MSG-treated rats but none (0/10) of the controls manifested hydronephrosis. MSG-treated rats had significantly higher levels of serum creatinine and potassium including urine output volume, urinary excretion sodium and citrate compared to controls. In contrast, MSG-treated rats had significantly lower ammonium and magnesium urinary excretion. CONCLUSION: Oral MSG consumption appears to cause alkaline urine and may increase the risks of kidney stones with hydronephrosis in rats. Similar effects in humans must be verified by dedicated studies.

Disease patterns among Thai adult population: an analysis of data from the hospitalization National Health Insurance System 2010.

BACKGROUND: Disease pattern is an important informational tool used by policymakers in setting priorities, strategies and allocating budgets to address the precursors or causes of health problems. OBJECTIVE: To analyze the common diseases in the adult population using in-patient information from the three health insurance coverage schemes in the fiscal year 2010. MATERIAL AND METHOD: The authors analyzed the data on in-patients with 23 major disease groups as per ICD-10 coding. The data were analyzed to obtain the number of patients, number of admissions, number of hospital mortalities, mortality rates and length of hospital stays. RESULTS: The total number of adult in-patients was 3,876,792 presenting for admission 4,863,935 times. Infectious and parasitic diseases were the most common causes of admission. Diseases of the circulatory system resulted in the highest number of mortality rate (8.72%). Intracerebral hemorrhage, neoplasm, septicemia, liver failure, coronary heart disease, HIV/AIDS, status epilepticus, pneumonia, accidents and acute renal failure were the top ten diseases with a high mortality rate. CONCLUSION: The review indicated communicable diseases are the most common disease group although non-communicable diseases were also important because of their high mortality rate.

Health insurance system and healthcare provision: nationwide hospital admission data 2010.

BACKGROUND: The three major health insurance systems are different in their medical service coverage, reimbursement process and choice of providers; leading to the question of how great are the variations in the healthcare offered and disease outcomes. OBJECTIVE: To assess whether differences exist and to analyze the effects of on healthcare provision and disease outcomes in the adult population across the three health insurance systems. MATERIAL AND METHOD: The authors analyzed the disease outcomes of the 23 major ICD-10 disease groups among the three major health insurance systems to obtain the death rates, levels of healthcare provision and the hospital charges. Factors influencing mortality rates were evaluated by multiple logistic regression analysis. RESULTS: The community, general, tertiary care and private hospitals provided hospitalization for 41.4%, 22%, 27.3% and 9.3% of hospitalized adult patients, respectively. Infectious & parasitic diseases were the most common causes of admissions. Disease of the digestive system was the most common cause of admission in general hospitals while malignancy was the most common in the tertiary care hospitals. Patients with congenital malformation, neoplasm, mental and behavioral disorder and diseases of the eye were commonly treated at tertiary care hospitals. The mean and median of hospital charges were highest in the Civil Servant Medical Benefit System (CSMBS) (26,668; 10,209 Baht), followed by the Social Security System (SSS) (21,455; 9,713 Baht) and the Universal Coverage System (UC) (13,086; 5,246 Baht). The respective overall mortality rates for the CSMBS, SSS and UC were 4.40%, 1.38% and 3.32%. After adjustment, however a significant association between UC and mortality was found with an odds ratio of 1.43 (1.40-1.45) as compared to CSMBS. In addition, other factors most influencing mortality rates were male sex, elderly age, and the levels of healthcare. CONCLUSION: The differences in charges for some groups of diseases and significantly different clinical outcomes across schemes existed. The differences in disease outcomes were not adjusted for socioeconomic status and disease severity, requiring a cautious interpretation; nevertheless, an association with a higher mortality rate under the UC scheme for inpatient services need prompt further study

Comparison of free fructose and glucose to sucrose in the ability to cause fatty liver.

BACKGROUND: There is evidence that disaccharide sucrose produce a greater increase in serum fructose and triglycerides (TGs) than the effect produced by their equivalent monosaccharides, suggesting that long-term exposure to sucrose or fructose + glucose could potentially result in different effects. AIM OF THE STUDY: We studied the chronic effects of a combination of free fructose and glucose relative to sucrose on rat liver. METHODS: Rats were fed either a combination of 30% fructose and 30% glucose (FG) or 60% sucrose (S). Control rats were fed normal rat chow (C). All rats were pair fed and were followed for 4 months. After killing, blood chemistries and liver tissue were examined. RESULTS: Both FG-fed- and S-fed rats developed early features of metabolic syndrome when compared with C. In addition, both diets induced hepatic alterations, including variable increases in hepatic TG accumulation and fatty liver, an increase in uric acid content in the liver, as well as an increase in hepatic levels of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-alpha) measured in liver homogenates. CONCLUSIONS: Diets containing 30% of fructose either as free fructose and glucose, or as sucrose, induce metabolic syndrome, intrahepatic accumulation of uric acid and TGs, increased MCP-1 and TNF-alpha as well as fatty liver in rats. It will be relevant to determine clinically whether pharmacological reduction in uric acid levels might have a therapeutic advantage in the treatment of non-alcoholic fatty liver disease.

Combination of captopril and allopurinol retards fructose-induced metabolic syndrome.

BACKGROUND: Both ACE inhibitors and allopurinol have been shown to partially prevent metabolic syndrome induced by fructose. We tested the hypothesis that combined therapy might be more effective at blocking the metabolic syndrome induced with fructose. METHODS: Male Sprague-Dawley rats were fed a high fructose diet with or without allopurinol, captopril, or the combination for 20 weeks. A control group received a normal diet. All groups were pair-fed to assure equivalent caloric intake. RESULTS: Despite reduced energy intake, the fructose-fed rats developed features of metabolic syndrome including elevated blood pressure, abdominal obesity, hypertriglyceridemia, hyperuricemia and hyperinsulinemia. While both allopurinol and captopril alone tended to reduce features of the metabolic syndrome, the combined therapy was synergistic, with significant reduction in blood pressure, less accumulation of abdominal fat, an improvement in the dyslipidemia and a complete prevention of insulin resistance. CONCLUSION: A high fructose diet can induce metabolic syndrome even in the setting of caloric restriction. Captopril and allopurinol synergistically reduce features of the metabolic syndrome, especially hypertension, insulin resistance and dyslipidemia. Combination allopurinol and ACE inhibitor therapy might provide a superior means to prevent diabetes and cardiovascular disease.

Do thiazides worsen metabolic syndrome and renal disease? The pivotal roles for hyperuricemia and hypokalemia.

PURPOSE OF REVIEW: The aims of this article are to review the current controversies related to the use of thiazide diuretics as first-line treatment of hypertension and to discuss the causal roles for hyperuricemia and hypokalemia on the adverse consequences of thiazide usage. RECENT FINDINGS: Thiazides significantly reduce morbidity and mortality in hypertensive subjects. There remains, however, debate about thiazide usage as first-line treatment of hypertension. This negative impact of thiazides may be partially attributed to the ability of thiazides to exacerbate features of metabolic syndrome or increase the risk for developing diabetes. Several clinical trials suggest that thiazide-induced hyperuricemia and hypokalemia may account for some of these negative effects. Thiazide treatment is also associated with a decline of renal function in spite of a lowering blood pressure. In this review, we discuss the clinical and experimental evidence supporting a potential role of hyperuricemia and hypokalemia on the development of renal injury and worsening of the metabolic syndrome. SUMMARY: Hyperuricemia and hypokalemia may have pivotal roles in the exacerbation of the metabolic syndrome in response to thiazides. We propose that controlling serum uric acid and serum potassium could improve thiazide efficacy and also reduce its risk for inducing metabolic syndrome or diabetes.

Hypokalemic nephropathy is associated with impaired angiogenesis.

Hypokalemic nephropathy is associated with alterations in intrarenal vasoactive substances, leading to vasoconstriction, salt-sensitivity, and progression of interstitial fibrosis. In this study, we investigated whether hypokalemic nephropathy might also involve impaired renal angiogenesis. Sprague-Dawley rats that were fed low-potassium diets developed peritubular capillary loss that began in the inner stripe of the outer medulla (week 2) and progressed to the outer stripe of the outer medulla (week 4) and cortex (week 12). These changes were associated with increased macrophage infiltration, increased expression of both monocyte chemoattractant protein-1 and TNF-alpha, and a loss of vascular endothelial growth factor and endothelial nitric oxide synthase. Renal thiobarbituric acid-reactive substances, markers of oxidative stress, were increased late in disease. In conclusion, hypokalemic nephropathy is associated with impaired renal angiogenesis, evidenced by progressive capillary loss, reduced endothelial cell proliferation, and loss of VEGF expression.

Thiazide diuretics exacerbate fructose-induced metabolic syndrome.

Fructose is a commonly used sweetener associated with diets that increase the prevalence of metabolic syndrome. Thiazide diuretics are frequently used in these patients for treatment of hypertension, but they also exacerbate metabolic syndrome. Rats on high-fructose diets that are given thiazides exhibit potassium depletion and hyperuricemia. Potassium supplementation improves their insulin resistance and hypertension, whereas allopurinol reduces serum levels of uric acid and ameliorates hypertension, hypertriglyceridemia, hyperglycemia, and insulin resistance. Both potassium supplementation and treatment with allopurinol also increase urinary nitric oxide excretion. We suggest that potassium depletion and hyperuricemia in rats exacerbates endothelial dysfunction and lowers the bioavailability of nitric oxide, which blocks insulin activity and causes insulin resistance during thiazide usage. Addition of potassium supplements and allopurinol with thiazides might be helpful in the management of metabolic syndrome.

Effects of ischemia-reperfusion injury on renal ammonia metabolism and the collecting duct.

Acute renal injury induces metabolic acidosis, but its specific effects on the collecting duct, the primary site for urinary ammonia secretion, the primary component of net acid excretion, are incompletely understood. We induced ischemia-reperfusion (I/R) acute renal injury in Sprague-Dawley rats by clamping the renal pedicles bilaterally for 30 min followed by reperfusion for 6 h. Control rats underwent sham surgery without renal pedicle clamping. I/R injury decreased urinary ammonia excretion significantly but did not persistently alter urine volume, Na(+), K(+), or bicarbonate excretion. Histological examination demonstrated cellular damage in the outer and inner medullary collecting duct, as well as in the proximal tubule and the thick ascending limb of the loop of Henle. A subset of collecting duct cells were damaged and/or detached from the basement membrane; these cells were present predominantly in the outer medulla and were less frequent in the inner medulla. Immunohistochemistry identified that the damaged/detached cells were A-type intercalated cells, not principal cells. Both TdT-mediated dUTP nick-end labeling (TUNEL) staining and transmission electron microscopic examination demonstrated apoptosis but not necrosis. However, immunoreactivity for caspase-3 was observed in the proximal tubule, but not in collecting duct intercalated cells, suggesting that mechanism(s) of collecting duct intercalated cell apoptosis differ from those operative in the proximal tubule. We conclude that I/R injury decreases renal ammonia excretion and is associated with intercalated cell-specific detachment and apoptosis in the outer and inner medullary collecting duct. These effects likely contribute to the metabolic acidosis frequently observed in acute renal injury.

Fructose, but not dextrose, accelerates the progression of chronic kidney disease.

The metabolic syndrome has recently been recognized as a risk factor for kidney disease, but the mechanisms mediating this risk remain unclear. High fructose consumption by animals produces a model of the metabolic syndrome with hypertension, hyperlipidemia, and insulin resistance. The present study was conducted to test the hypothesis that consumption of a high-fructose diet could accelerate the progression of chronic kidney disease. Three groups of 14 male Sprague-Dawley rats were pair fed a specialized diet containing 60% fructose (FRU) or 60% dextrose (DEX) or standard rat chow (CON). After the animals were fed their assigned diet for 6 wk, five-sixths nephrectomy was performed, and the assigned diet was continued for 11 wk. Proteinuria was significantly increased and creatinine clearance was decreased in the FRU group compared with the CON and DEX groups, and blood urea nitrogen was higher in the FRU group than in the CON and DEX groups. Kidneys from the FRU group were markedly larger than kidneys from the CON and DEX groups. Glomerular sclerosis, tubular atrophy, tubular dilatation, and cellular infiltration appeared markedly worse in kidneys from the FRU group than in kidneys from the DEX and CON groups. Monocyte chemoattractant protein-1 (MCP-1) was measured in renal tissue homogenate and found to be increased in the FRU group. In vitro studies were conducted to determine the mechanism for increased renal MCP-1, and fructose stimulation of proximal tubular cells resulted in production of MCP-1. In conclusion, consumption of a high-fructose diet greatly accelerates progression of chronic kidney disease in the rat remnant kidney model.

Lead, at low levels, accelerates arteriolopathy and tubulointerstitial injury in chronic kidney disease.

Chronic lead exposure has been epidemiologically linked with hypertension and renal disease. Clinical studies suggest that low lead levels may contribute to renal progression. However, experimental studies have not examined whether low levels of lead accelerate progression in experimental chronic renal disease. Sprague-Dawley rats were administered lead (L; 150 ppm in drinking water, n = 16) for 4 wk, followed by remnant kidney (RK) surgery with continuation of lead for an additional 12 wk; control rats (n = 9) were treated similarly but did not receive lead. Lead treatment was well tolerated and resulted in modest elevations in whole blood lead levels (26.4 +/- 4.5 vs. 1 +/- 0 mug/dl, week 16, P < 0.001). Lead treatment was associated with higher systolic blood pressure (P < 0.05) and worse renal function (creatinine clearance 1.4 +/- 0.4 vs. 1.8 +/- 0.5 ml/min, RK+L vs. RK, P < 0.05), and with a tendency for greater proteinuria (6.6 +/- 6.1 vs. 3.6 +/- 1.5 mg protein/mg creatinine, RK+L vs. RK, P = 0.08). While glomerulosclerosis tended to be worse in lead-treated rats (37.6 +/- 11 vs. 28.8 +/- 2.3%, RK+L vs. RK, P = 0.06), the most striking finding was the development of worse arteriolar disease (P < 0.05), peritubular capillary loss (P < 0.05), tubulointerstitial damage, and macrophage infiltration (P < 0.05) in association with significantly increased renal expression of monocyte chemoattractant protein-1 mRNA. In conclusion, lead accelerates chronic renal disease, primarily by raising blood pressure and accelerating microvascular and tubulointerstitial injury.

Effect of reduced renal mass on renal ammonia transporter family, Rh C glycoprotein and Rh B glycoprotein, expression.

Kidneys can maintain acid-base homeostasis, despite reduced renal mass, through adaptive changes in net acid excretion, of which ammonia excretion is the predominant component. The present study examines whether these adaptations are associated with changes in the ammonia transporter family members, Rh B glycoprotein (Rhbg) and Rh C glycoprotein (Rhcg). We used normal Sprague-Dawley rats and a 5/6 ablation-infarction model of reduced renal mass; control rats underwent sham operation. After 1 wk, glomerular filtration rate, assessed as creatinine clearance, was decreased, serum bicarbonate was slightly increased, and Na(+) and K(+) were unchanged. Total urinary ammonia excretion was unchanged, but urinary ammonia adjusted for creatinine clearance, an index of per nephron ammonia metabolism, increased significantly. Although reduced renal mass did not alter total Rhcg protein expression, both light microscopy and immunohistochemistry with quantitative morphometric analysis demonstrated hypertrophy of both intercalated cells and principal cells in the cortical and outer medullary collecting duct that was associated with increased apical and basolateral Rhcg polarization. Rhbg expression, analyzed using immunoblot analysis, immunohistochemistry, and measurement of cell-specific expression, was unchanged. We conclude that altered subcellular localization of Rhcg contributes to adaptive changes in single-nephron ammonia metabolism and maintenance of acid-base homeostasis in response to reduced renal mass.

Effect of elevated serum uric acid on cisplatin-induced acute renal failure.

Marked hyperuricemia is known to cause acute renal failure via intrarenal crystal deposition. However, recent studies suggest mild hyperuricemia may have vasoactive and proinflammatory effects independent of crystal formation. We therefore tested the hypothesis that mild hyperuricemia might exacerbate renal injury and dysfunction in a model of cisplatin-induced acute renal failure in the rat. Cisplatin was administered to normouricemic and hyperuricemic rats (the latter generated by administering the urate oxidase inhibitor, oxonic acid). Recombinant urate oxidase (rasburicase) was administered in a third group to assess the effect of lowering uric acid on outcomes. Other control groups include normal rats and hyperuricemic rats without cisplatin-induced injury. Cisplatin induced injury of the pars recta (S3) segment of the proximal tubule in association with a mild monocyte infiltration. Hyperuricemic rats showed significantly greater tubular injury and proliferation with significantly greater macrophage infiltration and increased expression of monocyte chemoattractant protein-1. However, renal function was not different between normouricemic and hyperuricemic rats with cisplatin injury. Treatment with rasburicase reversed the inflammatory changes and lessened tubular injury with an improvement in renal function (relative to the hyperuricemic group). No intrarenal crystals were observed in any groups. These data provide the first experimental evidence that uric acid, at concentrations that do not cause intrarenal crystal formation, may exacerbate renal injury in a model of acute renal failure. The mechanism may relate to a proinflammatory pathway involving chemokine expression with leukocyte infiltration.

Uric acid, the metabolic syndrome, and renal disease.

Metabolic syndrome, characterized by truncal obesity, hypertriglyceridemia, elevated BP, and insulin resistance, is recognized increasingly as a major risk factor for kidney disease and also is a common feature of patients who are on dialysis. One feature that is common to patients with metabolic syndrome is an elevated uric acid. Although often considered to be secondary to hyperinsulinemia, recent evidence supports a primary role for uric acid in mediating this syndrome. Specifically, fructose, which rapidly can cause metabolic syndrome in rats, also raises uric acid, and lowering uric acid in fructose-fed rats prevents features of the metabolic syndrome. Uric acid also can accelerate renal disease in experimental animals and epidemiologically is associated with progressive renal disease in humans. It is proposed that fructose- and purine-rich foods that have in common the raising of uric acid may have a role in the epidemic of metabolic syndrome and renal disease that is occurring throughout the world.

Ceftazidime overdose-related nonconvulsive status epilepticus after intraperitoneal instillation.

We report a case of ceftazidime-related nonconvulsive status epilepticus (NCSE) in a 70-year-old female patient with continuous ambulatory peritoneal dialysis (CAPD)-related peritonitis. She was given ceftazidime intravenously which was then changed to intraperitoneal installation after clinical improvement. She received 11 g of ceftazidime via intraperitoneal installation for two days after being discharged from the hospital. Her consciousness was altered with mutism, asterisxis, and horizontal nystagmus. Her EEG showed continuous generalized three spikes-and-wave per second that were abolished after intravenous diazepam. Ceftazidime-related NCSE was suggested and ceftazidime therapy was stopped. Hemodialysis was done while phenytoin was also given to control the convulsions. Her consciousness improved after hemodialysis. Serum ceftazidime measured before and after hemodialysis on the second and third day were 105.2/39.4, 36.2/5.2 microg/mL (normal peak level 55 microg/mL), respectively. Repeated evaluation on day 6 showed normal EEG without epileptiform activity. She was later discharged with full recovery.

The effects of potassium and magnesium supplementations on urinary risk factors of renal stone patients.

The effects of potassium and magnesium supplementation on urinary risk factors for renal stone disease were studied in 61 renal stone patients. The subjects were divided into four groups and supplemented for a period of one month with potassium chloride (KCl, Group 1), potassium sodium citrate (K Na citrate, Group 2), magnesium glycine (Mg glycine, Group 3) and potassium magnesium citrate (K Mg citrate, Group 4) with a daily dose of 42 mEq potassium, 21 mEq magnesium or sodium and 63 mEq citrate, accordingly. The results showed that serum potassium and magnesium of all four groups normalized after the supplementation. Though urinary potassium significantly increased in all three groups supplemented with elemental potassium containing solutions [i.e. KCl (p < 0.001), K Na citrate (p < 0.001) and K Mg citrate (p < 0.001)] only K Na citrate and K Mg citrate, caused a significant increase in urinary pH and citrate but decrease in calcium. Supplementation with Mg glycine in Group 3 although caused a significant increase in urinary magnesium, its effects on urinary pH, citrate and calcium, however, were similar to KCl, in that they caused a significant decrease in urinary pH without any change in urinary citrate or calcium. Supplementation with K Mg citrate in Group 4 seems to have given the best results, as far as lowering stone risk factors in that it caused an increase in urinary pH, potassium and citrate and decreased calcium excretions similar to K Na citrate in Group 2. In addition, K Mg citrate also caused the enrichment of urine with magnesium, another inhibitor of calcium-containing stones. Although the four supplements had no effect on urinary saturation of calcium oxalate salt, their effects on the saturations of brushite (CaHPO4 x 2H2O), octacalcium phosphate (Ca8H2 (PO4)6 x 5H2O) and uric acid were clearly associated with changes in urinary pH. Therefore, in Group 1 and 3, subjects having a decrease in urinary pH, also experienced a significant increase in uric acid saturation. Though the saturation of brushite and octacalcium phosphate in Group 2 and 4 and the sodium acid urate in Group 2 were significantly increased, these urinary risk factors could be overcome, however, by the concomitant increase in urinary citrate. The present results demonstrate that for those stone vulnerable subjects having a high risk of potassium and magnesium depletion, to obtain the best therapeutic results, they should be provided supplementations of both potassium and magnesium together and also in the forms that would result in the delivery of an alkali loading effect.

Urinary citrate excretion in patients with renal stone: roles of leucocyte ATP citrate lyase activity and potassium salts therapy.

BACKGROUND: Hypocitraturia is a major metabolic abnormality in rural Northeast Thais with renal stones. These people also have low serum and urinary potassium and consume a high carbohydrate and low fat diet, which together might influence the intracellular metabolism and urinary excretion of citrate. METHODS: In Study A, we measured plasma and urinary chemistries and assayed leucocyte ATP citrate lyase (ACL) activity in 30 normal urban control subjects (Group A1) and 30 rural renal stone patients (Group A2) in Northeast Thailand. Some of the subjects from both groups were also used to evaluate the intake of carbohydrate, protein and fat. In Study B, we examined the effects of potassium salts therapy with another group of 30 rural renal stone patients: Group B1 (n = 15) treated with potassium chloride and Group B2 (n = 15) with potassium-sodium citrate (with an aim to achieve 42 mEq potassium, 21 mEq sodium and 62 mEq citrate per day for 1 month). RESULTS: In Study A, the leucocyte ACL activity of Group A1 was much lower than that of Group A2 (3.2 +/- 0.7 vs. 9.3 +/- 3.8 micromol acetylhydroxamate/mg protein/30 min, p < 0.0001). The plasma potassium, urinary excretions of potassium and citrate in Group A1 were higher than in Group A2. When data of the two groups were combined, urinary citrate excretion was inversely correlated with leucocyte ACL activity (r = 0.6783, p < 0.001). While the dietary protein intake did not differ between Groups A1 and A2, the carbohydrate intake by Group A1 was significantly lower (65.2 +/- 7.9% vs. 83.1 +/- 2.9%, p < 0.01) and fat higher (21.0 +/- 6.4% vs. 6.2 +/- 4.1%, p < 0.002) than Group A2. After treatment with potassium chloride (Group B1), only the potassium was increased (p < 0.001), while those treated with potassium-sodium citrate (Group B2) experienced a significant increase in urinary pH (p < 0.002), potassium (p < 0.001) and citrate (p < 0.001), and a decrease in leucocyte ACL activity (p < 0.001). CONCLUSIONS: Compared to normal subjects, renal stone patients have low urinary citrate excretion with high leucocyte ACL activity. In Northeast Thailand, low potassium status and a high carbohydrate and low fat diet may cause the increased ACL activity. However, hypokaliuria, hypocitraturia and high leucocyte ACL activity can be corrected by potassium-sodium citrate salt therapy.