Insulin resistance increases the risk of urinary stone formation in a rat model of metabolic syndrome

OBJECTIVE

To investigate the association between metabolic syndrome and urinary stone disease, and whether insulin resistance associated with adiposity affects the risk of urinary stone formation, using a rat model of metabolic syndrome.

MATERIALS AND METHODS

Four‐week‐old male Otsuka Long‐Evans Tokushima ‘Fatty’ (OLETF, a model of human type 2 diabetes and metabolic syndrome) rats, and Long‐Evans Tokushima (LETO, a non‐diabetic control) rats (10 each) were given a standardized diet and free access to water. Body weight and serum and urinary biochemistry were determined every 4 weeks. Ten‐week‐old male OLETF and LETO rats were divided into three groups of nine each and treated with vehicle or oral administration of 3 or 10 mg/kg/day pioglitazone, an agent that improves insulin resistance. After 4 weeks, body weight and serum and urinary biochemistry were determined.

RESULTS

The OLETF rats had significantly lower urinary pH and citrate excretion, and higher urinary uric acid and calcium excretion, than the LETO rats, with increases in body weight, serum triglyceride, glucose and insulin. The administration of pioglitazone to the OLETF rats for 4 weeks significantly increased urinary pH dose‐dependently. There was no change in the urinary excretion of citrate, uric acid, calcium, oxalate or magnesium.

CONCLUSION

These results indicate that metabolic syndrome causes the changes in urinary constituents, leading to increased risk of both uric acid and calcium stone formation. Improvement in insulin resistance, a central cause of metabolic syndrome, might prevent uric acid stone formation by raising urinary pH.     

Effects of metabolic syndrome on kidney transplantation outcomes: a systematic review and meta‐analysis

Metabolic syndrome (MS) has been associated with proteinuria and reduced glomerular filtration rate. Immunosuppressive agents increase the incidence of traditional risk factors for cardiovascular disease (CVD) and have known effects on MS components after kidney transplantation. The purpose of this meta‐analysis was to evaluate the impact of MS on relevant outcomes after kidney transplantation. MEDLINE, EMBASE, and Cochrane Library were searched up to November 7, 2015. Papers that compared patients with and without MS and assessed one of the following outcomes, graft loss, death by cardiovascular disease, and all‐cause mortality, were included. Of 585 studies identified, five studies including 1269 patients were evaluated. MS was identified as a risk factor for graft loss [relative risk, 3.06; 95% confidence interval (CI), 2.17, 4.32; I² = 0%; P heterogeneity = 0.72] and death by CVD (relative risk, 3.53; 95% CI, 1.27, 9.85; I² = 0%; P heterogeneity = 0.40). Results on the association between MS and all‐cause mortality were inconclusive (relative risk, 2.61; 95% CI, 0.70, 9.81; I² = 58%; P heterogeneity = 0.09). Graft loss and death by CVD were associated with the presence of MS after transplantation. Randomized clinical trials should be conducted to define whether interventions on each MS component would result in better outcomes after transplantation.     

Calcium oxalate crystal deposition in metabolic syndrome model rat kidneys

Objective: Although an epidemiological link between the metabolic syndrome and kidney stone formation has been reported, the mechanism by which metabolic syndrome promotes kidney stone formation has yet to be elucidated. We investigated calcium oxalate (CaOx) kidney stone formation in a rat metabolic syndrome model. Methods: We induced hyperoxaluria in 8‐week‐old male Otsuka Long‐Evans Tokushima fatty (OLETF) rats, and a control strain, Long‐Evans Tokushima Otsuka (LETO) rats, by administering 1.0% ethylene glycol (EG) as their drinking water for 2 weeks. Rats were divided into four groups: LETO‐C (control, n = 7); LETO‐SF (stone forming, n = 8); OLETF‐C (n = 7); and OLETF‐SF (n = 8). Urine and blood samples were collected for biochemistry testing, and the kidneys were harvested for estimation of crystal deposition and determinations of the expression of osteopontin (OPN) and monocyte chemoattractant protein‐1 (MCP‐1). Results: Administration of EG induced hyperoxaluria to the same degree in both strains. The OLETF‐SF group showed a higher grade of renal crystal deposition and significantly higher renal calcium content than the LETO‐SF group. Although the OLETF‐C group excreted significantly higher amounts of uric acid and more acidic urine than the LETO‐C group, similar differences were not observed in rats given EG. Significant upregulation of both OPN and MCP‐1 was seen in the kidneys of hyperoxaluric rats, with higher levels of expression in the OLETF‐SF group than the LETO‐SF group. Conclusions: The present results show for the first time that OLETF rats form more renal CaOx crystal deposits compared with control rats under EG‐induced hyperoxaluric conditions. The model described here should be useful for investigating the mechanisms by which the metabolic syndrome promotes CaOx kidney stone formation.     

A pilot dynamic analysis of formative factors of nephrolithiasis related to metabolic syndrome: evidence in a rat model

Introduction and objectiveTo examine the dynamic changes in the formative factors of nephrolithiasis and the final micromorphological changes in an obesity-initiated metabolic syndrome (MS) rat model.MethodsForty five-week-old male Sprague–Dawley (SD) rats were randomly divided into four groups: the regular diet group (RD), high-fat diet group (HFD), regular diet with drug (ethylene glycol and ammonium chloride) group (RDD), and high-fat diet with drug group (HFDD). A dynamic assessment of MS components (body weight (BW), body length (BL), Lee’s index (LI), blood glucose (BG), total cholesterol (TC), and triglycerides (TGs)) and stone-forming factors (urinary pH, urinary calcium, and urinary oxalate acid) was carried out. In addition, the levels of oxidative stress (OS) markers (CAT, SOD, TAC, GSH-PX, and MDA) were measured, and histological analysis was carried out at the end of 16 weeks.ResultsMS-related parameters, such as BW, LI, BG, TC, and TG, were significantly higher in HFD-fed rats than in RD-fed rats (p < 0.001). In the HFDD group, significantly lower urinary pH, hyperoxaluria, and hypocalciuria were noted in the dynamic assessment of stone-forming factors (p < 0.001). CAT, TAC, and MDA were notably changed in the HFD-fed groups, particularly the HFDD rats. Histological analysis showed that the renal tubules of HFDD rats had the highest scores for both inflammation and renal crystallization deposition (p < 0.05).ConclusionsOur results suggest that male SD rats with MS are prone to developing nephrolithiasis. Validation in an in vivo model may lead to an understanding of the underlying pathophysiological mechanisms of action of MS-related nephrolithiasis in humans.

Key messages

• Male SD rats with metabolic syndrome are more prone to developing calcium oxalate nephrolithiasis after treatment with ethylene glycol and ammonium chloride compared to control lean rats.
• MS-related nephrolithiasis in rats induced by ethylene glycol and ammonium chloride is mainly related to increased hyperoxaluria and inflammation and decreased antioxidant levels.
• High-fat diet-fed SD rats treated with ethylene glycol and ammonium chloride are a stable and valid in vivo model for understanding the potential mechanism of action of MS-related nephrolithiasis.

     

Impact of metabolic syndrome on the incidence of chronic kidney disease: a Chinese cohort study

Aim: Metabolic syndrome (MetS) is a major culprit in cardiovascular disease and chronic kidney disease (CKD) in Western populations. We studied the longitudinal association between MetS and incident CKD in Chinese adults. Methods: A cohort study was conducted in a nationally representative sample of 4248 Chinese adults in Taiwan. The MetS was defined according to a unified criteria set by several major organizations and CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min per 1.73 m². Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) adjusted for sex, age, body mass index (BMI) and serum levels of total cholesterol. Results: The prevalence of MetS among participants at baseline recruitment was 15.0% (637/4248). During a median follow‐up period of 5.40 years, 208 subjects (4.9%) developed CKD. The multivariate‐adjusted HR of CKD in participants with MetS compared with those without was 1.42 (95% CI = 1.03, 1.73). Additionally, there was a significantly graded relationship between the number of the MetS components and risk of CKD. Further, the relation between MetS and incident CKD was more robust in subjects with BMI >27.5 kg/m² than in those with lower BMI. Conclusion: The results suggest that the presence of MetS was significantly associated with increased risk of incident CKD in a Chinese population. These findings warrant future studies to test the impact of preventing and treating MetS on the reduction of the occurrence of CKD.     

Percutaneous nephrolithotomy of a staghorn stone in thoracic ectopic kidney

Congenital thoracic ectopic kidney is a very rare developmental anomaly and the rarest form of all ectopic kidneys. It is usually asymptomatic and discovered incidentally on routine chest radiography. Herein we reported the first case of staghorn stone in a thoracic kidney managed successfully by percutaneous nephrolithotomy.     

Association between the metabolic syndrome and chronic kidney disease in Chinese adults.

BACKGROUND: The metabolic syndrome is a common risk factor for cardiovascular and chronic kidney disease (CKD) in Western populations. We examined the relationship between the metabolic syndrome and risk of CKD in Chinese adults. METHODS: A cross-sectional survey was conducted in a nationally representative sample of 15 160 Chinese adults aged 35-74 years. The metabolic syndrome was defined as the presence of three or more of the following risk factors: elevated blood pressure, low high density lipoprotein (HDL)-cholesterol, high triglycerides, elevated plasma glucose and abdominal obesity. CKD was defined as an estimated glomerular filtration rate<60 ml/min/1.73 m2 and elevated serum creatinine was defined as >or=1.14 mg/dl in men and >or=0.97 mg/dl in women (>or=95th percentile of serum creatinine in Chinese men and women aged 35-44 years without hypertension or diabetes, respectively). RESULTS: The multivariate-adjusted odds ratios [95% confidence interval (CI)] of CKD and elevated serum creatinine in participants with compared to those without the metabolic syndrome were 1.64 (1.16, 2.32) and 1.36 (1.07, 1.73), respectively. Compared to participants without any components of the metabolic syndrome, the multivariate-adjusted odds ratios (95% CI) of CKD were 1.51 (1.02, 2.23), 1.50 (0.97, 2.32), 2.13 (1.30, 3.50) and 2.72 (1.50, 4.93) for those with 1, 2, 3, and 4 or 5 components, respectively. The corresponding multivariate-adjusted odds ratios (95% CI) of elevated serum creatinine were 1.11 (0.88, 1.40), 1.39 (1.07, 2.04), 1.47 (1.06, 2.04) and 2.00 (1.32, 3.03), respectively. CONCLUSIONS: These findings suggest that the metabolic syndrome might be an important risk factor for CKD in Chinese adults.     

Prophylaxis of infection-induced kidney stone formation

Summary Lowering supersaturation with respect to struvite and carbonate apatite is the most important prophylactic measure in patients with infection-induced kidney stone disease. This is best achieved by combining culture-specific antibiotics with urinary acidification. Urinary infection with non-urease-producing Escherichia coli, probably promoting struvite particle formation, must be eradicated. Possible measures for improving urothelial anti-adherence properties or reducing bacterial adherence are discussed.     

Chloride channel mutations in hypercalciuric kidney stone disease

Recent advances in molecular biology have characterized a new class of chloride channels that are referred to as voltage-gated chloride channels. To date, 9 such voltage-gated chloride channels have been identified in mammals. These are CLC-1 to CLC-7, CLC-Ka, and CLC-Kb, which are encoded by the genesCLCN1 toCLCN7, CLCNKA, andCLCNKB, respectively. Mutations in 2 of these genes, referred to asCLCN5 andCLCNKB, have been defined in the hypercalciuric nephrolithiasis disorders of Dent's disease and a form of Bartter's syndrome, respectively. In addition, other forms of Bartter's syndrome have been defined, with mutations involving the bumetanide-sensitive sodium-potassium-chloride cotransporter (NKCC2) and the potassium channel, ROMK. Finally, mutations of the thiazide-sensitive sodium chloride cotransporter (NCCT) are associated with Gitelman's syndrome, in which hypocalciuria and hypomagnesemia are notable features. These molecular genetic studies have increased our understanding of the renal tubular mechanisms that regulate mineral homeostasis. This paper was presented at the 2nd International Forum “The Frontiers of Nephrology,” Tokyo, May 10, 1998.     

Systemic implications of urinary stone disease

Urinary stone disease is the third most common condition affecting the urinary tract. It contributes to a great deal of morbidity for both men and women, and cost the United States (US) over 5.3 billion dollars in 2000 alone. Moreover, it is associated with systemic diseases such as hypertension, diabetes, and other components of the metabolic syndrome. Reciprocally, these systemic diseases may be contributing to the rising incidence in urinary stone disease. Previously described mechanisms of stone formation attribute stone development and growth to the urinary milieu. While this may partly influence the process, it cannot account for the associations between systemic diseases and stones observed in large community-based studies. Here we present a review of the evidence demonstrating a link between urinary stone disease and components of the metabolic syndrome. We believe a vascular etiology for the initiation of urinary stones may tie these processes together.     

Rare cause of weight loss in a kidney transplant recipient: iron overload

Various reasons such as malignancies and chronic infections may cause weight loss in kidney transplant patients. In this report, iron overload as a rare cause of weight loss in a kidney transplant patient is presented. Forty-seven-year-old male patient who transplanted from a deceased donor 5 years ago was hospitalized because of 20?kg of weight loss. In medical history, he had history of hemodialysis for 89 months and received 100–300?mg of intravenous iron therapy per week before transplantation and transfused eight units of blood. In physical examination, weight and height were 45?kg and 185?cm, respectively. Respiratory and cardiac auscultation was normal. Laboratory results revealed as follow: glucose 76?mg/dL, urea 60?mg/dL, creatinine 1.35?mg/dL, aspartate aminotransferase 74?U/L, alanine aminotransferase 77?U/L, C-reactive protein 2.59?mg/dL, albumin 3.3?g/dL, globulin 3.4?g/dL, white blood cells 3200/mm³, hemoglobin 13.1?g/dL and platelets 190,000/mm³. Chest and abdominal tomography didn’t reveal any pathology. Portal Doppler ultrasound showed signs of early cirrhosis. Viral and autoimmune hepatitis markers were negative. Ferritin was 5300?ng/mL and transferrin saturation was 82%. In liver biopsy, hemosiderosis was diagnosed and heterozygous H63D gene mutation was detected. Totally, 19 units of phlebotomy were performed. Liver function tests and serum ferritin decreased gradually. At outpatient follow-up in 6 months, he returned to former weight. In conclusion, there can be several causes of weight loss in kidney transplant patients. Iron overload can come across as a rare cause of weight loss. In these patients, ferritin levels should be checked and diagnosis should be clarified by liver biopsy and gene mutation analysis.     

Gastric bypass model in the obese rat to study metabolic mechanisms of weight loss

A rat model replicating gastric bypass with Roux-en-Y (GB) as used in morbidly obese patients, evolved in our laboratory in stages, using the Zucker rat as an obese model (GB) is presented. In the final model, a 20% gastric fundic pouch to limit the gastric reservoir was created using two staple lines (Ethicon). A 4- to 5-mm end-to-side gastrojejunostomy and a 6- to 8-mm jejunojejunostomy, at 10 cm length of the Roux-en-Y limb, placed 16 cm below the ligament of Treitz, was hand sewn to create a limited area of nutrient digestion and absorption. Controls underwent sham operation. Rats were divided into: (i) sham-op ad lib-fed (Control); (ii) GB; and (iii) sham-op pair fed (PF) in two experiments. In Experiment 1, 24 Zuckers (control n = 8; GB n = 8; PF n = 8) were studied to assess the effectiveness of the model for weight loss. In Experiment 2, 24 Zuckers (8/group) were studied to confirm the effects of the operation on weight loss and on metabolic parameters. Boost was given for 4 days starting 24 h postop and then ground chow was given. Daily food intake (FI), meal size (MZ), meal number (MN), and body weight (BW) were measured. Rats were sacrificed on Day 20 in Experiment 1 and on Day 10 in Experiment 2. Serum metabolites and body fat weight were measured. Data were evaluated using Student's t test. Controls steadily gained BW (5.2-6.1 g/day), reaching approximately 500 g. In GB: FI, MZ, MN, BW, glucose, free fatty acids, insulin, and body fat decreased (P < 0.05). In PF: BW, insulin, triglycerides, and body fat decreased. A dependable, reproducible gastric bypass with Roux-en-Y obesity model was developed. This permits the study of biochemical and eventually molecular mechanism(s) of weight loss resulting from the operation.     

Impact of insulin resistance,insulin and adiponectin on kidney stones in the Japanese population

Objectives: It has been reported that kidney stones are linked to metabolic syndrome (MetS), which is characterized by insulin resistance. The aim of the present study was to examine the association of insulin resistance, insulin and adiponectin with kidney stones in a Japanese population. Methods: From February 2007 to March 2008, 1036 (529 men and 507 women) apparently healthy Japanese subjects, aged 35–79 years, were analyzed. Weight, height, waist circumference and blood pressure were measured. Overnight fasting blood was collected to measure insulin and adiponectin levels. Homeostasis model assessment of insulin resistance (HOMA‐IR) was calculated to assess insulin resistance. Logistic regression analysis was used to estimate the odds ratio (OR) and 95% confidence intervals for a self‐reported history of kidney stones across tertiles of HOMA‐IR, insulin and adiponectin. Results: Of the participants, 84 men (15.6%) and 35 women (6.9%) had a history of kidney stones. Age, body mass index, waist circumference, systolic and diastolic blood pressures, HOMA‐IR and insulin were significantly higher in women with than in women without kidney stones. There was no difference in adiponectin level between subjects with and without a history of kidney stones in either sex. Furthermore, a significant positive trend was observed in the age‐adjusted OR for a history of kidney stones across insulin tertiles (P‐value for trend = 0.04) in women. Conclusions: For Japanese women, HOMA‐IR and insulin are associated with a history of kidney stones. The findings suggest that MetS components could increase the risk of kidney stones through subclinical hyperinsulinemia and insulin resistance.