Renal ammonium excretion after an acute acid load: blunted response in uric acid stone formers but not in patients with type 2 diabetes.

Idiopathic uric acid nephrolithiasis is characterized by elevated urinary net acid excretion and insufficient buffering by ammonium, resulting in excessively acidic urine and titration of the relatively soluble urate anion to insoluble uric acid. Patients with type 2 diabetes have similar changes in urinary pH, net acid excretion, and ammonium in 24-h urine collections at baseline, even after controlling for dietary factors, and are at increased risk for uric acid nephrolithiasis. However, not all patients with type 2 diabetes develop kidney stones, suggesting that uric acid stone formers may have additional urinary defects, perhaps not apparent at baseline. We performed a metabolic study of 14 patients with idiopathic uric acid nephrolithiasis, 13 patients with type 2 diabetes, and 8 healthy control subjects of similar body mass index. After equilibration on a fixed diet for 5 days, subjects were given a single oral acid load (50 meq ammonium chloride), and urine was collected hourly for 4 h. Uric acid stone formers had a lower ammonium excretory response to acute acid loading compared with diabetic and nondiabetic nonstone formers, suggesting that an ammonium excretory defect unique to uric acid stone formers was unmasked by the acid challenge. The Zucker diabetic fatty rat also did not show impaired urinary ammonium excretion in response to acute acid challenge. A blunted renal ammonium excretory response to dietary acid loads may contribute to the pathogenesis of idiopathic uric acid nephrolithiasis.

Renal lipid accumulation, oxidative stress and uric acid handling in a rodent model of obesity and metabolic syndrome.

Hyperuricemia is more prevalent among people with obesity and metabolic syndrome, and is associated with adverse clinical outcomes. We hypothesized that increased renal reabsorption of uric acid (UA) in obesity and metabolic syndrome may be an adaptive response of the kidney when faced with fatty acid-induced oxidative stress. To test this hypothesis, we examined lipid accumulation, markers of oxidative stress, and renal UA handling in Zucker diabetic fatty (ZDF) rats, and in matched lean control animals. Rats were randomized to either normal rodent chow or a diet supplemented with antioxidants (α-tocopheryl acetate, sodium selenite, zinc sulfate, and ascorbic acid), and were followed up for either 4 or 20 weeks after randomization. Dietary antioxidant supplementation had no significant effects in lean control rats but led to partial improvement in markers of elevated oxidative stress in the kidney of ZDF rats. Renal UA handling was not affected by antioxidant supplementation. We observed robust correlations between renal lipid content and oxidative stress markers in the pooled experimental groups, particularly in older animals after 20 weeks on the study diets. Dietary antioxidant supplementation did not prevent the gradual decline in renal function observed in older ZDF rats. These findings suggest that hyperuricemia in the ZDF rat model of obesity and the metabolic syndrome is not caused by renal oxidative stress, that there may be a pathophysiological link between lipid accumulation and oxidative stress in the kidney, and that antioxidant supplementation does not prevent age-related decline in renal function in ZDF rats.

Metabolic and cardiovascular effects of chronic mild hyperuricemia in rodents.

Mildly elevated serum uric acid levels are common in people with metabolic syndrome and type 2 diabetes mellitus (T2DM), but whether elevated uric acid has a causal role in the pathogenesis of diabetes remains uncertain. We tested whether chronic mild hyperuricemia in rodents under controlled laboratory conditions can cause glucose intolerance in otherwise healthy animals, or whether it can worsen glucometabolic control in animals that are genetically predisposed to T2DM. We used an established model of experimental hyperuricemia in rodents with potassium oxonate dietary supplementation, which led to sustained, approximately two-fold elevation of uric acid compared with control animals. We also reversed the hyperuricemic effect of oxonate in some animals by treatment with a xanthine oxidase inhibitor. Manipulation of serum uric acid levels in Sprague-Dawley rats for up to 18 weeks did not affect fasting glucose and glucose tolerance. Blood pressure was also not affected by hyperuricemia in rats fed a Western-type diet. We next sought to determine whether uric acid may aggravate or accelerate the onset of glucometabolic abnormalities in rats already predisposed to T2DM. Chronic oxonate treatment in Zucker diabetic fatty (ZDF) and lean control rats for up to 6 weeks did not affect fasting glucose, insulin, and glucose tolerance in ZDF rats. Taken together, these findings indicate that elevated uric acid does not directly contribute to the pathogenesis of glucose intolerance and T2DM in rodents.

Triglycerides in the human kidney cortex: relationship with body size.

Obesity is associated with increased risk for kidney disease and uric acid nephrolithiasis, but the pathophysiological mechanisms underpinning these associations are incompletely understood. Animal experiments have suggested that renal lipid accumulation and lipotoxicity may play a role, but whether lipid accumulation occurs in humans with increasing body mass index (BMI) is unknown. The association between obesity and abnormal triglyceride accumulation in non-adipose tissues (steatosis) has been described in the liver, heart, skeletal muscle and pancreas, but not in the human kidney. We used a quantitative biochemical assay to quantify triglyceride in normal kidney cortex samples from 54 patients undergoing nephrectomy for localized renal cell carcinoma. In subsets of the study population we evaluated the localization of lipid droplets by Oil Red O staining and measured 16 common ceramide species by mass spectrometry. There was a positive correlation between kidney cortex trigyceride content and BMI (Spearman R = 0.27, P = 0.04). Lipid droplets detectable by optical microscopy had a sporadic distribution but were generally more prevalent in individuals with higher BMI, with predominant localization in proximal tubule cells and to a lesser extent in glomeruli. Total ceramide content was inversely correlated with triglycerides. We postulate that obesity is associated with abnormal triglyceride accumulation (steatosis) in the human kidney. In turn, steatosis and lipotoxicity may contribute to the pathogenesis of obesity-associated kidney disease and nephrolithiasis.

Discrimination of brief speech sounds is impaired in rats with auditory cortex lesions.

Auditory cortex (AC) lesions impair complex sound discrimination. However, a recent study demonstrated spared performance on an acoustic startle response test of speech discrimination following AC lesions (Floody et al., 2010). The current study reports the effects of AC lesions on two operant speech discrimination tasks. AC lesions caused a modest and quickly recovered impairment in the ability of rats to discriminate consonant-vowel-consonant speech sounds. This result seems to suggest that AC does not play a role in speech discrimination. However, the speech sounds used in both studies differed in many acoustic dimensions and an adaptive change in discrimination strategy could allow the rats to use an acoustic difference that does not require an intact AC to discriminate. Based on our earlier observation that the first 40 ms of the spatiotemporal activity patterns elicited by speech sounds best correlate with behavioral discriminations of these sounds (Engineer et al., 2008), we predicted that eliminating additional cues by truncating speech sounds to the first 40 ms would render the stimuli indistinguishable to a rat with AC lesions. Although the initial discrimination of truncated sounds took longer to learn, the final performance paralleled rats using full-length consonant-vowel-consonant sounds. After 20 days of testing, half of the rats using speech onsets received bilateral AC lesions. Lesions severely impaired speech onset discrimination for at least one-month post lesion. These results support the hypothesis that auditory cortex is required to accurately discriminate the subtle differences between similar consonant and vowel sounds.