Diana Jalal

Uric acid and chronic kidney disease: which is chasing which?

Serum uric acid is commonly elevated in subjects with chronic kidney disease (CKD), but was historically viewed as an issue of limited interest. Recently, uric acid has been resurrected as a potential contributory risk factor in the development and progression of CKD. Most studies documented that an elevated serum uric acid level independently predicts the development of CKD. Raising the uric acid level in rats can induce glomerular hypertension and renal disease as noted by the development of arteriolosclerosis, glomerular injury and tubulointerstitial fibrosis. Pilot studies suggest that lowering plasma uric acid concentrations may slow the progression of renal disease in subjects with CKD. While further clinical trials are necessary, uric acid is emerging as a potentially modifiable risk factor for CKD. Gout was considered a cause of CKD in the mid-nineteenth century, and, prior to the availability of therapies to lower the uric acid level, the development of end-stage renal disease was common in gouty patients. In their large series of gouty subjects Talbott and Terplan found that nearly 100% had variable degrees of CKD at autopsy (arteriolosclerosis, glomerulosclerosis and interstitial fibrosis). Additional studies showed that during life impaired renal function occurred in half of these subjects. As many of these subjects had urate crystals in their tubules and interstitium, especially in the outer renal medulla, the disease became known as gouty nephropathy. The identity of this condition fell in question as the presence of these crystals may occur in subjects without renal disease; furthermore, the focal location of the crystals could not explain the diffuse renal scarring present. In addition, many subjects with gout also had coexistent conditions such as hypertension and vascular disease, leading some experts to suggest that the renal injury in gout was secondary to these latter conditions rather than to uric acid per se. Indeed, gout was removed from the textbooks as a cause of CKD, and the common association of hyperuricemia with CKD was solely attributed to the retention of serum uric acid that is known to occur as the glomerular filtration rate falls. Renewed interest in uric acid as a cause of CKD occurred when it was realized that invalid assumptions had been made in the arguments to dismiss uric acid as a risk factor for CKD. The greatest assumption was that the mechanism by which uric acid would cause kidney disease would be via the precipitation as crystals in the kidney, similar to the way it causes gout. However, when laboratory animals with CKD were made hyperuricemic, the renal disease progressed rapidly despite an absence of crystals in the kidney. Since this seminal study, there has been a renewed interest in the potential role uric acid may have in both acute and CKD. We briefly review some of the major advances that have occurred in this field in the last 15 years.

Increased Fructose Associates with Elevated Blood Pressure

The recent increase in fructose consumption in industrialized nations mirrors the rise in the prevalence of hypertension, but epidemiologic studies have inconsistently linked these observations. We investigated whether increased fructose intake from added sugars associates with an increased risk for higher BP levels in US adults without a history of hypertension. We conducted a cross-sectional analysis using the data collected from the National Health and Nutrition Examination Survey (NHANES 2003 to 2006) involving 4528 adults without a history of hypertension. Median fructose intake was 74 g/d, corresponding to 2.5 sugary soft drinks each day. After adjustment for demographics; comorbidities; physical activity; total kilocalorie intake; and dietary confounders such as total carbohydrate, alcohol, salt, and vitamin C intake, an increased fructose intake of > or =74 g/d independently and significantly associated with higher odds of elevated BP levels: It led to a 26, 30, and 77% higher risk for BP cutoffs of > or =135/85, > or =140/90, and > or =160/100 mmHg, respectively. These results suggest that high fructose intake, in the form of added sugar, independently associates with higher BP levels among US adults without a history of hypertension.

Uric Acid as a Target of Therapy in CKD

The prevalence of chronic kidney disease (CKD) has increased and will continue to increase in the United States and worldwide. This is alarming considering that CKD is an irreversible condition and patients who progress to chronic kidney failure have reduced quality of life and high mortality rates. As such, it is imperative to identify modifiable risk factors to develop strategies to slow CKD progression. One such factor is hyperuricemia. Recent observational studies have associated hyperuricemia with kidney disease. In addition, hyperuricemia is largely prevalent in patients with CKD. Data from experimental studies have shown several potential mechanisms by which hyperuricemia may contribute to the development and progression of CKD. In this article, we offer a critical review of the experimental evidence linking hyperuricemia to CKD, highlight gaps in our knowledge on the topic as it stands today, and review the observational and interventional studies that have examined the potential nephroprotective effect of decreasing uric acid levels in patients with CKD. Although uric acid also may be linked to cardiovascular disease and mortality in patients with CKD, this review focuses only on uric acid as a potential therapeutic target to prevent kidney disease onset and progression.

Disorders of hemostasis associated with chronic kidney disease.

Chronic kidney disease (CKD) is a growing global health problem. CKD is typically associated with a prothrombotic tendency in the early stages of the disease, whereas in its more advanced stage, that is, end-stage renal disease, patients suffer from a prothrombotic tendency and, in many cases, a bleeding diathesis. The exact etiology behind the coexistence of these conflicting hemostatic disorders is poorly understood. This review critically appraises studies examining the abnormalities in the hemostasis pathway in patients with CKD, as well as the therapeutic options that are currently available to treat these individuals.

Serum uric acid levels predict the development of albuminuria over 6 years in patients with type 1 diabetes: Findings from the Coronary Artery Calcification in Type 1 Diabetes study

BACKGROUND Recent studies suggest that uric acid is a mediator of diabetic nephropathy. We hypothesized that elevated serum uric acid levels are a strong predictor of albuminuria in patients with type 1 diabetes. METHODS We analyzed data from the Coronary Artery Calcification in Type 1 Diabetes study, a prospective observational study. A stepwise logistic regression model was applied to predict the development of micro- or macroalbuminuria after 6 years of follow-up in 324 participants who had no evidence of micro- or macroalbuminuria at baseline. A P-value <0.1 was used as the criteria for entry into and removal from the model. RESULTS The following factors were selected in the stepwise multivariate model as predictors of micro- or macroalbuminuria at the 6-year follow-up visit: baseline serum uric acid levels, HbA(1c) and pre-albuminuria. For every 1-mg/dl increase in serum uric acid levels at baseline, there was an 80% increased risk of developing micro- or macroalbuminuria at 6 years (odds ratio 1.8; 95% confidence interval 1.2, 2.8; P = 0.005). Additional covariates considered in the stepwise model were sex, age, duration of diabetes, angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker treatment, waist circumference, waist/hip ratio, body mass index, systolic and diastolic blood pressure, smoking, serum creatinine, cystatin C, high-density lipoprotein cholesterol and triglycerides. CONCLUSION Elevated serum uric acid levels are a strong predictor of the development of albuminuria in patients with type 1 diabetes.

Uric acid lowering to prevent kidney function loss in diabetes: The preventing early renal function loss (PERL) allopurinol study

Diabetic kidney disease causes significant morbidity and mortality among people with type 1 diabetes (T1D). Intensive glucose and blood pressure control have thus far failed to adequately curb this problem and therefore a major need for novel treatment approaches exists. Multiple observations link serum uric acid levels to kidney disease development and progression in diabetes and strongly argue that uric acid lowering should be tested as one such novel intervention. A pilot of such a trial, using allopurinol, is currently being conducted by the Preventing Early Renal Function Loss (PERL) Consortium. Although the PERL trial targets T1D individuals at highest risk of kidney function decline, the use of allopurinol as a renoprotective agent may also be relevant to a larger segment of the population with diabetes. As allopurinol is inexpensive and safe, it could be cost-effective even for relatively low-risk patients, pending the completion of appropriate trials at earlier stages.

Elevated serum uric acid levels are associated with non-alcoholic fatty liver disease independently of metabolic syndrome features in the United States: Liver ultrasound data from the National Health and Nutrition Examination Survey.

OBJECTIVE Experimental and observational studies suggest a role for uric acid in non-alcoholic fatty liver disease (NAFLD). We examined the association between serum uric acid levels and NAFLD in a large population-based study from the United States. MATERIALS/METHODS A cross-sectional analysis of 10,732 nondiabetic adults who participated in the National Health and Nutrition Examination Survey 1988-1994. Sex specific uric acid quartiles were defined: ≤5.2, 5.3-6.0, 6.1-6.9, and >6.9mg/dL for men and ≤3.7, 3.8-4.5, 4.6-5.3, and >5.3mg/dL for women. NAFLD presence and severity were defined by ultrasonographic detection of steatosis in the absence of other liver diseases. We modeled the probability that more severe NAFLD would be associated with the highest quartiles of uric acid. RESULTS Compared to the 1st quartile, the odds ratio for NAFLD was 1.79 (95% C.I. 1.49-2.15, p<0.001) and 3.14 (95% C.I. 2.63-3.75, p<0.001) for the 3rd and 4th quartiles, respectively. After adjusting for demographics, hypertension, waist circumference, triglycerides, high-density lipoprotein-cholesterol, homeostasis model assessment-estimated insulin resistance, estimated glomerular filtration rate, and aspartate aminotransferase, uric acid (4th quartile) was significantly associated with NAFLD (odds ratio 1.43; 95% C.I. 1.16-1.76, p<0.001). Positive parameter estimates suggest increasing uric acid is associated with greater severity of NAFLD. CONCLUSIONS Elevated uric acid level is independently associated with ultrasound-diagnosed NAFLD in a nationally representative sample of United States nondiabetic adults. Increasing uric acid is associated with increasing severity of NAFLD on ultrasonography. These findings warrant further studies on the role of uric acid in NAFLD.

The effect of two energy-restricted diets, a low-fructose diet versus a moderate natural fructose diet, on weight loss and metabolic syndrome parameters: a randomized controlled trial

One of the proposed causes of obesity and metabolic syndrome is the excessive intake of products containing added sugars, in particular, fructose. Although the ability of excessive intake of fructose to induce metabolic syndrome is mounting, to date, no study has addressed whether a diet specifically lowering fructose but not total carbohydrates can reduce features of metabolic syndrome. A total of 131 patients were randomized to compare the short-term effects of 2 energy-restricted diets-a low-fructose diet vs a moderate natural fructose diet-on weight loss and metabolic syndrome parameters. Patients were randomized to receive 1500, 1800, or 2000 cal diets according to sex, age, and height. Because natural fructose might be differently absorbed compared with fructose from added sugars, we randomized obese subjects to either a low-fructose diet (<20 g/d) or a moderate-fructose diet with natural fruit supplements (50-70 g/d) and compared the effects of both diets on the primary outcome of weight loss in a 6-week follow-up period. Blood pressure, lipid profile, serum glucose, insulin resistance, uric acid, soluble intercellular adhesion molecule-1, and quality of life scores were included as secondary outcomes. One hundred two (78%) of the 131 participants were women, mean age was 38.8 ± 8.8 years, and the mean body mass index was 32.4 ± 4.5 kg/m(2). Each intervention diet was associated with significant weight loss compared with baseline. Weight loss was higher in the moderate natural fructose group (4.19 ± 0.30 kg) than the low-fructose group (2.83 ± 0.29 kg) (P = .0016). Compared with baseline, each intervention diet was associated with significant improvement in secondary outcomes. Reduction of energy and added fructose intake may represent an important therapeutic target to reduce the frequency of obesity and diabetes. For weight loss achievement, an energy-restricted moderate natural fructose diet was superior to a low-fructose diet.

Sucrose induces fatty liver and pancreatic inflammation in male breeder rats independent of excess energy intake

Fructose induces metabolic syndrome in rats; but studies have been criticized for using high concentrations of fructose that are not physiologic, for using only pure fructose, and for not controlling for energy intake. We tested the hypothesis that a 40% sucrose diet (containing 20% fructose) might induce features of metabolic syndrome in male breeder rats independent of excess energy intake. Male Sprague-Dawley breeder rats were pair fed 40% sucrose or isocaloric starch diet for 4 months and evaluated for metabolic syndrome and diabetes. In vitro studies were performed in rat insulinoma cells (RIN-m5F) exposed to uric acid, and markers of inflammation were assessed. Rats fed a 40% sucrose diet developed accelerated features of metabolic syndrome with up-regulation of fructose-dependent transporter Glut5 and fructokinase. Fatty liver and low-grade pancreatic inflammation also occurred. Uric acid was found to stimulate inflammatory mediators and oxidative stress in islet cells in vitro. Sucrose, at concentrations ingested by a subset of Americans, can accelerate metabolic syndrome, fatty liver, and type 2 diabetes mellitus in male breeder rats; and the effects are independent of excess energy intake.

Uric Acid and Hypertension: Cause or Effect?

Uric acid was first associated with primary hypertension in 1874, yet its role in this condition remains unclear. Historically, uric acid was thought to be a secondary response to hypertension or its associated conditions. However, more recent experimental and clinical studies suggest that uric acid could have a contributory role in the pathogenesis of elevated blood pressure. More studies are needed to help dissect the potential mechanisms by which uric acid could initiate this response. It remains possible that uric acid is a marker for xanthine oxidase–associated oxidants and that the latter could be driving the hypertensive response. However, the weight of the evidence suggests that uric acid is a true modifying and possibly causal factor for human primary hypertension. Hence, early management of hyperuricemia might delay the development of essential hypertension.