Uric Acid: The Lower the Better?

BACKGROUND: Uric acid (UA) is still considered a risk factor, or even a causative agent, for chronic kidney disease (CKD); however, a few, important, clinical questions remain unanswered; in particular: when and whether urate-lowering therapy should be commenced in subjects with asymptomatic hyperuricemia and/or monosodium urate crystals deposition? What is the most appropriate UA target to be achieved and how long does it need to be maintained? How does treatment need be adjusted in patients with chronic kidney disease? SUMMARY: The observational and intervention studies available do not fully answer such questions, and a treatment to target trial is required. We provide here some preliminary opinion on how such a trial might be designed. A final unresolved issue relates to the possible (if any) dangers of overtreatment of hyperuricemia, leading to "hypouricemia," which may occur more frequently with newer, more potent, drugs. A U- or J-shaped association has been found between UA levels and mortality in epidemiologic studies; patients with congenital hypouricemia are more prone to exercise-induced renal failure; a theoretical concern, linked to more complete Xanthine Oxidase inhibition, may involve xanthine nephropathy, although up to now, it has been observed almost exclusively in patients with tumor lysis syndrome. Key Messages: Although there is no definite answer to the title question at the moment, available information tends to indicate a treatment target with serum UA levels between 5.0 and 6.0 mg/dL as reasonable.

Increased Urinary Cystatin-C Levels Correlate with Reduced Renal Volumes in Neonates with Intrauterine Growth Restriction.

BACKGROUND: Exposure to intrauterine growth retardation (IUGR) can have a negative impact on nephrogenesis resulting in limited fetal kidney development and supporting the hypothesis that IUGR represents a risk for renal function and long-term renal disease. Cystatin-C (Cys-C), a strong inhibitor of cysteine proteinases, is freely filtered by the kidney glomerulus and is reabsorbed by the tubules, where it is almost totally catabolized; what remains is subsequently eliminated in urine. In tubular diseases and in hyperfiltration conditions, it seems reasonable to postulate that Cys-C degradation would decrease, and consequently an increase in its urinary elimination would be observed. OBJECTIVES: The aim of this study was to investigate the urinary excretion of Cys-C simultaneously with the assessment of renal volumes in adequate for gestational age (AGA) and IUGR neonates in order to identify its clinical value in IUGR. METHODS: Urinary Cys-C levels were measured using the enzyme immunoassay DetectX® Human Cystatin C kit in IUGR and AGA neonates. Whole renal and renal cortex volumes were assessed with ultrasounds (Vocal II; Software, GE). RESULTS: Urinary Cys-C levels in IUGR were significantly higher than those found in AGA and were negatively correlated to reduced whole renal and renal cortex volumes. CONCLUSIONS: The increased levels of Cys-C in the urine of neonates with IUGR were significantly associated with reduced renal/renal cortex volumes, suggesting that Cys-C could be taken as a surrogate of nephron mass. It also could be used as an early biochemical marker to identify IUGR neonates at high risk of developing long-term renal disease and to select patients for monitoring during childhood.

Asymptomatic hyperuricemia following renal transplantation.

Evidence is accumulating indicating a role for uric acid in the genesis and progression of kidney disease, and a few studies are beginning to show a possible beneficial effect of urate-lowering therapy. Whether this holds true for renal allograft recipients is not clear. In this short review evidence from epidemiological as well as intervention studies is summarized and discussed, with some practical considerations presented at the end.

The Effect of Psychological Intervention on Thirst and Interdialytic Weight Gain in Patients on Chronic Hemodialysis: A Randomized Controlled Trial.

OBJECTIVE: Patients on hemodialysis (HD) are unable to eliminate excess fluid and must adhere to a regimen of dietary fluid restriction to prevent volume overload. Thirst represents a major obstacle to the achievement of such a goal. The aim of our study was (1) to assess the association of thirst and xerostomia, measured by validated questionnaires, Dialysis Thirst Inventory and Xerostomia Inventory with interdialytic weight gain (IDWG) and (2) to evaluate in a randomized controlled trial (RCT), the effect of psychological intervention on IDWG and thirst. STUDY DESIGN: Cross-sectional evaluation of association of thirst and IDWG and single-blind RCT of psychological intervention on IDWG management. SETTING: Outpatient dialysis unit. SUBJECTS: The cross-sectional evaluation included 117 patients on HD (age, 71 ± 13 years); among these, 54 were selected for the RCT. INTERVENTION: The questionnaires were administered to all the participating patients; IDWG (4-week average), Kt/V, predialysis blood pressure, dialyzate sodium, hematocrit, serum electrolytes, parathyroid hormone, and patients' medications were recorded. Fifty-four patients were randomized on a 1:1 basis to usual treatment (including dietary advice) or psychological intervention, consisting of group sessions, held once a week for 5 weeks; IDWG and all the other parameters were rechecked after 6 weeks and 6 months. MAIN OUTCOME MEASURE: IDWG change from baseline. RESULTS: Dialysis Thirst Inventory score was correlated with IDWG (ρ = 0.575; P < .001), body mass index (ρ = 0.257; P = .005), and inversely with age (ρ = -0.344; P < .001). A small but significant decrease of IDWG compared to baseline was observed in the intervention group (baseline 1332 ± 338 g/day; at 6 weeks, 1183 ± 258 g/day; at 6 months, 1203 ± 284 g/day; P < .001). No IDWG changes with respect to baseline occurred in controls (baseline 1310 ± 333 g/day; at 6 weeks, 1336 ± 340 g/day; at 6 months, 1323 ± 328 g/day; P = .57). The secondary outcomes were not affected by the intervention. CONCLUSIONS: The findings of our study show that a psychological support may help managing IDWG in HD patients.

Uric acid and chronic kidney disease: A time to act?

A role for uric acid in the pathogenesis and progression of renal disease had been proposed almost a century ago, but, too hastily dismissed in the early eighties. A body of evidence, mostly accumulated during the last decade, has led to a reappraisal of the influence of uric acid on hypertension, cardiovascular, and renal disease. The focus of this review will be solely on the relationship between serum uric acid and renal function and disease. We will review experimental evidence derived from animal and human studies, evidence gathered from a number of epidemiological studies, and from the few (up to now) studies of uric-acid-lowering therapy. Some space will be also devoted to the effects of uric acid in special populations, such as diabetics and recipients of kidney allografts. Finally we will briefly discuss the challenges of a trial of uric-acid-lowering treatment, and the recent suggestions on how to conduct such a trial.

Serum uric acid and pre-eclampsia: an update.

The association between uric acid (UA) and pre-eclampsia has been known for years, but the prognostic value of UA has been debated. This article will review recent evidences, evaluating UA as a prognostic factor for pre-eclampsia, both in the general population and in women with gestational hypertension, and as a predictor of disease severity and adverse maternal-fetal outcome. Finally, studies investigating UA as a putative pathogenic factor for pre-eclampsia are briefly mentioned.

Performance of aß1-40, aß1-42, total tau, and phosphorylated tau as predictors of dementia in a cohort of patients with mild cognitive impairment.

Mild cognitive impairment (MCI) is a common condition in the elderly which may remain stable along time (MCI-MCI) or evolve into Alzheimer's disease (MCI-AD) or other dementias. Cerebrospinal fluid (CSF) classical biomarkers, i.e., amyloid-ß 1-42 (Aß1-42), total tau (t-tau), and phosphorylated tau (p-tau) reflect the neuropathological changes taking place in AD brains, thus disclosing the disease in its prodromal phase. With the aim to evaluate the power of each biomarker and/or their combination in predicting AD progression, we have measured CSF Aß1-40, Aß1-42, t-tau, and p-tau in patients with AD, MCI-MCI, MCI-AD, and other neurological diseases without dementia (OND) followed up for four years. Aß1-42 levels were significantly lower in AD and MCI-AD than in MCI-MCI. T-tau and p-tau levels were significantly increased in AD and MCI-AD versus OND and MCI-MCI. The Aß1-42/Aß1-40 ratio showed a significant decrease in AD and MCI-AD as compared to MCI-MCI. Both Aß1-42/t-tau and Aß1-42/p-tau ratios showed significantly decreased values in AD and MCI-AD with respect to OND and MCI-MCI. Aß1-42/p-tau ratio was the best parameter for discriminating MCI-AD from MCI-MCI (sensitivity 81%, specificity 95%), being also correlated with the annual change rate in the Mini Mental State Examination annual change rate score (MMSE-ACR, rS = -0.71, p < 0.0001). Survival analysis showed that 81% of MCI with a low Aß1-42/p-tau ratio (<1372) progressed to AD. The best model of logistic regression analysis retained Aß1-42 and p-tau (sensitivity 75%, 95%CI: 70-80%; specificity 96%, 95%CI: 94-98%). We can conclude that Aß1-42 and p-tau reliably predict conversion to AD in MCI patients.

Prognostic significance of serum uric acid in women with gestational hypertension.

Aim of our study was to ascertain, prospectively, whether serum uric acid is a suitable predictor of preeclampsia and/or the delivery of small-for-gestational-age infants in women with gestational hypertension. We screened 206 primiparas, with a singleton pregnancy, referred for recent onset of hypertension. At presentation, we measured serum uric acid, creatinine, blood glucose, hemoglobin and platelet level, and 24-hour proteinuria, as well as office and 24-hour blood pressures. We followed the women until 1 month after delivery and recorded pregnancy outcome. After logistic regression analysis, uric acid resulted a significant predictor of preeclampsia, with an unadjusted odds ratio of 9.1 (95% CI: 4.8 to 17.4; P<0.001); after adjustment for age, gestation week, hemoglobin and platelet levels, serum creatinine, office and 24-hour average systolic and diastolic blood pressures, it was 7.1 (95% CI: 3.2 to 15.7; P<0.001). Regarding the association between maternal serum uric acid and the chance of giving birth to a small-for-gestational-age infant, the unadjusted odds ratio was 1.7 (95% CI: 1.4 to 2.2; P<0.001), and it was 1.6 (95% CI: 1.1 to 2.4; P=0.02) after adjustment. Receiver operating characteristic analysis showed that serum uric acid, at a 309-µmol/L cutoff, predicted the development of preeclampsia (area under the curve: 0.955), with 87.7% sensitivity and 93.3% specificity, and the delivery of small-for-gestational-age infants (area under the curve: 0.784) with 83.7% sensitivity and 71.7% specificity. In conclusion, the results of our study show that serum uric acid is a reliable predictor of preeclampsia in women referred for gestational hypertension.

[Uric acid and cardiorenal risk: marker or cause?]. / Acido urico e rischio cardiorenale: marker o concausa?

An association between high levels of serum uric acid and cardiovascular as well as renal disease has been proposed for many decades. However, only recently compelling basic science data, small clinical trials, and epidemiological studies have provided support to the idea of a true causal effect. In this noncomprehensive review, we present recently published data that evaluate the association between hyperuricemia and selected cardiovascular and renal diseases, with a final conclusion about the possibility of this association being causal.

Cerebrospinal fluid Tau/α-synuclein ratio in Parkinson's disease and degenerative dementias.

Although alpha-synuclein is the main constituent of Lewy bodies, cerebrospinal fluid determination on its own does not seem fundamental for the diagnosis of synucleinopathies. We evaluated whether the combination of classical biomarkers, Aß(1-42) , total tau, phosphorylated tau, and α-synuclein can improve discrimination of Parkinson's disease, dementia with Lewy bodies, Alzheimer's disease, and frontotemporal dementia. Aß(1-42) , total tau, phosphorylated tau, and α-synuclein were measured in a series of patients with Parkinson's disease (n = 38), dementia with Lewy bodies (n = 32), Alzheimer's disease (n = 48), frontotemporal dementia (n = 31), and age-matched control patients with other neurological diseases (n = 32). Mean α-synuclein levels in cerebrospinal fluid were significantly lower in the pathological groups than in cognitively healthy subjects. An inverse correlation of α-synuclein with total tau (r = -0.196, P < .01) was observed. In the group of patients with Parkinson's disease, Aß(1-42) , total tau, and phosphorylated tau values were similar to controls, whereas total tau/α-synuclein and phosphorylated tau/α-synuclein ratios showed the lowest values. Cerebrospinal fluid α-synuclein alone did not provide relevant information for Parkinson's disease diagnosis, showing low specificity (area under the curve, 0.662; sensitivity, 94%; specificity, 25%). Instead, a better performance was obtained with the total tau/α-syn ratio (area under the curve, 0.765; sensitivity, 89%; specificity, 61%). Combined determination of α-synuclein and classical biomarkers in cerebrospinal fluid shows differential patterns in neurodegenerative disorders. In particular, total tau/α-synuclein and phosphorylated tau/α-synuclein ratios can contribute to the discrimination of Parkinson's disease. © 2011 Movement Disorder Society.

An unusual case of rhabdomyolysis.

We report an unusual case of rhabdomyolysis due to coturnism (food poisoning caused by eating quails). The patient's clinical course is described, and possible pathogenetic mechanisms of this syndrome are briefly discussed.

Association of uric acid with change in kidney function in healthy normotensive individuals.

BACKGROUND: Despite recent evidence, the role of uric acid as a causal factor in the pathogenesis and progression of kidney disease remains controversial, partly because of the inclusion in epidemiologic studies of patients with hypertension, diabetes, and/or proteinuria. STUDY DESIGN: Prospective observational cohort. SETTING & PARTICIPANTS: 900 healthy normotensive adult blood donors (153 women, 747 men) evaluated at baseline and after 5 years. PREDICTOR: Serum uric acid level. OUTCOMES: Decrease in estimated glomerular filtration rate (eGFR) >10 mL/min/1.73 m(2), computed using the Modification of Diet in Renal Disease (MDRD) Study equation, with secondary analyses examining similar decreases using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and Cockcroft-Gault equations. RESULTS: During a median follow-up of 59 months, eGFR decreased from 97 +/- 16 to 88 +/- 14 mL/min/1.73 m(2). Higher serum uric acid levels were associated with a greater likelihood of eGFR decrease in both women and men (HR, 1.13 [95% CI, 1.04-1.39] per each 1-mg/dL increase in uric acid level); in multivariable analyses adjusting for age, sex, body mass index, blood glucose level, total cholesterol level, mean blood pressure, urine albumin-creatinine ratio, and serum triglyceride level, the association remained highly significant (HR, 1.28 [95% CI, 1.12-1.48]). Results were similar using different estimating equations and when the association was examined in sex-specific subgroups. LIMITATIONS: Analyses were based on a single baseline uric acid measurement. Women are underrepresented. CONCLUSIONS: In healthy normotensive individuals, serum uric acid level is an independent risk factor for decreased kidney function.

Day-to-day variability of electrocardiographic diagnosis of left ventricular hypertrophy in hypertensive patients. Influence of electrode placement.

OBJECTIVE: Although electrocardiography (ECG) is recommended in all subjects with hypertension, no information is available on the influence exerted by random changes in the placement of electrodes on the day-to-day variability of ECG criteria for diagnosis of left ventricular hypertrophy (LVH). METHODS: In a multicentre, randomized study, two standard 12-lead ECG were recorded, 24 h apart, from 276 consecutive hypertensive patients (mean age 65 +/- 12 years, 49.6% men). Overall, 142 patients were randomized to ECG with the position of electrodes marked on the skin using a dermographic pen and 134 to traditional ECG without marking the position of electrodes. Day-to-day variability of ECG criteria for LVH was compared between the two groups. RESULTS: Coefficients of variation (SD of the difference between paired voltage measurements divided by the mean value) varied consistently among subjects randomized to ECG without dermographic pen, ranging from 30% (R wave in lead I) to 81% (R wave in lead V5). Dermographic pen led to a lesser variability of ECG voltages with consequent reduction in the coefficients of variation, which ranged from 26% (R-wave amplitude in lead I) to 43% (R-wave amplitude in lead V5). The proportion of subjects who changed classification status for LVH ('reclassification rate') from the first to the second ECG session (LVH present in session 1 and absent in session 2, or vice versa) decreased for effect of dermographic pen from 11 to 4% (P = 0.040) with the Cornell voltage, from 19 to 11% (P = 0.029) with the Sokolow-Lyon voltage, and from 18 to 7% with the Romhilt-Estes criterion (P = 0.018), but not with other criteria. In particular, the typical strain and the Cornell strain were associated with the lowest reclassification rates regardless of dermographic pen. CONCLUSIONS: Random changes in the position of ECG electrodes strongly impair the day-to-day reproducibility of Cornell voltage, Sokolow-Lyon and Romhilt-Estes criteria for LVH. The typical strain and Cornell strain criteria showed a lesser spontaneous day-to-day variability.

Microalbuminuria and uric acid in healthy subjects.

BACKGROUND: Microalbuminuria has been linked to cardiovascular (CV) risk in patients with diabetes or hypertension, and in an unselected general population; serum uric acid (UA) is emerging as a novel risk factor for CV disease. The aim of our study was to evaluate the prevalence of excess microalbuminuria and its relation to established CV risk factors and serum UA in healthy subjects. METHODS: We screened 900 healthy blood donors (age range, 20-65 years; 747 men, 153 women), and measured total, HDL and LDL cholesterol, blood glucose, serum and urinary creatinine, serum UA, blood pressure (BP) and microalbuminuria (urinary albumin/creatinine ratio, ACR). The Framingham risk score was also calculated. RESULTS: After excluding 52 participants, we found that in 848 participants (702 men, 146 women) the overall prevalence of excess ACR, using a 30 mg/g creatinine cutoff, was 9.3% (9.7% of men, 7.5% of women, p=0.16); adopting a gender-dependent cutoff, we found that the overall prevalence was 13.6% (15.1% of men, 6.2% of women, p<0.01). ACR was highly correlated to diastolic (r=0.88, p<0.001) and systolic (r=0.74, p<0.001) BP, and also--though not as strongly--to serum UA (r=0.38, p<0.001). In a stepwise multiple regression model, systolic and diastolic BP, total cholesterol, serum creatinine and UA were segregated as independent predictors of microalbuminuria (model R=0.91, R square=0.83). Correlation of serum UA to ACR remained significant, albeit attenuated (r=0.09, p=0.02), after adjustment for serum creatinine, total cholesterol, systolic and diastolic BP. CONCLUSIONS: The results of our study show ACR to be abnormal in a significant proportion of seemingly healthy subjects, and serum UA to be an independent predictor of microalbuminuria.