Serum uric acid concentrations increase in chronic kidney disease (CKD) and may lead to tubular injury, endothelial dysfunction, oxidative stress, and intrarenal inflammation. Whether uric acid ...concentrations are associated with kidney failure and death in CKD is unknown.
Prospective observational cohort study.
3,885 individuals with CKD stages 2 to 4 enrolled in the Chronic Renal Insufficiency Cohort (CRIC) between June 2003 and September 2008 and followed up through March 2013.
Baseline uric acid concentrations.
Kidney failure (initiation of dialysis therapy or transplantation) and all-cause mortality.
During a median follow-up of 7.9 years, 885 participants progressed to kidney failure and 789 participants died. After adjustment for demographic, cardiovascular, and kidney-specific covariates, higher uric acid concentrations were independently associated with risk for kidney failure in participants with estimated glomerular filtration rates (eGFRs) ≥ 45mL/min/1.73m2 (adjusted HR per 1−standard deviation greater baseline uric acid, 1.40; 95% CI, 1.12-1.75), but not in those with eGFRs<30mL/min/1.73m2. There was a nominally higher HR in participants with eGFRs of 30 to 44mL/min/1.73m2 (adjusted HR, 1.13; 95% CI, 0.99-1.29), but this did not reach statistical significance. The relationship between uric acid concentration and all-cause mortality was J-shaped (P=0.007).
Potential residual confounding through unavailable confounders; lack of follow-up measurements to adjust for changes in uric acid concentrations over time.
Uric acid concentration is an independent risk factor for kidney failure in earlier stages of CKD and has a J-shaped relationship with all-cause mortality in CKD. Adequately powered randomized placebo-controlled trials in CKD are needed to test whether urate lowering may prove to be an effective approach to prevent complications and progression of CKD.
Higher serum uric acid levels, even within the reference range, are strongly associated with increased activity of the renin-angiotensin system (RAS) and risk of incident hypertension. However, the ...effect of lowering serum uric acid on RAS activity in humans is unknown, although the data that lowering serum uric acid can reduce BP are conflicting.
In a double-blind placebo-controlled trial conducted from 2011 to 2015, we randomly assigned 149 overweight or obese adults with serum uric acid ≥5.0 mg/dl to uric acid lowering with either probenecid or allopurinol, or to placebo. The primary endpoints were kidney-specific and systemic RAS activity. Secondary endpoints included mean 24-hour systolic BP, mean awake and asleep BP, and nocturnal dipping.
Allopurinol and probenecid markedly lowered serum uric acid after 4 and 8 weeks compared with placebo (mean serum uric acid in allopurinol, probenecid, and placebo at 8 weeks was 2.9, 3.5, and 5.6 mg/dl, respectively). The change in kidney-specific RAS activity, measured as change in the median (interquartile range) renal plasma flow response to captopril (in ml/min per 1.73 m
) from baseline to 8 weeks, was -4 (-25 to 32) in the probenecid group (
=0.83), -4 (-16 to 9) in the allopurinol group (
=0.32), and 1 (-21 to 17) in the placebo group (
=0.96), with no significant treatment effect (
=0.77). Similarly, plasma renin activity and plasma angiotensin II levels did not significantly change with treatment. The change in mean (±SD) 24-hour systolic BPs from baseline to 8 weeks was -1.6±10.1 with probenecid (
=0.43), -0.4±6.1 with allopurinol (
=0.76), and 0.5±6.0 with placebo (
=0.65); there was no significant treatment effect (
=0.58). Adverse events occurred in 9%, 12%, and 2% of those given probenecid, allopurinol, or placebo, respectively.
In contrast to animal experiments and observational studies, this randomized, placebo-controlled trial found that uric acid lowering had no effect on kidney-specific or systemic RAS activity after 8 weeks or on mean systolic BP. These data do not support the hypothesis that higher levels of uric acid are a reversible risk factor for increased BP.
OBJECTIVE:Disruption of vitamin D signaling in rodents causes activation of the rennin–angiotensin system (RAS) and development of hypertension. Observational studies in humans found lower ...circulating 25-hydroxyvitamin D 25(OH)D is associated with increased RAS activity and blood pressure (BP). We performed the first randomized control trial to investigate the effects of vitamin D supplementation on the RAS in humans.
METHODS:Vitamin D deficient, 25(OH)D ≤20 ng/ml), overweight individuals without hypertension were randomized into a double-blind, placebo-controlled trial of 8-weeks treatment with ergocalciferol or placebo. Kidney-specific RAS activity, measured using renal plasma flow response to captopril in high sodium balance, was assessed at baseline and 8 weeks, as was systemic RAS activity and 24-h ambulatory BP.
RESULTS:In total, 84 participants completed the study. Mean 25OHD levels increased from 14.7 to 30.3 ng/ml in the ergocalciferol group, P value < 0.0001, and from 14.3 to 17.4 ng/ml in the placebo group, P value = 0.3. The renal plasma flow response to captopril was 33.9 ± 56.1 ml/min per 1.73 m at baseline and 35.7 ± 47.7 ml/min per 1.73 m at 8 weeks in the ergocalciferol group (P value = 0.83); and was 37.3 ± 46.9 ml/min per 1.73 m at baseline and 35.9 ± 26.2 ml/min per 1.73 m at 8 weeks in the placebo group (P value = 0.78). Ergocalciferol had no effect on PRA, AngII, or 24-h BP measurements.
CONCLUSIONS:This trial found no benefit from correcting vitamin D deficiency on RAS activity or BP after 8 weeks. These findings are not consistent with the hypothesis that vitamin D is a modifiable target for lowering BP in vitamin D deficient individuals.
IMPORTANCE Loss-of-function mutations in the melatonin receptor are associated with insulin resistance and type 2 diabetes. Additionally, in a cross-sectional analysis of persons without diabetes, ...lower nocturnal melatonin secretion was associated with increased insulin resistance. OBJECTIVE To study the association between melatonin secretion and the risk of developing type 2 diabetes. DESIGN, SETTING, AND PARTICIPANTS Case-control study nested within the Nurses' Health Study cohort. Among participants without diabetes who provided urine and blood samples at baseline in 2000, we identified 370 women who developed type 2 diabetes from 2000-2012 and matched 370 controls using risk-set sampling. MAIN OUTCOME MEASURES Associations between melatonin secretion at baseline and incidence of type 2 diabetes were evaluated with multivariable conditional logistic regression controlling for demographic characteristics, lifestyle habits, measures of sleep quality, and biomarkers of inflammation and endothelial dysfunction. RESULTS The median urinary ratios of 6-sulfatoxymelatonin to creatinine were 28.2 ng/mg (5%-95% range, 5.5-84.2 ng/mg) among cases and 36.3 ng/mg (5%-95% range, 6.9-110.8 ng/mg) among controls. Women with lower ratios of 6-sulfatoxymelatonin to creatinine had increased risk of diabetes (multivariable odds ratio, 1.48 95% CI, 1.11-1.98 per unit decrease in the estimated log ratio of 6-sulfatoxymelatonin to creatinine). Compared with women in the highest ratio category of 6-sulfatoxymelatonin to creatinine, those in the lowest category had a multivariable odds ratio of 2.17 (95% CI, 1.18-3.98) of developing type 2 diabetes. Women in the highest category of melatonin secretion had an estimated diabetes incidence rate of 4.27 cases/1000 person-years compared with 9.27 cases/1000 person-years in the lowest category. CONCLUSIONS AND RELEVANCE Lower melatonin secretion was independently associated with a higher risk of developing type 2 diabetes. Further research is warranted to assess if melatonin secretion is a modifiable risk factor for diabetes within the general population.
The kidney is influenced by circadian rhythms and is entrained to the sleep-wake cycle allowing anticipation of the metabolic and physiological demands of the kidney throughout a 24-hour cycle. ...Although sleep disruption has been studied extensively in cardiovascular and metabolic disease, its association with chronic kidney disease has not been shown. We examined this in a prospective cohort study of 4238 participants from the Nurses’ Health Study and analyzed the association of self-reported sleep duration with decline in renal function over an 11-year period (1989 to 2000). Individuals who reported shorter sleep duration were more likely to experience a rapid decline in estimated glomerular filtration rate (30% or more). Compared with sleeping 7 to 8 hours per night, the adjusted odds ratios for a rapid decline in renal function were a significant 1.79 (95% CI, 1.06–3.03) for 5 hours or less sleep per night, a significant 1.31 (95% CI, 1.01–1.71) for 6 hours sleep per night, but an insignificant 0.88 (95% CI, 0.50–1.57) for 9 or more hours sleep per night. Similarly, there was a significant trend in the adjusted annualized decline in estimated glomerular filtration rate of 1.2 ml/min/1.73 m2/year, 0.9 ml/min/1.73 m2/year, 0.8 ml/min/1.73 m2/year, and 0.8 ml/min/1.73 m2/year for individuals sleeping 5 hours or less per night, 6 hours per night, 7 to 8 hours per night, and 9 hours or more per night, respectively. Thus, shorter sleep duration is prospectively and independently associated with faster decline in renal function.
Low nocturnal melatonin secretion is associated with cardiovascular risk factors, diabetes and hypertension, while individuals with prevalent cardiovascular disease have lower nocturnal melatonin ...levels. However, the prospective association of melatonin secretion with myocardial infarction (MI) has not been studied. We aimed to study the association between melatonin secretion and the risk of developing MI.
We performed a prospective nested case-control study of participants from the Nurses' Health Study cohorts I and II. A total of 209 incident cases of fatal and non-fatal MI were identified among women who provided first morning voided urine specimens at baseline and were matched to 209 controls. Nocturnal melatonin secretion was assessed using 6-sulfatoxymelatonin concentrations in morning urines normalised to the urines' creatinine concentration. Multivariable conditional logistic regression was used to analyse associations independent of important risk factors.
Lower melatonin secretion was significantly associated with a higher risk of MI. After conditioning on matching variables, the OR for every one unit lower log-transformed sulfatoxymelatonin/creatinine ratio was 1.51 (95% CI 1.16 to 1.96). In multivariable models controlling for factors included in the American Heart Association Cardiovascular Risk Score plus circadian factors, every one unit lower in the ratio was associated with a significantly increased risk of MI (OR, 1.40; 95% CI 1.02 to 1.93). Women in the highest category had an estimated absolute risk of MI of 84 cases per 100 000 person-years compared with 197 cases per 100 000 person-years in the lowest category. The association was strongly modified by body mass index (BMI) (p value for interaction=0.02).
Lower melatonin secretion was significantly associated with a greater risk of incident MI in women with increased BMI. Melatonin may be a novel and modifiable risk factor for MI among such women.
Background Increased systolic blood pressure variability between outpatient visits is associated with increased incidence of cardiovascular end points. However, few studies have examined the ...association of visit-to-visit variability in systolic blood pressure with clinically relevant kidney disease outcomes. We analyzed the association of systolic blood pressure visit-to-visit variability with renal and cardiovascular morbidity and mortality among individuals with diabetes and nephropathy. Study Design Observational analysis of IDNT (Irbesartan Diabetic Nephropathy Trial) and the RENAAL (Reduction of End Points in Non−Insulin-Dependent Diabetes With the Angiotensin II Antagonist Losartan) Study. Setting & Participants 2,739 participants with type 2 diabetes and nephropathy with at least 1 year of blood pressure measurements available. Predictors Systolic blood pressure visit-to-visit variability was calculated from the SD of the systolic blood pressure from 4 visits occurring 3-12 months postrandomization. Outcomes The kidney disease outcome was defined as time to confirmed doubling of serum creatinine level, end-stage renal disease, or death; the cardiovascular outcome was defined as time to cardiovascular death, myocardial infarction, stroke, hospitalization for heart failure, or revascularization. Results Mean visit-to-visit variability in systolic blood pressure from 3 to 12 months postrandomization was 12.0 ± 6.8 (SD) mm Hg. Following this ascertainment period, there were 954 kidney disease and 542 cardiovascular events. Greater systolic blood pressure visit-to-visit variability was associated independently with increased risk of the composite kidney disease end point (HR per 1-SD increment, 1.08 95% CI, 1.01-1.16; P = 0.02) and end-stage renal disease, but not with the cardiovascular outcome. Limitations Observational study with the potential for confounding. Conclusions In diabetic individuals with nephropathy, systolic blood pressure visit-to-visit variability is associated independently with hard kidney disease outcomes.
Insulin-like growth factors and their receptor (IGF-1R) have been implicated in cancer pathophysiology. We demonstrate that IGF-1R is universally expressed in various hematologic (multiple myeloma, ...lymphoma, leukemia) and solid tumor (breast, prostate, lung, colon, thyroid, renal, adrenal cancer, retinoblastoma, and sarcoma) cells. Specific IGF-1R inhibition with neutralizing antibody, antagonistic peptide, or the selective kinase inhibitor NVP-ADW742 has in vitro activity against diverse tumor cell types (particularly multiple myeloma), even those resistant to conventional therapies, and triggers pleiotropic antiproliferative/proapoptotic molecular sequelae, delineated by global transcriptional and proteomic profiling. NVP-ADW742 monotherapy or its combination with cytotoxic chemotherapy had significant antitumor activity in an orthotopic xenograft MM model, providing in vivo proof of principle for therapeutic use of selective IGF-1R inhibitors in cancer.
Histone deacetylases (HDACs) affect cell growth at the transcriptional level by regulating the acetylation status of nucleosomal histones. HDAC inhibition induces differentiation and/or apoptosis in ...transformed cells. We recently showed that HDAC inhibitors, such as suberoylanilide hydroxamic acid (SAHA), potently induce apoptosis of human multiple myeloma (MM) cells. In this study, we focused on MM as a model to study the transcriptional profile of HDAC inhibitor treatment on tumor cells and to address their pathophysiological implications with confirmatory mechanistic and functional assays. We found that MM cells are irreversibly committed to cell death within few hours of incubation with SAHA. The molecular profile of MM cells before their commitment to SAHA-induced cell death is hallmarked by a constellation of antiproliferative and/or proapoptotic molecular events, including down-regulation of transcripts for members of the insulin-like growth factor (IGF)/IGF-1 receptor (IGF-1R) and IL-6 receptor (IL-6R) signaling cascades, antiapoptotic molecules (e.g., caspase inhibitors), oncogenic kinases, DNA synthesis/repair enzymes, and transcription factors (e.g., XBP-1, E2F-1) implicated in MM pathophysiology. Importantly, SAHA treatment suppresses the activity of the proteasome and expression of its subunits, and enhances MM cell sensitivity to proteasome inhibition by bortezomib (PS-341). SAHA also enhances the anti-MM activity of other proapoptotic agents, including dexamethasone, cytotoxic chemotherapy, and thalidomide analogs. These findings highlight the pleiotropic antitumor effects of HDAC inhibition, and provide the framework for future clinical applications of SAHA to improve patient outcome in MM.
Increased systolic BP visit-to-visit variability (SBV) may be associated with higher overall mortality and cardiovascular events. However, few studies have examined these associations in patients ...with CKD, and the relation of SBV with CKD progression and ESRD has not been shown. This study analyzed the association of SBV with overall mortality, cardiovascular mortality, cardiovascular events, and renal events among individuals enrolled in the African American Study of Kidney Disease (AASK) trial.
This was a prospective observational study of 908 participants during the trial phase of the AASK study, with at least 1 year of BP measurements available and followed for 3-6.4 years. SBV was calculated as the SD of the systolic pressure from five visits occurring 3-12 months after randomization. The association of SBV with risk of overall mortality, cardiovascular mortality, a composite of fatal and nonfatal cardiovascular events, and a composite of renal events was assessed using proportional hazards regression and adjusting for multiple potential confounders.
Greater SBV was associated with higher overall mortality. The adjusted hazard ratio (95% confidence interval) was 2.82 (1.14-6.95) comparing the highest with lowest tertile of SBV. A similar comparison revealed that greater SBV was also associated with cardiovascular mortality (adjusted hazard ratio, 4.91; 1.12-21.50). SBV was associated with both the cardiovascular renal composite endpoints in unadjusted but not adjusted analyses.
In African Americans with CKD, SBV is strongly and independently associated with overall and cardiovascular mortality.
PDF
