A Comparative Study of Serum Phosphate and Related Parameters in Chronic Kidney Disease between the USA and Japan.

INTRODUCTION: Recent studies have suggested a higher incidence of cardiovascular disease (CVD) among patients with chronic kidney disease (CKD) in the USA than in Japan. Hyperphosphatemia, a possible risk for CVD, may explain this difference; however, international differences in phosphate parameters in CKD have not been well elaborated. METHODS: By using the baseline data from the USA and the Japanese nation-wide, multicenter, CKD cohort studies; the Chronic Renal Insufficiency Cohort Study (CRIC, N = 3,870) and the Chronic Kidney Disease-Japan Cohort Study (CKD-JAC, N = 2,632), we harmonized the measures and compared clinical parameters regarding phosphate metabolism or serum phosphate, fibroblast growth factor-23 (FGF23), and parathyroid hormone (PTH), in the cross-sectional model. RESULTS: Multivariable linear regression analyses revealed that serum phosphate levels were significantly higher in CRIC across all levels of estimated glomerular filtration rate (eGFR) with the greatest difference being observed at lower levels of eGFR. Serum FGF23 and 25-hydroxy vitamin D (25OHD) levels were higher in CRIC, while PTH levels were higher in CKD-JAC at all levels of eGFR. Adjustments for demographics, 25OHD, medications, dietary intake or urinary excretion of phosphate, PTH, and FGF23 did not eliminate the difference in serum phosphate levels between the cohorts (0.43, 0.46, 0.54, 0.64, and 0.78 mg/dL higher in CRIC within eGFR strata of >50, 41-50, 31-40, 21-30, and ≤20 mL/min/1.73 m2, respectively). These findings were consistent when only Asian CRIC participants (N = 105) were included in the analysis. CONCLUSION: Serum phosphate levels in CRIC were significantly higher than those of CKD-JAC across all stages of CKD, which may shed light on the international variations in phosphate parameters and thus in cardiovascular risk among CKD patients. The key mechanisms for the substantial differences in phosphate parameters need to be elucidated.

Combination Treatment with Sodium Nitrite and Isoquercetin on Endothelial Dysfunction among Patients with CKD: A Randomized Phase 2 Pilot Trial.

BACKGROUND AND OBJECTIVES: Endothelial dysfunction is common among patients with CKD. We tested the efficacy and safety of combination treatment with sodium nitrite and isoquercetin on biomarkers of endothelial dysfunction in patients with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This randomized, double-blind, placebo-controlled phase 2 pilot trial enrolled 70 patients with predialysis CKD. Thirty-five were randomly assigned to combination treatment with sodium nitrite (40 mg twice daily) and isoquercetin (225 mg once daily) for 12 weeks, and 35 were randomly assigned to placebo. The primary outcome was mean change in flow-mediated vasodilation over the 12-week intervention. Secondary and safety outcomes included biomarkers of endothelial dysfunction, inflammation, and oxidative stress as well as kidney function, methemoglobin, and adverse events. Intention-to-treat analysis was conducted. RESULTS: Baseline characteristics, including age, sex, race, cigarette smoking, history of hypertension and diabetes, use of renin-angiotensin system blockers, BP, fasting glucose, lipid profile, kidney function, urine albumin-creatinine ratio, and endothelial biomarkers, were comparable between groups. Over the 12-week intervention, flow-mediated vasodilation increased 1.1% (95% confidence interval, -0.1 to 2.3) in the treatment group and 0.3% (95% confidence interval, -0.9 to 1.5) in the placebo group, and net change was 0.8% (95% confidence interval, -0.9 to 2.5). In addition, changes in biomarkers of endothelial dysfunction (vascular adhesion molecule-1, intercellular adhesion molecule-1, E-selectin, vWf, endostatin, and asymmetric dimethylarginine), inflammation (TNF-α, IL-6, C-reactive protein, IL-1 receptor antagonist, and monocyte chemoattractant protein-1), and oxidative stress (oxidized LDL and nitrotyrosines) were not significantly different between the two groups. Furthermore, changes in eGFR, urine albumin-creatinine ratio, methemoglobin, and adverse events were not significantly different between groups. CONCLUSIONS: This randomized phase 2 pilot trial suggests that combination treatment with sodium nitrite and isoquercetin did not significantly improve flow-mediated vasodilation or other endothelial function biomarkers but also did not increase adverse events compared with placebo among patients with CKD. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Nitrite, Isoquercetin, and Endothelial Dysfunction (NICE), NCT02552888.

Masked Hypertension and Elevated Nighttime Blood Pressure in CKD: Prevalence and Association with Target Organ Damage.

BACKGROUND AND OBJECTIVES: Masked hypertension and elevated nighttime BP are associated with increased risk of hypertensive target organ damage and adverse cardiovascular and renal outcomes in patients with normal kidney function. The significance of masked hypertension for these risks in patients with CKD is less well defined. The objective of this study was to evaluate the association between masked hypertension and kidney function and markers of cardiovascular target organ damage, and to determine whether this relationship was consistent among those with and without elevated nighttime BP. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a cross-sectional study. We performed 24-hour ambulatory BP in 1492 men and women with CKD enrolled in the Chronic Renal Insufficiency Cohort Study. We categorized participants into controlled BP, white-coat, masked, and sustained hypertension on the basis of clinic and 24-hour ambulatory BP. We obtained echocardiograms and measured pulse wave velocity in 1278 and 1394 participants, respectively. RESULTS: The percentages of participants with controlled BP, white-coat, masked, and sustained hypertension were 49.3%, 4.1%, 27.8%, and 18.8%, respectively. Compared with controlled BP, masked hypertension independently associated with low eGFR (-3.2 ml/min per 1.73 m(2); 95% confidence interval, -5.5 to -0.9), higher proteinuria (+0.9 unit higher in log2 urine protein; 95% confidence interval, 0.7 to 1.1), and higher left ventricular mass index (+2.52 g/m(2.7); 95% confidence interval, 0.9 to 4.1), and pulse wave velocity (+0.92 m/s; 95% confidence interval, 0.5 to 1.3). Participants with masked hypertension had lower eGFR only in the presence of elevated nighttime BP (-3.6 ml/min per 1.73 m(2); 95% confidence interval, -6.1 to -1.1; versus -1.4 ml/min per 1.73 m(2); 95% confidence interval, -6.9 to 4.0, among those with nighttime BP <120/70 mmHg; P value for interaction with nighttime systolic BP 0.002). CONCLUSIONS: Masked hypertension is common in patients with CKD and associated with lower eGFR, proteinuria, and cardiovascular target organ damage. In patients with CKD, ambulatory BP characterizes the relationship between BP and target organ damage better than BP measured in the clinic alone.

Performance of estimated glomerular filtration rate prediction equations in preeclamptic patients.

Accurate estimation of the glomerular filtration rate (GFR) in patients with preeclampsia requires the collection of a 24-hour urine and can have important therapeutic and diagnostic implications. This procedure is often difficult or impossible to accomplish in this patient group. In this study, the Cockcroft-Gault, the Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formulas were evaluated for their accuracy in determining GFR in the setting of preeclampsia. The estimated GFRs calculated from the above formulas were compared with the creatinine clearance values obtained from a 24-hour urine collections in 543 preeclamptic patients recruited from several large hospitals. Additionally, a set of new equations, preeclampsia GFR (PGFR), based on ethnicity, was created. The Cockcroft-Gault, MDRD, and CKD-EPI formulas were inaccurate in predicting GFR and both were significantly less accurate than PGFR. The latter formula provided an estimated GFR that was much closer to the creatinine clearance. Current GFR estimation equations based on serum creatinine values in nonpregnant patients are not reliable measures of renal function in patients with preeclampsia. The use of a new formula (PGFR) is recommended.

Psychosocial status of hemodialysis patients one year after Hurricane Katrina.

BACKGROUND: Hemodialysis patients experience a high degree of psychosocial impairment. METHODS: The psychosocial status of hemodialysis patients after Hurricane Katrina was evaluated using the Hurricane Coping Self-Efficacy (HCSE) measure, the Short Form-12 Health Survey (physical component summary [PCS] and mental component summary [MCS]), and the Center for Epidemiologic Studies Short Depression Scale (CES-D). These scales were administered to 391 hemodialysis patients (86% participation rate), 7 to 14 months after Hurricane Katrina. RESULTS: The mean score (standard deviation) was 36.2 (9.6) for the HCSE scale, 37.1 (10.9) and 46.7 (12.7) for the PCS and MCS, respectively, and 10.0 (6.5) on the CES-D. Symptoms of depression (CES-D scores > or =10) were present in 45.5% of patients. After age, race, and gender adjustment, evacuating less than 2 days before Hurricane Katrina making landfall and more fear of dying were associated with less favorable scores on the HCSE, MCS, and CES-D scales. Patients placed in a shelter and with a longer displacement had significantly lower MCS scores and more depressive symptoms. More depressive symptoms were observed among patients hospitalized in the month after the storm. Those who evacuated to a hotel, with more fear of dying and who were hospitalized in the month after Hurricane Katrina had lower scores on the PCS. CONCLUSIONS: Impaired psychosocial status was common among dialysis patients surviving Hurricane Katrina and associated with reduced coping. These data demonstrate the need for screening and management of psychosocial issues in hemodialysis patients after disasters.

Estimation of glomerular filtration rate in preeclamptic patients.

Accurate estimation of the glomerular filtration rate (GFR) in patients with preeclampsia is often difficult or impossible to accomplish. In this study, the Cockcroft-Gault (CG), Modification of Diet in Renal Disease (MDRD), and MDRD2 formulas were evaluated for their accuracy in determining GFR in the setting of preeclampsia. The estimated GFR calculated from these formulas was compared with the creatinine clearance values obtained from a 24-hour urine collection in 209 preeclamptic patients recruited from five large hospitals. Additionally, a set of new equations that more accurately estimate GFR in preeclamptic patients based on ethnicity, preeclampsia GFR (PGFR), was created. Both the CG and MDRD formulas were inaccurate in predicting GFR in preeclamptic patients, and both were significantly less accurate than PGFR. In conclusion, current GFR estimation equations based on serum creatinine values in nonpregnant patients are not reliable measures of renal function in patients with preeclampsia. The use of a new (PGFR) formula is recommended.

Prevalence and predictors of posttraumatic stress disorder among hemodialysis patients following Hurricane Katrina.

BACKGROUND: Patients with end-stage renal disease reliant on maintenance hemodialysis therapy may be particularly susceptible to developing post-traumatic stress disorder (PTSD) after natural disasters. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: Patients who received treatment at 9 New Orleans, LA, metropolitan area hemodialysis units before Hurricane Katrina made landfall on August 29, 2005, were recruited for the study. Overall, 391 patients completed the interview between April and October 2006 (participation rate, 85.6%). PREDICTORS: Demographic, dialysis-related, and evacuation characteristics. OUTCOMES & MEASUREMENTS: PTSD was assessed by using the 17-item PTSD Checklist and defined using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria. RESULTS: Overall, 23.8% of hemodialysis patients reported symptoms consistent with PTSD. After adjustment for age and sex, black patients were 1.92 (95% confidence interval, 1.31 to 2.83) times more likely than whites to have PTSD. After age, race, and sex adjustment, PTSD was more common in hemodialysis patients who were in their first 2 years of treatment, were evacuated fewer than 2 days before the hurricane made landfall, were evacuated initially to a shelter, and missed 3 or more dialysis treatments because of Hurricane Katrina and its aftermath. Additionally, patients who remained displaced for 3 or more months were more likely to have PTSD. LIMITATIONS: Data were not available to distinguish between the presence of acute, chronic, or delayed-onset PTSD. CONCLUSIONS: A substantial proportion of hemodialysis patients had PTSD symptoms approximately 1 year after Hurricane Katrina. Emergency planning for hemodialysis patients should include the identification and treatment of PTSD after future disasters.

Phenotypic characteristics shared by preeclamptic patients and an animal model of the syndrome: report of a pilot study.

BACKGROUND: Preeclampsia is a disorder that affects between 3% and 10% of all pregnancies. Progress in the understanding of the etiology (or etiologies) of this disorder has been impeded by the lack of suitable animal models of its early pathogenesis. Etiologic possibilities abound, and there are a number of considerations that suggest that preeclampsia is not one disease but rather a group of diseases with similar phenotypic characteristics. A rat model of this syndrome has been developed by inducing excessive volume expansion using desoxycorticosterone acetate and by replacing the drinking water with 0.9% saline. These animals develop hypertension, proteinuria, and intrauterine growth restriction (IUGR). However, they do not develop glomerular endotheliosis or a reduced glomerular filtration rate (GFR). We therefore surveyed the charts of patients with a discharge diagnosis of preeclampsia. We addressed the question of whether there was a group of such patients with the characteristics of our rat model. These include hypertension, proteinuria, IUGR, and either normal or only mildly abnormal GFR. METHODS: We performed a retrospective chart review of 630 consecutive patients discharged with a diagnosis of preeclampsia. Of the patients, 1290 had all data available to allow appropriate analysis. RESULTS: A total of 29 patients demonstrated hypertension (>140/90 mm Hg), proteinuria (>300 mg/ 24 h), and IUGR and did not have any confounding comorbid conditions. Of these 29 patients, 18 had GFR that were within the range expected for gestational age or only slightly reduced. CONCLUSIONS: There is a group of patients that mirror the characteristics of our animal model. Accordingly, at least one etiology of preeclampsia is related to excessive expansion of the extracellular fluid volume.

Effects of the selective cyclooxygenase-2 inhibitor analgesic celecoxib on renal carbonic anhydrase enzyme activity: a randomized, controlled trial.

Rofecoxib and celecoxib were the first cyclooxygenase-2 (COX-2)-specific inhibitors to be marketed as effective anti inflammatory agents. The results of several recent trials and a meta analysis of currently available studies all demonstrate a greater incidence of increased blood pressure, edema, and cardiovascular events in subjects treated with rofecoxib compared with celecoxib. As an approach to the assessment of molecular mechanisms that may contribute to these cardiorenal differences, this study investigated the inhibitory effects of celecoxib on renal carbonic anhydrase enzyme activity in human hypertensive subjects because in vitro enzyme studies demonstrate such an effect. Ten subjects with stable, treated hypertension were randomized to 1 of 3 treatment sequences, which included, in differing order, 200 mg celecoxib twice a day, 250 mg acetazolamide twice a day, or placebo twice a day. Whereas acetazolamide caused a bicarbonate diuresis and a hyperchloremic metabolic acidosis, celecoxib appeared to have no detectable effect on renal carbonic anhydrase or acid-base homeostasis. Thus, in this short-term study of human subjects, therapeutic doses of celecoxib did not appear to have a clinically significant inhibitory action on renal carbonic anhydrase.

Childhood uric acid predicts adult blood pressure: the Bogalusa Heart Study.

Uric acid has been proposed as an important risk factor in the development of primary hypertension in humans. However, limited information is available linking childhood uric acid levels and blood pressure levels in adulthood. This study examined 334 whites and 243 blacks enrolled in the Bogalusa Heart Study as children aged 5 to 17 years and as adults aged 18 to 35 years. The average follow-up period was 12 years. Childhood uric acid was significantly correlated with childhood and adult blood pressure, both systolic and diastolic. In a multivariate regression analysis, adjusting for age, sex, race, childhood body mass index, childhood uric acid levels, and change in levels of uric acid were significant predictors of adult diastolic blood pressure, whereas change in uric acid was a significant predictor of adult systolic blood pressures. In conclusion, elevated childhood serum uric acid levels are associated with increased blood pressure beginning in childhood and higher blood pressure levels that persist into adulthood, in males and females, whites and blacks, suggesting that early elevations in serum uric acid levels may play a key role in the development of human hypertension.

Interferon-alpha-induced focal segmental glomerulosclerosis in chronic myelogenous leukemia: a case report and review of the literature.

Chronic myelogenous leukemia (CML), hepatitis C, and interferon alpha (IFNalpha) have all been associated with renal dysfunction. In this paper we present a patient with the diagnosis of nephrotic syndrome and a known history of hepatitis C who received IFNalpha therapy for newly diagnosed CML. The renal biopsy showed focal segmental glomerulosclerosis, which has only been previously reported in two cases of CML treated with IFNalpha. There have also been two cases of patients with hepatitis C associated with focal segmental glomerulosclerosis. Despite the underlying hepatitis C, this case represents renal abnormalities consistent with IFNalpha therapy for CML.

Nephrotic syndrome and interstitial nephritis associated with celecoxib.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are well known to cause fluid and electrolyte abnormalities and renal failure. NSAIDs also may cause an acute allergic interstitial nephritis (AIN) and the nephrotic syndrome, characterized by histologic pathology consistent with minimal change disease in patients with previously normal renal function. The nephrotoxic potential of cyclooxygenase 2 (COX-2) inhibitors has not been established because AIN associated with nephrotic syndrome has not been reported secondary to the COX-2 inhibitors. This case report describes the first case of AIN associated with nephrotic syndrome in a patient treated with the selective COX-2 inhibitor, celecoxib.