Robert P. Light

Paricalcitol reduces albuminuria and inflammation in chronic kidney disease a randomized double-blind pilot trial

Vitamin D receptor activation is associated with improved survival in patients with chronic kidney disease, but the mechanism of this benefit is unclear. To better understand the effects of vitamin D on endothelial function, blood pressure, albuminuria, and inflammation in patients with chronic kidney disease (2 patients stage 2, remaining stage 3), we conducted a pilot trial in 24 patients who were randomly allocated equally to 3 groups to receive 0, 1, or 2 &mgr;g of paricalcitol, a vitamin D analog, orally for 1 month. Placebo-corrected change in flow mediated dilatation with a 1-&mgr;g dose was 0.5% and 0.4% with a 2-&mgr;g dose (P>0.2). At 1 month, the treatment:baseline ratio of high sensitivity C-reactive protein was 1.5 (95% CI: 1.1 to 2.1; P=0.02) with placebo, 0.8 (95% CI: 0.3 to 1.9; P=0.62) with a 1-&mgr;g dose, and 0.5 (95% CI: 0.3 to 0.9; P=0. 03) with a 2-&mgr;g dose of paricalcitol. At 1 month, the treatment:baseline ratio of 24-hour albumin excretion rate was 1.35 (95% CI: 1.08 to 1.69; P=0.01) with placebo, 0.52 (95% CI: 0.40 to 0.69; P<0.001) with a 1-&mgr;g dose, and 0.54 (95% CI: 0.35 to 0.83; P=0. 01) with a 2-&mgr;g dose (P<0.001 for between group changes). No differences were observed in iothalamate clearance, 24-hour ambulatory blood pressure, or parathyroid hormone with treatment or on washout. Thus, paricalcitol-induced reduction in albuminuria and inflammation may be mediated independent of its effects on hemodynamics or parathyroid hormone suppression. Long-term randomized, controlled trials are required to confirm these benefits of vitamin D analogs.

Dry-Weight Reduction in Hypertensive Hemodialysis Patients (DRIP). A Randomized, Controlled Trial

Volume excess is thought to be important in the pathogenesis of hypertension among hemodialysis patients. To determine whether additional volume reduction will result in improvement in blood pressure (BP) among hypertensive patients on hemodialysis and to evaluate the time course of this response, we randomly assigned long-term hypertensive hemodialysis patients to ultrafiltration or control groups. The additional ultrafiltration group (n=100) had the dry weight probed without increasing time or duration of dialysis, whereas the control group (n=50) only had physician visits. The primary outcome was change in systolic interdialytic ambulatory BP. Postdialysis weight was reduced by 0.9 kg at 4 weeks and resulted in −6.9 mm Hg (95% CI: −12.4 to −1.3 mm Hg; P=0.016) change in systolic BP and −3.1 mm Hg (95% CI: −6.2 to −0.02 mm Hg; P=0.048) change in diastolic BP. At 8 weeks, dry weight was reduced 1 kg, systolic BP changed −6.6 mm Hg (95% CI: −12.2 to −1.0 mm Hg; P=0.021), and diastolic BP changed −3.3 mm Hg (95% CI: −6.4 to −0.2 mm Hg; P=0.037) from baseline. The Mantel-Hanzel combined odds ratio for systolic BP reduction of ≥10 mm Hg was 2.24 (95% CI: 1.32 to 3.81; P=0.003). There was no deterioration seen in any domain of the kidney disease quality of life health survey despite an increase in intradialytic signs and symptoms of hypotension. The reduction of dry weight is a simple, efficacious, and well-tolerated maneuver to improve BP control in hypertensive hemodialysis patients. Long-term control of BP will depend on continued assessment and maintenance of dry weight.

Role of Home Blood Pressure Monitoring in Overcoming Therapeutic Inertia and Improving Hypertension Control A Systematic Review and Meta-Analysis

Hypertension remains the most common modifiable cardiovascular risk factor, yet hypertension control rates remain dismal. Home blood pressure (BP) monitoring has the potential to improve hypertension control. The purpose of this review was to quantify both the magnitude and mechanisms of benefit of home BP monitoring on BP reduction. Using a structured review, studies were selected if they reported either changes in BP or percentage of participants achieving a pre-established BP goal between randomized groups using home-based and office-based BP measurements. A random-effects model was used to estimate the magnitude of benefit and relative risk. The search yielded 37 randomized controlled trials with 9446 participants that contributed data for this meta-analysis. Compared with clinic-based measurements (control group), systolic BP improved with home-based BP monitoring (−2.63 mm Hg; 95% CI, −4.24, −1.02); diastolic BP also showed improvement (−1.68 mm Hg; 95% CI, −2.58, −0.79). Reductions in home BP monitoring-based therapy were greater when telemonitoring was used. Home BP monitoring led to more frequent antihypertensive medication reductions (relative risk, 2.02 [95% CI, 1.32 to 3.11]) and was associated with less therapeutic inertia defined as unchanged medication despite elevated BP (relative risk for unchanged medication, 0.82 [95% CI, 0.68 to 0.99]). Compared with clinic BP monitoring alone, home BP monitoring has the potential to overcome therapeutic inertia and lead to a small but significant reduction in systolic and diastolic BP. Hypertension control with home BP monitoring can be enhanced further when accompanied by plans to monitor and treat elevated BP such as through telemonitoring.

Design and Update of a Classification System: The UCSD Map of Science

Global maps of science can be used as a reference system to chart career trajectories, the location of emerging research frontiers, or the expertise profiles of institutes or nations. This paper details data preparation, analysis, and layout performed when designing and subsequently updating the UCSD map of science and classification system. The original classification and map use 7.2 million papers and their references from Elsevier’s Scopus (about 15,000 source titles, 2001–2005) and Thomson Reuters’ Web of Science (WoS) Science, Social Science, Arts & Humanities Citation Indexes (about 9,000 source titles, 2001–2004)–about 16,000 unique source titles. The updated map and classification adds six years (2005–2010) of WoS data and three years (2006–2008) from Scopus to the existing category structure–increasing the number of source titles to about 25,000. To our knowledge, this is the first time that a widely used map of science was updated. A comparison of the original 5-year and the new 10-year maps and classification system show (i) an increase in the total number of journals that can be mapped by 9,409 journals (social sciences had a 80% increase, humanities a 119% increase, medical (32%) and natural science (74%)), (ii) a simplification of the map by assigning all but five highly interdisciplinary journals to exactly one discipline, (iii) a more even distribution of journals over the 554 subdisciplines and 13 disciplines when calculating the coefficient of variation, and (iv) a better reflection of journal clusters when compared with paper-level citation data. When evaluating the map with a listing of desirable features for maps of science, the updated map is shown to have higher mapping accuracy, easier understandability as fewer journals are multiply classified, and higher usability for the generation of data overlays, among others.

Relative plasma volume monitoring during hemodialysis AIDS the assessment of dry weight.

Among hemodialysis patients, the assessment of dry weight remains a matter of clinical judgment because tests to assess dry weight have not been validated. The objective of this study was to evaluate and validate relative plasma volume (RPV) monitoring as a marker of dry weight. We performed RPV monitoring using the Crit-Line monitor at baseline and at 8 weeks in 150 patients participating in the Dry-Weight Reduction in Hypertensive Hemodialysis Patients Trial. The intervention group of 100 patients had dry weight probed, whereas 50 patients served as time controls. RPV slopes were defined as flat when they were less than the median (1.33% per hour) at the baseline visit. Among predominantly (87%) black hemodialysis patients, we found that flat RPV slopes suggest a volume-overloaded state for the following reasons: (1) probing dry weight in these patients led to steeper slopes; (2) those with flatter slopes at baseline had greater weight loss; (3) both baseline RPV slopes and the intensity of weight loss were found to be important for subsequent change in RPV slopes; and, most importantly, (4) RPV slopes predicted the subsequent reduction in interdialytic ambulatory systolic blood pressure. Those with the flattest slopes had the greatest decline in blood pressure on probing dry weight. Both baseline RPV slopes and the change in RPV slopes were important for subsequent changes in ambulatory systolic blood pressure. We conclude that RPV slope monitoring is a valid method to assess dry weight among hypertensive hemodialysis patients.

Diagnosing Hypertension by Intradialytic Blood Pressure Recordings

BACKGROUND AND OBJECTIVES The diagnosis of hypertension among hemodialysis patients by predialysis or postdialysis blood pressure (BP) recordings is imprecise and biased and has poor test-retest reliability. The use of intradialytic BP measurements to diagnose hypertension is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A diagnostic-test study was done with interdialytic ambulatory BP as reference standard. Index BP recordings tested were: predialysis (method 1), postdialysis (method 2), intradialytic (method 3), intradialytic including predialyis and postdialysis (method 4), and the average of predialysis and postdialysis (method 5). Each index BP was recorded over six consecutive dialysis treatments. RESULTS There were differences among index BP measurements in reproducibility, bias, precision, and accuracy. Method 4 was the most reproducible (intraclass correlation coefficient = 0.70 for systolic and diastolic BP). All 5 measurement methods overestimated 44-h ambulatory systolic BP. Methods 2, 3, or 4 overestimated ambulatory systolic BP by only a small amount. Method 4 was the most precise and accurate. For diagnosis of hypertension, BP cut-point by method 4 of 135/75 mmHg, had a sensitivity of 90.4% and specificity of 75.9% for systolic BP (area under ROC curve 0.90). Median cut-off systolic BP of 140 mmHg from a single dialysis provides approximately 80% sensitivity and 80% specificity in diagnosing systolic hypertension; a median cut-off diastolic BP of 80 mmHg provides approximately 75% sensitivity and 75% specificity in diagnosing diastolic hypertension. CONCLUSIONS Consideration of intradialytic BP measurements together with predialysis and postdialysis BP measurements improves the reproducibility, bias, precision, and accuracy of BP measurement compared with predialysis or postdialysis measurements.

Diagnosing Obesity by Body Mass Index in Chronic Kidney Disease: An Explanation for the “Obesity Paradox?”

Although obesity is associated with poor outcomes, among patients with chronic kidney disease (CKD), obesity is related to improved survival. These results may be related to poor diagnostic performance of body mass index (BMI) in assessing body fat content. Accordingly, among 77 patients with CKD and 20 controls, body fat percentage was estimated by air displacement plethysmography (ADP), skinfold thickness, and body impedance analysis. Defined by BMI ≥30 kg/m2, the prevalence of obesity was 20% in controls and 65% in patients with CKD. Defined by ADP, the prevalence increased to 60% among controls and to 90% among patients with CKD. Although sensitivity and positive predictive value of BMI to diagnose obesity were 100%, specificity was 72%, but the negative predictive value was only 30%. BMI correctly classified adiposity in 75%. Regardless of the presence or absence of CKD, subclinical obesity (defined as BMI <30 kg/m2 but excess body fat by ADP) was often missed in people with low lean body mass. The adjusted odds ratio for subclinical obesity per 1 kg of reduced lean body mass by ADP was 1.14 (95% CI: 1.06 to 1.23; P<0.001). Skinfold thickness measurements correctly classified 94% of CKD patients, but bioelectrical impedance analyzer-assessed body fat estimation did so in only 65%. Air displacement plethysmography-, skinfold thickness-, and bioelectrical impedance analyzer-assessed body fat all provided reproducible estimates of adiposity. Skinfold thickness measurements may be a better test to classify obesity among those with CKD. Given the low negative predictive value of BMI for obesity, our study may provide an explanation of the “obesity paradox.”

Short-term vitamin D receptor activation increases serum creatinine due to increased production with no effect on the glomerular filtration rate

Vitamin D receptor activation has been associated with increased serum creatinine and reduced estimated glomerular filtration rates, raising concerns that its use may be detrimental to kidney function. Here we studied the effect of vitamin D receptor activation on serum creatinine, creatinine generation, and its clearance. We measured baseline serum creatinine and 24-h urine creatinine in 16 patients with chronic kidney disease. The measurements were repeated every day for 7 days, during which time the patients received 2 μg paricalcitol, an orally active vitamin D receptor activator, every morning. At 4 days after stopping the vitamin analog, measurements were continued for 3 days. Geometric mean parathyroid hormone levels decreased from 77 pg/ml at baseline to 43 pg/ml at the end of treatment and significantly rebounded to 87 pg/ml following paricalcitol withdrawal, thereby supporting the biological efficacy of the analog dose used. With this therapy, the serum creatinine significantly increased at a rate of 0.010 mg/dl/day and urine creatinine at a rate of 17.6 mg/day. Creatinine and iothalamate clearances did not change, whereas urine albumin decreased insignificantly. Thus, short-term vitamin D receptor activation increases creatinine generation and serum creatinine, but it does not influence the glomerular filtration rate.

Location Not Quantity of Blood Pressure Measurements Predicts Mortality in Hemodialysis Patients

Background: Blood pressure (BP) measurements obtained outside the dialysis unit are prognostically superior. Whether it is the greater number of measurements made outside the dialysis unit that correlates with prognosis or whether BPs outside dialysis units are ecologically more valid is unknown. Methods and Results: A prospective cohort study was conducted in 133 patients on chronic hemodialysis. BP was measured by the patients at home for 1 week, over an interdialytic interval by ambulatory recording, and by ‘routine’ and standardized methods in the dialysis unit for 2 weeks. Up to 6 BPs were randomly selected from a 44-hour recording of ambulatory or 1-week recording of home BPs, such that the dialysis unit BPs were exactly matched to the number of ambulatory or home BPs. The relationship with left ventricular hypertrophy and all-cause mortality was analyzed using receiver-operating characteristic curves and Cox proportional hazards analysis, respectively. Over a median follow-up of 24 months, 46 patients (31%) died. A BP change of 10/5 mm Hg increased the risk of all-cause mortality by 1.22 (95% CI 1.07–1.38)/1.18 (95% CI 1.05–1.31) with the average of the 44-hour recording and 1.20 (95% CI 1.07–1.34)/1.15 (95% CI 1.03–1.27) when up to 6 random BPs from the same ambulatory recording were drawn and averaged. With home BPs the hazard ratios were 1.17/1.15 per 10/5 mm Hg increase in BP with the average of 1-week recording and 1.18/1.13 when up to 6 random BPs were drawn and averaged. Limited duration ambulatory BP monitoring of any 6-hour interval during the first 24 h or 4-day home BP recorded after the midweek dialysis was similarly predictive of all-cause mortality. Conclusions: In patients on hemodialysis, the location, not the quantity, of the BP recordings obtained outside the dialysis unit is associated with target organ damage and mortality.

Intradialytic hypertension is a marker of volume excess

BACKGROUND Intradialytic blood pressure (BP) profiles have been associated with all-cause mortality, but its pathophysiology remains unknown. We tested the hypothesis that intradialytic changes in BP reflect excess volume. METHODS The dry weight reduction in hypertensive haemodialysis patients (DRIP) trial probed dry weight in 100 prevalent haemodialysis patients; 50 patients who did not have their dry weight probed served as time controls. In this post hoc analysis, intradialytic BP was recorded at each of the 30 dialysis treatments during the trial. The slope of intradialytic BP over dialysis was calculated by the log of BP regressed over time. Using a linear mixed model, we compared these slopes between control and ultrafiltration groups at baseline and over time, tested the effect of dry weight reduction on these slopes and finally tested the ability of change in intradialytic slopes to predict change in interdialytic systolic BP. RESULTS At baseline, intradialytic systolic and diastolic BP dropped at a rate of ~3%/h (P < 0.0001). Over the course of the trial, compared to the control group, the slopes steepened in the ultrafiltration group for systolic but not diastolic BP. Those who lost the most post-dialysis weight from baseline to 4 weeks and baseline to 8 weeks also experienced the greatest steepening of slopes. Each percent per hour steepening of the intradialytic systolic BP slope was associated with 0.71 mmHg [95% confidence interval (CI) 0.01-1.42, P = 0. 048] reduction in interdialytic ambulatory systolic pressure. CONCLUSIONS Intradialytic BP changes appear to be associated with change in dry weight among haemodialysis patients. Among long-term haemodialysis patients, intradialytic hypertension may, thus, be a sign of volume overload.