Long-term retinal, renal and cardiovascular outcomes in diabetic chronic kidney disease without proteinuria.

BACKGROUND: Patients with diabetes mellitus (DM) with chronic kidney disease (CKD) often have no proteinuria. METHODS: To compare the characteristics that differ between DM + CKD patients with and without proteinuria, we conducted a cross-sectional study followed by surveillance over a decade for 'hard' cardiovascular, renal and retinal outcomes. Groups were stratified by presence (n = 129) and absence (n = 284) of DM. Each stratum had three groups: no CKD, CKD without proteinuria and CKD with proteinuria. RESULTS: Compared to DM + CKD + proteinuria patients, those with DM + CKD but without proteinuria had similar clinical characteristics including estimated glomerular filtration rate. However, they had lower 24-h ambulatory systolic and diastolic blood pressure. Crude all-cause mortality rates per 1000 patient-years in the nondiabetic group with no CKD, CKD with no proteinuria and CKD with overt proteinuria were 29.3, 68.5 and 111.1, respectively. Respective rates in the diabetic group were 50.1, 105.7 and 136.8. Diabetes increased the risk of coronary (P = 0.01) and end-stage renal disease (ESRD) events (P = 0.05) even after multivariate adjustments. Proteinuria aggravated the risk of cardiovascular events, ESRD, death and time to first of these events similarly among diabetics with CKD compared to nondiabetics with CKD. Diabetic patients with CKD but no overt proteinuria were much more likely than nondiabetics to progress to overt proteinuria [adjusted hazard ratio 5.28 (95% confidence interval 1.64-17.02), P < 0.01). CKD was a risk factor for prevalent retinopathy and proteinuria was a risk factor for incident diabetic retinopathy. CONCLUSIONS: To protect sight, those with proteinuria and DM need regular retinal examinations. Since diabetic CKD patients without proteinuria are more likely to develop overt proteinuria, close follow-up and risk factor management among these patients appear to be more important than among nondiabetic patients with CKD and no proteinuria.

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.

Relationship between glycosylated hemoglobin and blood glucose during progression of chronic kidney disease.

BACKGROUND: The value of measurement of glycosylated hemoglobin (HgbA(1C)) in determining the degree of glycemic control in patients with chronic kidney disease (CKD) is unclear. METHODS: A single-center, prospective cohort study was conducted in 128 veterans with diabetes mellitus and CKD. HgbA(1C) was measured as clinically indicated and its relationship with random blood glucose (RBG) measurement evaluated prospectively over up to 10 years in three groups (end-stage renal disease (ESRD), CKD and controls who had diabetes but no CKD). RESULTS: Between 1995 and 2011, in the control group, glycemic control as assessed by HgbA(1C) was stable but improved when assessed by RBG. However, both the CKD and ESRD groups experienced declines in RBG and HgbA(1C). Declining HgbA(1C) and RBG were noted prior to onset of dialysis. A fall in HgbA(1C) remained after adjustment for RBG. A strong inverse relationship was seen between CKD stage and HgbA(1C) even after adjusting for RBG such that the relationship between RBG levels and HgbA(1C) was modified by CKD. CONCLUSIONS: In diabetic patients with late-stage CKD, glycemic control shows an improvement. However, HgbA(1C) <7% may overestimate the degree of glycemic control. Therefore, reliance on HgbA(1C) without home blood glucose monitoring may result in poor diabetes control.

Probing dry-weight improves left ventricular mass index.

BACKGROUND: Although probing dry-weight improves blood pressure control, its effect on echocardiographic left ventricular mass index (LVMI) is unknown. METHODS: Shortly following dialysis, 292 echocardiograms in 150 patients participating in the DRIP trial were obtained at baseline and longitudinally every 4 weeks on 2 occasions. RESULTS: At baseline, LVMI was 136.3 g/m(2) in the control group and 138.7 g/m(2) in the ultrafiltration group (p > 0.2 for difference). The change from baseline in LVMI in the control group was +3.5 g/m(2) at 4 weeks and +0.3 g/m(2) at 8 weeks (p > 0.2 for both changes). The change from baseline in LVMI in the ultrafiltration group was -7.4 g/m(2) at 4 weeks (p = 0.005) and -6.3 g/m(2) at 8 weeks (p = 0.045). With ultrafiltration, the change in LVMI diameter was -10.9 g/m(2) more compared to the control group at 4 weeks (p = 0.012) and -6.6 g/m(2) more compared to the control group at 8 weeks (p = 0.21). The reduction in interdialytic ambulatory blood pressure was also greater in response to probing dry-weight in those in the top half of LVMI at baseline (p = 0.02 for interaction effect at week 8). CONCLUSION: LVMI, an important determinant of prognosis among long-term dialysis patients, is responsive to probing dry-weight.

Physical activity is a determinant of circadian blood pressure variation in chronic kidney disease.

BACKGROUND: Circadian variation in blood pressure (BP), which is commonly blunted among patients with chronic kidney disease (CKD), has been associated with increased cardiovascular risk. The causes of this blunted circadian variation remain incompletely understood. METHODS: We hypothesized that physical activity is a determinant of circadian BP variation. Accordingly, we studied 101 patients with CKD (mean age 69 years, mostly men) with 24-hour ambulatory BP monitoring and simultaneous monitoring of physical activity on 2 occasions 4 weeks apart. RESULTS: Measured by wrist actigraphy, a higher level of physical activity was associated with lower overall mean BP. A higher level of activity also altered the circadian systolic BP rhythm; this alteration was characterized by both a higher amplitude of variation (and thus greater dipping) and restoration of acrophase (time at peak BP) to a less vulnerable period for cardiovascular events. Among the most sedentary participants, both systolic and pulse pressure acrophases were seen in the early hours of the morning which is also the most vulnerable period for cardiovascular events. CONCLUSION: Physical activity is an independent determinant of circadian variation in BP. We speculate that among patients with CKD, a sedentary lifestyle, rather than non-dipping, mediates increased cardiovascular risk.

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.

A longitudinal study of kidney structure and function in adults.

BACKGROUND: Although kidney size is commonly measured in patients with chronic kidney disease (CKD), its relationship with kidney function is poorly understood. We conducted this longitudinal study to better understand the relationship between kidney size and function. METHODS: We retrospectively studied 178 kidneys measured by ultrasound in 93 patients with CKD who did not have autosomal polycystic kidney disease. Renal function was measured using estimated glomerular filtration rate (GFR). A mixed model that accounted for repeated measurements or nested observations was used for statistical analysis. RESULTS: In cross-sectional analyses, the following independent variables emerged as predictors of kidney size: estimated GFR along with its squared term, height, age and interactions of each of these two independent variables with aetiology of CKD. In longitudinal analyses over a median follow-up of 3.7 years, after accounting for predictors of baseline kidney size such as aetiology, height and estimated GFR, we found that kidney atrophy occurred at a rate of 0.072 cm/year (SD 0.016, P = 0.007). This atrophy was 'blunted' with declining GFR. Each 1 mL/min/1.73 m(2)/year greater decline in eGFR abrogated kidney atrophy by 0.015 cm/year (P = 0.024). CONCLUSION: Although in cross-sectional surveys kidney size is directly related to function, the longitudinal relationship between form and function is inverted. Since the rate of change in GFR determines kidney atrophy, we conclude that kidney size is a determinant of renal prognosis.

Chronobiology of arterial hypertension in hemodialysis patients: implications for home blood pressure monitoring.

BACKGROUND: Hemodialysis patients have a steady increase in blood pressure (BP) during the 44-hour interdialytic interval when ambulatory BP monitoring is used. Home BP recording allows for a longer period of monitoring between dialysis treatments and may better define the chronobiological characteristics of arterial hypertension. This study sought to determine the optimal time to perform home BP monitoring in hemodialysis patients to improve the strength of prediction of 44-hour interdialytic ambulatory BP. STUDY DESIGN: Diagnostic test study. SETTING & PARTICIPANTS: This is an ancillary analysis of patients participating in the Dry-weight Reduction in Hypertensive Hemodialysis Patients (DRIP) trial. INDEX TEST: Home BP measured 3 times daily for 1 week by using a validated oscillometric monitor on 3 occasions at 4-week intervals after randomization. Home BP measured during the first third, second third, and last third of time elapsed after the dialysis treatment, as well as each third of the dialysis treatment, was compared with the overall ambulatory BP. REFERENCE TESTS: Interdialytic ambulatory BP measured on 3 occasions at 4-week intervals after randomization. RESULTS: During the interdialytic interval, we found an increase in systolic ambulatory BP of 0.30 +/- 0.36 mm Hg/h and an increase in systolic home BP of 0.40 +/- 0.25 mm Hg/h. This relationship in home BP reached a plateau after approximately 48 hours. A similar pattern was seen for diastolic home BP. Probing dry weight steepened the slope of ambulatory BP, but did not alter the time-dependent relationship of home BP. Home BP was on average higher (bias) by 14.1 (95% confidence interval, 12.0 to 16.2)/5.7 mm Hg (95% confidence interval, 4.6 to 6.9). The SD of differences between methods (precision) was 4.6/2.8 mm Hg. Measurement of BP during each third of the interdialytic interval gave the best precision, measured by using model fit compared with ambulatory BP measurements. LIMITATIONS: Our cohort was overrepresented by African American hemodialysis patients. Whether African American participants have a different pattern of BP response than non-African American participants in the interdialytic period is not known. CONCLUSIONS: Our findings suggest that time elapsed after a dialysis treatment must be considered in interpreting home BP recordings in hemodialysis patients. Home BP measured in each third of the interdialytic interval is likely to yield the most reliable BP estimate.

Circadian blood pressure classification scheme and the health of patients with chronic kidney disease.

BACKGROUND: In health, a sinusoidal rhythm is observed in systolic blood pressure (BP) that peaks (acrophase) during the waking hours (in-phase), but in those with chronic kidney disease (CKD) the acrophase is often observed during sleeping hours (out-of-phase). Yet in others the amplitude of the variation may be so blunted that acrophase may not be definable (phase-less). Circadian rhythms in systolic BP are often described by the dichotomous dipper classification but may not be adequate to fully characterize derangements in cyclical variation in BP. METHODS: To compare classification of circadian BP variation by phase-based classification to dipper-status we examined the cross-sectional relationship of these classification patterns to several markers of health such as health-related quality of life (Kidney Disease Quality of Life Survey, KDQOL) and physical activity (actigraphy over 2 weeks). We also assessed the relationship of circadian BP variation with circadian variation in urine electrolyte and albumin excretion rates. RESULTS: Among 103 veterans with CKD (97% men, age 69, diabetes mellitus 30%, eGFR 38.8 ml/min/1.73 m(2)) no differences were seen between dippers and non-dippers (n = 77, 75%) in eGFR, urinary Na and Cl excretion rates, or KDQOL. However, non-dippers had lower levels of physical activity and greater albuminuria compared to dippers. The same patients were classified to be in-phase (n = 36, 35%), phase-less (n = 19, 18%) or out-of-phase (n = 48, 47%). Patients in-phase had a higher eGFR and somewhat surprisingly also had the highest Na and Cl excretion rates compared to others. Those with out-of-phase systolic BP had the lowest physical composite score on KDQOL, the lowest level of physical activity, and the greatest amount of albuminuria. CONCLUSIONS: Among patients with CKD, circadian BP profile described by either dipper-based or phase-based classification is related to the level of physical activity and the severity of kidney damage. The circadian BP profile is related to overall health and nutritional intake only when using the phase-based classification. The value of these classification schemes to profile circadian BP will require longitudinal studies.

Prognostic value of circadian blood pressure variation in chronic kidney disease.

BACKGROUND: Reduced circadian variation in blood pressure (BP) has been associated with cardiovascular morbidity, mortality and accelerated progression of kidney disease, but its independent prognostic value remains unknown. METHODS: Using 2 definitions, one based on dipping and the other based on BP pattern (assessed by cosinor rhythmometry), we studied the prognosis of circadian BP variation among 322 patients, 179 (56%) of whom had chronic kidney disease (CKD). RESULTS: During a follow-up period extending for up to 8.7 years, 116 (36%) patients died and 57 (32%) patients with CKD developed end-stage renal disease (ESRD). Compared to 106 patients (33%) who were dippers, the unadjusted hazard ratio (HR) for death among non-dippers was 2.03 (95% CI 1.30-3.16, p = 0.002). However, this HR became nonsignificant [1.39 (95% CI 0.89-2.19), p = 0.15] when adjusted for age and 24-hour average systolic BP. Although non-dipping was marginally associated with ESRD [HR 1.98 (95% CI 0.996-3.92), p = 0.051], even this association was weakened when adjusted for overall 24-hour systolic BP (HR 1.67, p = 0.15). Similar to the dipping definition, the BP pattern-based definition was significantly associated with mortality (p = 0.005) but not with ESRD (p = 0.68). Compared to those 'in-phase,' the HR for death among those 'out-of-phase' was 1.86 (95% CI 1.25-2.75, p = 0.002). Although this HR when adjusted for overall mean BP remained significant, when further adjusted for age, it too became nonsignificant. CONCLUSION: Among elderly veterans with or without CKD, circadian variation in BP is associated with mortality, but not ESRD. However, after accounting for common clinical risk factors, this association of circadian BP variation with mortality or ESRD is abolished.

Home blood pressure measurements for managing hypertension in hemodialysis patients.

Home blood pressure (BP) monitoring serves as a practical method to detect changes in BP instead of ambulatory BP monitoring in hemodialysis patients. To evaluate the relationship of reduction in home BP compared to interdialytic ambulatory BP measurements we analyzed the data from the dry-weight reduction in hypertensive hemodialysis patients (DRIP) trial in which 100 patients had their dry weight probed based on clinical sign and symptoms and 50 patients served as controls. We measured home BP 3 times a day for 1 week using a validated oscillometric monitor on 3 occasions at 4-week intervals after randomization. Changes from baseline in home, predialysis BP and postdialysis BP were compared to interdialytic 44-hour ambulatory BP. Home and ambulatory BP monitoring was available in 141 of 150 (94%) patients. Predialysis systolic BP was not as sensitive as ambulatory BP in detecting change in BP with dry-weight reduction. Whereas postdialysis BP was capable of detecting an improvement in systolic BP in response to probing dry weight, by itself it does not provide evidence that change in postdialysis BP persists over the interdialytic period. Home BP reliably detected changes in ambulatory BP, albeit with less sensitivity at 4 weeks. However, at 4 and at 8 weeks, changes in home systolic BP were most strongly related to changes in interdialytic ambulatory systolic BP compared to predialysis and postdialysis BP. The reproducibility of BP measurements followed the order home > ambulatory >> predialysis > postdialysis. These data provide support for the use of home BP monitoring for the management of hypertension in hemodialysis patients.

GFR, proteinuria and circadian blood pressure.

BACKGROUND: Hypertension is common, and arterial pressure rhythms are impaired in patients with chronic kidney disease (CKD). Emerging evidence suggests that consideration of excretory function together with proteinuria may provide a more holistic assessment of the extent of derangement in renal function. METHODS: To evaluate the independent relationships of estimated GFR and proteinuria with the mean level of and the circadian variation in blood pressure, we evaluated 336 patients, 184 (55%) patients with CKD (eGFR <60 or urine protein/creatinine >0.22) and 152 (45%) without CKD. RESULTS: The mean level of systolic and diastolic BP increased with increasing severity of proteinuria as well as with increasing impairment in GFR. When proteinuria and eGFR were considered together in the same regression model, proteinuria-not eGFR-was related to the severity of hypertension. Non-dipping was present in 52% of those with eGFR >60 and 55% in those with no proteinuria. Non-dipping was seen early in the course of impaired GFR or proteinuria. Adjusted for proteinuria, the odds ratio for non-dipping in those with CKD was 1.71 (95% CI 1.03-2.84, P = 0.036). The odds ratio for non-dipping in those with proteinuria was 1.75 (95% CI 1.00-3.08, P = 0.049) when adjusted for CKD. A cosinor model that evaluates the midline estimating statistic of rhythm (MESOR) and circadian variation revealed that proteinuria was a stronger determinant of MESOR compared to the CKD stage; the CKD stage in addition to proteinuria did not further add to the determination of MESOR. The amplitude of variation was markedly blunted in patients with the earliest stages of derangement in kidney function whether it was assessed by proteinuria or eGFR. CONCLUSIONS: These results demonstrate a graded relationship of proteinuria and eGFR with the mean level of BP and a non-graded relationship with circadian variation. Consideration of these two simple tests of renal function may better assist in gauging the severity of hypertension in patients with CKD.

Diagnostic utility of blood volume monitoring in hemodialysis patients.

BACKGROUND: Assessment of volume state is difficult in hemodialysis patients. Whether continuous blood volume monitoring can improve the assessment of volume state is unclear. STUDY DESIGN: Diagnostic test study. SETTINGS & PARTICIPANTS: Asymptomatic long-term hemodialysis patients (n = 150) in 4 university-affiliated hemodialysis units. INDEX TESTS: Ultrafiltration rate (UFR) divided by postdialysis weight (UFR index), slopes of relative blood volume (RBV), RBV slope corrected for UFR and weight (volume index). REFERENCE TESTS: Dialysis-related symptoms and echocardiographic signs of volume excess and volume depletion, assessed by using inferior vena cava (IVC) diameter after dialysis and its collapse on inspiration. Volume excess was defined as values in the upper third of IVC diameter or lower third of IVC collapse on inspiration. Volume depletion was defined as values in the lower third of IVC diameter or upper third of IVC collapse on inspiration. RESULTS: Mean UFR was 8.3 +/- 3.8 (SD) mL/h/kg. Mean RBV slope was -2.32% +/- 1.50%/h. Mean volume index was -0.25% +/- 0.17%/h/mL/h ultrafiltration/kg. Volume index provided the best fit of observed RBV slopes. Volume index was related to dizziness, the need to decrease UFR, and placement in Trendelenburg position. RBV and volume index, but not UFR index, were related to echocardiographic markers of volume excess and depletion. Areas under the receiver operating characteristic curve to predict volume excess were 0.48 (95% confidence interval [CI], 0.33 to 0.63) for UFR index, 0.71 (95% CI, 0.60 to 0.83) for RBV slope, and 0.73 (95% CI, 0.59 to 0.86) for volume index. Areas under the receiver operating characteristic curve to predict volume depletion were 0.56 (95% CI, 0.38 to 0.74) for UFR index, 0.55 (95% CI, 0.38 to 0.72) for RBV slope, and 0.62 (95% CI, 0.48 to 0.76) for volume index. LIMITATIONS: Dialysis-related symptoms and echocardiographic findings are not validated measures of volume. Our results were not adjusted for demographic or clinical characteristics; performance characteristics of the indices may differ across populations. CONCLUSIONS: Volume index appears to be a novel marker of volume, but requires validation studies, and its utility needs to be tested in clinical trials.

Competing risk factor analysis of end-stage renal disease and mortality in chronic kidney disease.

BACKGROUND: Death and dialysis are competing outcomes in patients with chronic kidney disease (CKD). The factors associated with end-stage renal disease (ESRD) versus death in this population are unknown. The purpose of our study was to evaluate the competing risk of ESRD versus mortality and to evaluate the risk factors associated with these two outcomes. METHODS: We prospectively recruited 220 consecutive patients at a Veterans Administration Medical Center attending a renal clinic who met the definition of CKD (estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2) or urine protein/creatinine ratio of >0.22 g/g). Using age, race, proteinuria, eGFR, systolic blood pressure, and coronary artery disease as predictors, we calculated the competing end-points of ESRD or death using a competing Cox regression model. RESULTS: The cumulative incidence for ESRD was 17.6% and death 18.5% during follow-up that lasted up to 7 years. ESRD was predicted by younger age (hazard ratio (HR) 0.91/year), black race (HR 2.75), higher systolic blood pressure (HR 1.02/mm Hg), proteinuria (HR 1.37/log urine protein/creatinine ratio) and low eGFR (0.014/log eGFR ml/min/1.73 m(2)). Death was predicted by older age (HR 1.07/year), lower eGFR (HR 0.43/log eGFR ml/min/1.73 m(2)), proteinuria (HR 1.26/log urine protein/creatinine ratio) and coronary artery disease (HR 2.52). The coefficients were statistically different for age (p < 0.001), log eGFR (p < 0.001) and systolic blood pressure (p = 0.04) for ESRD and death outcomes. CONCLUSIONS: The risk for mortality is similar to the risk of ESRD in the CKD population of veterans seen by nephrologists. Risk factors for ESRD and death appear to differ in this population. Certain clinical and demographic factors may discriminate between the end-points of death or dialysis and may influence decisions about planning for ESRD.

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.

High-impact and transformative science (HITS) metrics: Definition, exemplification, and comparison.

Countries, research institutions, and scholars are interested in identifying and promoting high-impact and transformative scientific research. This paper presents a novel set of text- and citation-based metrics that can be used to identify high-impact and transformative works. The 11 metrics can be grouped into seven types: Radical-Generative, Radical-Destructive, Risky, Multidisciplinary, Wide Impact, Growing Impact, and Impact (overall). The metrics are exemplified, validated, and compared using a set of 10,778,696 MEDLINE articles matched to the Science Citation Index ExpandedTM. Articles are grouped into six 5-year periods (spanning 1983-2012) using publication year and into 6,159 fields constructed using comparable MeSH terms, with which each article is tagged. The analysis is conducted at the level of a field-period pair, of which 15,051 have articles and are used in this study. A factor analysis shows that transformativeness and impact are positively related (ρ = .402), but represent distinct phenomena. Looking at the subcomponents of transformativeness, there is no evidence that transformative work is adopted slowly or that the generation of important new concepts coincides with the obsolescence of existing concepts. We also find that the generation of important new concepts and highly cited work is more risky. Finally, supporting the validity of our metrics, we show that work that draws on a wider range of research fields is used more widely.

Relationships of N-terminal pro-B-natriuretic peptide and cardiac troponin T to left ventricular mass and function and mortality in asymptomatic hemodialysis patients.

BACKGROUND: Although the cardiac biomarker troponin T (cTnT) is related strongly to mortality in patients with end-stage renal disease, the independent association of N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) and cTnT levels in predicting outcomes is unknown. The objective of this study is to determine factors associated with NT-pro-BNP and cTnT and determine whether these levels are associated with mortality. STUDY DESIGN: Cohort study. SETTING & PARTICIPANTS: Asymptomatic hemodialysis patients (n = 150) in 4 university-affiliated hemodialysis units. EXPOSURE & OUTCOMES: For cross-sectional analysis, echocardiographic variables as exposures and NT-pro-BNP and cTnT levels as outcomes; for longitudinal analysis, association of NT-pro-BNP and cTnT levels as exposures to all-cause and cardiovascular disease mortality as outcomes. RESULTS: In a multivariate regression analysis, low midwall fractional shortening, a measure of poor systolic function, was an independent correlate of log NT-pro-BNP level (P < 0.01), whereas left ventricular mass index was an independent correlate of cTnT level (P < 0.01). During a median follow-up of 24 months, 46 patients died, 26 of cardiovascular causes. NT-pro-BNP levels had a strong graded relationship with all-cause (hazard ratios [HRs], 1.54, 4.78, and 4.03 for increasing quartiles; P < 0.001) and cardiovascular mortality (HRs, 2.99, 10.95, and 8.54; P < 0.01), whereas cTnT level had a weaker relationship with all-cause (HRs, 1.57, 2.32, and 3.39; P < 0.01) and cardiovascular mortality (HRs, 0.81, 2.12, and 2.14; P = 0.1). The combination of the 2 biomarker levels did not improve the association with all-cause or cardiovascular mortality compared with NT-pro-BNP level alone. NT-pro-BNP level was a marker of mortality even after adjusting for left ventricular mass index and midwall fractional shortening. LIMITATIONS: Our cohort was predominantly black and of limited sample size. CONCLUSION: NT-pro-BNP level strongly correlates with left ventricular systolic dysfunction and is associated more strongly with mortality than cTnT level in asymptomatic hemodialysis patients.

Proteinuria is a determinant of quality of life in diabetic nephropathy: modeling lagged effects with path analysis.

BACKGROUND: Diabetic nephropathy with overt proteinuria often progresses relentlessly to end-stage renal disease (ESRD). MATERIAL AND METHODS: To answer the question whether it is impaired glomerular filtration rate (GFR) or its precursor proteinuria which is more related with multiple domains of health-related quality of life (HRQOL), we measured GFR and proteinuria in 44 patients with type 2 diabetes and overt nephropathy and repeated the measurements after 4 months. 38 patients with ESRD due to diabetic nephropathy served as a control group. We used path analysis to examine the association of baseline proteinuria and GFR with baseline and subsequent HRQOL scales. RESULTS: Compared to patients with ESRD, patients with non-dialysis CKD had Kidney Disease Burden (KDB) that was, on a scale from 0 to 100, 19.8 better (95% CI 6.9-32.8) (p = 0.003). Mental component score (MCS) did not differ and physical component score (PCS) was worse in non-dialysis CKD patients by 8.5 (p < 0.001). Proteinuria at baseline was a predictor of PCS, MCS and KDB score at 4 months, suggesting a lagged effect of proteinuria on HRQOL after controlling for the autoregressive effects. GFR was not shown to have a significant impact on HRQOL. One log unit increase in proteinuria was associated with 3.8 (p = 0.011) fall in PCS, 3.3 (p = 0.043) fall in MCS and 10.6 (p = 0.006) fall in KDB. CONCLUSION: In patients with advanced diabetic nephropathy, we found that proteinuria has a lagged and profound effect on multiple domains of HRQOL.

Philanthro-metrics: Mining multi-million-dollar gifts.

The Million Dollar List (MDL, online at http://www.milliondollarlist.org) is a compilation of publicly announced charitable donations of $1 million or more from across the United States since 2000; as of December 2016, the database contains close to 80,000 gifts made by U.S. individuals, corporations, foundations, and other grant-making nonprofit organizations. This paper discusses the unique value of the Million Dollar List and provides unique insights to key questions such as: How does distance affect giving? How do networks impact million-dollar-plus gifts? Understanding the geospatial and temporal dimensions of philanthropy can assist researchers and policymakers to better understand the role of private funding in innovation and discovery. Moreover, the results from the paper emphasize the importance of philanthropy for fueling research and development in science, the arts, environment, and health. The paper also includes the limitations of the presented analyses and promising future work.

Multi-level computational methods for interdisciplinary research in the HathiTrust Digital Library.

We show how faceted search using a combination of traditional classification systems and mixed-membership topic models can go beyond keyword search to inform resource discovery, hypothesis formulation, and argument extraction for interdisciplinary research. Our test domain is the history and philosophy of scientific work on animal mind and cognition. The methods can be generalized to other research areas and ultimately support a system for semi-automatic identification of argument structures. We provide a case study for the application of the methods to the problem of identifying and extracting arguments about anthropomorphism during a critical period in the development of comparative psychology. We show how a combination of classification systems and mixed-membership models trained over large digital libraries can inform resource discovery in this domain. Through a novel approach of "drill-down" topic modeling-simultaneously reducing both the size of the corpus and the unit of analysis-we are able to reduce a large collection of fulltext volumes to a much smaller set of pages within six focal volumes containing arguments of interest to historians and philosophers of comparative psychology. The volumes identified in this way did not appear among the first ten results of the keyword search in the HathiTrust digital library and the pages bear the kind of "close reading" needed to generate original interpretations that is the heart of scholarly work in the humanities. Zooming back out, we provide a way to place the books onto a map of science originally constructed from very different data and for different purposes. The multilevel approach advances understanding of the intellectual and societal contexts in which writings are interpreted.