Effect of Intensive and Standard Clinic-Based Hypertension Management on the Concordance Between Clinic and Ambulatory Blood Pressure and Blood Pressure Variability in SPRINT.

Background Blood pressure ( BP ) varies over time within individual patients and across different BP measurement techniques. The effect of different BP targets on concordance between BP measurements is unknown. The goals of this analysis are to evaluate concordance between (1) clinic and ambulatory BP , (2) clinic visit-to-visit variability and ambulatory BP variability, and (3) first and second ambulatory BP and to evaluate whether different clinic targets affect these relationships. Methods and Results The SPRINT (Systolic Blood Pressure Intervention Trial) ambulatory BP monitoring ancillary study obtained ambulatory BP readings in 897 participants at the 27-month follow-up visit and obtained a second reading in 203 participants 293±84 days afterward. There was considerable lack of agreement between clinic and daytime ambulatory systolic BP with wide limits of agreement in Bland-Altman plots of -21 to 34 mm Hg in the intensive-treatment group and -26 to 32 mm Hg in the standard-treatment group. Overall, there was poor agreement between clinic visit-to-visit variability and ambulatory BP variability with correlation coefficients for systolic and diastolic BP all <0.16. We observed a high correlation between first and second ambulatory BP ; however, the limits of agreement were wide in both the intensive group (-27 to 21 mm Hg) and the standard group (-23 to 20 mm Hg). Conclusions We found low concordance in BP and BP variability between clinic and ambulatory BP and second ambulatory BP . Results did not differ by treatment arm. These results reinforce the need for multiple BP measurements before clinical decision making.

The SPRINT trial suggests that markers of tubule cell function in the urine associate with risk of subsequent acute kidney injury while injury markers elevate after the injury.

Urine markers can quantify tubular function including reabsorption (α-1 microglobulin [α1m]) and ß-2-microglobulin [ß2m]) and protein synthesis (uromodulin). Individuals with tubular dysfunction may be less able to compensate to insults than those without, despite similar estimated glomerular filtration rate (eGFR) and albuminuria. Among Systolic Blood Pressure Intervention Trial (SPRINT) participants with an eGFR under 60 ml/min/1.73m2, we measured urine markers of tubular function and injury (neutrophil gelatinase-associated lipocalin [NGAL], kidney injury molecule-1 [KIM-1], interleukin-18 [IL-18], monocyte chemoattractant protein-1, and chitinase-3-like protein [YKL-40]) at baseline. Cox models evaluated associations with subsequent acute kidney injury (AKI) risk, adjusting for clinical risk factors, baseline eGFR and albuminuria, and the tubular function and injury markers. In a random subset, we remeasured biomarkers after four years, and compared changes in biomarkers in those with and without intervening AKI. Among 2351 participants, 184 experienced AKI during 3.8 years mean follow-up. Lower uromodulin (hazard ratio per two-fold higher (0.68, 95% confidence interval [0.56, 0.83]) and higher α1m (1.20; [1.01, 1.44]) were associated with subsequent AKI, independent of eGFR and albuminuria. None of the five injury markers were associated with eventual AKI. In the random subset of 947 patients with repeated measurements, the 59 patients with intervening AKI versus without had longitudinal increases in urine NGAL, IL-19, and YKL-40 and only 1 marker of tubule function (α1m). Thus, joint evaluation of tubule function and injury provided novel insights to factors predisposing to AKI, and responses to kidney injury.

PTH, FGF23, and Intensive Blood Pressure Lowering in Chronic Kidney Disease Participants in SPRINT.

BACKGROUND AND OBJECTIVES: The Systolic Blood Pressure Intervention Trial (SPRINT) demonstrated that intensive BP lowering reduced the risk of cardiovascular disease, but increased eGFR decline. Serum parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF23) concentrations are elevated in CKD and are associated with cardiovascular disease. We evaluated whether intact PTH or intact FGF23 concentrations modify the effects of intensive BP control on cardiovascular events, heart failure, and all-cause mortality in SPRINT participants with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We measured PTH and FGF23 in 2486 SPRINT participants with eGFR<60 ml/min per 1.73 m2 at baseline. Cox models were used to evaluate whether serum PTH and FGF23 concentrations were associated with cardiovascular events, heart failure, and all-cause mortality, and whether PTH and FGF23 modified the effects of intensive BP control. RESULTS: The mean age of this subcohort was 73 years, 60% were men, and mean eGFR was 46±11 ml/min per 1.73 m2. Median PTH was 48 (interquartile range [IQR], 35-67) pg/ml and FGF23 was 66 (IQR, 52-88) pg/ml. There were 261 composite cardiovascular events, 102 heart failure events, and 179 deaths within the subcohort. The adjusted hazard ratio (HR) per doubling of PTH concentration for cardiovascular events, heart failure, and all-cause mortality were 1.29 (95% confidence interval [95% CI], 1.06 to 1.57), 1.32 (95% CI, 0.96 to 1.83), and 1.04 (95% CI, 0.82 to 1.31), respectively. There were significant interactions between PTH and BP arm for both the cardiovascular (P-interaction=0.01) and heart failure (P-interaction=0.004) end points. Participants with a PTH above the median experienced attenuated benefits of intensive BP control on cardiovascular events (adjusted HR, 1.02; 95% CI, 0.72 to 1.42) compared with participants with a PTH below the median (adjusted HR, 0.67; 95% CI, 0.45 to 1.00). FGF23 was not independently associated with any outcome and did not modify the effects of the intervention. CONCLUSIONS: SPRINT participants with CKD and a high serum PTH received less cardiovascular protection from intensive BP therapy than participants with a lower serum PTH.

Catheter outcomes in the short-term inpatient setting: a controlled quality improvement study comparing citrate and heparin lock.

Heparin and citrate are used as catheter lock solutions to reduce risk of catheter dysfunction and infection in hemodialysis. There is a paucity of data comparing these two locks in the short-term, inpatient setting. We compared the efficacy of 2.2% acid citrate dextrose (ACD) versus 5000 U/ml heparin as catheter lock in the inpatient setting. The study was conducted at two sites within our system, with ACD locks used at site 1 and heparin locks at site 2. We assessed catheters for catheter dysfunction and infection. Both nontunneled dialysis catheters (NTDC) and tunneled dialysis catheters (TDC) were evaluated. We studied 250 catheters and 139 met inclusion criteria: 90 catheters in the ACD group and 49 in the heparin group. ACD had superior outcomes for NTDC; event rate was 0.052 for NTDC/ACD and 0.125 for NTDC/heparin (p = 0.032). There was no difference for TDC. Univariate (odds ratio [OR]: 1.88, confidence interval [CI]: 0.931, 3.82) and multivariate (OR: 1.35, CI: 0.64, 2.87) analyses demonstrated a trend toward increased odds of event with heparin. Catheter lock with 2.2% ACD has lower risk of catheter dysfunction as compared with that of 5000 U/ml heparin in the short-term inpatient setting in NTDC and similar risk in TDC.

Warfarin-related nephropathy occurs in patients with and without chronic kidney disease and is associated with an increased mortality rate.

An acute increase in the international normalized ratio (INR; a comparison of prothrombin time to monitor the effects of warfarin) over 3 in patients with chronic kidney disease (CKD) is often associated with an unexplained acute increase in serum creatinine (SC) and an accelerated progression of CKD. Kidney biopsy in a subset of these patients showed obstruction of the renal tubule by red blood cell casts, and this appears to be the dominant mechanism of the acute kidney injury. We termed this warfarin-related nephropathy (WRN), and previously reported cases of WRN only in patients with CKD. We now assess whether this occurs in patients without CKD, its risk factors, and consequences. In 15,258 patients who initiated warfarin therapy during a 5-year period, 4006 had an INR over 3 and SC measured at the same time; however, the large data set precluded individual patient clinical assessment. A presumptive diagnosis of WRN was made if the SC increased by over 0.3 mg/dl within 1 week after the INR exceeded 3 with no record of hemorrhage. WRN occurred in 20.5% of the entire cohort, 33.0% of the CKD cohort, and 16.5% of the no-CKD cohort. Other risk factors included age, diabetes mellitus, hypertension, and cardiovascular disease. The 1-year mortality was 31.1% with compared with 18.9% without WRN, an increased risk of 65%. Thus, WRN may be a common complication of warfarin therapy in high-risk patients and CKD doubles this risk. The mechanisms of these risks are unclear.

Blood culture isolates in hemodialysis vascular catheter-related bacteremia.

Hemodialysis requires reliable and recurrent access to the central circulation and arteriovenous fistulas or grafts are the preferred modes of vascular access. However, in many patients the use of external tunneled vascular catheters may be necessary. The major complication of tunneled catheters is infection. Understanding local epidemiologic patterns of dialysis catheter-related bacteremia may help in the management of these patients. To address this issue, we reviewed the 5-year microbiologic culture results from all bacteremic hemodialysis patients with tunneled catheters at our institution. During this period, there were 203 organisms isolated from 153 positive blood cultures. Gram-positive, Gram-negative, and fungal species represented 55.7%, 43.3%, and 1% of isolates, respectively. Positive blood cultures classified according to the presence of a single Gram-positive or single Gram-negative organism, single fungus, or polymicrobial organisms, accounted for 41.8%, 29.4%, 0.6% and 28.1% of infectious events. From 2000-2004, there was a numerical trend toward a decrease in Gram-positive infection (64.3% versus 34.8% respectively, P = 0.12) and a numerical trend toward an increase in Gram-negative and polymicrobial bacteremias (17.9 versus 21.7, P = 0.07 and 17.9 versus 43.5, P = 0.09, respectively). These data indicate that bacteremic events in hemodialysis patients with vascular catheters are commonly due to a single Gram-positive organism, but the incidence of Gram-negative and polymicrobial bacteremia may be increasing. If confirmed in a prospective trial, adjustment of empiric antibiotic regimens for suspected catheter-associated bacteremia may be indicated.

Glomerular beta-galactosidase expression following transduction with microsphere-adenoviral complexes.

The aortic injection of adenoviral-microsphere complexes is a useful technique for in vivo gene transfer (transduction) to the glomerulus. In this approach, the appearance of the foreign transprotein in the glomerulus may result from glomerular cell gene transfer and local synthesis or hepatic cell transduction followed by synthesis, secretion, and deposition in the glomerulus. We postulated that glomerular expression of the foreign transgene was the result of glomerular cell transduction. To test this question, male SD rats underwent aortic injections with adenovirus containing the LacZ expression cassette [expressing beta-galactosidase (betagal)] coupled to 16 microm diameter microspheres. After 48 hours, histologic staining confirmed glomerular expression of the betagal transprotein and reverse transcription in situ polymerase chain reaction demonstrated the presence of the betagal transgene in the glomerulus. In addition, hepatic expression of the betagal transprotein was minimal and substantially less than that observed in the glomeruli. These data support the contention that adenoviral-microsphere complexes result in glomerular cell transduction with the desired transgene, followed by local transprotein synthesis. This approach may prove useful for facilitating glomerular gene transfer in the development of gene therapy for glomerulonephritis.