Determinants of impaired renal and vascular function are associated with elevated levels of procoagulant factors in the general population

Essentials

• Why venous thrombosis is more prevalent in chronic kidney disease is unclear.
• We investigated whether renal and vascular function are associated with hypercoagulability.
• Coagulation factors showed a procoagulant shift with impaired renal and vascular function.
• This suggests that renal and vascular function play a role in the etiology of thrombosis.

Summary

Background

Impaired renal and vascular function have been associated with venous thrombosis, but the mechanism is unclear.

Objectives

We investigated whether estimated glomerular filtration rate (eGFR), urinary albumin‐creatinine ratio (UACR), and pulse wave velocity (PWV) are associated with a procoagulant state.

Methods

In this cross‐sectional analysis of the NEO Study, eGFR, UACR, fibrinogen, and coagulation factors (F)VIII, FIX and FXI were determined in all participants (n = 6536), and PWV was assessed in a random subset (n = 2433). eGFR, UACR and PWV were analyzed continuously and per percentile: per six categories for eGFR (> 50^th [reference] to < 1st) and UACR (< 50^th [reference] to > 99th), and per four categories (< 50^th [reference] to > 95th percentile) for PWV. Linear regression was used and adjusted for age, sex, total body fat, smoking, education, ethnicity, total cholesterol, C‐reactive protein (CRP) and vitamin K antagonists use (FIX).

Results

Mean age was 55.6 years, mean eGFR 86.0 (12SD) mL 1.73 m^?² and median UACR 0.4 mg mmol^?1 (25th, 75th percentile; 0.3, 0.7). All coagulation factors showed a procoagulant shift with lower renal function and albuminuria. For example, FVIII was 22 IU dL^?1 (95% CI, 13–32) higher in the eGFR < 1st percentile compared with the > 50th percentile, and FVIII was 12 IU dL^?1 (95% CI, 3–22) higher in the UACR > 99th percentile compared with the < 50th percentile. PWV was positively associated with coagulation factors FIX and FXI in continuous analysis; per m/s difference in PWV, FIX was 2.0 IU dL^?1 (95% CI, 0.70–3.2) higher.

Conclusions

Impaired renal and vascular function was associated with higher levels of coagulation factors, underlining the role of renal function and vascular function in the development of venous thrombosis.

     

Influence of Renal Function on the Pharmacokinetics,Pharmacodynamics, Efficacy,and Safety of Non–Vitamin K Antagonist Oral Anticoagulants

With the growing integration of non–vitamin K antagonist oral anticoagulants (NOACs) into clinical practice, questions have arisen regarding their use in special populations, including groups that may have been underrepresented in clinical trials. Patients with renal impairment, particularly in the lower echelons of renal function, are one such group. In an effort to elucidate the current evidence regarding the use of NOACs in patients with renal impairment, a systematic assessment of the literature was performed. The MEDLINE database was interrogated for studies and analyses evaluating the influence of renal function on the pharmacokinetics, pharmacodynamics, efficacy, and safety of NOACs published from January 1, 2000, through August 2, 2017. The 82 relevant publications retrieved highlight the diversity in the NOAC class regarding the impact of renal function on drug clearance, drug exposures, and clinical trial outcomes. In several large clinical trials, subgroup analyses revealed no significant differences when patients were stratified by creatinine clearance as a measure of renal function. Efficacy findings, in particular, were largely aligned with the overall population in the included studies. However, relative risks of bleeding were shown to vary, sometimes driven by changes in bleeding event rates in the comparator arm (eg, warfarin, enoxaparin). With few exceptions, minimal influence of mild renal impairment was observed on the relative efficacy and safety of NOACs. Taken together, the evidence suggests that the presence of renal impairment merits careful consideration of anticoagulant choice but should not deter physicians from appropriate use of NOACs.     

End-Stage Renal Disease and Mortality Outcomes Across Different Glomerulonephropathies in a Large Diverse US Population

Objective

To compare renal function decline, incident end-stage renal disease (ESRD), and mortality among patients with 5 common glomerular diseases in a large diverse population.

Predialysis Kidney Function and Its Rate of Decline Predict Mortality and Hospitalizations After Starting Dialysis

Objective

To determine whether kidney function level and its rate of decline in the immediate predialysis period among veterans transitioning to end-stage renal disease (ESRD) predict postdialysis mortality and hospitalization.

Serum carbohydrate antigen 153 and renal function in patients with type 2 diabetes mellitus

Objective

The aim of our study was to investigate the correlation between serum carbohydrate antigen 153 (CA153) and renal function in patients with type 2 diabetes mellitus (T2DM).

Methods

A total of 184 patients with T2DM were included, and renal function was assessed by the modification of diet in renal disease (MDRD) formula adjusted coefficient of the Chinese people.

Results

Serum CA153 concentrations were positively correlated with blood glucose (BG) and glycated hemoglobin (HbA1c) (r = .204, P = .005; r = .165, P = .025) in patients with T2DM. There was a negative correlation between serum CA153 and estimated glomerular filtration rate (GFR) (r = −.229, P = .002) in whole patients with T2DM; similarly, the correlations were observed in both women and men (r = −.228, P = .028 for women, r = −.231, P = .028 for men). Multiple linear regression analysis suggested that serum CA153 was still significantly correlated with estimated GFR (beta = −0.286, P < .001).

Conclusions

Serum CA153 is negatively correlated with estimated GFR in patients with T2DM, and serum CA153 may be a potentially useful clinical biomarker to assess renal function in the study population.

     

Influences of season and of temperature, photoperiod, and subcutaneous melatonin infusion on the glomerular filtration rate of ewes

Abstract: Influences of season and of temperature, photoperiod, and subcutaneous melatonin infusion on glomerular filtration rate (GFR) were measured in ewes. There was a seasonal difference of GFR between summer (June-August) and winter (December-February) in Tokyo (35°, 35°N); GFR was significantly ( P < 0.05) higher in summer (4.2 ± 0.3 ml/ min/kg) than in winter (3.0 ± 0.2 ml/min/kg). GFR was measured after exposure to three types of photoperiod, 24L: 0D, 12L: 12D, and 0L: 24D, for 7 to 8 days. The value for GFR obtained at 20°C was significantly lower ( P < 0.05) with 0L: 24D than with the other two photoperiodic conditions. GFR obtained during subcutaneous melatonin infusion (20μg/hr for 16 hr/ day for 7 days) with 24L: 0D conditions was significantly ( P < 0.05) lower (2.5 ± 0.1 ml/min/kg) than without infusion (3.8 ± 0.3 ml/ min/kg) and was about the same as that obtained in animals under 0L: 24D conditions. At 30°C, GFR exhibited no difference between the 3 photoperiodic conditions and was always lower than that found at 20°C. Possible influences of melatonin on GFR are discussed.     

Association between Serum Potassium and Outcomes in Patients with Reduced Kidney Function

Background and objectives

Patients with CKD are more likely than others to have abnormalities in serum potassium (K⁺). Aside from severe hyperkalemia, the clinical significance of K⁺ abnormalities is not known. We sought to examine the association of serum K⁺ with mortality and hospitalization rates within narrow eGFR strata to understand how the burden of hyperkalemia varies by CKD severity. Associations were examined between serum K⁺ and discontinuation of medications that block the renin-angiotensin-aldosterone system (RAAS), which are known to increase serum K⁺.

Design, setting, participants, & measurements

A cohort of patients with CKD (eGFR<60 ml/min per 1.73 m²) with serum K⁺ data were studied (n=55,266) between January 1, 2009, and June 30, 2013 (study end). Serum K⁺, eGFR, and covariates were considered on a time-updated basis. Mortality, major adverse cardiovascular events (MACE), hospitalization, and discontinuation of RAAS blockers were considered per time at risk.

Results

During the study, serum K⁺ levels of 5.5–5.9 and ≥6.0 mEq/L were most prevalent at lower eGFR: they were present, respectively, in 1.7% and 0.2% of patient-time for eGFR of 50–59 ml/min per 1.73 m² versus 7.6% and 1.8% of patient-time for eGFR<30 ml/min per 1.73 m². Serum K⁺ level <3.5 mEq/L was present in 1.2%–1.4% of patient-time across eGFR strata. The median follow-up time was 2.76 years. There was a U-shaped association between serum K⁺ and mortality; pooled adjusted incidence rate ratios were 3.05 (95% confidence interval, 2.53 to 3.68) and 3.31 (95% confidence interval, 2.52 to 4.34) for K⁺ levels <3.5 mEq/L and ≥6.0 mEq/L, respectively. Within eGFR strata, there were U-shaped associations of serum K⁺ with rates of MACE, hospitalization, and discontinuation of RAAS blockers.

Conclusions

Both hyperkalemia and hypokalemia were independently associated with higher rates of death, MACE, hospitalization, and discontinuation of RAAS blockers in patients with CKD who were not undergoing dialysis. Future studies are needed to determine whether interventions targeted at maintaining normal serum K⁺ improve outcomes in this population.     

Captopril and atenolol are equally effective in retarding progression of diabetic nephropathy

Summary The progression of diabetic nephropathy can be positively influenced by maintaining a low blood pressure level. This has been shown in studies with conventional antihypertensive treatment as well as with ACE inhibitors. Whether the latter group of drugs is more effective remains to be proven and was the aim of our study. In a prospective randomized study we compared the effects of ACE inhibition and -blockade on retarding progression of renal function in IDDM patients with an early stage of overt diabetic nephropathy. Twenty-nine patients were studied for 2 years, 15 were randomized for treatment with captopril and 14 for atenolol. Every 6 weeks blood pressure and urinary albumin and total protein excretion were measured. GFR was measured every 6 months as ⁵¹Cr-EDTA clearance. Baseline values for blood pressure, renal function and albuminuria were identical in the two groups. The effect of both drugs on blood pressure was not significantly different. In the captopril-treated patients MAP before and after 2 years was 110±3 (SEM) and 100±2 mm Hg, respectively and in the atenolol-treated patients 105±2 vs 101±2 mm Hg. Both drugs reduced albuminuria and total proteinuria to the same extent. With captopril albuminuria decreased from 1549 (989–2399) to 851 (537–1380) mg/24 h and proteinuria from 2.5 (1.6–3.8) to 1.2 (0.8–1.8) g/24 h. With atenolol albuminuria decreased from 933 (603–1445) to 676 (437–1047) mg/ 24 h and proteinuria from 1.5 (1.0–2.4) to 0.9 (0.6–1.5) g/24 h. The rate of decline of GFR was similar with both treatments, on captopril –4.9±2.1 and on atenolol –3.7±1.6 ml · min^–1· year^–1. No major side effects with either drug were observed. We conclude that, in this 2-year study, captopril and atenolol are equally effective in retarding progression of diabetic nephropathy.Abbreviations IDDM insulin-dependent diabetes mellitus - ACE angiotensin converting enzyme - ECC endogenous creatinine clearance - MAP mean arterial pressure - GFR glomerular filtration rate