Influence of Renal Impairment on Outcome for Thrombolysis-Treated Acute Ischemic Stroke: ENCHANTED (Enhanced Control of Hypertension and Thrombolysis Stroke Study) Post Hoc Analysis.

BACKGROUND AND PURPOSE: Renal dysfunction (RD) is associated with poor prognosis after stroke. We assessed the effects of RD on outcomes and interaction with low- versus standard-dose alteplase in a post hoc subgroup analysis of the ENCHANTED (Enhanced Control of Hypertension and Thrombolysis Stroke Study). METHODS: A total of 3220 thrombolysis-eligible patients with acute ischemic stroke (mean age, 66.5 years; 37.8% women) were randomly assigned to low-dose (0.6 mg/kg) or standard-dose (0.9 mg/kg) intravenous alteplase within 4.5 hours of symptom onset. Six hundred and fifty-nine (19.8%) patients had moderate-to-severe RD (estimated glomerular filtration rate, <60 mL/min per 1.73 m2) at baseline. The impact of RD on death or disability (modified Rankin Scale scores, 2-6) at 90 days, and symptomatic intracerebral hemorrhage, was assessed in logistic regression models. RESULTS: Compared with patients with normal renal function (>90 mL/min per 1.73 m2), those with severe RD (<30 mL/min per 1.73 m2) had increased mortality (adjusted odds ratio, 2.07; 95% confidence interval, 0.89-4.82; P=0.04 for trend); every 10 mL/min per 1.73 m2 lower estimated glomerular filtration rate was associated with an adjusted 9% increased odds of death from thrombolysis-treated acute ischemic stroke. There was no significant association with modified Rankin Scale scores 2 to 6 (adjusted odds ratio, 1.03; 95% confidence interval, 0.62-1.70; P=0.81 for trend), modified Rankin Scale 3 to 6 (adjusted odds ratio, 1.20; 95% confidence interval, 0.72-2.01; P=0.44 for trend), or symptomatic intracerebral hemorrhage, or any heterogeneity in comparative treatment effects between low-dose and standard-dose alteplase by RD grades. CONCLUSIONS: RD is associated with increased mortality but not disability or symptomatic intracerebral hemorrhage in thrombolysis-eligible and treated acute ischemic stroke patients. Uncertainty persists as to whether low-dose alteplase confers benefits over standard-dose alteplase in acute ischemic stroke patients with RD. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01422616.

Reduced glomerular filtration rate in pre-dialysis non-diabetic chronic kidney disease patients is associated with impaired baroreceptor sensitivity and reduced vascular compliance.

Small uncontrolled studies of dialysis-dependent CKD (chronic kidney disease) patients have demonstrated abnormalities of cardiovascular autonomic control and vascular compliance, which may contribute to adverse cardiovascular morbidity in this population. However, there is little information utilizing newer non-invasive techniques in pre-dialysis patients with increasing degrees of uraemia. In the present study, 55 non-dialysis-dependent non-diabetic CKD patients with mean GFR (glomerular filtration rate) of 27 ml x min(-1) x m(-2) were studied. All patients underwent a 10-min period of electrocardiographic and non-invasive blood pressure monitoring. Cardiac BRS (baroreceptor sensitivity) was calculated from the combined alpha-index. PWV (pulse wave velocity) measurement and determination of arterial wave reflexion by applanation tonometry was performed in all patients. Mean (S.D.) cardiac BRS was 10.8 (7.1) ms/mmHg and mean (S.D.) PWV was 8.6 (1.7) m/s. Reduced GFR was correlated with increased PWV and decreased cardiac BRS. On logistic regression analysis with adjustment for clinical significant risk factors, severely impaired renal function (assessed by GFR < 15 ml x min(-1) x m(-2)) was associated with increased large artery stiffness [odds ratio for PWV = 3.14 (95% confidence intervals, 1.03-9.53); P = 0.04] and increased cardiovascular autonomic dysfunction [odds ratio for BRS = 0.87 (95% confidence intervals, 0.75-1.80); P = 0.06]. In conclusion, non-dialysis dependent non-diabetic CKD patients with decreasing GFR have reduced cardiac BRS and increased large artery stiffness. This may have important prognostic and therapeutic consequences for the management of vascular disease in a pre-dialysis population.

Prognostic potential of brain natriuretic peptide (BNP) in predialysis chronic kidney disease patients.

In the present study, we investigated the potential of N-BNP (N-terminal B-type natriuretic peptide) as a prognostic marker for risk of CV (cardiovascular) events, overall mortality and progression to ESRD (end-stage renal disease) in a cohort of 83 pre-dialysis CKD (chronic kidney disease) patients without clinical evidence of heart failure. During the study, ten patients reached the combined end point of overall mortality and/or CV event. Univariate factors associated with the combined end point were plasma N-BNP (P < 0.0005), creatinine (P < 0.002), systolic blood pressure (P < 0.009) and age (P < 0.015). N-BNP levels were higher in patients with CV events (P < 0.0005). Cox model regression analysis yielded log10 N-BNP (hazard ratio, 9.608; P < 0.007) and pre-existing CV disease (hazard ratio, 4.571; P < 0.029) as independent predictors of overall mortality or CV events. Kaplan-Meier analysis curves for the subgroup with supramedian creatinine levels (225 micromol/l) showed significant separation of the curves stratified for plasma N-BNP levels above and below the group median (291 pmol/l) for all end points. Receiver-operator-characteristic curves for N-BNP (355 pmol/l cut-off) demonstrated a specificity of 65.8% at a sensitivity of 100% for predicting CV events/overall mortality. The measurement of plasma N-BNP may aid in the risk stratification of pre-dialysis CKD patients. The high sensitivity and negative predictive value (100%) may enable the selection of patients who could safely be excluded from further investigations, resulting in better focusing of resources.

Cardiac baroreceptor sensitivity: a prognostic marker in predialysis chronic kidney disease patients?

BACKGROUND: Small, uncontrolled studies of dialysis-dependent chronic kidney disease (CKD) patients have demonstrated abnormalities of cardiovascular autonomic control and vascular compliance, which may contribute to adverse cardiovascular morbidity in this population. However, there is little information utilizing newer, noninvasive techniques in predialysis patients with increasing degrees of uremia. METHODS: One hundred and five nondialysis CKD patients with a median GFR of 23 mL/min/1.73 m(2) (range: 6 to 102) at baseline were studied. Cardiac baroreceptor sensitivity (BRS) was recorded by time- and frequency-domain techniques, and its relationship with increasing degrees of uremia studied. During a mean follow-up period of 42 months (range: 3 to 70), primary (death, dialysis, transplantation) and secondary (fatal and nonfatal cardiovascular events) outcome measures were recorded. The importance of cardiac BRS in comparison to other important renal and cardiovascular prognostic variables in predicting outcome was assessed. RESULTS: Median cardiac BRS by time domain analysis at baseline was 8.85 msec/mm Hg (interquartile range: 6.85), and impaired cardiac BRS was related to reduced GFR, increasing age, and hypertension on quantile regression analysis. 'Impaired' cardiac BRS was associated with a trend toward increased likelihood of both primary and secondary outcomes, and may act as a surrogate measure of other cardiovascular risk factors, including age, hyperlipidemia, hypertension, previous cardiovascular disease, and doubling of creatinine. CONCLUSION: Nondialysis-dependent CKD patients have impaired cardiac BRS, and this was related to decreasing GFR. There was a trend toward poorer prognosis in patients with impaired cardiac BRS that requires further study. Cardiac BRS may provide a simple, bedside, noninvasive assessment of overall cardiovascular risk in this population.

Cardiovascular autonomic dysfunction in uremia.

Cardiovascular morbidity and mortality is common in chronic renal failure patients, and may be explained in part by abnormalities in cardiovascular autonomic regulation. This review discusses the results of cardiovascular autonomic function studies in chronic renal failure patients. While covering most methods of assessing autonomic function, we focus particularly on power spectral analysis methods. These newer techniques are non-invasive, reproducible, and allow the rapid assessment of the integrity of cardiovascular autonomic reflexes at the bedside. The abnormalities of parasympathetic, sympathetic and cardiac baroreceptor function seen in dialysis-dependent patients are highlighted, and their significance in intra-dialytic hypotension and cardiovascular mortality as well as the effects of dialysis and transplantation on these parameters examined. Importantly, studies of cardiovascular autonomic dysfunction in pre-dialysis chronic renal failure patients, when abnormalities may be amenable to intervention to prevent progression and premature cardiovascular morbidity and mortality, are reviewed.