John P. Middleton

Modifiable risk factors associated with sudden cardiac arrest within hemodialysis clinics

Sudden cardiac arrest is the most common cause of death among patients with end-stage kidney disease (ESKD) maintained on hemodialysis. Here we sought to identify dialysis-related factors associated with this increased risk in a case-control study encompassing 43,200 patients dialyzed in outpatient clinics of a large organization. Within this group, we compared the clinical and dialysis-specific data of 502 patients who experienced a sudden cardiac arrest with 1632 age- and dialysis-vintage-matched controls. There were 4.5 sudden cardiac arrest events per 100,000 dialysis treatments during the 3-year study period. These patients were significantly more likely to have been exposed to low potassium dialysate of less than 2 meq/l. These differences could not be explained by predialysis serum potassium levels. There was no evidence for a beneficial effect of low potassium dialysate even among those with higher predialysis serum potassium levels. Other factors strongly associated with sudden cardiac arrest by multivariable analysis included increased ultrafiltration volumes, exposure to low calcium dialysate, and predialysis serum creatinine levels. These relationships persisted after adjustment for covariates, but traditional risk factors such as history of coronary heart disease and congestive heart failure were not significantly influential. Hence, our study suggests that modifications of the hemodialysis prescription may improve the risk of sudden cardiac arrest in patients with ESKD.

Chronic kidney disease is associated with increased risk of sudden cardiac death among patients with coronary artery disease

Sudden cardiac death is the most common cause of mortality among patients with end-stage kidney disease maintained on hemodialysis. To examine whether this increased risk is also seen with less advanced kidney disease, we studied the relationship between glomerular filtration rate and risk of sudden cardiac death in patients with moderate kidney disease and known coronary artery disease. This retrospective longitudinal study encompassed 19,440 consecutive patients who underwent cardiac catheterization at a single academic institution. There were 522 adjudicated sudden cardiac death events, yielding an overall rate of 4.6 events per 1000 patient years. This figure reflected rates of 3.8 events in 14,652 patients with estimated glomerular filtration rates (eGFR) > or =60 (stage 2 CKD or better) and 7.9 events in 4788 patients with glomerular filtration rates <60 (stage 3-5 CKD), all normalized to 1000 patient-years. After adjusting for differences in known cardiac risk factors and other covariates in a multivariate Cox proportional hazards model, the eGFR was independently associated with sudden cardiac death (hazard ratio (HR)=1.11 per 10 ml/min decline in the eGFR). Our analysis found that reductions in the eGFR in CKD stages 3-5 are associated with a progressive increase in risk of sudden cardiac death in patients with coronary artery disease. Additional studies are needed to better characterize the mechanisms by which reduced kidney function increases this risk.

Clinical trial of focal segmental glomerulosclerosis in children and young adults

This NIH-funded multicenter randomized study of focal segmental glomerulosclerosis (FSGS) treatment compared the efficacy of a 12-month course of cyclosporine to a combination of oral pulse dexamethasone and mycophenolate mofetil in children and adults with steroid-resistant primary FSGS. Of the 192 patients enrolled, 138 were randomized to cyclosporine (72) or to mycophenolate/dexamethasone (66). The primary analysis compared the levels of an ordinal variable measuring remission during the first year. The odds ratio (0.59) for achieving at least a partial remission with mycophenolate/dexamethasone compared to cyclosporine was not significant. Partial or complete remission was achieved in 22 mycophenolate/dexamethasone- and 33 cyclosporine-treated patients at 12 months. The main secondary outcome, preservation of remission for 26 weeks following cessation of treatment, was not significantly different between these two therapies. During the entire 78 weeks of study, 8 patients treated with cyclosporine and 7 with mycophenolate/dexamethasone died or developed kidney failure. Thus, our study did not find a difference in rates of proteinuria remission following 12 months of cyclosporine compared to mycophenolate/dexamethasone in patients with steroid-resistant FSGS. However, the small sample size might have prevented detection of a moderate treatment effect.

Predictors of Survival after Cardiac Arrest in Outpatient Hemodialysis Clinics

Cardiac arrest (CA) is the most common cause of death in hemodialysis patients, and factors that improve survival after arrest are unknown. This study sought to identify modifiable factors that are associated with survival after CA in hemodialysis clinics. Patients who experienced in-center CA in the Gambro Healthcare System in the United States from 2002 to 2005 were identified. Patient characteristics at the time of arrest were compared between survivors and nonsurvivors at 24 h and 6 mo after CA. A total of 729 patients sustained in-clinic CA; 310 (42.5%) patients survived 24 h, and 80 (11%) patients survived 6 mo. Traditional risk factors, including cardiovascular comorbidities, diabetes, hemoglobin, and dialysis adequacy, did not predict survival at either time point. After adjustment for case-mix factors, presence of indwelling catheter, and concomitant medications, only use of beta blockers (BBL), calcium-channel blockers (CCB), and angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) remained significantly associated with survival (BBL odds ratio [OR] 0.32 [95% confidence interval (CI) 0.17 to 0.61]; CCB OR 0.42 [95% CI 0.23 to 0.76]; ACEI/ARB OR 0.51 [95% CI 0.28 to 0.95]). The beneficial effect of ACEI/ARB and BBL on survival increased sequentially with higher medication dosages. Prescription of BBL at the time of the event was the only predictive variable of survival at 24 h. Therefore, traditional cardiovascular risk factors were not associated with survival after CA in this hemodialysis cohort. The benefits that are associated with BBL, CCB, and ACEI/ARB suggest that these medications may improve the chances of survival after CA.

The Rationale and Design of the AASK Cohort Study

Hypertensive kidney disease commonly progresses. The primary objective of the AASK (African American Study of Kidney Disease and Hypertension) Cohort Study is to determine prospectively the course of kidney function and risk factors for kidney disease progression in African Americans with hypertensive kidney disease who receive recommended anti-hypertensive therapy. The AASK Cohort Study is a prospective, observational study that is an extension of the AASK trial. The AASK trial tested the effects of three medications used as initial anti-hypertensive therapy (ramipril, metoprolol, and amlodipine) and two levels of BP control. Of the 1094 trial participants, approximately 650 to 700 individuals who have not reached ESRD will likely enroll in the Cohort Study. Risk factors to be studied include environmental, genetic, physiologic, and socioeconomic variables. The primary renal outcome is a composite clinical outcome defined by doubling of serum creatinine, ESRD, or death. Medication treatment for hypertension, beginning with the angiotensin converting enzyme inhibitor ramipril, is offered to all participants. In this fashion, the study directly controls two of the major determinants of kidney disease progression: treatment of hypertension and use of renoprotective, anti-hypertensive medication. The minimum duration of follow-up in the Cohort Study is 5 yr (total of 9 to 12 yr, including the period of the AASK trial). Ultimately, data from the AASK Cohort Study should enhance our understanding of the risk factors and processes that determine the progression of kidney disease. Such results might eventually lead to new strategies that delay or prevent ESRD.

Analysis of Early Hypertension and Clinical Outcome With Bevacizumab: Results From Seven Phase III Studies

BACKGROUND Hypertension is associated with antivascular endothelial growth factor treatment, but the clinical implications of hypertension are uncertain. To assess the prognostic and predictive value of bevacizumab-related hypertension, a comprehensive analysis of whether hypertension and efficacy outcomes are associated was conducted on seven company-sponsored placebo-controlled phase III studies of bevacizumab. METHODS Patient-specific data were available from 6,486 patients with metastatic colorectal, breast, non-small cell lung, pancreatic, and renal cell cancers. Primary hypertension endpoint was a blood pressure (BP) increase of >20 mmHg systolic or >10 mmHg diastolic within the first 60 days of treatment. Additional endpoints included other predefined thresholds of change in BP and severity of hypertension graded using the National Cancer Institutes Common Terminology Criteria for Adverse Events. To analyze the general prognostic importance of an early BP increase, multivariate Cox regression models were used to assess the correlation between BP changes and progression-free (PFS) and overall survival (OS) outcomes in the control groups. To analyze whether early BP increases could predict for benefit from bevacizumab, similar analyses were conducted in the bevacizumab-treated and control groups. RESULTS In six of seven studies, early BP increase was neither predictive of clinical benefit from bevacizumab nor prognostic for the course of the disease. For study AVF2107g, early increased BP was associated with longer PFS and OS times in the bevacizumab group but shorter OS time in the control group. CONCLUSIONS Early treatment-related BP increases do not predict clinical benefit from bevacizumab based on PFS or OS outcomes. BP increases do not appear to have general prognostic importance for patients with advanced cancer.

Functional expression of human 5-HT1A receptors and differential coupling to second messengers in CHO cells

SummaryThe signal transduction linkages of the cloned human 5-HT1A receptor as expressed stably in CHO cells were studied. A transfected clonal cell line which expresses 900 ± 36 fmol 5-HT1A receptor/mg protein (designated CHO-5-HT1A/WT-27) responded to 5-HT and/or 8-OH-DPAT by coupling to several second messenger pathways. The 5-HT1A receptor inhibited, but did not stimulate, membrane adenylyl cyclase activity and whole cell cAMP accumulation in a dose-dependent manner (for 5-HT, IC50 = 146 ± 27 and 55 ± 12 nM, respectively). Activation of the receptor was associated with other signal transduction linkages: (i) a 40–50% increase in hydrolysis of inositol phosphates (for 5-HT, EC50 = 1.33 ± 0.15 μM for 5-HT), (ii) a transient elevation of cytosolic Ca2+ levels (apparent at 1–100 μM 5-HT) which was not affected by chelation of extracellular Ca2+ by EGTA, and (iii) an augmentation of [3H]-arachidonic acid release pharmacologically with the calcium ionophore A23187 or by activation of endogenous thrombin or P2 purinergic receptors (for 5-HT, EC50 = 1.22 ± 0.17 μM). This pathway may be an amplification mechanism for signaling in anatomic regions with high concentrations of several neuro-transmitters, hormones or autacoids, such as at neuronal junctions or near areas of platelet aggregation. All linkages were sensitive to pertussistoxinpre-treatment (IC50≈0.5–0.6 ng/ml × 4.5 h for all pathways), suggesting the involvement of Gi protein(s) in these signal transduction pathways. Coupling to varied signal transduction pathways in a single cell system may be a common feature of receptors which classically inhibit adenylyl cyclase such as the 5-HT1A receptor.

Dialysate Calcium Concentration and the Risk of Sudden Cardiac Arrest in Hemodialysis Patients

BACKGROUND AND OBJECTIVES The optimal dialysate calcium concentration to maintain normal mineralization and reduce risk of cardiovascular events in hemodialysis patients is debated. Guidelines suggest that dialysate Ca concentration should be lowered to avoid vascular calcification, but cardiac arrhythmias may be more likely to occur at lower dialysate Ca. Concurrent use of QT-prolonging medications may also exacerbate arrhythmic risk. This study examined the influence of serum Ca, dialysate Ca, and QT interval-prolonging medications on the risk of sudden cardiac arrest in a cohort of hemodialysis patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This case-control study among 43,200 hemodialysis patients occurred between 2002 and 2005; 510 patients who experienced a witnessed sudden cardiac arrest were compared with 1560 matched controls. This study examined covariate-adjusted sudden cardiac arrest risk associations with serum Ca, dialysate Ca, serum dialysate Ca gradient, and prescription of QT-prolonging medications using logistic regression techniques. RESULTS Patients assigned to low Ca dialysate<2.5 mEq/L were more likely to be exposed to larger serum dialysate Ca gradient and had a greater fall in BP during dialysis treatment. After accounting for covariates and baseline differences, low Ca dialysate<2.5 mEq/L (odds ratio=2.00, 95% confidence interval=1.40-2.90), higher corrected serum Ca (odds ratio=1.10, 95% confidence interval=1.00-1.30), and increasing serum dialysate Ca gradient (odds ratio=1.40, 95% confidence interval=1.10-1.80) were associated with increased risk of sudden cardiac arrest, whereas there were no significant risk associations with QT-prolonging medications. CONCLUSIONS Increased risk of sudden cardiac arrest associated with low Ca dialysate and large serum dialysate Ca gradients should be considered in determining the optimal dialysate Ca prescription.

Automated External Defibrillators and Survival from Cardiac Arrest in the Outpatient Hemodialysis Clinic

Automated external defibrillators (AED) have been recommended for use in outpatient dialysis clinics to improve outcomes from cardiac arrest, the most common cause of death in patients with ESRD. The effectiveness of this policy is unknown. The study cohort consisted of 43,200 hemodialysis patients in the US Gambro Healthcare System from 2002 to 2005. Of these, 729 patients who sustained an in-center cardiac arrest were identified. Baseline characteristics at the time of the event were compared between patients who underwent hemodialysis in clinics with and without an AED on site. Unadjusted survival and survival adjusted for potential confounders was measured using Cox proportional hazards regression models. Unadjusted survival at 30 d was 19 versus 15% (P = 0.12) and 9.5 versus 7.8% at 1 yr (P = 0.39) in the AED-present and AED-absent groups, respectively. AED presence was not associated with outcome in unadjusted analysis (hazard ratio [HR] 0.91; 95% confidence interval [CI] 0.78 to 1.07; P = 0.26). Univariable analysis identified age (HR 1.07 per decade; 95% CI 1.01 to 1.13), serum albumin (HR 0.91 per 0.7-mg/dl increase; 95% CI 0.82 to 1.01), and indwelling dialysis catheters (HR 1.21; 95% CI 1.02 to 1.42) as potential confounders. Medications including angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, beta blockers, calcium channel blockers, other BP medications, aspirin, antibiotics, and antiarrhythmics were associated with survival and considered confounders. After controlling for case mix and confounders, AED presence was not associated with outcome (HR 0.98; 95% CI 0.82 to 1.18; P = 0.83). Presence of AED in the dialysis clinic is not sufficient by itself to improve the abysmal outcome from in-clinic cardiac arrest in hemodialysis patients in the United States.

G-protein-coupled receptor kinase 4 polymorphisms and blood pressure response to metoprolol among African Americans: Sex-specificity and interactions

BACKGROUND African Americans have a disproportionate burden of hypertension and comorbid disease. Pharmacogenetic markers of blood pressure response have yet to be defined clearly. This study explores the association between G-protein-coupled receptor kinase type 4 (GRK4) variants and blood pressure response to metoprolol among African Americans with early hypertensive nephrosclerosis. METHODS Participants from the African American Study of Kidney Disease and Hypertension (AASK) trial were genotyped at three GRK4 polymorphisms: R65L, A142V, and A486V. A Cox proportional hazards model, stratified by gender, was used to determine the relationship between GRK4 variants and time to reach a mean arterial pressure (MAP) of 107 mm Hg, adjusted for other predictors of blood pressure response. Potential interactions between the three polymorphisms were explored by analyzing the effects of gene haplotypes and by stratifying the analysis by neighboring sites. RESULTS The hazard ratio with 95% confidence interval by A142V among men randomized to a usual MAP (102-107 mm Hg) was 1.54 (1.11-2.44; P = 0.0009). The hazard ratio by A142V with R65/L65 or L65/L65 was 2.14 (1.35-3.39; P = 0.001). Haplotype analyses were consistent but inconclusive. There was no association between A142V and blood pressure response among women. CONCLUSIONS Results suggest a sex-specific relationship between GRK4 A142V and blood pressure response among African-American men with early hypertensive nephrosclerosis. Men with a GRK4 A142 were less responsive to metoprolol if they had a GRK4 L65 variant. The effect of GRK4 variants and blood pressure response to metoprolol should be studied in larger clinical trials.