Jesse Goldman

A Phase III, Randomized, Double-Blind, Placebo-Controlled Study of Tenecteplase for Improvement of Hemodialysis Catheter Function: TROPICS 3

BACKGROUND AND OBJECTIVES Despite widespread use of tunneled hemodialysis (HD) catheters, their utility is limited by the development of thrombotic complications. To address this problem, this study investigated whether the thrombolytic agent tenecteplase can restore blood flow rates (BFRs) in dysfunctional HD catheters. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS In this randomized, double-blind study, patients with dysfunctional tunneled HD catheters, defined as a BFR <300 ml/min at -250 mmHg pressure in the arterial line, received 1-hour intracatheter dwell with tenecteplase (2 mg) or placebo. The primary endpoint was the percentage of patients with BFR > or =300 ml/min and an increase of > or =25 ml/min above baseline 30 minutes before and at the end of HD. Safety endpoints included the incidence of hemorrhagic, thrombotic, and infectious complications. RESULTS Eligible patients (n = 149) were treated with tenecteplase (n = 74) or placebo (n = 75). Mean baseline BFR was similar for the tenecteplase and placebo groups at 151 and 137 ml/min, respectively. After a 1-hour dwell, 22% of patients in the tenecteplase group had functional catheters compared with 5% among placebo controls (P = 0.004). At the end of dialysis, mean change in BFR was 47 ml/min in the tenecteplase group versus 12 ml/min in the placebo group (P = 0.008). Four catheter-related bloodstream infections (one tenecteplase, three placebo) and one thrombosis (tenecteplase) were observed. There were no reports of intracranial hemorrhage, major bleeding, embolic events, or catheter-related complications. CONCLUSIONS Tenecteplase improved HD catheter function and had a favorable safety profile compared with placebo.

Establishing A New Option for Target-organ Protection : Rationale for ARB Plus ACE Inhibitor Combination Therapy

Activation of the renin-angiotensin system (RAS) plays an important role in the promotion of cardiovascular disease and target-organ damage, mediated in part by hypertension. Combination therapy targeting RAS activation may reduce target-organ damage and provide superior blood pressure (BP) control; combining angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) represents one possible approach. In monotherapy studies, both ACE inhibitors and ARBs have demonstrated similar positive effects on BP and on RAS-related target-organ damage, including nephropathy and congestive heart failure. Studies of combination therapy, most of which involved addition of an ARB to existing ACE inhibitor therapy, have demonstrated benefits among patients with congestive heart failure and renal disease. However, variances in study design and populations, dosing and titration methods, and clinical end points, in addition to inherent differences between agents, limit the ability to reach clinically meaningful conclusions about the value of dual RAS inhibition. Trials designed to document such efficacy are currently underway.

Tenecteplase for the improvement of blood flow rate in dysfunctional hemodialysis catheters.

BACKGROUND We evaluated the efficacy and safety of the thrombolytic agent tenecteplase for the treatment of dysfunctional hemodialysis (HD) catheters. METHODS Data were pooled from 2 Phase III clinical studies: the randomized, placebo-controlled TROPICS 3 trial and the open-label TROPICS 4 trial. Eligible patients received either an initial dose of tenecteplase (2 mg/lumen) or placebo (TROPICS 3 only) for a 1-h intracatheter dwell. Treatment success was defined as blood flow rate (BFR) ≥ 300 ml/min and a ≥ 25 ml/min increase from baseline BFR, without line reversal, 30 min before and at the end of HD. All TROPICS 4 patients and the TROPICS 3 patients enrolled after the final protocol amendment without treatment success received an instillation of tenecteplase at the end of the initial visit for an extended dwell of up to 72 h. RESULTS A total of 372 patients with dysfunctional catheters were enrolled in the 2 studies. Of the 297 patients treated with tenecteplase at the initial visit, 31% achieved treatment success, with a mean (SD) change from baseline BFR of 73 (120) ml/min. Among the 179 patients who received a 1-h dwell of study drug followed by extended-dwell tenecteplase, 46% had treatment success at the end of the next HD session. Six catheter-related bloodstream infections and 2 thromboses were reported in patients following tenecteplase exposure. CONCLUSION Tenecteplase, administered as a 1-h dwell or a 1-h dwell followed by an extended dwell, was associated with improved BFR in dysfunctional HD catheters in the TROPICS 3 and 4 clinical trials.

The Heterogeneity and Diversity of Hypertension in CKD

H hypertension (HTN) has been approached as a unique diseasewith emphasis on conforming to a unified and singular approach. Booker T. Washington once said “In all things social we can be as separate as the fingers, yet one as the hand in all things essential to mutual progress.” There has been a similar approach toward HTN throughout this country and the world. We have united hand and fist in the fight against HTN. Health professionals and society have made a concerted effort to raise awareness, identify, and treat this disease. The Million Hearts initiative launched by the US Department of Health and Human Services aims to reduce heart attacks and strokes through improvements in blood pressure control. The World Health Organization has recognized HTN control as a global health priority. HTN is, indeed, an important global concern both because it is widespread and deadly. It affects over 1 billion people throughout the world and approximately 30% of adults in theUnited States. Consequently, 9.4million deaths occur worldwide as a result of HTN and its consequences. CKD and HTN have an overlapping relationship, and these 2 conditions are often tightly intertwined as either etiology or consequence of one another. As seen on this issue’s cover image, the majority of those with CKD have HTN and the rate rises with increasing CKD stage. In this issue, the review by Horowitz and Zager provides insight into the epidemiology and the varied interactions within HTN and CKD. They provide a comprehensive overview of the rates of HTN in CKD from several observations and clinical trials and further discuss the causal impact on morbidity andmortality. Judd and Calhoun discuss the nuances and special considerations of a HTN-CKD relationship by delineating different mechanisms and etiologies of blood pressure elevations in CKD. This discussion strongly informs management strategies. Obvious to this audience, a cornerstone of CKD treatment, in terms of slowing progression and delaying onset of ESRD, has been therapy with antihypertensive medications, particularly those directed at the renin-angiotensin system. Bomback and colleagues offers a comprehensive discussion of the pharmacology and relevance of these medications in treatment strategies specific to the HTN of CKD. We, as health care providers, have made great strides in the battle against HTN. The awareness, treatment, and control of HTN have improved. In the United States, scores of thousands of lives and billions of health care dollars have been saved annually. The global impact on morbidity and mortality is frankly enormous.

Metabolic Disturbances of Acid–Base and Electrolytes

After studying this chapter, you should be able to: Use a systematic approach to identify the types of acid–base disorders. Be proficient in calculating the anion gap (AG) and the delta:delta equations. Differentiate among common causes of elevated AG and non-AG acidoses. Identify common causes of metabolic alkalosis. List the common causes, clinical symptoms, and physical examination signs of: Hyponatremia Hypernatremia Hypokalemia Hyperkalemia Hypocalcemia Hypercalcemia Hypomagnesemia Hypermagnesemia Hypophosphatemia Hyperphosphatemia Determine the treatment options for the electrolyte disorders listed.

Acute Renal Injury

After studying this chapter, you should be able to: Understand the pathophysiology of acute kidney injury (AKI). Recognize factors associated with the development and worsening of AKI. Elicit a concise, pertinent history and conduct a targeted physical exam in patients with acute kidney disease. Interpret urinary sediment and urinary index results. Formulate a differential diagnosis of AKI based upon history, physical findings, and laboratory data.Recognize the types of current treatment modalities and their limitations in AKI.