Intensity of renal replacement therapy in acute kidney injury: perspective from within the Acute Renal Failure Trial Network Study

Determination of the optimal dose of renal replacement therapy in critically ill patients with acute kidney injury has been controversial. Questions have recently been raised regarding the design and execution of the US Department of Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network (ATN) Study, which demonstrated no improvement in 60-day all-cause mortality with more intensive management of renal replacement therapy. In the present article we present our rationale for these aspects of the design and conduct of the study, including our use of both intermittent and continuous modalities of renal support, our approach to initiation of study therapy and the volume management during study therapy. In addition, the article presents data on hypotension during therapy and recovery of kidney function in the perspective of other studies of renal support in acute kidney injury. Finally, we address the implications of the ATN Study results for clinical practice from the perspective of the study investigators.     

Pro/con clinical debate: Is high-volume hemofiltration beneficial in the treatment of septic shock?

Although there have been exciting advances in the management of sepsis and septic shock, mortality still remains high. Recent data suggest that high-volume hemofiltration (HVHF) may play a role in these patients. In contrast to the usual rate of hemofiltration, HVHF is felt to be better able to remove the inflammatory mediators associated with sepsis and septic shock. Such an approach is currently incapable of selectively removing specific mediators. This may be a problem when one considers that several mediators may in fact be beneficial. When determining whether HVHF should be instituted in a patient with septic shock, one need remember that its role is far from clear and its usefulness remains the subject of much debate. Although early data is encouraging, it is clear that additional data is required before HVHF becomes standard management. The authors of this pro/con debate, which is based on a clinical scenario, first describe their own position and then respond to their opponent''s position.     

The effect of intensive plasma water exchange by hemofiltration on hemodynamics and soluble mediators in canine endotoxemia

High volume hemofiltration (HVHF) (200 ml/kg/h) improves hemodynamics in experimental septic shock but is difficult to apply clinically. Accordingly, we studied whether less intensive HVHF (80 ml/kg/h) can still improve hemodynamics in experimental septic shock. We also investigated its effect on the serum concentrations of several inflammatory mediators, including endothelin (ET-1), endotoxin (LPS), tumor necrosis factor-alpha (TNF-alpha), and 6-keto prostaglandin F(1alpha) (6-kepto PGF(1alpha)). Sixteen anesthetized dogs were connected to a continuous veno-venous hemofiltration (CVVH) (filtration: 80 ml/kg/h) or sham circuit and endotoxin (0.5 mg/kg) was infused intravenously over 5 min. Hemodynamic variables were measured at baseline and at 15, 45, 90, and 180 min. The major hemodynamic finding was that endotoxin-induced hypotension was significantly attenuated by intensive CVVH (p < 0.04). Changes in cardiac output and right ventricular ejection fraction were equal in both groups. ET-1 levels, but not LPS, TNF-alpha, or 6-keto PGF(1alpha), were lower during CVVH (p = 0.042). Endotoxin or TNF-alpha were not found in the ultrafiltrate. Median clearances of ET-1 and 6-keto PGF(1alpha) during intensive CVVH were 8.8 and 25.9 ml/m, respectively. We conclude that intensive CVVH attenuates the early component of endotoxin-induced hypotension and reduces serum concentrations of endothelin-1. The effect of CVVH on blood pressure is not explained by convective clearance of the mediators in question.     

AKI in Low-Risk versus High-Risk Patients in Intensive Care

Background and objectives

AKI in critically ill patients is usually part of multiorgan failure. However, nonrenal organ failure may not always precede AKI and patients without evidence of these organ failures may not be at low risk for AKI. This study examined the risk and outcomes associated with AKI in critically ill patients with and without cardiovascular or respiratory organ failures at presentation to the intensive care unit (ICU).

Design, setting, participants, & measurements

A large, academic medical center database, with records from July 2000 through October 2008, was used and the authors identified a low-risk cohort as patients without cardiovascular and respiratory organ failures defined as not receiving vasopressor support or mechanical ventilation within the first 24 hours of ICU admission. AKI was defined using Kidney Disease Improving Global Outcomes criteria. The primary end points were moderate to severe AKI (stages 2–3) and risk-adjusted hospital mortality.

Results

Of 40,152 critically ill patients, 44.9% received neither vasopressors nor mechanical ventilation on ICU day 1. Stages 2–3 AKI occurred less frequently in the low-risk patients versus high-risk patients within 24 hours (14.3% versus 29.1%) and within 1 week (25.7% versus 51.7%) of ICU admission. Patients developing AKI in both risk groups had higher risk of death before hospital discharge. However, the adjusted odds of hospital mortality were greater (odds ratio, 2.99; 95% confidence interval, 2.62 to 3.41) when AKI occurred in low-risk patients compared with those with respiratory or cardiovascular failures (odds ratio, 1.19; 95% confidence interval, 1.09 to 1.3); interaction P<0.001.

Conclusions

Patients admitted to ICU without respiratory or cardiovascular failure have a substantial likelihood of developing AKI. Although survival for low-risk patients is better than for high-risk patients, the relative increase in mortality associated with AKI is actually greater for low-risk patients. Strategies aimed at preventing AKI should not exclude ICU patients without cardiovascular or respiratory organ failures.     

Prevention of acute renal failure

Acute renal failure (ARF) comprises a family of syndromes that is characterized by an abrupt and sustained decrease in the glomerular filtration rate. In the ICU, ARF is most often due to sepsis and other systemic inflammatory states. ARF is common among the critically ill and injured and significantly adds to morbidity and mortality of these patients. Despite many advances in medical technology, the mortality and morbidity of ARF in the ICU continue to remain high and have not improved significantly over the past 2 decades. Primary strategies to prevent ARF still include adequate hydration, maintenance of mean arterial pressure, and minimizing nephrotoxin exposure. Diuretics and dopamine have been shown to be ineffective in the prevention of ARF or improving outcomes once ARF occurs. Increasing insight into mechanisms leading to ARF and the importance of facilitating renal recovery has prompted investigators to evaluate the role of newer therapeutic agents in the prevention of ARF.     

Effects of hypercapnia on BP in hypoalbuminemic and Nagase analbuminemic rats

STUDY OBJECTIVE: To determine if animals with abnormally low albumin levels are more susceptible to the effects of hypercapnia on BP compared to normal animals. DESIGN: Prospective, controlled laboratory experiment. SETTING: University research laboratory. Animals: Eighteen male Sprague-Dawley rats: 6 rats 10 to 12 weeks old (young Sprague-Dawley [YSD]), 6 rats 6 to 9 months old (old Sprague-Dawley [OSD]), and 6 rats 10 to 12 weeks old (Nagase analbuminemic mutant Sprague-Dawley [NAR]). METHODS: Under general anesthesia and paralysis, we varied the Paco(2) by changing the respiratory rate on mechanical ventilation. Mean arterial pressure (MAP) was monitored in a continuous fashion. We obtained arterial blood for blood gas and electrolyte analysis, and nitric oxide (NO) production. RESULTS: OSD rats had reduced serum albumin, while NAR rats were analbuminemic. Although NAR animals had a decreased buffer capacity compared to age-matched control animals (0.010 vs 0.013, p < 0.05), the MAP decreased in an identical fashion in all three groups. NO production increased with hypercapnia but was similar in all three groups. However, NAR rats had consistently higher plasma strong ion gap (2.8 to 4.1 mEq/L greater) compared to either YSD or OSD rats (p < 0.01), and baseline strong ion difference (mean +/- SD) was significantly lower in NAR rats (28.7 +/- 2.1 mEq/L) compared to either YSD rats (33.0 +/- 5.1 mEq/L) or OSD rats (31.2 +/- 5.1 mEq/L) [p < 0.05]. CONCLUSIONS: These findings suggest that analbuminemic or hypoalbuminemic rats are not more susceptible to hypercapnia-induced hemodynamic instability. Baseline values for apparent strong ion difference are lower in NA rats consistent with a reduced buffer base resulting from analbuminemia.     

Improving outcomes from acute kidney injury: report of an initiative

Acute kidney injury (AKI) is a clinical condition characterized by acute decline in renal function, with manifestations ranging from minimal elevation of serum creatinine concentration to anuric renal failure. Keeping in view that acquisition of knowledge and research in this important area requires multi-disciplinary collaboration, a group representing members of the Acute Dialysis Quality Initiative and nephrology and critical care societies has established the Acute Kidney Injury Network (AKIN). The First Consensus Conference of this network focused on defining diagnostic and staging criteria for AKI. Changes in serum creatinine levels and urine output were used to define and stage three levels of renal dysfunction. These criteria require evaluation and validation in prospective clinical studies and, perhaps, modifications as more sensitive markers of kidney injury are identified. Other issues that need to be examined include global epidemiology and outcome of AKI and development of strategies to improve outcomes. The vital role of multi-disciplinary conferences for disseminating knowledge and clarifying issues in clinical practice was recognized.