Theresa Z. O'Connor

Combined Angiotensin Inhibition for the Treatment of Diabetic Nephropathy

BACKGROUND Combination therapy with angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) decreases proteinuria; however, its safety and effect on the progression of kidney disease are uncertain. Methods We provided losartan (at a dose of 100 mg per day) to patients with type 2 diabetes, a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 300, and an estimated glomerular filtration rate (GFR) of 30.0 to 89.9 ml per minute per 1.73 m(2) of body-surface area and then randomly assigned them to receive lisinopril (at a dose of 10 to 40 mg per day) or placebo. The primary end point was the first occurrence of a change in the estimated GFR (a decline of ≥ 30 ml per minute per 1.73 m(2) if the initial estimated GFR was ≥ 60 ml per minute per 1.73 m(2) or a decline of ≥ 50% if the initial estimated GFR was <60 ml per minute per 1.73 m(2)), end-stage renal disease (ESRD), or death. The secondary renal end point was the first occurrence of a decline in the estimated GFR or ESRD. Safety outcomes included mortality, hyperkalemia, and acute kidney injury. Results The study was stopped early owing to safety concerns. Among 1448 randomly assigned patients with a median follow-up of 2.2 years, there were 152 primary end-point events in the monotherapy group and 132 in the combination-therapy group (hazard ratio with combination therapy, 0.88; 95% confidence interval [CI], 0.70 to 1.12; P=0.30). A trend toward a benefit from combination therapy with respect to the secondary end point (hazard ratio, 0.78; 95% CI, 0.58 to 1.05; P=0.10) decreased with time (P=0.02 for nonproportionality). There was no benefit with respect to mortality (hazard ratio for death, 1.04; 95% CI, 0.73 to 1.49; P=0.75) or cardiovascular events. Combination therapy increased the risk of hyperkalemia (6.3 events per 100 person-years, vs. 2.6 events per 100 person-years with monotherapy; P<0.001) and acute kidney injury (12.2 vs. 6.7 events per 100 person-years, P<0.001). Conclusions Combination therapy with an ACE inhibitor and an ARB was associated with an increased risk of adverse events among patients with diabetic nephropathy. (Funded by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development; VA NEPHRON-D ClinicalTrials.gov number, NCT00555217.).

Design of Combination Angiotensin Receptor Blocker and Angiotensin-Converting Enzyme Inhibitor for Treatment of Diabetic Nephropathy (VA NEPHRON-D)

Both angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) can slow the progression of diabetic nephropathy. Even with ACEI or ARB treatment, the proportion of patients who progress to end-stage renal disease (ESRD) remains high. Interventions that achieve more complete blockade of the renin-angiotensin system, such as combination ACEI and ARB, might be beneficial. This approach may decrease progression of nondiabetic kidney disease. In diabetic nephropathy, combination therapy decreases proteinuria, but its effect in slowing progression is unknown. In addition, the potential for hyperkalemia may limit the utility of combined therapy in this population. VA NEPHRON-D is a randomized, double-blind, multicenter clinical trial to assess the effect of combination losartan and lisinopril, compared with losartan alone, on the progression of kidney disease in 1850 patients with diabetes and overt proteinuria. The primary endpoints are time to (1) reduction in estimated GFR (eGFR) of > 50% (if baseline < 60 ml/min/1.73 m(2)); (2) reduction in eGFR of 30 ml/min/1.73 m(2) (if baseline > or = 60 ml/min/1.73 m(2)); (3) progression to ESRD (need for dialysis, renal transplant, or eGFR < 15 ml/min/1.73 m(2)); or (4) death. The secondary endpoint is time to change in eGFR or ESRD. Tertiary endpoints are cardiovascular events, slope of change in eGFR, and change in albuminuria at 1 yr. Specific safety endpoints are serious hyperkalemia (potassium > 6 mEq/L, requiring admission, emergency room visit, or dialysis), all-cause mortality, and other serious adverse events. This paper discusses the design and key methodological issues that arose during the planning of the study.

Design of the VA/NIH Acute Renal Failure Trial Network (ATN) study: intensive versus conventional renal support in acute renal failure:

The optimal management of renal replacement therapy (RRT) in acute renal failure (ARF) is uncertain. The VA/NIH Acute Renal Failure Trail Network Study (ATN Study) tests the hypothesis that a strategy of intensive RRT will decrease 60-day all-cause mortality in critically ill patients with ARF. Dose separation between the two treatment arms is achieved by increasing the frequency of intermittent hemodialysis (IHD) and sustained low efficiency dialysis (SLED) treatments from three times per week to six times per week, and by increasing continuous venovenous hemodiafiltration (CVVHDF) effluent volume from 20 mL/kg/hr to 35 mL/kg/hr. In both treatment arms, subjects convert between IHD and CVVHDF or SLED as hemodynamic status changes over time. This strategy attempts to replicate the conversion between modalities of RRT that occurs in clinical practice. However, in order to implement this strategy, flexible criteria needed to be developed to provide a balance between the need for uniformity of treatment between groups and practitioner discretion regarding modality of RRT to maintain patient safety. In order to address safety and ethical issues similar to those raised by the Office of Human Research Protections in its review of the ARDS Network studies, a survey of practitioner practices was performed and observational data on the management of RRT in comparable critically ill patients with ARF managed outside of the research context is being collected prospectively. These data will help inform the studys DSMB and site IRBs of the relationship between the studys treatment arms and concurrent clinical practice.

Efficacy trial of live, cold-adapted and inactivated influenza virus vaccines in older adults with chronic obstructive pulmonary disease: a VA cooperative study

We assessed whether trivalent live, cold-adapted influenza virus (CAIV-T) vaccine provides added protection when co-administered with trivalent inactivated influenza virus vaccine (TVV) in patients with chronic obstructive pulmonary disease (COPD). Subjects (N=2215) were randomly assigned to receive either TVV intramuscularly (IM) and CAIV-T intranasally (TC), or TVV and placebo (TP). The vaccines were well-tolerated. Efficacy of TC compared to TP was not statistically significant and was 0.16 for any influenza virus strain (95% confidence limit (CL): -0.22, 0.43), 0.26 for A (H3N2) virus (95% CL: -0.17, 0.53), and -0.05 for type B virus (95% CL: -1.13, 0.48). However, there was a possible advantage for TC over TP in reducing respiratory consequences of an influenza season measured by pulmonary function and symptoms at end of study.

Predictors of Health Utility among 60-Day Survivors of Acute Kidney Injury in the Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network Study

BACKGROUND AND OBJECTIVES Health-related quality of life (HRQOL) after acute kidney injury (AKI) is an area of great importance to patients. It was hypothesized that HRQOL after AKI would relate to intensity of dialysis during AKI and dialysis dependence at follow-up. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network Study was a multicenter, prospective, randomized trial of intensive versus less intensive renal replacement therapy in critically ill patients with AKI. Of 1124 participants, 415 survived at least 60 days and completed the Health Utilities Index (HUI), which measures 8 health attributes and calculates an overall HRQOL score, also called a utility score. How strongly pre-intensive care unit (ICU) health, severity of illness, hospital course, intensity of dialysis, and outcome were associated with 60-day HUI scores was assessed, after adjustment for demographics. RESULTS The overall HUI score was 0.40 +/- 0.37, indicating severely compromised health utility and was associated with only admission from home and hospital and ICU length of stay (LOS). Ambulation was better among those with a shorter hospital and ICU LOS. Better cognition was associated with dialysis independence and with fewer comorbid chronic illnesses. Emotion was associated with only hospital LOS. Pain was associated with ICU LOS. CONCLUSIONS Health utility was low in this cohort of patients after AKI, and intensity of dialysis did not affect subsequent health utility. The effects of a lengthy hospitalization generally outweighed the effects of delayed recovery of kidney function on HRQOL after AKI.

Model to Predict Mortality in Critically Ill Adults with Acute Kidney Injury

BACKGROUND AND OBJECTIVES Acute kidney injury (AKI) requiring dialysis is associated with high mortality. Most prognostic tools used to describe case complexity and to project patient outcome lack predictive accuracy when applied in patients with AKI. In this study, we developed an AKI-specific predictive model for 60-day mortality and compared the model to the performance of two generic (Sequential Organ Failure Assessment [SOFA] and Acute Physiology and Chronic Health Evaluation II [APACHE II]) scores, and a disease specific (Cleveland Clinic [CCF]) score. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Data from 1122 subjects enrolled in the Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network study; a multicenter randomized trial of intensive versus less intensive renal support in critically ill patients with AKI conducted between November 2003 and July 2007 at 27 VA- and university-affiliated centers. RESULTS The 60-day mortality was 53%. Twenty-one independent predictors of 60-day mortality were identified. The logistic regression model exhibited good discrimination, with an area under the receiver operating characteristic (ROC) curve of 0.85 (0.83 to 0.88), and a derived integer risk score yielded a value of 0.80 (0.77 to 0.83). Existing scoring systems, including APACHE II, SOFA, and CCF, when applied to our cohort, showed relatively poor discrimination, reflected by areas under the ROC curve of 0.68 (0.64 to 0.71), 0.69 (0.66 to 0.73), and 0.65 (0.62 to 0.69), respectively. CONCLUSIONS Our new risk model outperformed existing generic and disease-specific scoring systems in predicting 60-day mortality in critically ill patients with AKI. The current model requires external validation before it can be applied to other patient populations.

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.

Recognizing Influenza in Older Patients with Chronic Obstructive Pulmonary Disease Who Have Received Influenza Vaccine

A substudy analysis was conducted to determine the clinical characteristics associated with symptomatic, laboratory-documented influenza (LDI) among 2215 veterans with chronic obstructive pulmonary disease who participated in Department of Veterans Affairs Cooperative Study 448 and who received trivalent inactivated influenza virus vaccine with or without intranasal live-attenuated, cold-adapted influenza vaccine. Of 585 evaluable first occurrences of acute respiratory illnesses, 94 (16%) were LDI. Respiratory symptoms of cough, sputum production, and dyspnea occurred in >90% of patients with LDI; 68% had documented or subjective fever, and 81% had myalgias. Stepwise logistic regression identified only fever and myalgia as being statistically associated with LDI. During the influenza outbreak period, the positive predictive value of fever and myalgia was 41%. Clinical criteria were poor predictors of LDI in these older, vaccinated patients with chronic lung disease. Additional studies are warranted to define optimal methods for the diagnosis of influenza among older persons with chronic obstructive pulmonary disease.

Human Coronavirus and Acute Respiratory Illness in Older Adults with Chronic Obstructive Pulmonary Disease

Abstract BackgroundThe clinical features and incidence of human coronavirus (HCoV) infections in chronically ill older adults need better definition MethodsHCoV infection was determined on the basis of a 4-fold increase in serum antibody and the detection of HCoV by reverse-transcription polymerase chain reaction. Laboratory-documented influenza (LDI) was detected by serologic assay and culture. HCoV illnesses were compared with other acute respiratory illnesses identified by active surveillance, during the 1998–99 winter respiratory-virus season, of 2215 patients with chronic obstructive pulmonary disease who were ⩾50 years old and who received influenza vaccines ResultsHCoV-229E and HCoV-OC43 were associated with 90 (14%) of 665 illnesses (HCoV-229E in 22, HCoV-OC43 in 67, and both in 1), LDI with 107 (16%) of 678 illnesses. In multivariate logistic regression analysis, myalgia was less likely with HCoV infection than with LDI (OR, 0.27 [95% confidence limit, 0.13–0.58]). A majority of these HCoV and LDI illnesses exhibited each of 11 symptoms and signs of acute respiratory illness. Spirometric results worsened most often with LDI, and many acute respiratory illnesses, regardless of etiology, were associated with hospitalization. A total of 8 illnesses were associated with HCoV-NL63, 1 with HCoV-HKU1 ConclusionsThe frequencies of HCoV and LDI illnesses were similar. HCoV illness was less severe than LDI illness, was accompanied by multiple respiratory and systemic symptoms, and was associated with hospitalization

Lessons for successful study enrollment from the Veterans Affairs/National Institutes of Health acute renal failure trial network study

BACKGROUND AND OBJECTIVES Design elements of clinical trials can introduce recruitment bias and reduce study efficiency. Trials involving the critically ill may be particularly prone to design-related inefficiencies. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Enrollment into the Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network Study was systematically monitored. Reasons for nonenrollment into this study comparing strategies of renal replacement therapy in critically ill patients with acute kidney injury were categorized as modifiable or nonmodifiable. RESULTS 4339 patients were screened; 2744 fulfilled inclusion criteria. Of these, 1034 were ineligible by exclusion criteria. Of the remaining 1710 patients, 1124 (65.7%) enrolled. Impediments to informed consent excluded 21.4% of potentially eligible patients. Delayed identification of potential patients, physician refusal, and involvement in competing trials accounted for 4.4, 2.7, and 2.3% of exclusions. Comfort measures only status, chronic illness, chronic kidney disease, and obesity excluded 11.8, 7.8, 7.6, and 5.9% of potential patients. Modification of an enrollment window reduced the loss of patients from 6.6 to 2.3%. CONCLUSIONS The Acute Renal Failure Trial Network Studys enrollment efficiency compared favorably with previous intensive care unit intervention trials and supports the representativeness of its enrolled population. Impediments to informed consent highlight the need for nontraditional acquisition methods. Restrictive enrollment windows may hamper recruitment but can be effectively modified. The low rate of physician refusal acknowledges clinical equipoise in the study design. Underlying comorbidities are important design considerations for future trials that involve the critically ill with acute kidney injury.