Longitudinal Chronic Renal Failure Study
A Multi-center Research Project Funded by the Renal Research Institute
Coordinating Center Investigators
Dr. Rajiv Saran (P.I.), Dr. Eric W. Young, Dr. Robert A. Wolfe, Mr. Randall L. Webb, University of Michigan Kidney Epidemiology and Cost Center, Schools of Medicine and Public Health
Dr. Friedrich K. Port, Dr. Philip J. Held, University Renal Research and Education Association, Ann Arbor, MI
Clinical Site Investigators
Drs. Joseph Messana, Sean Leavey, Austin Stack, et al. University of Michigan Med. Center
Drs. Chi-yuan Hsu and Glen Chertow, University of California at San Francisco
Drs. Ron Falk and Margaret Kaiser, University of North Carolina
Dr. George Eisele, Medical College of Albany
Drs. Finkelstein and Hugh Carey, Yale University
Dr. Nathan Levin, Beth Israel Medical Center
Background
Most research in ESRD has focused on patients after they start care for ESRD. Although some studies have looked retrospectively at the pre-ESRD medical care of ESRD patients, they did not include control groups who had not (yet) reached ESRD. There are many unanswered questions about potential benefits associated with various pre-ESRD interventions (singly or combined), specifically regarding the potential for slowing the progression of renal failure (preserving renal function) and the health state at the initiation of ESRD therapy. Such factors include nutrient intake, catabolism, control of blood pressure, lipids, acid base balance, phosphorus, glucose, etc during the pre-ESRD phase of chronic renal failure. Recent studies have suggested a strong correlation of pre-ESRD nutritional status and cardiac disease with mortality after the onset of ESRD. The applicability of the prospective MDRD study to the average patient with renal functional impairment is unclear, because of its patient selection and very severe dietary protein restrictions. A real world approach to the more common patient seen with renal impairment (e.g. including diabetics) will give important new insights.
Outcomes after the onset of ESRD are likely also influenced by the same factors that are important before the onset of ESRD. Additionally, health status at the start of ESRD therapy is likely associated with the timing of the initiation of dialysis, which may be anywhere in the spectrum of a relatively early for a healthy start of dialysis or relatively late, e.g. after onset of uremic symptoms. Initiation of ESRD treatment may be accelerated by the presence of clinical symptoms. Leavey et al at the USRDS have shown that impaired baseline nutritional parameters are associated with significantly poorer patient survival as late as 4 to 5 years later. The DOQI guidelines have emphasized the role of deteriorating nutrition as an indication for immediate start of dialysis. The timing and choice of vascular access may also be associated with subsequent outcomes. Prior research into these issues has been limited by the lack of large prospective studies that assess complications and mortality risk during the time of pre-ESRD chronic renal failure and particularly during the interval between early and late initiation of dialysis (lead time bias). Early start of dialysis may have important quality of life (QoL) and cost implications because of (or despite) the added time on dialysis. A balanced assessment is therefore needed, specifically regarding the possible negative shorter term effects of starting dialysis earlier than absolutely necessary and the potential positive longer term effects of preventing complications and hospitalizations associated with a healthy start. Randomization of patients into early versus late initiation of dialysis has several ethical problems, which are avoided by the proposed observational study in which physician and patient preference lead to variability in the timing of ESRD therapy.
A prospective approach that collects data longitudinally during the various stages of chronic renal failure and into ESRD offers the best approach to address the hypotheses listed below.
Hypotheses
Study Question 1: Can the progression of renal insufficiency be stopped or delayed?
Hypothesis 1: Several interventions and patient factors can modify the rate of progression to ESRD. Treatment factors include dietary prescription, protein and calorie nutrient intake, blood pressure control, type of antihypertensive medications, control of anemia, vitamin D deficiency, phosphate, and lipids plus, for diabetics, glucose control. Patient factors include underlying renal disease, age, sex, race, compliance, education etc.
Study Question 2: Can ESRD and pre-ESRD outcomes be modified by pre-ESRD care?
Hypothesis 2: All else equal (through statistical adjustments), several pre-ESRD patient and treatment factors are associated with better patient outcomes both during ESRD and before reaching ESRD. Such outcomes include patient survival, cause specific death rates, hospitalization rate and days, employment, cardiac and vascular events, changes in nutritional status, type and timing of initial vascular access, quality of life and cost. Treatment and patient factors include those listed in hypothesis #1 plus early "healthy" start versus late start of dialysis.
Study Question 3: What is the magnitude of overall cost effectiveness (cost per patient year) associated with "healthy" start versus late start of dialysis, if any?
Hypothesis 3: "Healthy" start is a cost-effective approach. Although starting dialysis when indicated rather than late is associated with the additional cost of dialysis during an interval in which late starters would not yet be on dialysis, the subsequent cost saving per patient year through better health and reduced hospitalization exceeds the cost of early dialysis.