"MORTALITY RISKS AMONG NEW END-STAGE KIDNEY DISEASE (ESKD) PATIENTS IN THE UNITED STATES"

Dr Austin G. Stack MBBCh, MRCPI, MS

Assistant Professor in Medicine, University of Texas Medical School at Houston, Texas, U.S.A.

Austin.Stack@uth.tmc.edu Introduction Despite major advances in the provision and delivery of renal replacement therapy for new end-stage renal disease (ESKD) patients, mortality and morbidity rates remain unacceptably high 1. This is particularly true in the United States where the annual mortality rates for newly diagnosed ESKD patients exceed 20% 1. Indeed, despite increased attention to dialysis delivery, vascular access and anemia management, phosphorous control and several other comorbid factors, the survival of new ESKD patients has only improved modestly over the past decade 2-5. Moreover, the realization that the rates of ESKD are increasing at an alarming rate on a background of a chronic kidney disease (CKD) epidemic has generated national and international concern and prompted organizations such as National Kidney Foundation (NKF) to develop strategic plans for the detection, prevention and management of CKD and its attendant complications 6-8. The inclusion of CKD in the U.S. Surgeon Generals mandate for public health entitled "Healthy People 2010" has also elevated the importance of this chronic disease as a major public health concern 8. In this paper we discuss the mortality consequences of CKD at dialysis initiation and review some of the recent advances in the identification of specific mortality predictors. Mortality Rates among New ESRD Patients in the United States Although kidney transplantation is the optimal form of renal replacement therapy in patients with ESKD as it offers the best prognosis for survival and quality of life, only 2.5% of all new ESKD patients receive this therapy in the United States 1. For the remaining 97.5%, the choice is between hemodialysis (HD) or peritoneal dialysis (PD), treatment options that are associated with substantially poorer survival and reduced quality of life. In 1998, the adjusted first-year death rate for all new dialysis patients was 24 per 100 patient years at risk [Slide 1]. A comparison of mortality rates

of successive cohorts over the past decade reveals only a modest improvement from 27.5 deaths per 100 patient years at risk in 1989. This improved survival is arguably the result of improved delivery of healthcare to a population with substantial comorbidity burden whose median age at dialysis initiation increased from 58 years in 1989 to 63 years in 1998. However, the mortality risks for new ESKD patients are not equal across therapies. As shown in Slide 2, adjusted death rates were lowest for transplant recipients (3.7 deaths per 100 patients years), than for patients treated with either peritoneal dialysis (18.3 deaths per 100 patients yrs at risk) or hemodialysis (25 death per 100 patient years at risk), differences that have persisted in successive cohorts of new ESKD patients. These data reinforce the paradigm that renal transplantation should be pursued for all new ESKD patients as it provides optimal survival and that strategies that enhance donation rates should be pursued aggressively. Despite the poorer outcomes for PD and HD-treated patients in the U.S compared to renal transplantation, there is an encouraging general trend of declining death rates during the first year for all successive incident cohorts. Predictors of Mortality among new ESRD Patients Given the public health importance of CKD, efforts to reduce its prevalence and impact on morbidity and mortality should be based on proven epidemiological principles and evidence-based medicine. Accordingly, we have chosen select published studies that have determined the prevalence and mortality impact of putative risk factors in cross-sectional and longitudinal studies. In each case, attention was focused on the internal and external validity of the study in order to estimate risk factor prevalence and determine the magnitude of each factor in multivariable adjusted analyses. Demographic Factors Age, Gender and Race Virtually all mortality analysis of new ESKD patients have that age is an independent predictor of predictor. In a recent population-based analysis of new ESKD patients, we found that a 10-year increment in age was associated with 35% increased mortality 9. This risk however, was not equally distributed among age groups as highlighted in Slide 3 with patients in the oldest age categories experiencing between a 3 and 5-fold increase in mortality [Slide 3]. These findings coupled with the reality of an aging population at ESKD onset (due to increased acceptance of older patients) points to future increases in overall mortality. It has been reported that gender differences exist in the survival of new ESKD patients. Bloembergen et al found that males receiving chronic dialysis had a 22%

higher mortality than females in an analysis of data from the U.S. Renal Data System 10. However, analysis of more recent cohorts from the same database with more comprehensive adjustment for casemix has not confirmed these findings. Stack et al found no significant gender differences in an analysis of 107,922 new ESRD patients who were placed on dialysis between May 1995 and July 1997 [Adjusted Relative Risk; males/females (RR)=0.99, Confidence Interval (CI) 0.971.02]. The rapid growth of minority groups with ESKD in the U.S. population has forced the renal community to examine the delivery of care and associated outcomes in these groups. African Americans and Hispanic patients are the fastest growing racial minority groups with ESKD in the United States. A surprising paradox of these minority populations relates to their superior survival advantage despite disparities in the provision and delivery of care both prior to ESKD initiation and while on dialysis 1. For example, the adjusted 2-year survival for Blacks is 71.5% compared to 61% for Whites. This survival advantage is also apparent up to 5 years of follow up (42.3% for Blacks compared to 30.4% for Whites). Indeed we have shown that Black patients who reach ESKD, on average, experience a 20% lower adjusted mortality risk compared with Whites while Hispanic patients have a 30% lower adjusted mortality [Slide 4]11. An important aspect of future research is to address the disparities in the provision of health care among race and ethnic groups while seeking to identify factors associated with apparent greater survival. Comorbidity Predictors Pre-existing cardiovascular conditions Cardiovascular disease is the single greatest contributor to mortality among patients with ESKD 1. Cardiac disease accounts for over 50% of all patient deaths in the ESKD population. These rates are between 5 to 20 times greater than those of the nonuremic population, a statistic that has not changed substantially over the last decade. Recent studies have demonstrated a substantial burden of cardiovascular disease among new ESKD patients at dialysis onset 12-14 [Slide 5]. These include coronary artery disease, congestive heart failure, left ventricular hypertrophy, cardiomegaly, peripheral vascular disease, and cerebrovascular disease. It has also become apparent that many of these conditions increase in prevalence over time as renal function deteriorates, suggesting that the most appropriate and effective time for intervention is early in the pre-ESKD period 15 [Slide 6]. Moreover, most if not all these conditions have been shown to contribute independently to mortality among new ESKD patients [Slide 7] 11,14,16. To limit the impact of these conditions on subsequent mortality it is necessary to use aggressive primary and secondary prevention strategies, targeting risk factors and treating established disease with proven therapies. It should be noted

however, that although the prevention and treatment of CV disease is well established in the general population, many clinical trials have excluded patients with CKD, a population that carries substantial risk 17. Nutritional Factors It is estimated that between 30% to 50% of patients with ESKD suffer from proteinenergy malnutrition. Although there is no single measurement that completely describes the nutritional status of a person, several anthropomorphic and laboratory measures exist. These include commonly measured nutritional markers such as body mass index (BMI), modified subjective global assessment (mSGA), normalized protein catabolic rate (nPCR), serum albumin and serum creatinine 18-21. In addition several other parameters such as serum transferrin, prealbumin, and IGF-1 have been utilized as indicators of nutritional status 22, 23. Most published studies have evaluated the impact of these indices in prevalent cohorts of dialysis patients and therefore have not tested the predictive value of these measurements in new ESKD patients. However, analyses of more recent cohorts have confirmed their utility in multivariate adjusted analyses. By far the most powerful and robust predictor of all cause and cardiovascular mortality is serum albumin. Lowrie and Lew found a strong inverse relationship between serum albumin and all-cause mortality in a retrospective analysis of more than 12,000 prevalent dialysis patients. The relative risk of death for patients with a serum albumin < 2.5 g/dl was close to 20-fold greater compared to patients with a serum albumin of 4.0-4.5g/dl. These findings have been subsequently confirmed in analyses of more recent cohorts with inclusion of new ESKD patients. In the Dialysis Outcomes and Practice Patterns Study (DOPPS), an international prospective study of hemodialysis patients, the mortality impact of several of these anthropomorphic indicators was assessed 21. Lower baseline measurements of BMI, serum albumin and serum creatinine were independently associated with increased mortality [Slide 8, 9 and Slide 10]. Moreover, decreases in BMI, serum albumin and serum creatinine over a six-month follow-up were also significantly associated with increased mortality risk. These data highlight the importance of a composite panel of indicators to assess nutritional status in the dialysis population and provide identifiable targets that may be modified by interventional strategies and assessed in a longitudinal fashion. Inflammatory Predictors It has recently emerged that CKD is an inflammatory state with upregulation of proinflammatory genes and cytokine expression 24. The overall contribution of this inflammatory milieu to adverse clinical outcomes in ESKD populations has not yet been clearly elucidated in incident ESKD patients but there is mounting evidence to suggest that chronic inflammation may be an independent contributor to overall and

cardiovascular mortality in the chronic dialysis population 25, 26. Both direct measures of the inflammatory axis and indirect surrogates have been observed to predict allcause and cardiovascular mortality in dialysis cohorts. Zimmerman et al found a stepwise increase in all-cause and cardiovascular mortality rate with increasing quartiles of C-reactive protein (CRP) [Slide 11] 26. In his analysis of 280 stable hemodialysis patients, patients with CRP levels in the highest quartile (>15.7) experienced almost a 5-fold increase in all-cause and cardiovascular mortality compared with patients who had CRP levels less than 3.3. This effect was independent of several other known mortality predictors. The relationship between the inflammatory milieu and death has also been assessed in national cohorts using the absolute neutrophil count as an indirect measure of the degree of inflammation [Slide 12] 21, 27. Trinh et al, using DOPPS data, demonstrated a trend of increasing mortality risk for patients who had an elevated neutrophil count at study start 21. In addition, they found that longitudinal increases in the neutrophil count over time correlated with increased mortality. The exact cause of this up-regulated pro-inflammatory system is unclear but it is likely that it reflects the total comorbidity burden at ESKD onset as well as progressive renal impairment. The evidence thus far points to chronic up-regulated inflammatory process in the uremic patient, which has significant adverse consequences on nutritional health, cardiovascular outcomes and overall mortality. It is tempting to speculate that strategies aimed at reducing the degree of inflammatory activation will have a positive impact on clinical outcomes; however, to date no such studies have yet tested this hypothesis. Vascular Access The importance of creating a long lasting functional vascular access among hemodialysis patients has been well documented in several recent papers and reviews 28, 29. The current body of literature supports the creation of an arteriovenous (AV) fistula in preference to an AV graft over tunneled vascular catheters. These recommendations have been embodied in the recent NKF DOQI guidelines and have taken on unprecedented attention in the renal community given the associated morbidity and mortality, not to mention the enormous cost 30. Dhingra et al have addressed the mortality impact of different types of vascular access in a recent analysis of data from the Dialysis Morbidity and Mortality Study Wave 1 [Slide 13] 31. Among 1,101 incident patients, the adjusted relative risk of death from allcauses was significantly higher for patients who were dialyzed with a tunneled catheter or AV graft compared with an AV fistula. Moreover, a cause-specific death analysis, which followed a similar pattern, suggested that many of these deaths were due to cardiac and infection causes. These data reinforce the concept that the primary AVF contributes critically to improved survival of new ESRD patients and should be the goal for all patients who are initiated on hemodialysis. Unfortunately, there are

substantial differences in the prevalence of fistula use in the U.S. due to differences in practice patterns. Such heterogeneity will almost certainly lead to variability in patient outcomes, an issue that has been addressed in detail by the DOQI guidelines. An also concerning revelation is the unusually low overall rates of AVF placement in the US compared to Europe countries, a phenomenon that may be in part responsible for the superior survival of European dialysis patients [Slide 14] 32. To improve rates of AVF creation, a multidisciplinary approach is required with contributions from all members of the CKD team specifically targeting: late referral patterns of care; increased use of preoperative vascular mapping, and the need for dedicated surgeons with demonstrable experience in the area of vascular surgery. Late Referral and Late Initiation of Dialysis The revelation that a substantial proportion of patients with CKD are being referred late to nephrologists in the United States has identified a major public problem [Slide 15]33-36. Moreover, the observation that late-referred patients experience significantly higher mortality risks compared to those referred early has highlighted a significant gap in the continuity of care of patients with CKD and a missed opportunity effective intervention [Slide 16] 35-38. Stack reported that 32% of U.S. patients with CKD had their first encounter with a nephrologist less than 4 months before ESKD start using data from the DMMS W2 study 35. In another nationally representative study, Kausz et al observed that 23% of U.S patients were initiated on dialysis late (a glomerular filtration rate of < 5ml/min per 1.73m2), substantially lower than the NKF-DOQI recommended level of 10.5 ml/min per 1.73m2 39. In the survival analysis, Stack reported a significant 68% higher mortality over the first year of dialysis for late referred compared to early referred patients [Slide 17]. The figures are striking similar to those of other published studies both in the U.S. and abroad. In these studies there was compelling evidence that late-referred patients received poorer care with a higher prevalence of anemia, and malnutrition and temporary vascular catheters, and lower rates of erythropoietin use and permanent vascular access devices (both AV grafts and fistulas) compared to early referrals. Although it is unclear as to which components contribute to the marked survival benefit of early referral subjects, it is likely multifactorial from a broad-spectrum of specific interventions. This is a niche where significant progress must be made to order to improve survival rates of new ESKD patients and enhance quality of life. There are however, several unanswered questions. First, how should the care of the CKD (pre-ESKD) population be coordinated and organized to ensure a seamless transition from CKD to ESKD? What processes of care will work best so that primary physicians and other sub-specialists can work harmoniously with the nephrologist in an efficient and effective manner? Cardioprotective Medications in new ESRD patients

In the general population, several agents have been shown to reduce all-cause and cardiovascular mortality in patients who are at high-risk for cardiovascular disease 4042 . As patients with ESKD have a 10-fold higher rates of cardiovascular disease compared to the general population, this population would seem to be the ideal candidate for such cardioprotective measures. The recent work of Kestenbaum et al and Seliger et al, both from Seattle, has provided associative evidence that calcium cannel blockers and HMG-coenzyme A inhibitors may be beneficial in reducing mortality rates among newly diagnosed ESRD patients 43, 44. Kestenbaum et al found that the mortality risk was 21 % lower among patients who used calcium channel blockers at ESRD onset compared to those who did not while Seliger demonstrated a 32% lower mortality among patients who used statins at ESKD onset compared to non-users. In each respective study, the survival benefit was associated with significantly lower cardiovascular mortality rates. Although the observational nature of these studies does not confirm an independent cause-effect relationship, it is tempting to propose the use of these medications in this population, at least until the results of current randomized clinical trials are available. It should be noted that there is a substantial underutilization of cardioprotective medications among patients with CKD-not yet on dialysis and new ESKD patients with known cardiac disease [Slide 18 and 19]. This is quite a surprising fact as these patients are at extreme risk for adverse cardiovascular events and may benefit most from interventions that have proven efficacy in the general population. Conclusion The last decade has witnessed an explosive growth in epidemiological studies investigating the natural history of chronic kidney disease (CKD) and end-stage renal disease (ESKD). The principal driving force for this interest stems from two facts: first, the CKD-ESKD burden has reached epidemic proportions in several international countries and carries a high attendant morbidity and mortality. Second, the mortality rates from ESKD are alarmingly high. Over the next decade, it is imperative that we move forward and tackle each stage of CKD in a disciplined scientific manner, identifying opportunities for intervention and preventing progression to more advanced stages [Slide 20]. In order to achieve this, it is imperative that there are continued improvements in all aspects of CKD management in order to optimize patient survival and quality of life. Careful planning, effective delivery methods and appropriate resource utilization should serve as the cornerstone for achieving these goals. Slide Presentation References

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