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Circulation. 2007;115:50-58
Published online before print December 18, 2006, doi: 10.1161/CIRCULATIONAHA.106.637751
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(Circulation. 2007;115:50-58.)
© 2007 American Heart Association, Inc.


Health Services and Outcomes Research

Atherosclerotic Renovascular Disease in Older US Patients Starting Dialysis, 1996 to 2001

Haifeng Guo, MS; Philip A. Kalra, MD, FRCP; David T. Gilbertson, PhD; Jiannong Liu, PhD; Shu-Cheng Chen, MS; Allan J. Collins, MD; Robert N. Foley, MB

From the United States Renal Data System Coordinating Center (H.G., D.T.G., J.L., S.-C.C., A.J.C., R.N.F.), Minneapolis, Minn; Department of Renal Medicine (P.A.K.), Hope Hospital, Salford, United Kingdom; and Department of Medicine (A.J.C., R.N.F.), University of Minnesota, Minneapolis.

Correspondence to Robert N. Foley, MB, United States Renal Data System, 914 S 8th St, Suite S-253, Minneapolis, MN 55404. E-mail RFoley{at}usrds.org

Received May 3, 2006; accepted October 31, 2006.


*    Abstract
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*Abstract
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Background— Temporal trends regarding the epidemiology of atherosclerotic renovascular disease (ARVD) in dialysis populations are poorly defined.

Methods and Results— United States Renal Data System data were used to identify patients aged 67 years or older at dialysis inception between 1996 and 2001 (n=146 973). Medicare claims in the preceding 2 years were used to identify ARVD and revascularization procedures. Prior ARVD rose from 7.1% to 11.2% between 1996 and 2001 (adjusted odds ratio [AOR], 1.68). Other associations included hypertensive end-stage renal disease (ESRD; AOR, 2.21), ESRD network (AOR, 0.44 in network 17 versus 1.00 in network 1), peripheral vascular disease (AOR, 1.65), black race (AOR, 0.44), urologic cause of ESRD (AOR, 0.57), age >85 years (AOR, 0.58), substance dependency (AOR, 0.62), and inability to ambulate or transfer (AOR, 0.67). The proportion of ARVD patients undergoing revascularization rose from 14.6% to 16.7% between 1996 and 2001 (AOR, 1.27). Other associations included hypertension (AOR, 2.10), ESRD network (AOR, 2.07 for network 13 versus 1.00 in network 1), age >85 years (AOR, 0.53), and black race (AOR, 0.54). The rise in ARVD was not reflected in the proportion of patients with renovascular disease listed as cause of ESRD on the Medical Evidence Report at dialysis inception (5.5% in 1996, 5.0% in 2001).

Conclusions— ARVD diagnoses have become more common in older patients beginning dialysis therapy. The association of demographic factors including age, race, and geographic residence with utilization patterns suggests possible barriers to care.


Key Words: atherosclerosis • epidemiology • kidney • revascularization


*    Introduction
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The number of patients receiving renal replacement therapy for end-stage renal disease (ESRD) is steadily increasing worldwide. Incidence rates almost doubled in the United States between 1991 and 2000 and are projected to increase by an additional 50% by 2015.1,2 The increasing burden of ESRD reflects in part the burgeoning numbers of elderly patients, for whom the risk of chronic kidney disease is several times that of younger patients.3 One would expect the changing age profile of the dialysis population to be accompanied by increases in the proportion of ESRD caused by diseases of aging, and atherosclerotic renovascular disease (ARVD) is a paradigmatic disease of aging. It has been shown to occur as an incidental finding in 6.8% of the elderly population,4 and an incidence rate of {approx}3.7 cases per 1000 patient-years has been reported in the US Medicare population.5 ARVD is often associated with other vascular pathologies, such as atherosclerotic heart disease,6,7 congestive heart failure,8,9 cerebrovascular disease,10 and peripheral vascular disease.11,12

Clinical Perspective p 58

Few studies have examined the clinical epidemiology of ARVD in latter-day ESRD populations. Over a decade has elapsed since Mailloux and colleagues13 reported that 12.2% of their dialysis population had ARVD, a finding associated with higher than expected mortality rates. The purpose of the present study was to examine the clinical epidemiology of ARVD in dialysis patients at a national level, with emphasis on annual trends in disease burden.


*    Methods
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*Methods
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Objectives
The main objective of the present study was to examine annual trends in the proportion of patients starting dialysis therapy with ARVD. Other objectives included enumeration of the following associations of ARVD: annual trends in the use of revascularization, associations of revascularization, and prognostic associations, with or without revascularization.

Patients
We studied US patients with the following characteristics: (1) aged 67 years or older at initiation of maintenance dialysis therapy; (2) initiated dialysis therapy in the years 1996 through 2001; and (3) had Medicare as primary payer for at least 2 years before initiating dialysis therapy. This design was used to determine whether a diagnosis of ARVD, with or without revascularization, was made in the 2 years preceding dialysis initiation. All data were obtained from the United States Renal Data System (USRDS) database, which includes all patients entering the renal replacement therapy program. Patient characteristics at initiation of dialysis were obtained from the USRDS profile and the Centers for Medicare & Medicaid Services Medical Evidence Report (CMS-2728). The Medical Evidence Report was also used to identify patients with renovascular disease (renal artery stenosis, renal artery occlusion, cholesterol emboli, or renal emboli) listed as the primary renal disease at dialysis inception. Note that ARVD and renovascular disease as the primary renal disease are defined differently, with ARVD based on reimbursement claims before dialysis and renovascular disease as the primary renal disease based on physician ratings at the time dialysis began. Estimated glomerular filtration rate at initiation of dialysis was calculated from serum creatinine values from the Medical Evidence Report with the Modification of Diet in Renal Disease study formula14: Glomerular filtration rate = 186x(serum creatinine in mg/dL)–1.154xage–0.203x(1.210 if black race)x0.742 (if female gender).

The USRDS database was linked to back-cast Medicare claims, a database containing all claims before dialysis initiation, including part A claims (inpatient, outpatient, home health agency, hospice, and skilled nursing services) and part B claims (physicians and suppliers). International Classification of Diseases, 9th Revision, Clinical Modification, and Current Procedural Terminology codes, shown in the Appendix (in the online-only Data Supplement), were used to define ARVD and renal revascularization before dialysis initiation and cardiovascular events after dialysis initiation. One or more appropriate codes were required to define ARVD and renal revascularization. Cardiovascular events after initiation of dialysis were defined as the presence of 1 inpatient hospitalization, skilled nursing facility, or home health agency code; 2 outpatient or physician/supplier codes; or 1 outpatient and 1 physician/supplier code <1 year apart. Dates of transplantation and death were obtained from the USRDS database.

Statistical Analysis
A {chi}2 analysis was used for bivariable comparisons and logistic regression for multivariable comparisons of patients with and without ARVD. Comparisons of ARVD patients with and without revascularization were handled similarly. For outcome events after dialysis initiation, potential follow-up extended from dialysis initiation until December 31, 2002, with censoring at renal transplantation. Multivariable Cox proportional hazard models were used to test associations between ARVD and outcome events, adjusted for baseline characteristics. Findings were similar when analyses were replicated with varying lengths of study entry period; similarly, the findings were identical whether geographic network was treated as a fixed effect or a random effect. Hence, only findings from analyses that used a 2-year entry period and the treating geographic network as a fixed effect are reported here. SAS version 8.2 (SAS Institute Inc, Cary, NC) was used for data analysis.

The authors had full access to the data and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.


*    Results
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*Results
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Overall, 9.2% of the 146 973 study patients had a diagnosis of ARVD in the 2-year period before dialysis initiation (Table 1Down). The proportion of patients with prior ARVD rose during the study period, from 7.1% in 1996 to 11.2% in 2001, with a corresponding adjusted odds ratio (AOR) from multivariable analysis of 1.68 when 2001 was compared with 1996. Regarding the major groupings of primary cause of ESRD, hypertension was associated with an AOR of 2.21 compared with diabetes mellitus as the reference category.


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TABLE 1. Baseline Characteristics: Overall Population and Subgroup With ARVD


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TABLE 1. Continued

Patients from ESRD network 17 (Northern California and Pacific Islands) were 0.44 times and those from network 13 (Arkansas, Louisiana, and Oklahoma) were 0.56 times as likely to have ARVD as those from network 1 (New England), which served as the reference group. Other main associations (arbitrarily defined as AOR >1.25 or <0.80) included a greater likelihood of ARVD with peripheral vascular disease (AOR, 1.65) and atherosclerotic heart disease (1.26) and a lower likelihood of ARVD with black race (0.44), other race (0.53), other urologic disease as the cause of ESRD (0.57), age >85 years (0.58), drug or alcohol dependency (0.62), Hispanic ethnicity (0.64), cystic kidney disease (0.66), inability to ambulate or transfer (0.67), body mass index >30 kg/m2 (0.69), and estimated glomerular filtration rate <5 mL · min–1 · 1.73 m–2 (0.70).

Of patients with ARVD, 16.2% underwent renal revascularization before beginning dialysis (Table 2Down). On multivariable analysis, revascularization was more likely later in the study period, especially in 2000 and 2001. Hypertension as the primary cause of ESRD showed the highest AOR for revascularization (2.10). The likelihood of revascularization also varied considerably on a regional basis. With network 1 (New England) as the reference category, revascularization was most likely in network 13 (Arkansas, Louisiana, and Oklahoma; AOR, 2.07), network 14 (Texas; 1.79), and network 6 (Georgia, North Carolina, and South Carolina; 1.72) and least likely in network 3 (New Jersey, Puerto Rico, and US Virgin Islands; 0.96), network 2 (New York; 1.00), and network 1 (New England; AOR 1.00 by definition). Associations with AOR >1.25 included hypertension as the primary cause of renal disease (2.10) and peripheral vascular disease (1.36). Associations with AOR <0.80 were cystic kidney disease (0.31), age >85 years (0.53), black race (0.54), cancer (0.69), inability to transfer or ambulate (0.72), body mass index <18.5 kg/m2 (0.72), Hispanic ethnicity (0.77), and glomerulonephritis (0.79).


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TABLE 2. Baseline Characteristics: Overall Population With ARVD and Subgroup With ARVD Who Underwent Revascularization


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TABLE 2. Continued

Renovascular disease was listed as the primary cause of ESRD at dialysis initiation for 5.2% of subjects (Table 1Up), and 38.3% of these had prior ARVD, with a corresponding AOR of 5.38. Of ARVD patients with renovascular disease listed as primary cause of ESRD, 28.8% underwent revascularization (AOR, 2.66; Table 2Up). The Figure shows the proportions of patients with renovascular disease listed on the Medical Evidence Report as the primary cause of ESRD at initiation and with diagnostic claims indicating ARVD in the 2 years before dialysis. Although the former remained relatively static (5.5% in 1996 and 5.0% in 2001), the latter rose progressively (7.1% in 1996 and 11.2% in 2001).


Figure 1180171
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Proportions of patients with renovascular disease listed as primary cause of ESRD at dialysis initiation (—{blacklozenge}—) and with diagnostic claims indicating atherosclerotic renovascular disease in the 2 years before dialysis initiation (—{blacksquare}—).

Table 3 shows the prognostic associations of ARVD, which included greater likelihood of atherosclerotic heart disease (adjusted hazard ratio 1.28), congestive heart failure (adjusted hazard ratio 1.12), cerebrovascular accident or transient ischemic attack (adjusted hazard ratio 1.20), and peripheral vascular disease (adjusted hazard ratio 1.56) but not mortality (adjusted hazard ratio 0.94). Similar findings were seen in an analysis comparing patients with and without renovascular disease listed on the Medical Evidence Report as the primary cause of ESRD. Table 3 also shows an analysis in which ARVD with and without revascularization was compared with the reference category of patients without ARVD. These analyses suggested that ARVD patients who had undergone revascularization before initiation of dialysis had a lower likelihood of death and a greater likelihood of atherosclerotic heart disease, cerebrovascular accident or transient ischemic attack, and peripheral vascular disease than those who had not undergone revascularization.


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TABLE 3. Prognostic Associations of ARVD, Revascularization After ARVD, and Renovascular Disease as Primary Cause of ESRD (Follow-Up to December 31, 2002)


*    Discussion
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*Discussion
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The proportion of elderly US patients commencing dialysis with a prior diagnosis of ARVD rose steadily during the 5-year study period. Hypertensive ESRD was the most frequent primary disease category associated with ARVD, whereas the main comorbid factors associated with a greater likelihood of ARVD were peripheral vascular disease and atherosclerotic heart disease. The variation of ARVD prevalence across the dialysis networks was striking. Overall, 16.2% of ARVD patients had renal revascularization before beginning dialysis, and as with ARVD prevalence, the proportion undergoing revascularization rose throughout the study period. The disparity between claims diagnoses and the listed cause of ESRD at inception was notable. Although ARVD was associated with higher rates of cardiovascular disease on dialysis therapy, mortality rates were marginally lower, a finding that is difficult to explain. Among ARVD patients, revascularization exhibited a similar pattern: association with lower death rates but higher rates of cardiovascular events.

We found that the proportion of patients with diagnostic claims indicating prior ARVD was almost twice the proportion with renovascular disease listed as the primary cause of ESRD. Many cases of ARVD may in fact be incidental and causally unrelated to any accompanying renal failure.15 Also, accurate attribution of the cause of ESRD is often difficult, especially in patients with vascular diseases, who often have increased burdens of risk factors for parenchymal renal disease. In an earlier study of the USRDS population, Fatica and colleagues16 found that renovascular disease was the attributable cause of ESRD in only 2.1% of incident dialysis patients in 1997. This figure contrasts starkly with the 27% reported by van Ampting and colleagues,17 admittedly among only 49 patients commencing dialysis. It is clearly difficult to determine whether the present findings reflect coding issues (such as overuse of hypertension as a default category when rating the cause of ESRD), differing thresholds for the use of diagnostic tests of the renal arteries, or a true change in the biological causes of ESRD. However, given the high prevalence of true ARVD in other carefully studied populations, it is difficult not to speculate that the burden of ARVD in US ESRD patients is substantial and growing.5–8,10–12

Paralleling the increase in ARVD prevalence recorded during the 5-year study period was a modest stepwise increase in the use of renal revascularization among ARVD patients who commenced dialysis (14% greater likelihood in 2001 than in 1996). Although case series have demonstrated that a small proportion of patients with critical ARVD can be rescued from dialysis by renal revascularization procedures,18–20 to date, there is no randomized controlled trial evidence that revascularization can improve renal functional outcome, and especially prevent dialysis need, in ARVD patients.21–24 As also noted in the elderly nondialysis Medicare population, revascularization was performed in {approx}16% of all patients diagnosed with ARVD,5 and selection for revascularization appeared to be a nonrandom process.

Several associations suggested that the utilization of diagnostic and therapeutic resources may have been influenced by nonbiological factors. For example, age >75 years, especially age >85 years, and black race were associated with substantially lower likelihoods of ARVD and substantially lower likelihoods of revascularization when ARVD was diagnosed. Similarly, ESRD networks showed substantial variability in the proportion of patients diagnosed with ARVD and in the proportion of ARVD patients undergoing revascularization.

We found that ARVD was associated with increased rates of cardiovascular events, an association pattern replicated when ARVD patients who had undergone revascularization were compared with those who had not. Paradoxically, however, ARVD and revascularization were associated with marginally lower death rates than their respective comparators. Similar findings were seen among ARVD patients identified in the nondialyzed general Medicare population.5 Although a clear explanation cannot be provided, survivor bias may explain the paradox of higher cardiovascular disease event rates and lower death rates while undergoing dialysis. Thus, patients with ARVD who survive to ESRD may be resistant to death from cardiovascular disease in ways yet to be determined. Similarly, selection of intrinsically healthier patients could explain the lower mortality seen in ARVD patients who underwent revascularization before dialysis inception. Clearly, careful prospective studies are needed to unravel this paradox. In this regard, Mailloux and colleagues13 found 5-year survival of ARVD patients as low as 18%, lower than all other disease categories except diabetes mellitus.

The limitations of the present study should be mentioned. It was retrospective, and many of the major study outcomes were based on administrative claims data. The validity of using ARVD claims to establish ARVD could not be ascertained. Other studies, however, suggest that diagnoses based on administrative claims tend to be specific but insensitive in patients with chronic kidney disease.25 Conceivably, ARVD may often be an incidental finding during the diagnostic workup in patients with disease in nonrenal vascular beds. Medicare coverage is available to the older US patient population, and one should exercise caution in generalizing the present findings to younger populations or other countries. Definitions of comorbidity were based on the Medical Evidence Report. Although this has been shown to underestimate disease burdens,26 the error is unlikely to differ dramatically from year to year or between populations with and without ARVD.

Despite its limitations, we believe that the present study provides useful information. It suggests that ARVD is a common entity in older dialysis patients in the United States. It also suggests that although ARVD may be among the most rapidly rising causes of ESRD, current data systems are poorly designed to capture this disturbing trend. Most strikingly, it suggests considerable variation in the frequency of ARVD diagnosis and the use of renal revascularization for ARVD treatment among the geographic ESRD networks and in certain subgroups of the US population.


*    Acknowledgments
 
The authors thank Beth Forrest and Nan Booth, MSW, MPH, of the USRDS Coordinating Center for manuscript preparation and editing, respectively.

Sources of Funding

The data reported here have been supplied by the USRDS. This study was performed as a deliverable under contract No. N01-DK-9-2343 (National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Md).

Disclosures

None.


*    References
up arrowTop
up arrowAbstract
up arrowIntroduction
up arrowMethods
up arrowResults
up arrowDiscussion
*References
 
1. US Renal Data System. USRDS 2003 Annual Data Report. Bethesda Md: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2003.

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3. Coresh J, Astor BC, Greene T, Eknoyan G, Levey AS. Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis. 2003; 41: 1–12.[Medline] [Order article via Infotrieve]

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5. Kalra PA, Guo H, Kausz AT, Gilbertson DT, Liu J, Chen SC, Ishani A, Collins AJ, Foley RN. Atherosclerotic renovascular disease in United States patients aged 67 years or older: risk factors, revascularization, and prognosis. Kidney Int. 2005; 68: 293–301.[CrossRef][Medline] [Order article via Infotrieve]

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17. van Ampting JM, Penne EL, Beek FJ, Koomans HA, Boer WH, Buetler JJ. Prevalence of atherosclerotic renal artery stenosis in patients starting dialysis. Nephrol Dial Transplant. 2003; 18: 1147–1151.[Abstract/Free Full Text]

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20. Marone LK, Clouse WD, Dorer DJ, Brewster DC, Lamuraglia GM, Watkins MT, Kwolek CJ, Cambria RP. Preservation of renal function with surgical revascularization in patients with atherosclerotic renovascular disease. J Vasc Surg. 2004; 39: 322–329.[CrossRef][Medline] [Order article via Infotrieve]

21. van Jaarsveld BC, Krijnen P, Pieterman H, Derkx FH, Deinum J, Postma CT, Dees A, Woittiez AJ, Bartelink AK, Man in ’t Veld AJ, Schalekamp MA; Dutch Renal Artery Stenosis Intervention Cooperative Study Group. The effect of balloon angioplasty on hypertension in atherosclerotic renal-artery stenosis. N Engl J Med. 2000; 342: 1007–1014.[Abstract/Free Full Text]

22. Plouin PF, Chatellier G, Darne B, Reynaud A; Essai Multicentrique Medicaments vs Angioplastie (EMMA) Study Group. Blood pressure outcome of angioplasty in atherosclerotic renal artery stenosis: a randomized trial. Hypertension. 1998; 31: 823–829.[Abstract/Free Full Text]

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CLINICAL PERSPECTIVE

Shared risk factors and societal aging lead us to hypothesize that atherosclerotic renovascular disease (ARVD) might account for a growing proportion of end-stage renal disease that requires dialysis therapy in the United States. We looked for a diagnosis of ARVD in the preceding 2 years in 146 973 older patients who started dialysis in the United States between 1996 and 2001. Prior ARVD was more common in successive years, rising from 7.1% in 1996 to 11.2% in 2001. Diagnostic and therapeutic management of ARVD varied substantially by geographic location. Although mortality rates in ARVD patients were similar to those without ARVD, ARVD patients who underwent revascularization had lower mortality rates than those who did not. The present study suggests that ARVD may be a rapidly emerging cause of end-stage renal disease in the United States. Viewed in the context of an aging society, the rising burden of disease suggests that ARVD may become a principal cause of end-stage renal disease in the future.


*    Footnotes
 
The online-only Data Supplement is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA. 106.637751/DC1.




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