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Epidemiology and Outcomes |

,||,¶
* Divisions of Nephrology;
General Internal Medicine, Department of Medicine,
Health Services Research Enhancement Award Program,
Department of Dermatology, VA Medical Center San Francisco; and || Department of Epidemiology and Biostatistics; and ¶ Department of Medicine, University of California, San Francisco, San Francisco, California
Address correspondence to: Dr. Ann M. OHare, Box 111J, Nephrology, VA Medical Center San Francisco, 4150 Clement Street, San Francisco, CA 94121. Phone: 415-221-4810 ext 4953; Fax: 415-750-6949; E-mail: Ann.O'Hare{at}med.va.gov
| Abstract |
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60 ml/min per 1.73 m2), 30% (n = 1742) had moderate renal insufficiency (GFR 30 to 59 ml/min per 1.73 m2), and 8% (n = 484) had severe renal insufficiency or renal failure (GFR <30 ml/min per 1.73 m2) but were not on dialysis. The percentages of patients who presented with gangrene or ischemic ulceration rather than rest pain increased with declining renal function (70, 77, and 87%; P < 0.001), as did 1-yr mortality risk (17, 27, and 44%; P < 0.001). After adjustment for demographic and clinical characteristics, patients with a GFR of 30 to 59 ml/min per 1.73 m2 (odds ratio, 1.32; 95% confidence interval, 1.13 to 1.53) and <30 ml/min per 1.73 m2 (odds ratio, 2.97; 95% confidence interval, 2.39 to 3.69) had a significantly increased odds of death within 1 yr of cohort entry. Both moderate and severe renal insufficiency are associated with an increased odds of death in patients with critical limb ischemia. Death rates were particularly high among those with a GFR <30 ml/min per 1.73 m2. This finding may be partly explained by their more frequent presentation with ischemic ulceration or gangrene rather than rest pain. | Introduction |
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The prevalence and incidence of PAD is high among patients with renal insufficiency (35). Among the select group of patients who undergo a lower extremity revascularization procedure for PAD (6,7), renal disease seems to be a risk factor for both short- and long-term mortality. However, little is known about the mortality risk associated with renal insufficiency among more broadly defined PAD cohorts. Accurate knowledge of mortality risk associated with renal insufficiency among patients who present with PAD could provide key information to guide patient and clinician decision-making and risk-reduction efforts.
We hypothesized that greater degrees of renal impairment at initial presentation with PAD would be associated with higher mortality among cohort patients, as has been demonstrated for those with other forms of cardiovascular disease such as acute myocardial infarction (MI) and congestive heart failure (CHF) (811). We hypothesized further that higher mortality in the group with renal impairment would be related to the presence of more advanced signs and symptoms of PAD at cohort entry. We tested these hypotheses in a national cohort of male veterans with incident critical limb ischemia defined as rest pain, ischemic ulceration, or gangrene.
| Materials and Methods |
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We identified 7580 male veterans who received their first diagnosis of critical limb ischemia between January 1, 2000, and September 30, 2002, and had at least one subsequent diagnostic code entry for critical limb ischemia within 1 yr of cohort entry. Among these, 299 patients were excluded because they had undergone at least one episode of dialysis in the VA during the preceding year, and 1494 patients were excluded because they did not have a serum creatinine measurement within 3 mo of cohort entry. A total of 5787 patients thus were available for analysis.
Primary Predictor Variable
The primary predictor variable for the present analysis was the most recent level of renal function within 3 mo before the diagnosis of critical limb ischemia. We used the abbreviated Modification of Diet in Renal Disease (MDRD) formula to estimate GFR using serum creatinine, age, and race (15). Patients were classified by level of renal function according to National Kidney Foundation Dialysis Outcomes Quality Initiative guidelines: GFR >60 ml/min per 1.73 m2 (normal or mildly reduced renal function), GFR 30 to 59 ml/min per 1.73 m2 (moderate renal insufficiency), and <30 ml/min per 1.73 m2 (severe renal insufficiency or renal failure not on dialysis) (16).
Secondary Predictor Variables
Multivariate analyses were adjusted for patient age; race (black versus nonblack); and history of hypertension, diabetes, coronary artery disease (CAD), CHF, cerebrovascular disease, and chronic obstructive pulmonary disease (COPD) at the time of entry into the cohort and most recent serum glucose level within 3 mo. Data on comorbid conditions were ascertained by ICD-9 and CPT code searches of inpatient, outpatient, and fee-basis files back to 1997 and the Decision Support System laboratory results file back to 1999 (for serum glucose measurements).
Outcome Variable
The study outcome was death within 1 yr after entry into the cohort. Mortality follow-up was ascertained using the VA Beneficiary Identification and Records Locator Systems (BIRLS) database. Recent studies suggest sensitivity rates >94% for BIRLS (1719).
Statistical Analyses
We compared baseline characteristics across renal function categories using a t test for normally distributed continuous variables, a Mann-Whitney U test for nonnormally distributed continuous variables, and a
2 test for categorical variables. Each renal insufficiency group was compared directly with the referent category with preserved renal function. We used mixed-effects logistic regression analysis to determine the odds of presenting with tissue damage (gangrene or ischemic ulceration) rather than rest pain across renal function categories. We measured the serial impact of adjustment for patient demographic and clinical characteristics and clinical presentation of limb ischemia on the overall association of renal insufficiency with mortality using staged mixed-effects logistic regression analyses in which we sequentially adjusted for these factors. To explore further the impact of clinical presentation on the association of renal insufficiency with mortality, we performed stratified analyses by clinical presentation (rest pain, ischemic ulceration, and gangrene) after adjustment for patient demographic and clinical characteristics.
We tested for interactions between diabetes and between clinical presentation and renal function in the overall model. All models were adjusted for a random effect for centers. Age was modeled as a quadratic term and serum glucose was modeled by quartile because these variables were nonlinearly associated with the outcome. Glucose measurements were missing for 74 (1%) patients, and race was either missing or unknown for 991 (17%) patients. For these variables, we introduced a separate missing category to retain in the analysis patients with missing values for any one of these variables. These analyses were conducted using STATA Statistical Software (College Station, TX).
| Results |
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| Discussion |
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Peripheral arterial disease awareness among both patients and physicians is notoriously low (2). Furthermore, the impact of renal insufficiency on mortality in this group is unknown. The present study confirms the existence of a strong association between renal insufficiency and death in an incident cohort with critical limb ischemia as has been reported among patients with other forms of cardiovascular disease such as acute MI and CHF (811). Strikingly, the 50% 1-yr mortality rate for cohort patients who had a GFR <30 ml/min per 1.73 m2 and presented with gangrene approaches rates reported for elderly patients who have renal insufficiency and are treated for CHF and acute MI (811). The presence of renal insufficiency in patients with critical limb ischemia thus should alert the clinician to the presence of a substantially elevated risk for mortality. High mortality in cohort patients with renal insufficiency also underlines the importance of identifying optimal PAD treatment options and of understanding the reasons for elevated mortality risk for this group.
Several previous studies have reported high rates of gangrene and ulceration among dialysis patients who undergo lower extremity revascularization (6,7,20). However, these studies focused on patient characteristics at the time of surgery rather than at the time of initial diagnosis with critical limb ischemia. The present analysis demonstrates that even at the time of initial presentation with critical limb ischemia and after adjustment for potential confounders, patients with a GFR <30 ml/min per 1.73 m2 are more likely to have ischemic tissue damage rather than rest pain. This does not seem to be true, however, for patients with moderate renal insufficiency. The greater tendency of patients with a GFR <30 ml/min per 1.73 m2 to present with ischemic tissue damage (gangrene or ulceration) rather than rest pain may contribute both to increased mortality risk and high overall mortality rates in this group. These findings underscore the importance of further investigation toward understanding why critical limb ischemia is more likely to be diagnosed after the development of tissue damage. One possibility is that physicians and patients may be less inclined to diagnose and intervene for early disease in this population. Alternatively, PAD may progress more rapidly or may follow a different course presenting with less typical symptoms among patients with more advanced renal insufficiency.
The major limitation of this study is that data on ischemia severity are based on ICD-9 coding. These codes do not provide detailed information on the severity of ischemic ulceration and gangrene or on the severity of comorbid conditions included in the analysis; thus, there may be residual confounding by these factors. Furthermore, because ICD-9 codes for PAD in the VA are highly specific but only moderately sensitive (13) and because patients with critical limb ischemia may be coded under less specific PAD codes (e.g., PAD not otherwise specified), mortality rates reported here for patients with critical limb ischemia may not be generalizable to all veterans with this condition.
Several other factors may also limit the generalizability of study findings. The slightly higher mortality rate in the study population compared with those who lack serum creatinine data suggests that our cohort may have been sicker than the group excluded. The absence of non-VA medical claims data may also have led to inclusion of patients who had experienced a previous episode of critical limb ischemia outside the VA before the study period. It is also unclear whether our findings are generalizable to women and to nonveterans. Finally, limitations related to the use of the MDRD equation in the absence of directly measured renal function include that it has not been validated in this or similar cohorts and creatinine measurements for cohort patients were not calibrated to the MDRD reference laboratory (15).
| Conclusion |
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| Acknowledgments |
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We acknowledge the informational support provided on VA databases provided by Philip Colin and Peggy Kraft at VIREC and the Decision Support System Support Office, Dr. Elisabeth McSherry and Steve Porter. We also thank Donald R. Miller and Dr. Ann M. Borzecki of the Center for Health Quality, Outcomes and Economic Research, Bedford VAMC (Bedford, MA) for providing valuable informational support on the validity of ICD-9 diagnostic codes for PAD in the VA.
| Footnotes |
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| References |
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