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Which Targets in Clinical Practice Guidelines Are Associated with Improved Survival in a Large Dialysis Organization?

Francesca Tentori^*,, William C. Hunt^*, Mark Rohrscheib, Min Zhu^*, Christine A. Stidley^*,, Karen Servilla, Dana Miskulin, Klemens B. Meyer^,||, Edward J. Bedrick^¶, H. Keith Johnson^|| and Philip G. Zager^*,

^* Dialysis Clinic Inc., Health Sciences Center and ^¶ Department of Mathematics and Statistics, University of New Mexico, and Nephrology Section, New Mexico Veterans Affairs Health Care System, Albuquerque, New Mexico; Tufts-New England Medical Center, Boston, Massachusetts; and ^|| Dialysis Clinic Inc., Nashville, Tennessee

Correspondence: Dr. Philip G. Zager, University of New Mexico, Department of Internal Medicine, ACC 5, Albuquerque NM 87131. Phone: 505-247-4044; Fax: 505-247-1297; E-mail: pzag{at}unm.edu

Received for publication November 16, 2006. Accepted for publication May 2, 2007.

	Abstract

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Professional organizations have developed practice guidelines in the hope of improving clinical outcomes. The National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (KDOQI) has set targets for dialysis dosage (single-pool Kt/V), hematocrit, serum albumin, calcium, phosphorus, parathyroid hormone, and BP for hemodialysis (HD) patients. Several guidelines are largely based on results from observational studies. In contrast to other parameters, BP values within the KDOQI guidelines have been associated with increased mortality. Therefore, it was postulated that having multiple parameters that satisfy the current guidelines, except those for BP, is associated with improved survival among HD patients. A retrospective analysis was conducted of incident HD patients who were treated at facilities operated by Dialysis Clinic Inc., a not-for-profit dialysis provider, between January 1, 1998, and December 31, 2004 (n = 13,792). Cox proportional hazards models were used to assess the association between satisfying guidelines and mortality. Values within guidelines for single-pool Kt/V, hematocrit, serum albumin, calcium, phosphorus, and parathyroid hormone were associated with decreased mortality (P 0.0001). The largest survival benefit was found for serum albumin (hazard ratio [HR] 0.27; 95% confidence interval [CI] 0.24 to 0.31). Satisfying these six guidelines simultaneously was associated with an 89% reduction in mortality (HR 0.11; 95% CI 0.06 to 0.19]). Conversely, BP values satisfying the guideline were associated with increased mortality (HR 1.90; 95% CI 1.73 to 2.10). Because this target was largely extrapolated from the general population, a randomized, controlled trial is needed to identify the optimal BP for HD patients.

	Introduction

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Increasing attention to the delivery of high-quality care has led many professional health care organizations to develop clinical practice guidelines. These guidelines define standards of care and are intended to reduce variability in practice patterns and improve clinical outcomes. Interest in "pay-for-performance"¹ is expected to accelerate the implementation of practice guidelines.²

In an effort to improve clinical outcomes among patients with ESRD, the National Kidney Foundation (NKF) launched the Dialysis Outcomes Quality Initiative (DOQI) clinical practice guidelines in 1995. In 1999, the program was extended to earlier stages of chronic kidney disease and was renamed the Kidney Disease Outcomes Quality Initiative (KDOQI). Work groups composed of domain experts formulate clinical practice guidelines on the basis of structured evidence review. In the absence of definitive published clinical data, expert opinion has influenced some guideline recommendations. This process led to the publication of KDOQI practice guidelines and target ranges for several parameters that cover many aspects of care for hemodialysis (HD) patients, including dialysis dosage,³ anemia,⁴ nutrition,⁵ bone and mineral metabolism⁶ and cardiovascular disease.⁷ Most recently, updates on anemia,⁸ dialysis adequacy, and vascular access⁹ have been published.

Several investigators have reported decreased mortality among patients who satisfy KDOQI guidelines for individual parameters, including dialysis dosage, serum albumin, anemia, and mineral metabolism.^10–13 HD patients who had arteriovenous fistulas and satisfied guidelines for dialysis dosage, serum albumin, and anemia simultaneously had fewer hospitalizations and lower mortality during a 1-yr follow-up¹⁴ than patients who did not satisfy all three of these guidelines. Similar results were recently shown in the ESRD Quality (EQUAL) study, a prospective study of process of care and outcomes in HD.¹⁵ However, no previously published studies examined mortality among patients who simultaneously satisfied anemia, dialysis dosage, calcium, phosphorus, and parathyroid hormone (PTH) guidelines.

The evidence supporting the current KDOQI guidelines was not always derived from randomized, controlled trials in the target population. Specifically, the BP target ranges were extrapolated from the general population; therefore, the evidence was graded as weak. Despite these limitations, professional organizations and large dialysis organizations have urged health care providers to attempt to achieve the recommended BP targets. However, to our knowledge, no studies have examined the relationship between BP values that satisfy the KDOQI targets and mortality. This is an important issue, because HD patients with mild to moderate hypertension may have a lower mortality risk compared with patients whose BP satisfies the current target.^16–18 Therefore, it is reasonable to postulate that adherence to the current BP guideline may have a detrimental effect on survival. This study was designed to explore the relationships between all-cause mortality and satisfying KDOQI guidelines for dialysis dosage (single-pool Kt/V [spKt/V]), hematocrit, serum albumin, calcium, phosphorus, and PTH individually and in combination. We also assessed the relationship between BP values that satisfy the KDOQI guideline and mortality.

	RESULTS

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A total of 13,792 patients met the inclusion criteria. Follow-up began 120 d after start of HD and continued until death (n = 5270); kidney transplantation (n = 1184); switch to peritoneal dialysis (n = 372); absence from Dialysis Clinic Inc. (DCI) for >90 d (n = 2585); or the end of follow-up on December 31, 2005 (n = 4381). Median follow-up was 569 d. The study sample was representative of the United States Renal Data System incident cohort with respect to the distributions of age, gender, and cause of ESRD (Table 1). However, because of the large sample size, even small differences in age and cause of ESRD attained statistical significance. Black patients were slightly overrepresented in the study sample. Overall, the proportion of patients who satisfied guidelines at baseline was extremely low (Table 1). For instance, only 19% of participants had hematocrit 33% at baseline.

View this table: [in this window] [in a new window]   Table 1. Demographic and clinical characteristics of the study sample and USRDS 1999 to 2002 incident cohort aged 20 yra

View larger version (20K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 1. Proportion of patients with values satisfying Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines (parameters were defined as satisfying the KDOQI guideline when at least 67% [100% for parathyroid hormone [PTH]) of measurements in the quarter were within the guidelines) over time since first hemodialysis treatment. The analysis was restricted to a cohort of participants who survived 3 yr (n = 4002). The proportion of patients with values within guidelines for single-pool Kt/V (spKt/V), hematocrit (Hct), albumin, and PTH was significantly higher after 12 quarters on hemodialysis. Values within guideline for serum calcium declined over time (P < 0.001 for all parameters). Value within guidelines for phosphorus did not change significantly.

Satisfying guidelines for multiple laboratory parameters simultaneously was associated with decreased mortality. The HR for mortality decreased as the number of parameters for which guidelines were satisfied increased from one to six (Table 3). Compared with patients who satisfied guidelines on zero parameters, patients who satisfied guidelines for all six parameters simultaneously experienced an 89% reduction in mortality (HR 0.11; 95% CI 0.06 to 0.19). However, only a small proportion of patients satisfied guidelines for all six parameters. The median number of parameters satisfying guidelines was three, and the associated HR was 0.39 (95% CI 0.31 to 0.49).

	DISCUSSION

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The relationship between mortality and adherence to guidelines for anemia, dialysis dosage, and serum albumin observed in this study is in concert with a recent report.¹⁴ In both studies, mortality decreased as the number of parameters satisfying guidelines increased. However, Rocco et al.¹⁴ examined measurements from a single 3-mo period and the follow-up period was limited to 1 yr. The results of this study are also in agreement with recent studies that examined achievement of guidelines for bone mineral metabolism.^10–13 However, previous studies largely relied on single baseline laboratory values rather than longitudinal monthly data. Using Centers for Medicare and Medicaid data, Wolfe et al.¹⁹ demonstrated that facilities in the lowest quintile of guideline adherence for spKt/V and hematocrit had 22 and 14% greater mortality, respectively, compared with facilities in the highest quintile (P < 0.001). In the Dialysis Outcomes Practice Pattern Study (DOPPS), a two-fold increase in mortality was demonstrated among patients with a baseline serum albumin concentration <3.3 g/dl.¹¹ Noordzij et al.¹³ demonstrated that elevations in serum phosphorus and calcium-phosphate product were associated with increased mortality.

As in previous studies, the strongest association with reduced mortality was observed for serum albumin 4.0 g/dl.^10,11,20,21 The magnitude of the HR associated with satisfying the serum albumin guideline was similar to that observed for satisfying guidelines for serum calcium, phosphorus, PTH, hematocrit, and spKt/V simultaneously. The independent predictive ability of these variables is supported by the multiplicative reduction of HR to a level of 0.11 when all were combined. Although satisfying guidelines for multiple parameters presents a therapeutic challenge, we observed significant increases in guideline adherence for spKt/V, hematocrit, and serum albumin over time. This may reflect in part improved clinical practice patterns and in part survivor bias. Because results of models stratified by baseline values were identical, it is not likely that patient selection contributed to our findings.

Mortality was increased among patients who satisfied guidelines for predialysis BP. These results are in concert with previous studies describing the association between BP and mortality among HD patients.^16,17,22,23 Surprising, despite the current recommended BP target of <130/80 mmHg for patients with diabetes,^7,24 BP values in this range were associated with a greater mortality risk in participants with than without diabetes. This may reflect the likely higher prevalence of cardiac and/or autonomic dysfunction among patients with diabetes.²⁵ Unfortunately, data on these conditions were not routinely collected in DCI's medical information system during the study period.

The evidence in support of the current BP guidelines was largely extrapolated from the general population and graded as weak.⁷ However, in view of the complex pathophysiology of ESRD, the ideal BP target among HD patients may differ from that in the general population.^26–28 Furthermore, clinical practice guidelines extrapolated from the general population may not be applicable to specific groups of patients with multiple comorbidities. Boyd et al.²⁹ recently demonstrated that adhering to guidelines that were developed for the general population may have undesirable effects when applied to the elderly. Therefore, professional associations should exercise caution when promulgating specific guidelines that are not based on evidence obtained in the target population.

This study contains several limitations inherent to retrospective analyses. First, because of the lack of consistently high-quality data, our modeling procedures did not include some potentially important covariates (e.g., medication use, fasting serum lipid profiles, presence or absence of symptomatic intradialytic hypotension).^30–36 Second, it may be argued that our results simply reflect a higher case-mix burden among patients with values that failed to satisfy the guidelines. Our models were adjusted for several case-mix factors that have been shown to be strong determinants of mortality, including age, race, cause of ESRD, and serum albumin. However, data on comorbid conditions were not available. Although comorbidity has been shown to be significantly associated with mortality even after accounting for serum albumin and other case-mix factors,³⁷ a recent study showed that its contribution to a survival model is not as large as expected. In this analysis of the European Renal Association Registry, comorbidity explained only 1.9% of the variance in mortality, whereas 14.4% was explained by age, gender, primary renal disease, treatment modality, and country.³⁸ These observations suggest that although the absence of these data is a limitation, it is unlikely that our results would significantly change if comorbidity were accounted for. Third, as in other large dialysis organizations, BP was measured in accordance with standard clinical practice rather than American Heart Association guidelines.³⁹ Finally, the study period did not coincide with the widespread implementation of KDOQI guidelines.

This study also has several strengths. First, all laboratory parameters were measured longitudinally in the same central laboratory, reducing a significant component of variability. Second, use of the DCI medical information system ensured high-quality data as a result of electronic data transfer, built-in range checks, and ongoing data monitoring. Third, participating facilities were geographically dispersed and included patients who were treated both by academic and by private practitioners. Therefore, the study had a diverse and representative patient population.

We demonstrated significant reductions in mortality associated with adherence to KDOQI guidelines for spKt/V, hematocrit, serum albumin, calcium, phosphorus, and PTH. Therefore, clinical practice patterns associated with increased adherence should be identified and implemented throughout large dialysis organizations. In contrast, BP values satisfying the KDOQI guideline were associated with increased mortality. It is reasonable to postulate that arterial and cardiac structure and function vary significantly among HD patients with different BP values. Therefore, the ideal BP target may differ on the basis of these clinical characteristics. Because even a well-designed retrospective study can demonstrate only associations, a prospective, randomized, controlled trial is necessary to establish the optimal BP target among HD patients.

	CONCISE METHODS

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Study Sample
We studied all incident patients who were aged 20 yr and began HD at a DCI clinic between January 1, 1998, and December 31, 2004, and had survived at least 120 d after the first outpatient HD treatment. Patients were excluded when they had previously been treated by peritoneal dialysis or had received a kidney transplant; when they began maintenance HD outside DCI; or when gender, age, or date of diagnosis of ESRD was missing. Follow-up began 120 d after the first outpatient HD treatment and continued until death; kidney transplantation; switch to peritoneal dialysis; absence from DCI for >90 d; or the end of follow-up on December 31, 2005.

Data Sources
Data were obtained from DCI's proprietary computerized medical information system (DARWIN). DARWIN has been used to support DCI's participation in previous multicenter studies, including the Hemodialysis (HEMO)⁴⁰ and Choices for Healthy Outcomes in Caring for End-Stage Renal Disease (CHOICE) studies.⁴¹ Dates of death were obtained from the Centers for Medicare and Medicaid Services Death Notification forms (form 2746) and confirmed by directly contacting the clinics.

Laboratory Methods
All laboratory parameters were measured monthly, except for PTH, which was measured quarterly. Venous blood samples for routine laboratory determinations were obtained immediately before the dialysis treatment and shipped to the DCI central laboratory (Nashville, TN) for analysis. Blood urea nitrogen was measured by Enzymatic Urease (Roche, Nutley, NJ), hematocrit by Advia (Bayer, Tarrytown, NY), serum albumin by bromocresol green (Roche), calcium by Cresolphthalein Complexone (Roche), serum phosphorus by Phosphomolybdate-UV (Roche), and PTH by N-tact PTH SP IRMA (DiaSorin, Stillwater, MN). spKt/V was computed using formal urea kinetic modeling. Serum calcium concentrations were corrected using the concomitant serum albumin concentrations.⁴² BP was measured in accordance with standard clinical practices in place at each facility.

Values Satisfying KDOQI Guidelines
We selected the last measurement in each calendar month for spKt/V, hematocrit, serum albumin, calcium, phosphorus, and PTH and the last BP measurement in each calendar week. Each individual value was classified as to whether it satisfied the guidelines using the following criteria: spKt/V 1.2,^3,9 hematocrit 33%,^4,8 serum albumin 4.0 g/dl,⁵ calcium 8.4 to 9.5 mg/dl,⁶ phosphorus 3.5 to 5.5 mg/dl,⁶ PTH 150 to 300 pg/ml,⁶ and predialysis BP 140/90 mmHg.⁷

Statistical Analyses
We used a Cox proportional hazards model to investigate the association between mortality and satisfying the guideline for a given parameter. Satisfying the guideline at a specific point in time was defined in a time-varying manner using all measurements taken during a 90-d window beginning 120 and ending 30 d before death.

There were typically three measurements of spKt/V, hematocrit, serum albumin, calcium, and phosphorus; a single measurement of PTH; and 12 measurements of predialysis BP in the 90-d window. When there were fewer, the window was extended, up to a maximum of 180 d, until the desired number of measurements was included. The desired number of measurements was generally obtained within the 90-d period for each parameter (81 to 94%) and almost always within 120 d (96 to 99%). We treated the number of values within each window satisfying the guidelines as a categorical variable. A missing value indicator was used when there was fewer than the desired number of measurements in the window. Additional covariates in the Cox models included demographic characteristics (age, gender, race, cause of ESRD, and year HD was started) and, when appropriate, spKt/V and serum albumin, defined as the average value during the same 90-d window used for the parameter of interest. Separate models were constructed for each parameter considered.

To identify potential modifying effects, we constructed an additional series of models with interactions between values satisfying the guidelines and age, gender, race, cause of ESRD, and year of diagnosis (1998 to 2000 versus 2001 to 2004). In these models, the number of measurements satisfying guidelines was treated as a linear effect. We also considered the possibility that baseline status might influence the associations: The association of guideline adherence and mortality among patients whose values satisfied guidelines at baseline might differ from the associations among patients whose values did not satisfy guidelines at baseline. To explore this possibility, we stratified the models on whether the baseline parameter values satisfied guidelines. Baseline was defined as the first measurement within 60 d of initiating HD. Finally, we looked at the association of mortality with the number of parameters that satisfied guidelines during the 90-d window. A parameter was defined to satisfy guidelines during the 90-d period when at least two thirds of the individual measurements satisfied guidelines.

For each parameter considered, we constructed plots showing the proportion of patients who satisfied guidelines during time since the start of HD. A patient was classified as satisfying guidelines for a 3-mo period when at least two thirds of the measurements satisfied guidelines. We constructed plots for participants who were followed for at least 3 yr. To evaluate whether the observed trends were due to survivor bias, we also constructed plots for patients who were followed for at least 1 yr and for all participants.

Summaries for demographic variables are shown as percentages. A two-tailed t test was used to compare the DCI population with the United States Renal Data System HD population. McNemar test was used to compare the proportion of patients who satisfied guidelines between the first and 12th quarters after the start of HD. Model results are summarized by HR and 95% CI. Statistical analyses were conducted in SAS version 9.1 (SAS Institute, Cary, NC). Statistical significance was defined as P < 0.05.

	Disclosures

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None.

	Acknowledgments

 
This study was funded by DCI, a not-for-profit organization.

Results of this study were presented in part at the annual meeting of the American Society of Nephrology; November 8 through 13, 2005; Philadelphia, PA.

Special thanks to all DCI patients, without whom this study would not have been possible. We thank all DCI facilities and medical directors for collaborative assistance and Doug Lindsey, Meg Lamey, and Kelly Utterback for technical support.

	Footnotes

 
Published online ahead of print. Publication date available at www.jasn.org.

F.T. and W.C.H. contributed equally to this work.

	References

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