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Evaluation of an anemia algorithm in chronic hemodialysis patients.

Learning objectives

After reading the article, the reader will be able to:

1. Identify some common complications associated with anemia.

2. Describe the pathogenesis of anemia of chronic kidney disease (CKD).

3. Understand the clinical benefits of treating anemia associated with CKD.

4. Discuss current National Kidney Foundation recommendations/guidelines on the management of anemia of CKD.

5. Understand the relevance of evaluating the clinical use of algorithms.

A wide range of complications develops as a consequence of kidney failure. Disorders related to fluid and electrolyte imbalance may include hypervolemia, hyperkalemia, nausea and vomiting, hyperparathyroidism, bone disease and hypertension (Mitch, 2005; Snively, 2004). One of the most common complications associated with chronic kidney disease is anemia (Pendse & Singh, 2005). Anemia itself can be disruptive by causing weakness, fatigue, and tachycardia, and can also further potentiate other existing complications, such as left ventricular hypertrophy and arrhythmias (Eckardt, 2005; Levin, 2002; Levin, 2004).

Managing anemia is essential in optimizing quality of life, in enhancing well-being, and in reducing hospitalizations and morbidity. Because of practice variability and inconsistencies in patient care delivery, the National Kidney Foundation (2001) established national guidelines to help guide anemia management. These guidelines are consistent with Canadian guidelines that were released in 1999 (Barrett et al., 1999). The Northern Alberta Renal Program (NARP) in Edmonton, Alberta, adopted these guidelines and implemented an anemia algorithm, the "Anemia Protocol," (see Figure One, pages 49 and 50) to assist health professionals to assess, treat, and monitor anemia in patients with chronic kidney disease. The "Anemia Protocol" was adopted in 2004 in three satellite dialysis units of NARP. Since implementation of the "Anemia Protocol", there had not been a formal evaluation as to the overall effectiveness of the algorithm.

Background

The pathogenesis of anemia of chronic kidney disease (CKD), like anemia in general, can develop from decreased red blood cell (RBC) production, from accelerated and premature RBC destruction, or from acute or chronic blood loss. The primary cause of anemia seen in patients with CKD is from hypoproliferative anemia (Barrett et al., 1999; Ly, Marticorena, & Donelly, 2004). As outlined by Bahlmann et al. (2003), the pathogenesis of hypoproliferative anemia is usually multifactorial, but the primary cause is from insufficient production of erythropoietin (EPO). In advanced kidney failure, the number of functioning renal tubular cells is decreased, resulting in decreased stimulation of hematopoiesis. EPO is an erythroid specific growth factor that binds with erythroid progenitors to enhance the proliferation and differentiation of erythroblasts into reticulocytes. After two to three days, reticulocytes are then released into the blood stream where the mature RBCs normally survive for 120 days (Bahlmann et al., 2003; Pfeilschifter & Huwiler, 2004). The lifespan of RBCs in patients with CKD is decreased to 60 to 90 days. The pathogenesis of shortened lifespan of RBCs is not clear, but it is thought that the uremic environment may alter the cell physiology (Ly et al., 2004). Along with reduced EPO, shortened RBC lifespan contributes to the development of anemia of CKD.

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Like anemia in general, patients with anemia of CKD may also experience fatigue, weakness, headaches, and tachycardia (Odden, Wholley, & Shlipak, 2004). In the long term, if untreated, anemia is associated with a number of physiological abnormalities, including decreased cardiac function, impaired cognitive and mental function, decreased exercise tolerance and quality of life, and may also weaken an already altered immune system (Eckardt, 2005; Levin, 2004; Roman et al., 2004; Weiner et al., 2005).

Many authors report a link between anemia and cardiovascular disease (Eckardt, 2005; Kausz, Solid, Pereira, Collins, & St. Peter, 2005; Levin, 2002; Pereira & Sarnak, 2003; Silverberg et al., 2004; Snively, 2004; Strippoli, Craig, Manno, & Schena, 2004). Anemia has been implicated in the worsening of cardiac function as well as having a role in increasing left ventricular mass (Silverberg, Wexler, & Ianina, 2004; Wexler et al., 2005). In order to maintain tissue oxygen supply, adaptive cardiovascular mechanisms are induced. Stroke volume and heart rate are increased, resulting in cardiac stress and the development of left ventricular dilation and hypertrophy and cardiomyopathy (Snively, 2004). It is estimated that at the time of dialysis initiation, three-quarters of patients already have left ventricular hypertrophy, and that, in itself, is a strong predictor of mortality (Ayus et al., 2005; Jones, Schenkel, & Just, 2005; Weiner et al., 2005).

Cardiac disease and anemia also decrease physical capacity and exercise tolerance, in turn affecting the well-being of patients with CKD (Odden et al., 2004). The mechanism by which physical capacity is reduced in patients with CKD is unclear, but it has been postulated that it may be due to patients' cardiac status, nutritional status, or anemic state (Odden et al., 2004). Odden et al. (2004) studied a cohort of 954 hemodialysis patients from the San Francisco area to examine the influence of psychosocial factors on cardiac outcomes in participants with known coronary disease. They found that both CKD and anemia were independently associated with reduced self-assessed physical function and exercise capacity. The authors concluded that patients with CKD already have lowered physical capacity that is further reduced in the presence of anemia.

Anemia is also associated with increased hospitalizations, health care costs, and mortality due to various complications. Kausz, Solid, Pereira, Collins, and St. Peter (2005) looked at a national cohort of more than 130,000 American hemodialysis patients and compared the differences between patients who were able to achieve hemoglobin (Hgb) >110 g/L and patients who were not able to achieve this level. Patients who were not able to achieve Hgb >110 g/L had more co-morbid conditions, more hospital admissions, and more blood transfusions.

The clinical benefits of treating anemia of CKD are well documented, such as improved survival, decreased morbidity, improved cardiac function, and enhanced cognitive acuity (Collins et al., 2001; Furuland et al., 2003; Ma, Ebben, Xia, & Collins, 1999; National Kidney Foundation, 2001; Odden et al., 2004). Because effective treatment of anemia is associated with improved clinical outcomes and quality of life, and reduced hospitalizations and mortality, anemia management is a major goal of CKD management. Historically, management and treatment options for anemia of CKD have been limited. Administering blood transfusions was the common treatment option for managing and treating anemia. However, blood administration carries the risk of transmitting infectious agents, as well as potentially increasing antibodies, making transplantation a challenge, and suppressing production of EPO in some patients (Jones, Ibels, Schenkel, & Zagari, 2004; Raghavan & Marik, 2005). It is now recommended that blood transfusions be reserved for severely anemic patients who are symptomatic or for erythropoietin-resistant patients who have chronic blood loss (National Kidney Foundation, 2001).

Since the introduction of exogenous erythropoiesis-stimulating agents in Canada in 1986, the management and treatment of anemia of CKD has been revolutionized. The gene encoding EPO was cloned in 1985, leading to the production of recombinant human erythropoietin (r-HuEPO). Since its introduction, many patients are spared from transfusion dependency (Adamson & Eschbach, 1989; Eschbach, 1995). R-HuEPO is a recombinant version of EPO. They are glycoproteins that mimic natural EPO to stimulate the bone marrow to produce RBCs, which, in turn, increase oxygen availability to tissues (Debska-Slizien, Owczarzak, Lysiak-Szydlowska, & Ruthkowski, 2004; Graf, Lacombe, & Braun, 2000; Macdougall, 2000). Currently, there are two agents available in Canada: epoetin alpha (Eprex[R]) and darbepoietin alpha (Aranesp[R]). The cost associated with the use of r-HuEPO is high. It is estimated that the average cost for a patient, using 80 micrograms of darbepoietin alpha every two weeks, is $5,500.00 per year. As of December 2000, more than 75% of hemodialysis patients are on r-HuEPO, compared to 10.3% in 1989 (Canadian Institute for Health Information, 2002).

Although there is strong evidence to support maintaining Hgb >110 g/L, there is still insufficient evidence to routinely maintain Hgb >130 g/L (National Kidney Foundation, 2001). In fact, there have been inferences with higher Hgb targets and all-cause mortality, arteriovenous thrombosis and poor blood pressure control (Navaneethan, Bonifati, Schena, & Strippoli, 2006; Phrommintikul, Haas, Elsik, & Krum, 2007). Therefore, targeting the Hgb value above the current recommendation with r-HuEPO is not warranted until further evidence supports its safety and efficacy.

Despite the routine use of r-HuEPO and its associated costs, variations in anemia management practices continue to exist. This can be attributed to differences in target range and action threshold among health care providers. Since the National Kidney Foundation released its recommendations on the management of anemia in 1997 (National Kidney Foundation, 2001), many centres have developed and implemented anemia algorithms. Algorithms provide standardized approaches for assessing anemia, for initiating treatment, and for monitoring progression. Although there are many reports on the development and implementation of anemia algorithms, there are few studies that have evaluated the effectiveness of an algorithm in anemia management (see Table One). Patterson and Allon (1998) reported that with the use of an anemia algorithm, the number of patients who were able to achieve target hematocrit (Hct) levels increased from 27% to 61% during months four to six of the algorithm use. During the same period, the proportion of patients whose transferrin saturation was < 18%, decreased from 47% to 20%. Weekly epoetin alpha dose also decreased with the use of an algorithm. To, Stoner, Stolley, Buenvaje, and Ziegler (2001) compared the management of anemia (without an algorithm) by physicians to the management of anemia by pharmacists (with an algorithm). Patients who were managed with an anemia algorithm had equivalent outcomes to those managed without. Hct levels without an algorithm were 32% to 38.7%, compared to 32.8% to 39.7%. There was a non-significant reduction in the total number of units of epoetin alpha used and a nonsignificant increase in oral iron use but, at the same time, there was a significant increase in intravenous iron use. Brimble, Rabbat, McKenna, Lambert, and Carlisle (2003) also demonstrated that the use of an algorithm can safely achieve target Hgb values, but did not offer any advantage over not using an algorithm due to the substantial improvement in the control group. However, there was a substantial cost savings in the protocol group. Finally, Kimura, Masuda, and Kawabat (2004), similar to the earlier study by To et al. (2001), compared the management of anemia (without an algorithm) by physicians to the management of anemia (with an algorithm) by pharmacists. They found that with the use of an algorithm and the correction of iron deficiency, target Hct (>30%) increased from 17% to 78% and the dosages of epoetin alpha was reduced.
Table One. Studies of anemia algorithms

Authors Measurement Sample Method Outcomes

Patterson - Hct: 30 HD Prospective, With use of
& Allon 32-34% patients cohort study algorithm:
(1998) (satellite) over 6 months

 - TSAT > - 57 [+ or - # of patients
 17% -] 16 years with target Hct
 [up arrow] from
 27-61%

 - ferritin - 16 men, 14 - # of patients
 >500 ng/mL women below target Hct
 [down arrow] from
 46% to 18% (p
 =0.004)

 - DM (40%), - # of patients
 HTN (33%), above target did
 not [up arrow]

 GN (13%), - # of patients
 PCKD (3%), with TSAT < 18%,
 [down arrow] from
 47% to 20% (p
 =0.04)

 unknown - weekly Epo dose
 (7%) [down arrow] from
 11 200 [+ or
 -]1,400 to 9,400
 [+ or -] 1,200 (p
 = 0.06)

 - Kt/V: 1.46
 [+ or
 -]0.21

To et al. Based on 49 HD Retrospective -Hct without
(2001) K/DOQI patients cohort study algorithm: 35.36%
 guidelines: over 6 months [+ or -]3.33 vs.
 36.21% [+ or
 -]3.46 with
 algorithm (p =
 0.2)

 - Hct: - 60 [+ or - total Epo used
 33-36% -] 12 years without
 algorithm: 8.5
 million units
 compared to 7.7
 million units
 with algorithm (p
 = 0.37)

 - TSAT: - 48 men, 1 - total oral iron
 20-50% woman used without
 algorithm: 85,605
 mg compared to
 95,550 mg with
 algorithm (p
 =0.64)

 - ferritin: - DM (47%), - total IV iron
 100-800 GN (20%), used without
 ng/mL algorithm: 13,600
 mg vs. 33,025 mg
 with algorithm (p
 <0.001)

 HTN (18%),
 other (14%)

Brimble et Based on 215 HD Randomized - 42.8% of all
al. K/DOQI patients controlled patients were
(2003) guidelines: trial able to achieve
 (algorithm vs. target Hgb
 no algorithm) levels
 over 8 months

 - Hgb: - control (11-12.5 g/dL),
 11-12.5 group: 65.8 compared to 47.4%
 g/dL years with at the start of
 37% women, the study (p
 44.4% with =0.001)
 DM

 - TSAT: - protocol - without
 20-50% group: 65.7 algorithm:
 years with 49.1-62.0% (p =
 42.1% women, 0.05)
 30.8% with
 DM

 - ferritin: - with algorithm:
 45.8-63.6% (p =
 0.02)

 100-800 - use of
 ng/mL algorithm >5
 months, reduction
 of Eprex[R] by
 2788 units/wk (p
 <0.05)

Kimura et - Hct >30% 45 HD Prospective - # of patients
al. patients cohort study with Hct >30%,
(2004) over 9 months [up arrow] from
 17.1-78%

 - ferritin - 66.1 - monthly
 >100 ng/mL years Eprex[R] used,
 [down arrow] from
 91,500 units to
 64,200 units with
 use of algorithm

 - 22 men, 23
 women

Note: Hct = hematocrit, TSAT = transferrin saturation,
HD = hemodialysis, DM = diabetes mellitus,
GN = glomerulonephritis, PCKD = polycystic kidney disease,
HTN = hypertension


Purpose

The purpose of this study was to evaluate the effectiveness of the "Anemia Protocol" algorithm that was adopted by the Northern Alberta Renal Program (NARP). The "Anemia Protocol" algorithm, initiated at three satellite dialysis units of NARP, may provide consistencies in anemia management by having a set target range for hemoglobin level and iron indices, and the necessary actions to achieve these targets. This was the first study to evaluate the effectiveness of an algorithm, using darbepoietin alpha as the r-HuEPO of choice. The outcomes of hemoglobin level, iron indices (ferritin and transferrin saturation), recombinant human erythropoietin (r-HuEPO) and iron use, and cost related to r-HuEPO and iron use were examined monthly. Effectiveness was defined as an increase in hemoglobin levels and a reduction in use and subsequent cost of r-HuEPO and iron supplements. The following questions were addressed:

1. Is there a significant difference in hemoglobin levels pre- and post-implementation of the "Anemia rotocol" algorithm?

2. Is there a significant reduction in anemia pre- and postimplementation of the "Anemia Protocol" algorithm?

3. Is there a significant difference in iron indices level pre- and post-implementation of the "Anemia Protocol" algorithm?

4. Is there a significant difference in use of r-HuEPO and iron supplements pre- and post-implementation of the "Anemia Protocol" algorithm?

5. Is there a significant difference in cost of r-HuEPO and iron supplements pre- and post-implementation of the "Anemia Protocol" algorithm?

Methods

A cohort design was used to evaluate the effectiveness of the "Anemia Protocol" algorithm in chronic hemodialysis patients. A cohort of patients was followed, who received maintenance hemodialysis for a nine-month period at three satellite dialysis units in the Northern Alberta Renal Program (NARP). Patients eligible for the study were 18 years of age or older and had received hemodialysis treatments at each of the respective satellite dialysis units for the nine-month study period. Patients excluded from the study were those who did not complete their maintenance hemodialysis at the respective dialysis units, those who were transplanted or switched to peritoneal dialysis, those who were hospitalized, those who received epoetin alpha as the r- HuEPO of choice, and those who received blood transfusions during the study period.

There were 242 patients eligible for the study. Of the 242 patients, 70 patients were excluded because they did not dialyze for the entire nine months at their respective dialysis unit. A further 74 patients were excluded from the study for the following reasons: 41 for hospitalization (reasons for admissions were not gathered in this study), 22 for receiving blood transfusions, three for using epoetin alpha, and eight for having incomplete data. The total number of patients enrolled in the study was 98, 26 from satellite dialysis unit one, 46 from satellite dialysis unit two, and 26 from satellite dialysis unit three.

From patient health records, outcome variables of hemoglobin (Hgb) level, iron indices, r-HuEpo dose, iron supplement dose, and factors related to hypo-responsiveness were reviewed monthly. Data were collected from three time periods: pre-implementation (T1), intra-implementation (T2), and post-implementation (T3). T1 is the timeframe of three months before the implementation of the "Anemia Protocol" algorithm. After the introduction of the algorithm, a period of three months (T2) was included for staff to become familiar with the use of the algorithm; T3 is the three months following the implementation of the "Anemia Protocol" algorithm.

Blood work, including Hgb levels and iron indices, was measured in patients at the beginning of each month at the dialysis units. In patients with CKD, target values for ferritin and transferrin saturation were [greater than or equal to]100 ng/mL and [greater than or equal to]20%, respectively. As standard protocol in the dialysis units, if there was a 15-20 g/L discrepancy in Hgb level from the previous value, the result was reported to the responsible nephrologist. The following week, r-HuEPO and iron dosages were then adjusted according to the "Anemia Protocol" algorithm.

Health records of patients were assessed monthly for a period of nine months to ensure that the inclusion criteria were met. Demographic information (age, gender) and clinical information (etiology of chronic kidney disease, comorbidities, and time on dialysis) were recorded. Patient health records were reviewed to document any hospital admissions or blood transfusions received; patients who received epoetin alpha or blood transfusions, or were admitted during the nine-month period at each of the satellite units were excluded from the study. Hemoglobin, ferritin and transferrin saturation levels, and values that may affect hypo-responsiveness to r-HuEPO (parathyroid hormone and albumin levels, and dialysis adequacy parameters: percent reduction of urea (PRU) and Kt/V) were also documented. Health records were also screened for any documentation of infection and/or gastrointestinal bleeding. Finally, costs related to r-HuEPO and iron use were calculated based on the University of Alberta Hospital Pharmacy Pricing Guideline.

Data analysis

Data were analyzed using SPSS (version 13.0, SPSS, Inc., Chicago, IL) software. Descriptive statistics were performed on the demographic and clinical variables to provide an overview of the subjects involved in the study. Repeated measures ANOVA was used to compare the Hgb levels, iron indices, r-HuEPO and iron dosages, and costs related to r-HuEPO and iron use, to determine if there was a significant difference pre-, during, and post-implementation of the "Anemia Protocol". The presence/absence of anemia, pre- and post-implementation, was compared using Chi-square ([X.sup.2]). A p <0.05 was considered statistically significant.

Ethical considerations

Ethical approval was obtained from the Health Research Ethics Board, University of Alberta. The director of Nursing and Medical Lead of NARP were also approached for approval to review patient health records. All patient information was kept confidential and used only for the purpose of this study. Data were organized by code numbers only, and will be kept in a locked filing cabinet for seven years.

Results

Patients (n =98) had a mean age of 64.5 [+ or -] 16.5 years, with a range of 21 to 91 years. There were a total of 54 men (55%). The causes of chronic kidney disease included diabetes (31.6%), glomerulonephritis (25.5%), hypertension (13.2%), renal/vascular disease (2%), pyelonephritis (4%), polycystic kidney disease (2%), and other/unknown (21.4%), such as drug toxicities and amyloidosis. Baseline patient characteristics are summarized in Table Two. There were no significant differences in age, duration of dialysis, or incidence of diabetes, hypertension, coronary artery disease, cerebral vascular accident, peripheral vascular disease, malignancies, lung disease, or other diseases, such as liver disease, gallbladder disease or gastrointestinal diseases associated with bleeding among the three satellite dialysis units.

Hemoglobin levels and incidence of anemia

Over the nine-month study period, there was no significant change in Hgb levels (F =2.075, df =5, p =0.075), nor was there a significant difference in Hgb levels and site of dialysis (F =0.243, df =2, p =0.785). Anemia in the study was defined as hemoglobin <110 g/L. The presence/absence of anemia, pre- and post-implementation, was compared using Chisquare ([X.sup.2]). There was no significant difference in the incidence of anemia throughout the study period ([X.sup.2] =6, p =0.429). Incidence of anemia was 28% pre-implementation, 34% intra-implementation, and 32% post-implementation of the anemia algorithm (see Table Three).
Table Three. Laboratory values pre-, intra-, and post-algorithm implementation

 T1 (Pre-Implementation)
 1 2 3

* Hgb, g/L
Mean [+ or -] SD 116 [+ or -] 13 117 [+ or -] 13 117 [+ or -] 12
Median 117 118 118.5
(range) (86 - 158) (83 - 153) (88 - 144)

Anemia
(Hgb <110g/L), n 28 25 29

Ferritin, g/L
Mean [+ or -] SD 516 [+ or -] 517 [+ or -] 453 [+ or -]
 334 329 294

Median 449 429 400
(range) (13 - 432) (27 - 1432) (24 - 1129)

** % de TSAT

Mean [+ or -] SD 35 [+ or -] 13 35 [+ or -] 15 33 [+ or -] 15
Median 33 32 29
(range) (10 - 92) (10 - 5) (8 - 97)

Serum
albumin, g/L
Mean [+ or -] SD 38.7 [+ or -] 3 38.9 [+ or -] 3 39.1 [+ or -] 3
Median 39 39 39
(range) (30 - 47) (31 - 46) (31 - 45)

*** PTH,
pmol/L
Mean [+ or -] SD
Median
(range)

# PRU, %
Mean [+ or -] SD 75.1 [+ or -] 75.2 [+ or -] 75.6 [+ or -]
 5.3 5.6 5.0
Median 75.5 76.1 75.5
(range) (57.4 - 84.7) (54.0 - 86.0) (52.6 - 86.4)

# Kt/V
Mean [+ or -] SD 1.6 [+ or -] 1.6 [+ or -] 1.7 [+ or -]
 0.2 0.3 0.2
Median 1.63 1.64 1.63
(range) (0.98 - 2.23) (0.81 - 2.26) (0.83 - 2.34)

## Tested for 1 1 1
GIB, n

Presence of 1 1 2
infection, n

 T2 (Intra-Implementation)

 4 5 6

* Hgb, g/L

Mean [+ or -] SD 115 [+ or -] 11 114 [+ or -] 11 112 [+ or -] 12
Median 116 113 113
(range) (86 - 140) (85 - 141) (72 - 146)

Anemia
(Hgb <110g/L),n 30 35 35

Ferritin, g/L
Mean [+ or -] SD 482 [+ or -] 498 [+ or -] 491 [+ or -]
 338 346 305
Median 423 438 453
(range) (48 - 1650) (32 - 1650) (29 - 1408)

** % de TSAT
Mean [+ or -] SD 34 [+ or -] 16 32 [+ or -] 13 34 [+ or -] 15
Median 32 29 31
(range) (13 - 97) (8 - 91) (13 - 84)

Serum
albumin, g/L
Mean [+ or -] SD 38.8 [+ or -] 38.6 [+ or -] 38.9 [+ or -]
 3.6 3.4 3.6

Median 39 39 39
(range) (28 - 47) (28 - 47) (25 - 46)
*** PTH,

pmol/L
Mean [+ or -] SD
Median
(range)

# PRU, %
Mean [+ or -] SD 76.0 [+ or -] 75.1 [+ or -] 75.8 [+ or -]
 5.3 5.6 5.1
Median 76.3 75.1 76.5
(range) (50.2 - 85.6) (49.8 - 90.1) (50.6 - 85.3)

# Kt/V
Mean [+ or -] SD 1.7 [+ or -] 1.6 [+ or -] 1.7 [+ or -]
 0.3 0.2 0.2
Median 1.68 1.61 1.68
(range) (0.80 - 2.31) (0.77 - 2.35) (0.99 - 2.29)

## Tested for 0 0 0
GIB, n

Presence of 1 2 1
infection, n

 T3 (Post-Implementation)

 7 8 9

* Hgb, g/L
Mean [+ or -] 114 [+ or -] 13 113 [+ or -] 11 114 [+ or -] 12
SD
Median 114 114 114
(range) (80-149) (89-139) (89-140)

Anemia
(Hgb <110g/L),n 29 33 33

Ferritin, g/L
Mean [+ or -] 517 [+ or -] 491 [+ or -] 468 [+ or -]
SD 310 308 286
Median 456 465 434
(range) (61-1233) (39-1535) (52-1591)

** % de TSAT
Mean [+ or -] 37 [+ or -] 16 32 [+ or -] 12 33 [+ or -] 12
SD
Median 33 31 31
(range) (15-96) (9-77) (11-79)

Serum
albumin, g/L
Mean [+ or -] 38.9 [+ or -] 38.9 [+ or -] 38.0 [+ or -]
SD 3.2 3.1 4.1
Median 39 39 38
(range) (32-46) (31-46) (21-46)

*** PTH,
pmol/L
Mean [+ or -] 27.1 [+ or -]
SD
 34.3
Median 15.7
(range) (1.3-193)

# PRU, %
Mean [+ or -] 75.4 [+ or -] 75.5 [+ or -] 75.4 [+ or -]
SD 5.4 5.4 4.9
Median 75.7 76.0 75.9
(range) (54.5-84.9) (49.6-84.3) (53.6-83.0)

# Kt/V
Mean [+ or -] 1.7 [+ or -] 1.6 [+ or -] 1.7 [+ or -]
SD 0.2 0.3 0.3
Median 1.64 1.63 1.63
(range) (0.91-2.13) (0.78-2.23) (0.83-2.85)

## Tested for 1 0 1
GIB, n

Presence of 1 0 1
infection, n


Iron indices

Similar to Hgb levels, there was no significant change in ferritin levels over the nine-month study period (F =1.205, df =4, p =0.309). There was also no significant difference in ferritin levels and site of dialysis (F =2.937, df =2, p =0.058). However, there was a significant increase in the transferrin saturation (TSAT) level over the nine-month study period (F =2.146, df =7, p =0.041) (see Table Three).

Dose and cost of Aranesp and iron supplements

Doses of darbepoietin alpha and iron supplement remained constant from pre-implementation to post-implementation of the anemia algorithm (F =0.445, df =3, p =0.745) (see Table Four). The cost of darbepoietin alpha over the nine-month study period did not show any signifi- cant change (F =0.494, df =3, p =0.707). There was also no significant change in cost of iron supplements (F =1.973, df =4, p =0.090), nor was there a significant difference in costs of iron supplements and site of dialysis (F =1.52, df =2, p =0.223).

Clinical outcomes

Although not statistically significant, there were noted differences in incidence of anemia and Hgb and ferritin levels, darbepoietin alpha and iron dose and its associated costs, preversus post-implementation of the "Anemia Protocol" algorithm (see Table Five). Incidence of anemia had increased, with a reflective decrease in Hgb levels after the implementation of the algorithm. The amount and cost of darbepoietin alpha used have also increased in the post-implementation timeframe. Although transferrin saturation level remained constant pre- versus post-implementation of the anemia algorithm, ferritin levels were increased.
Table Five. Clinical outcomes

 Intra-implementation Post-implementation
 Compared to Pre Compared to Pre

Hemoglobin [down arrow] [down arrow]
Incidence of Anemia [up arrow] [up arrow]
Ferritin [up arrow] [up arrow]
Transferrin saturation Same same
Aranesp dose & cost [up arrow] [up arrow]
Iron dose & cost
 Oral iron [down arrow] [down arrow]
 Iron Dextran [up arrow] [up arrow]
 Venofer [up arrow] [down arrow]

 Post-implementation
 Compared to Intra

Hemoglobin same
Incidence of Anemia [down arrow]
Ferritin [up arrow]
Transferrin saturation same
Aranesp dose & cost [up arrow]
Iron dose & cost
 Oral iron [down arrow]
 Iron Dextran [down arrow]
 Venofer [down arrow]



Discussion

Findings indicate that even though the three satellite dialysis units in the NARP were able to achieve NKF-K/DOQI and the Canadian Society of Nephrology (CSN) recommended Hgb levels, between 112 [+ or -]12 g/L to 117 [+ or -]12 g/L, there still remained patients with Hgb levels as low as 72 g/L. Similarly, transferrin saturation levels throughout the study were from 32 [+ or -]13% to 37 [+ or -]16%. The lowest range of transferrin saturation was between 8% and 10%. As alluded to earlier, algorithms need to be periodically reviewed and may need revision to target this group of patients with sub-optimal levels.

Although this study did not show significant differences in costs of darbepoietin alpha and iron supplements, it may be of interest to also measure the indirect and longterm costs associated with the implementation of the algorithm, including the time that was allotted to managing the algorithm. It may also be of interest to look at r-HuEPOresistance. Some patients were receiving darbepoietin alpha 150 mcg IV weekly and others every two weeks. Would there be a significant difference in clinical outcomes if doses were decreased to every two-week dosing? A further analysis of the reasons for hospital admissions can also be of benefit, to assess whether there is an association with increased/decreased hemoglobin and cardiovascular risks and associated complications.

Poor documentation and missing data hindered adequate collection of information. In fact, eight patients had to be excluded from the study due to missing data. Documentation of the presence of gastrointestinal bleeding and/or infection was only dependent on the accuracy of nurses or physicians' documentation of events/symptoms. Furthermore, adjustments of the doses of darbepoietin alpha and iron supplements were at the discretion of two nurses; there was no system in place to review the accuracy of their interpretation. The compliance/ adherence of nurses to the algorithm throughout the study is also unclear.

Conclusion

This study did not show significant change in anemia or anemia management pre- versus post-implementation of the "Anemia Protocol" algorithm in the Northern Alberta Renal Program. Although not statistically significant, the study did note some clinical differences with the use of the "Anemia Protocol." Review of outcomes from this study highlighted problems with anemia management in a small group of patients who continued to have low Hgb levels, in spite of adequate iron stores and EPO therapy. However, this is not to imply that algorithms are not useful/valuable in clinical settings. Review/revision of the algorithm is warranted. Since the release of recommendations from the NKFK/ DOQI anemia work-group and subsequent CSN guidelines, many dialysis units adopted these guidelines and implemented algorithms as part of their anemia management. Although it is useful to have standardized approaches to anemia management, as they may limit practice variability, effectiveness of the algorithm needs to be regularly evaluated to ensure that intended clinical outcomes are achieved.

Editor's note: An updated version of the "Anemia Protocol" now being used in the Northern Alberta Renal Program is available on request from Julie Nhan at e-mail: Julie.Nhan@capitalhealth.ca

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Julie Nhan, RN, MN, CNeph(C), Nurse Practitioner, Northern Alberta Renal Program, University of Alberta Hospital, Edmonton, Alberta. Louise Jensen, RN, PhD, Professor, Faculty of Nursing, University of Alberta, Edmonton, Alberta. Alan McMahon, MD, FRCPC, Associate Professor, Faculty of Medicine, University of Alberta, Medical Director, Northern Alberta Renal Insufficiency Clinic, Edmonton, Alberta. Address correspondence to Julie Nhan, University of Alberta Hospital, 8440 112 Street, Edmonton, Alberta T6G 2B7 E-mail: Julie.Nhan@capitalhealth.ca Submitted for publication: January 5, 2007. Accepted for publication in revised form: June 16, 2007.

By Julie Nhan, RN, MN, CNeph(C), Louise Jensen, RN, PhD, and Alan McMahon, MD, FRCPC
Table Two. Baseline characteristics of patients

Variable SDU 1* (n=26) SDU 2* (n=46) SDU 3* (n=26) P
 value

Gender, n (%)

 Men 12 (46.2) 26 (56.5) 16 (61.5) 0.518
 Women 14 (53.8) 20 (43.5) 10 (38.5)

Age

 Mean [+ or -] SD 60.6 [+ or -] 67.1 [+ or -] 63.4 [+ or -] 0.568
 (years) 15.2 16.6 17.3

 Range 27 - 83 21 - 91 25 - 87

Duration of
dialysis

 Mean [+ or -] SD 5.2 [+ or -] 4.4 [+ or -] 3.9 [+ or 0.135
 (years) 2.9 2.5 -]4.1

Diagnosis, n (%)

 Diabetes 6 (23.1) 13 (28.2) 12 (46.1) 0.075

 Glomerulonephritis 9 (34.6) 13 (28.2) 3 (11.5)

 Hypertension 2 ( 7.7) 5 (10.9) 6 (23.1)

 Renal/Vascular 0 2 ( 4.3) 0

 Pyelonephritis 1 ( 3.8) 3 ( 6.5) 0

 Polycystic Kidney 2 ( 7.7) 0 0

 Unknown/Other 6 (23.1) 10 (21.7) 5 (19.2)

Co-morbidities, n
(%)

 Diabetes 8 (30.8) 18 (39.1) 13 (50.0) 0.364

 Hypertension 18 (69.2) 38 (82.6) 16 (34.8) 0.128

 #CAD 14 (53.8) 20 (43.5) 12 (46.2) 0.696

 #CVA 4 (15.4) 6 (13.0) 1 ( 3.8) 0.363

 #PVD 4 (15.4) 2 ( 4.3) 5 (19.2) 0.116

 Malignancies 4 (15.4) 1 ( 2.2) 4 (15.4) 0.078

 Lung Disease 3 (11.5) 3 ( 6.5) 3 (11.5) 0.692

 Other 13 (50.0) 19 (41.3) 7 (26.9) 0.226

* 1 = Satellite Dialysis Unit (SDU) 1
* 2 = Satellite Dialysis Unit (SDU) 2
* 3= Satellite Dialysis Unit (SDU) 3
# CAD = coronary artery disease
# CVA = cerebral vascular accident
# PVD = peripheral vascular disease

Table Four. Aranesp and iron dose and its associated costs

 T1 (Pre-Implementation)
 1 2 3
* EPO, meg
Mean[+ or -]SD 159+138 159+144 154+121
Median 120 120 120
(range) (0-640) (0-640) (0-640)

Cost of
EPO, $
Mean[+ or -]SD 452.82[+ or -] 452.54[+ or -] 435.88+
 387.21 403.74 343.03
Median 337.68 337.68 337.68
(range) (0- (0- (0-
 1800.96) 1800.96) 1800.96)

Iron dextran,
Mg
Mean[+ or -]SD 80.61[+ or -] 84.59[+ or -] 97.45+
 140.44 142.97 146.50
(range) (0-400) (0-400) (0-400)

Venofer, mg
Mean[+ or -]SD 19.39+ 15-31+ 31.63+
 82.06 72.30 129.71
(range) (0-400) (0-400) (0-1000)
Oral iron, n 5 6 8

Cost of
Iron, $
Mean[+ or -]SD 19.37[+ or -] 18.91 + 26.64+
 34.71 32.52 49.89
(range) (0-150) (0-150) (0-375)

 T2 (Intra-Implementation)
 1 2 3
* EPO, meg
Mean[+ or -]SD 152+120 151+114 165+129
Median 120 120 140
(range) (0-640) (0-600) (0-600)

Cost of
EPO, $
Mean[+ or -]SD 431.86+ 428.70+ 466.61 +
 339.76 325.34 364.62
Median 337.68 337.68 393.96
(range) (0- (0- (0-
 1800.96) 1688.40) 1688.40)

Iron dextran,
mg
Mean[+ or -]SD 102.04+ 118.37+ 93.88+
 170.49 158.18 136.08
(range) (0-1000) (0-400) (0-400)

Venofer, mg
Mean[+ or -]SD 39.8+ 21.43+ 28.57+
 136.78 78.98 121.84
(range) (0-1000) (0-400) (0-1000)
Oral iron, n 8 5 5

Cost of
Iron, $
Mean[+ or -]SD 30.15+ 25.54+ 24.44+
 53.07 33.79 46.90
(range) (0-375) (0-150) (0-375)

 T3 (Post-Implementation)
 1 2 3
*EPO, meg
Mean[+ or -]SD 162+124 167+127 162+129
Median 140 160 140
(range) (0-600) (0-600) (0-640)
Cost of
EPO, $
Mean[+ or -]SD 461.44+ 477.23+ 464.60+
 348.73 354.22 359.74
Median 450.24 450.24 450.24
(range) (0- (0- (0-
 1688.40) 1800.96) 1800.96)
Iron dextran,
mg
Mean[+ or -]SD 79.59+ 104.08+ 103.06+
 128.40 189.98 176.71
(range) (0-400) (0-1200) (0-1200)
Venofer, mg
Mean[+ or -]SD 13.27+ 23.47+ 15.31+
 48.99 99.28 59.81
(range) (0-200) (0-800) (0-400)
Oral iron, n 5 5 3
Cost of
Iron, $
Mean[+ or -]SD 16.88+ 21.65+ 21.71+
 24.52 33.48 32.07
(range) (0-178.80) (0-178.80) (0-178.80)

* Epo: Aranes
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Title Annotation:CONTINUING EDUCATION SERIES
Author:Nhan, Julie; Jensen, Louise; McMahon, Alan
Publication:CANNT Journal
Geographic Code:1CANA
Date:Jul 1, 2007
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