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Anemia of chronic renal insufficiency: defining the scope of the challenge: case study of the anemic patient.

Introduction

Chronic renal insufficiency (CRI) is a serious disorder that generally progresses over time to end-stage renal disease (ESRD), necessitating either dialysis or renal transplantation to sustain life. CRI typically gives rise to a host of cormorbidities, and patients who reach ESRD often present with left ventricular hypertrophy (LVH), anemia, congestive heart failure, metabolic bone disease, and malnutrition. Clinical research has demonstrated that these conditions often develop early in the course of CRI, greatly increasing the risk for morbidity and mortality over the course of disease progression (McClellan, Knight, Karp, & Brown, 1997; National Institutes of Health, 1993; Obrador, Ruthazer, Aova, & Pereira, 1999; Pereira, 2000).

Clinical evidence has demonstrated that anemia is partially or wholly responsible for many of the debilitating symptoms that have historically been attributed to uremia (Figure 1) (Besarab, 1997). However, despite the preponderance of evidence that illustrates the negative short- and long-term ramifications of anemia, it is a silent disorder that is often underrecognized and undertreated in patients with CRI. Indeed, assessment of patients who are initiating dialysis indicate that 51% have hematocrit (Hct) levels below 28%, and 80% have not received any therapy to treat anemia (Obrador, et al., 1999). Early intervention to manage anemia may help reduce the detrimental effects attributed to this condition.
Figure 1: Manifestations of Anemia

* Lethargy

* Cardiac enlargement

* Malaise/depression

* Angina

* Impaired cognition

* Impaired immune systems

* Anorexia

* Intolerance to cold

* Endocrine/metabolic
abnormalities

* Cardiorespiratory
disturbances

* Gastrointestinal
disturbances

* Tendency toward bleeding

* Reduced exercise tolerance

* Weakness

* Shortness of breath

* Exertional chest pain

* Impaired concentration

* Headache

* Pallor

* Neuromuscular symptoms

* Cutaneous disturbances

* Musculoskeletal symptoms

* Pruritus


Defining and Identifying CRI

Creatinine clearance is an indirect measure of kidney function that is used by many clinicians to confirm the diagnosis of CRI. Historically, there has been some confusion regarding the level of creatinine which is indicative of CRI. The National Institutes of Health (NIH) recently attempted to clarify this issue by defining CRI as a serum creatinine level exceeding 1.5 mg/dL in men, 1.2 mg/dL in women, or age-specific normal values in children. Although these creatinine levels signal significant kidney impairment, the systemic manifestations of CRI are typically minimal, and most patients are asymptomatic (National Institutes of Health, 1999).

Despite widespread use, serum creatinine does not accurately measure or represent true kidney function and is an insensitive marker of early CRI (McClellan, et al, 1997; National Institutes of Health, 1999). Factors such as changes in dietary creatine absorption, fluctuations in muscle mass, or secretion of creatinine by renal tubules and extrarenal sources can lead to low or stable serum creatinine concentrations, even in the presence of severe renal damage. Indeed, studies have shown that serum creatinine levels can be normal in the presence of a glomerular filtration rate (GFR) as low as 20 mL/min/1.73 [m.sup.2] (Obrador & Pereira, 1998) (Note: Normal GFR levels are 115 to 125 mL/min/1.73 [m.sup.2] for men and 90 to 100 mL/min/1.73 [m.sup.2] for women.) As a result, loss of kidney function, especially in the early stages of renal deterioration, may be missed when serum creatinine alone is used to assess function, or when isolated measurements are used. The need to follow changes in clinical and laboratory parameters over time is fundamental. Because deterioration in kidney function occurs progressively, regular clinical and laboratory follow-up can proactively detect subtle trends indicative of worsening kidney function.

Several other laboratory tests may provide a more comprehensive and accurate assessment of kidney function. The GFR--a direct measure of kidney function--provides the best overall index of kidney function (Levey, et al., 1999). GFR correlates directly with the severity of renal impairment, is less likely to be affected by external variables, and declines before the onset of uremia. Patients with CRI typically have a GFR between 30 and 75 mL/minute (National Institutes of Health, 1999; Obrador & Pereira, 1998). Because GFR is difficult to measure in clinical practice, most clinicians estimate it from the serum creatinine concentration and other factors (Table 1). Monitoring the trends in GFR is crucial, and a determination of whether GFR is stable, increasing, or decreasing is often more vital than the absolute value. Screenings for microalbuminuria and proteinuria can also be useful indicators that can signal the need for a more in-depth evaluation. Detection of microalbuminuria is an early indicator of renal injury requiring intervention. Similarly, detection of protein during routine dipstick testing often indicates significant glomerular damage.

The best evaluation of the scope of the CRI population was provided by the NIH's Third National Health and Nutrition Examination Survey (NHANES III). This 7-year retrospective analysis examined the occurrence of renal impairment among a representative sample of the U.S. population (n = 18,723), and used these data to project the probable prevalence of CRI in the United States. Results were categorized on the basis of serum creatinine levels and revealed an estimated population of 6,200,000 patients with a serum creatinine of 1.5 mg/dL or higher (Jones, et al., 1998).

The Anemia of CRI

Anemia is a characteristic manifestation of CRI. In normal individuals, hypoxia signals the kidneys to secrete the natural hormone erythropoietin, thereby stimulating the hematopoietic cascade responsible for the production of red blood cells. In patients with CRI, the diseased kidneys are typically unable to secrete an appropriate quantity of erythropoietin, and a normocytic, normochromic anemia results--decreased production of erythropoietin parallels the deterioration in renal function. Other factors may also contribute to the severity of anemia in CRI, including: (at a shortened life span for red blood cells, (b) iron or other nutritional deficiencies, (c) uremic inhibitors, and (d) etiologies such as infection and inflammation that can inhibit normal red cell development (Remuzzi & Rossi, 1996).

No clear definition of anemia in patients with CRI has been established. In other fields of medicine, anemia is identified when hemoglobin (Hb) levels are below the physiological normal ranges of 13 to 16 g/dL in men and 12 to 14 g/dL in women (Remuzzi & Rossi, 1996). In dialysis patients, a comprehensive review of the benefits associated with higher Hb levels by the National Kidney Foundation's Kidney Disease Outcomes Quality, Initiative (K/DOQI) Anemia Work Group resulted in a recommended target Hb range of 11 to 12 g/dL (National Kidney Foundation, 1997). Studies are underway to establish a clear target Hb range for patients with CRI. Although anemia in patients with early CRI may be asymptomatic, our experience has demonstrated that patients often report being cold and fatigued. Our practice initiates therapy with an erythropoietic stimulant for any CRI patient who presents with a Hb less than 10 g/dL (Hct 30%).

Anemia is known to develop early in the course of CRI--well before the need for renal replacement therapy (Levin, 1999). The overriding prevalence of anemia in patients with CRI was demonstrated in a retrospective analysis of factors associated with suboptimal care before initiation of dialysis in the United States (n = 131,484). In this study, 68% of patients had hematocrit (Hct) levels less than 30% immediately before starting dialysis; 51% had Hct values below 28%. Overall, only 23% of patients were receiving Epoetin (recombinant human erythropoietin) therapy before they began dialysis; Epoetin had not been prescribed for 80% of patients whose Hct level was less than 28% (Figure 2) (Obrador, Ruthazer, Arora Kausz, & Pereira, 1999). (3)

Adverse Sequelae of the Anemia of CRI

The anemia of CRI can have debilitating effects that compromise quality of life and are associated with significant morbidity and mortality. Manifestations of anemia are apparent throughout the body and have historically been attributed to progressive kidney disease and uremia. Evidence, however, demonstrates that anemia is partially or wholly responsible for these symptoms (Besarab, 1997).

Commonly cited manifestations of anemia include lethargy, weakness, increased angina, shortness of breath, and impairments in cognitive function and exercise tolerance (National Kidney Foundation, 2001). Several studies have shown an association between anemia and the risk for future hospitalization. In a retrospective study of 362 patients with CRI conducted by Holland and Lain (2000), the presence of anemia independently predicted hospitalization; that is, patients with anemia were hospital-free for a median of 13.3 months, compared with 21.5 months for those with higher Hb levels.

A growing body of evidence also indicates that anemia is independently associated with an increase in mortality in patients who progress from CRI to ESRD. The National Kidney Foundation's DOQI Anemia Workgroup reviewed the literature for both CRI and dialysis patients and found that Hb levels less than 11 g/dL were associated with increased morbidity and mortality compared with higher Hb levels (National Kidney Foundation, 9001). Similarly, a large, retrospective, observational study of 75,983 patients showed an association between higher Hct levels and improved patient survival. The authors concluded that in a population of hemodialysis patients characterized during a 6-month entry period and then followed for a full year, there was an association between Hct level and survival. Patients whose Hct was maintained between 33% and 36% had the best chance of surviving into the next year. By comparison, patients whose Hct was less than 33% had a higher risk of all-cause and cardiac death (Mann, 1999).

LVH and Anemia

The relationship between LVH and anemia has been well documented. Hypertrophy of cardiac muscle develops in response to increased workloads, such as those caused by hypertension and anemia. Chronic anemia can cause a hyperdynamic state in which cardiac work and the cardiac index increase. When Hb and Hct decrease, there is a concomitant rise in cardiac output as the body attempts to increase tissue oxygenation. Over time, this perpetual overwork results in hypertrophy of the left ventricle (Silverberg, Blum, Peer, & Iaina, 1998)).

In a study of 175 patients with CRI by Levin and colleagues, each 1g/dL decrease in Hb increased the risk of LVH by 6% (Levin, Singer, Thompson, Ross, & Lewis, 1996). Similarly, a study reporting on 246 evaluable patients from a cohort of 446 patients with CRI found that for every 0.5 g/dL decrease in Hb, the relative risk of left ventricular growth increased by 32% (p = 0.004) (Levin, 1999).

LVH is a significant problem in the CRI population and appears to develop early in the course of the disease (Figure 3) (Levin, et al., 1996). A prospective cohort study conducted in Canada revealed LVH in 74% of patients just starting dialysis (n = 433) (Harnett, et al., 1995). Similarly, a study investigating the prevalence of comorbid conditions associated with CRI (n = 175) found that while the overall prevalence of LVH was about 40%, the prevalence rose as kidney function declined: (a) 26.7% of patients whose CrCl was higher than 50 mL/minute, (b) 30.8% of patients whose CrCl was 25 to 49 mL/minute, and (c) 45.2% of patients whose CrCl was less than 25 mL/minute (p = 0.05) (Levin, et al., 1996).

The effect of anemia on LVH has also been shown in patients who progress from CRI to ESRD. In an analysis of several studies, Mann (1999) reported that partial correction of anemia improves cardiac function and modifies the structure of the cardiovascular system. Results include a decrease in cardiac output and improvements in LVH, as demonstrated by decreases in mean LV end-diastolic diameter, end-systolic diameter, posterior wall thickness, and muscle mass index.

These data suggest that aggressive treatment of anemia is as important in the period before dialysis as during dialysis. The NIH observes that predialysis treatment of anemia may be critical to reduce cardiovascular morbidity and mortality, since complications such as long-standing LVH associated with anemia may be poorly reversible--or irreversible--if delayed until dialysis (National Institutes of Health, 1993).

Case Study

TK is a 69-year-old male with long-standing diabetes. The patient has been followed by his primary care physician, and is referred to the nephrology team for an assessment of kidney function. Laboratory parameters upon presentation include: (a) Hb = 9.5 g/dL (Hct [approximately equal to] 28.5%), (b) creatinine = 2.0 mg/dL, (c) calculated creatinine clearance = 35 mL/minute (using the Cockcroft-Gault formula), (d) 24-hour urine protein = 2.0 g/dL, (e) intact parathyroid hormone (iPTH) = 150 pg/mL, (f) calcium = 8.6 mg/dL, (g) phosphate = 3.3 pg/mL, (g) transferrin saturation = 29%, (h) serum ferritin = 255 ng/mL, and (h) blood pressure = 155/90 mmHg. The nurse assessed the patient's medication regimen and found that diabetes was being controlled by an oral sulfonylurea. Other medications included a diuretic, oral iron, and aspirin. Analysis of trends from previous laboratory tests revealed that kidney function had been declining progressively, with a corresponding deterioration in parameters measuring anemia and parathyroid function. The patient complained about easy fatiguability, especially on exertion, that he attributed to advancing age. Two-dimensional echocardiography revealed LVH, marked by an increase in the intraventricular septum and posterior wall thickness, and LV dilatation.

Discussion

This case describes a patient profile that is common upon presentation to the nephrology team, including: (a) a progressive decrease in renal function, (b) a decline in Hb levels that is affecting patient quality of life, (c) a deterioration in calcium/phosphate balance, and (d) an increase in iPTH levels. In this case, the patient was not receiving interventions to adequately control anemia, blood pressure, proteinurea, or the potential development of bone disease.

The case highlights the fact that failure to manage controllable etiologies such as anemia and high blood pressure early in the course of CRI can heighten the risk for comorbidities such as LVH, decreased exercise tolerance, and impaired quality-of-life. Studies have shown that timely, proactive, nephrology-directed, management of these etiologies can help reduce the risk for morbidity and mortality. However, early referral to the nephrology team is crucial to ensure optimal care. For example, one study that tracked mortality found that patients who died within the first year of dialysis were under a nephrologist's care for only 36 days (median) before the onset of renal replacement therapy. By comparison, in patients who survived more than 1 year, nephrologists had directed care for 30 months (median) (Innes, Rowe, Burden, & Morgan, 1992). In a similar study, medium- and high-risk patients with ESRD who had been referred early in the course of CRI had substantially better survival than those who were referred later in their illness (Khan, Catto, Edward, & MacLeod, 1994).

Several potential interventions can be enacted by the nephrology team to help improve the quality-of-care and mitigate the risks associated with disease progression, including: (a) establishing collaborative relationships with primary care physicians to ensure early evaluation, referral, and treatment of patients with CRI, (b) adapting screening methods that will help increase the likelihood of early identification of kidney disease, (c) following trends in laboratory values, and (d) treating conditions such as anemia and high blood pressure aggressively early in the course of CRI.

Conclusion

Anemia is a serious consequence of CRI associated with significant short- and long-term clinical and functional morbidities. Despite the preponderance of evidence, reports indicate that anemia is often underrecognized and undertreated in this population. Nephrology nurses and other team members should work closely with internists, primary care physicians, and other specialties that treat high-risk patients to provide education and mentoring that stress the importance of proactive and ongoing assessment of kidney function. Early, proactive, management of anemia, blood pressure, and other controllable etiologies associated with chronic kidney disease may decrease the incidence and severity of comorbdities, thereby improving long-term patient outcomes.
Table 1: Cockcroft-Gault Formula

Estimate of GFR in mL/min/1.73 [m.sup.2]

GFR = (140 - age) (weight in kilograms)/
72 x serum creatinine (in mg/dL) x (0.85 if female)

Figure 2: Percentage of Anemic CRI Patients (Hct <28%) Treated
with Epoetin (Obrador, et al. 1999)

treated with rHuEPO        20%

Not treated with rHuEPO    80%

Note: Table made from pie chart.

Figure 3: Prevalence of LVH in Patients with CRI
(Levin, et al. 1996)

CrCl >50      26.7

CrCl 25-49    30.8

CrCl <25      45.2

Categories of Renal Function: Creatitine Clearance (mL/min)

Note: Table made from bar graph.


Note: This article is supported by a financial grant from Amgen Inc. The manuscript has undergone an anonymous peer review. The information does not necessarily reflect the opinions of ANNA or the sponsor.

References

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Besarab, A., Bolton, W.K., Churchill, D.N., Fishbane, S., Foley R.N., Kausz, A., Kliger, A.S., Levin, A., Lindberg, J., Nissenson, A.R., Pereira, B.J.G., Sherman, R.A., & Stivelman, J.C., Zabetakis, P.M. (2000). Renal Anemia Management Period. Thousand Oaks, CA: Amgen Inc.

Harnett, J.D., Kent, G.M., Foley, R.N., & Parfrey, P.S. (1995). Cardiac function and hematocrit level. American Journal of Kidney Disease, 25:S3-S7.

Holland, D.C, & Lam ,M. (2000). Predictors of hospitalization and death among pre-dialysis patients: a retrospective cohort study. Nephrology, Dialysis, & Transplantation, 15:650-658.

Innes, A., Rowe, P.A., Burden, R.P., Morgan, A.G. (1992). Early deaths on renal replacement therapy: the need for early nephrological referral. Nephrology, Dialysis, & Transplantation, 467-471.

Jones, C.A., McQuillan, G.M., Kusek, J.W., Eberhardt, M.S., Herman, W.H., Coresh, J., Salive, M., Jones, C.P, & Agodoa, L.Y. (1998). Serum creatinine levels in the US population: third national health and nutrition examination study. American Journal of Kidney Disease, 32:992-999. Published erratum appears in American Journal of Kidney Disease, 2000:35:178.

Khan, I.H., Catto, G.R., Edward, N., & MacLeod, A.M. (1994). Chronic renal failure: factors influencing referral. Quarterly Journal of Medicine, 87:559-564.

Levey, A.S., Bosch, J.P., Lewis, J.B., Greene, T., Rogers, N., Roth, D. (1999). A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Annals of Internal Medicine, 130:461-470.

Levin, A. (1999). Anaemia in the patient with renal insufficiency: documenting the impact and reviewing the treatment strategies. Nephrology, Dialysis, & Transplantation, 14:292-296.

Levin, A., Singer, J., Thompson, C.R., Ross, H., & Lewis, M. (1996). Prevalent left ventricular hypertrophy in the predialysis population: identifying opportunities for intervention. American Journal of Kidney Disease, 27:347-354.

Mann, J.F.E. (1995). Hypertension and cardiovascular effects--long-term safety and potential long-term benefits of r-HuEPO. Nephrology, Dialysis, & Transplantation, 10:80-84.

McClellan, W.M., Knight, D.F., Karp, H., & Brown, W.W. (1997). Early detection and treatment of renal disease in hospitalized diabetic and hypertensive patients: important differences between practice and published guidelines. American Journal of Kidney Disease, 29:368-375.

National Institutes of Health. (1993). NIH Consensus Statement. Morbidity and Mortality of Dialysis. Bethesda, MD: National Institutes of Health: NIH Consensus Development Conference: Author.

National Institutes of Health. (1999). Healthy People 2010: Chronic Kidney Disease (4.3-4.26). Bethesda, MD: Author.

National Kidney Foundation. (2001). K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney Disease. American Journal of Kidney Disease, 37:S182-S238.

Obrador, G.T., Ruthazer, R., Arora, P., Kausz, A.T., & Pereira, B.J.G. (1999). Prevalence of and factors associated with suboptimal care before initiation of dialysis in the United States. Journal of the American Society of Nephrology, 10:1793-1800.

Obrador, G.T., Pereira, B.J.G. (1998). Early referral to the nephrologist and timely initiation of renal replacement therapy: a paradigm shift in the management of patients with chronic renal failure. American Journal of Kidney Disease, 31:398-417.

Pereira, B.J.G. (2000). Optimization of pre-ESRD care: the key to improved dialysis outcomes. Kidney International, 57:351-365.

Remuzzi, G., Rossi, E.C. (1996). Hematologic consequences of renal failure. In: Brenner, B.M., ed. The Kidney, 5th ed. (pp. 2171-2172). Philadelphia, PA: W.B. Saunders Company.

Silverberg, D., Blum, M., Peer, G., laina, A. (1998). Anemia during the predialysis period: a key to cardiac damage in renal failure. Nephron, 80:1-5.

Janice Bigger, RN, CNN, is a clinical nephrology nurse at Metrolina Nephrology in Gastonia, North Carolina. Data used in this article were based, in part, on the Renal Anemia Management Period Monograph (Besarab, et al., 2000).
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Title Annotation:Educational Supplement
Author:Bigger, Janice
Publication:Nephrology Nursing Journal
Date:Feb 1, 2001
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