Kristine S. Schonder
LEARNING OBJECTIVES
Upon completion of the chapter, the reader will be able to:
1. List the risk factors for development and progression of chronic kidney disease (CKD).
2. Explain the mechanisms associated with progression of CKD.
3. Outline the desired outcomes for treatment of CKD.
4. Develop a therapeutic approach to slow progression of CKD, including lifestyle modifications and pharmacologic therapies.
5. Identify specific consequences associated with CKD.
6. Design an appropriate therapeutic approach for specific consequences associated with CKD.
7. Recommend an appropriate monitoring plan to assess the effectiveness of pharmacotherapy for CKD and specific consequences.
8. Educate patients with CKD about the disease state, the specific consequences, lifestyle modifications, and pharmacologic therapies used for treatment of CKD.
KEY CONCEPTS
Chronic kidney disease (CKD) is a progressive disease that eventually leads to kidney failure (end-stage kidney disease [ESKD]).
Early detection and treatment of CKD are fundamental factors in minimizing morbidity and mortality associated with CKD.
Declining kidney function disrupts the homeostasis of the systems regulated by the kidney, leading to fluid and electrolyte imbalances, anemia, and metabolic bone disease.
Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers decrease protein excretion and are the drugs of choice for hypertension in patients with CKD.
The most common complication of CKD is anemia, which is caused by a decline in erythropoietin production by the kidneys and can lead to cardiovascular disease (CVD).
The goal of anemia management in CKD is to maintain hemoglobin levels between 11 g/dL (110 g/L or 6.8 mmol/L) and 12 g/dL (120 g/L or 7.4 mmol/L), which generally requires a combination of erythropoiesis-stimulating agents (ESAs) and iron supplements.
Bone and mineral metabolism disorders stem from disruptions in calcium, phosphorus, and vitamin D homeostasis through the interaction with the parathyroid hormone.
The management of secondary hyperparathyroidism (sHPT) involves correction of serum calcium and phosphorus levels, and decreasing parathyroid hormone secretion.
Patient education and planning for dialysis should begin at stage 4 CKD, before ESKD is reached, to allow for time to establish appropriate access for dialysis.
Dialysis involves the removal of metabolic waste products and excess fluids and electrolytes by diffusion and ultrafiltration from the bloodstream across a semipermeable membrane into an external dialysate solution.
The kidney is made up of approximately 2 million nephrons that are responsible for filtering, reabsorb-ing and excreting solutes and water. As the number of functioning nephrons declines, the primary functions of the kidney that are affected include:
• Production and secretion of erythropoietin
• Activation of vitamin D
• Regulation of fluid and electrolyte balance
• Regulation of acid–base balance
Chronic kidney disease (CKD), also known as chronic kidney insufficiency, progressive kidney disease, or nephropathy, is defined as the presence of kidney damage or decreased glomerular filtration rate (GFR) for 3 months or more.1 Generally, CKD is a progressive decline in kidney function (a decline in the number of functioning nephrons) that occurs over a period of several months to years. A decline in kidney function that occurs more rapidly, over a period of days to weeks, is known as acute kidney injury (AKI), which is discussed in Chapter 25. The decline in kidney function in CKD is often irreversible. Therefore, measures to treat CKD are aimed at slowing the progression to end-stage kidney disease (ESKD).
EPIDEMIOLOGY AND ETIOLOGY
The National Kidney Foundation (NKF) developed a classification system for CKD (Table 26–1).1 The staging system defines the stages of CKD based on GFR level, but also accounts for evidence of kidney damage in the absence of changes in GFR, as in stage 1 CKD. The GFR is calculated using the abbreviated Modification of Diet in Renal Disease study equation:
GFR = 186 × (SCr)–1.194 × (age)–0.214 × (0.742 if female) × (1.21 if African American)
Based on the National Health and Nutrition Examination Survey (NHANES) 2003 to 2006, the prevalence of CKD in the United States is 16%, corresponding to more than 31 million people.2 This number is increased from 12.8% reported with the previous NHANES report from 1988 to 1994,2 which is attributed to the increased prevalence of diabetes and hypertension, and the aging population.3
CKD is a progressive disease that eventually leads to ESKD. The prevalence of ESKD has increased more than fivefold since 1980 to more than 500,000 people in 2006 with nearly 111,000 new cases of ESKD diagnosed in 2006.2 The prevalence of ESKD is related to ethnicity, affecting 3.6 times more African Americans and 1.8 times more Native Americans as Caucasians.2
Table 26–1 NKF-K/DOQI Classification for CKD
This is likely because these ethnicities have increased risk and prevalence of the causes of CKD, including diabetes mellitus (DM) and hypertension, and other vascular diseases.1
Because of the progressive nature of CKD, determination of risk factors for CKD is difficult. Risk factors identified for CKD are classified into three categories (Table 26–2):
• Susceptibility factors, which are associated with an increased risk of developing CKD, but are not directly proven to cause CKD. These factors are generally not modifiable by pharmacologic therapy or lifestyle modifications.
• Initiation factors, which directly cause CKD. These factors are modifiable by pharmacologic therapy.
• Progression factors, which result in a faster decline in kidney function and cause worsening of CKD. These factors may also be modified by pharmacologic therapy or lifestyle modifications to slow the progression of CKD.
Susceptibility Factors
Susceptibility factors can be readily used to develop screening programs for CKD. For example, older patients, those with low kidney mass or birth weight, and those with a family history of kidney disease should be routinely screened for CKD. Minority and low socioeconomic communities may be targets for more widespread CKD screening programs. Other factors, such as hyperlipidemia, are not directly proven to cause CKD, but can be modified by drug therapies.
Hyperlipidemia
Patients with CKD have a higher prevalence of dyslipidemia compared to the general population. The dyslipidemia in CKD is manifested as an elevation in total cholesterol (TC) levels, low-density lipoprotein cholesterol (LDL-C) levels, triglycerides, and lipoprotein(a) levels, and decreases in high-density lipoprotein cholesterol (HDL-C) levels. The prevalence within the CKD population appears to be related somewhat to the degree of proteinuria. In nephrotic syndrome, with urine protein excretion rates that exceed 3 g/24 hour, almost all patients have some degree of dyslipidemia.4 Mounting evidence suggests that hyperlipidemia can promote kidney injury and subsequent progression of CKD. The mechanism is similar to that of atherosclerosis, whereby lipid deposition causes activation of macrophages and monocytes, which secrete growth factors that stimulate cell proliferation and oxidation of lipoproteins. These lead to endothelial dysfunction, cellular injury, and fibrosis in the kidney.5
Table 26–2 Risk Factors Associated With CKD
|
Susceptibility |
|
• Advanced age |
|
• Reduced kidney mass |
|
• Low birth weight |
|
• Racial/ethnic minority |
|
• Family history of kidney disease |
|
• Low income or education |
|
• Systemic inflammation |
|
• Dyslipidemia |
|
Initiation |
|
• Diabetes mellitus |
|
• Hypertension |
|
• Autoimmune disease |
|
• Polycystic kidney disease |
|
• Drug toxicity |
|
• Urinary tract abnormalities (infections, obstruction, stones) |
|
Progression |
|
• Hyperglycemia: Poor blood glucose control (in patients with diabetes) |
|
• Hypertension: Elevated blood pressure |
|
• Proteinuria |
|
• Tobacco smoking |
Initiation Factors
The three most common causes of CKD in the United States are DM, hypertension, and glomerulonephritis. Together these account for about 75% of the cases of CKD (37% for diabetes, 24% for hypertension, and 14% for glomerulonephritis).6 These are discussed in further detail below.
Diabetes
DM is the most common cause of CKD, causing 43% of all ESKD, which is increased from 13% in 1980.6 The risk of developing diabetic kidney disease (DKD) associated with DM is closely linked to hyperglycemia and is similar for both type 1 and type 2, although it is slightly higher in patients with type 2 DM.7 An estimated 3% of patients with DM will develop ESKD, which is 12 times greater than those without DM.8
Hypertension
The second most common cause of CKD is hypertension.6 It is more difficult to determine the true risk of developing CKD in patients with hypertension because the two are so closely linked, with CKD also being a cause of hypertension. The prevalence of hypertension is correlated with the degree of kidney dysfunction (decreased GFR) with 40% of patients with CKD stage 1, 55% of patients with CKD stage 2, and over 75% of patients with CKD stage 3 presenting with hypertension.1 The risk of developing ESKD is linked to both systolic and diastolic blood pressure.9 A blood pressure greater than 210/120 mm Hg is associated with a 22% increased relative risk of developing ESKD, compared with a blood pressure less than 120/80 mm Hg.9
Glomerulonephritis
The etiologic and pathophysiologic features of glomerular diseases vary with the specific disease, making it difficult to extrapolate the risk for progression of CKD in patients affected by glomerular diseases. Certain glomerular diseases are known to rapidly progress to ESKD, while others progress more slowly or may be reversible.
Progression Factors
Progression factors can be used as predictors of CKD. The most important predictors of CKD include proteinuria, elevated blood pressure, hyperglycemia, and tobacco smoking.
Proteinuria
The presence of protein in the urine is a marker of glomerular and tubular dysfunction and is recognized as an independent risk factor for the progression of CKD.10 Furthermore, the degree of proteinuria correlates with the risk for progression of CKD. An increase of 1 g of protein excretion per day is associated with a fivefold increase in the risk of progression of CKD, regardless of the cause of CKD.11 The mechanisms by which proteinuria potentiates CKD are discussed later. Microalbuminuria (greater than 30 mg albumin excreted per day) is also linked with vascular injury and increased cardiovascular mortality.12
Elevated Blood Pressure
Systemic blood pressure correlates with glomerular pressure and elevations in both systemic blood pressure and glomerular pressure contribute to glomerular damage. The rate of GFR decline is related to elevated systolic blood pressure and mean arterial pressure. The decline in GFR is estimated to be 14 mL/min per year with a systolic blood pressure of 180 mm Hg. Conversely, the decline in GFR decreases to 2 mL/min per year with a systolic blood pressure of 135 mm Hg.13
Elevated Blood Glucose
The reaction between glucose and protein in the blood produces advanced glycation end products (AGEs), which are metabolized in the proximal tubules. Hyperglycemia increases the synthesis of AGEs in patients with diabetes and the corresponding increase in metabolism is suspected to be a cause of DKD.14
Tobacco Smoking
Smoking is an independent risk factor for the development of microalbuminuria in primary hypertension. In patients with CKD, smoking is also an independent and dose-dependent risk factor for development of CKD and microalbuminuria, and progression to ESKD.15 The risk is more pronounced in men compared to women (odds ratio [OR] 3.59), independent of other risk factors.15 Smoking increases the risk for progression to ESKD in patients with CKD from any cause, and can increase the risk as much as 10-fold, compared to nonsmokers.15
The effects of smoking on the kidney are multifactorial and occur in both healthy individuals and those with CKD. Smoking induces intimal thickening and hyperplasia of the glomerulus, and raises systemic blood pressure.15Similar effects were seen with chewing tobacco. These effects are related to the amount of nicotine exposure.15
PATHOPHYSIOLOGY
A number of factors can cause initial damage to the kidney. The resulting sequelae, however, follow a common pathway that promotes progression of CKD and results in irreversible damage leading to ESKD (Fig. 26–1).
The initial damage to the kidney can result from any of the initiation factors listed in Table 26–2. Regardless of the cause, however, the damage results in a decrease in the number of functioning nephrons. The remaining nephrons hypertrophy to increase glomerular filtration and tubular function, both reabsorption and secretion, in attempt to compensate for the loss of kidney function. Initially, these adaptive changes preserve many of the clinical parameters of kidney function, including creatinine and electrolyte excretion. However, as time progresses, angiotensin II is required to maintain the hyperfiltration state of the functioning nephrons. Angiotensin II is a potent vasoconstrictor of both the afferent and efferent arterioles, but has a preferential effect to constrict the efferent arteriole, thereby increasing the pressure in the glomerular capillaries. Increased glomerular capillary pressure expands the pores in the glomerular basement membrane, altering the size-selective barrier and allowing proteins to be filtered through the glomerulus.16
Protein excretion through the nephron, or proteinuria, increases nephron loss through various complex mechanisms. Filtered proteins are reabsorbed in the renal tubules, which activates the tubular cells to produce inflammatory and vasoactive cytokines and triggers complement activation.16 These cytokines cause interstitial damage and scarring in the renal tubules, leading to damage and loss of more nephrons. Ultimately, the process leads to progressive loss of nephrons to the point where the number of remaining functioning nephrons is too small to maintain clinical stability, and kidney function declines.
ASSESSMENT
Because CKD often presents without symptoms, assessment for CKD relies on appropriate screening strategies in all patients with risk factors for developing CKD (Table 26–2). Evaluation for CKD and the subsequent treatment strategies are dependent on the diagnosis, comorbid conditions, severity and complications of disease, and risk factors for the progression of CKD. Early treatment of CKD and the associated complications of CKD are the most important factors to decrease morbidity and mortality associated with CKD. However, the probability of patients not diagnosed with CKD to have an assessment of serum creatinine (SCr) or urine protein excretion ranges from 0.01 to 0.04, depending on insurance coverage.17 Screening for CKD should be performed in all people with an increased risk for developing CKD, including patients with DM, hypertension, genitourinary abnormalities, autoimmune disease, increased age, or a family history of kidney disease. The assessment for CKD should include measurement of SCr, urinalysis, blood pressure, serum electrolytes, and/or imaging studies.
FIGURE 26–1. Proposed mechanisms for progression of kidney disease. (From Joy MS, Kshirsagar A, Franceschini N. Chronic kidney disease: Progression-modifying therapies. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: McGraw-Hill; 2008: 749, with permission.)
The primary marker of structural kidney damage is proteinuria, even in patients with normal GFR. Clinically significant proteinuria is defined as urinary protein excretion greater than 300 mg/day or greater than 20 mcg/min in a timed urine collection. Significant proteinuria can also be determined by a spot urine dipstick greater than 30 mg/dL or a urine protein/creatinine ratio greater than 200 mg/g.1Microalbuminuria is defined as 30 to 300 mg of albumin excreted in the urine per day or a urine albumin/creatinine ratio greater than 30 mg/day.1 The NKF recommends routine assessment of proteinuria to detect CKD. A urine dipstick positive for the presence of protein warrants quantification of proteinuria. Patients with a urine protein/creatinine ratio greater than 200 mg/g or urine albumin/creatinine ratio greater than 30 mg/g should undergo diagnostic evaluation; patients with values below these levels should be reevaluated routinely.1 Assessment of microalbuminuria is particularly important in patients with DM. Screening for microalbuminuria should be performed 5 years after the diagnosis of type 1 DM and at the time of diagnosis of type 2 DM.18
Other markers for structural kidney damage that can be used in place of proteinuria include abnormalities in urinary sediment, such as hematuria, or abnormalities in imaging studies or kidney biopsy.1
Complications
The decline in kidney function is associated with a number of complications, which will be discussed later in the chapter, including:
• Fluid and electrolyte disorders
• Anemia
• Metabolic bone disease
TREATMENT
Desired Outcomes
The primary goal is to slow and prevent the progression of CKD. This requires early identification of patients at risk for CKD to initiate interventions early in the course of the disease.
Clinical Presentation and Diagnosis of CKD
General
The development of CKD is usually subtle in onset, often with no noticeable symptoms.
Symptoms
Stages 1 and 2 CKD are generally asymptomatic.
Stages 3 and 4 CKD may be associated with minimal symptoms.
Stage 5 CKD can be associated with pruritus, dysgeusia, nausea, vomiting, constipation, muscle pain, fatigue, and bleeding abnormalities.
Signs
Cardiovascular: Worsening hypertension, edema, dyslipidemia, left ventricular hypertrophy, electrocardiographic changes and chronic heart failure.
Musculoskeletal: Cramping.
Neuropsychiatric: Depression, anxiety, impaired mental cognition.
GI: Gastroesophageal reflux disease, GI bleeding, and abdominal distention.
Genitourinary: Changes in urine volume and consistency, “foaming” of urine (indicative of proteinuria), and sexual dysfunction.
Laboratory Tests
Stages 1 and 2 CKD: Increased blood urea nitrogen (BUN) and serum creatinine (SCr) and decreased GFR.
Stages 3, 4, and 5 CKD: Increased BUN and SCr; decreased GFR.
Advanced stages: Increased potassium, phosphorus, and magnesium; decreased bicarbonate (metabolic acidosis); calcium levels are generally low in earlier stages of CKD and may be elevated in stage 5 CKD, secondary to the use of calcium-containing phosphate binders.
Decreased albumin, if inadequate nutrition intake in advanced stages.
Decreased red blood cell (RBC) count, hemoglobin (Hgb) and hematocrit (Hct); iron metabolism may also be altered (iron level, total iron binding capacity [TIBC], serum ferritin level, and transferrin saturation [TSAT]). Erythropoietin levels are not routinely monitored and are generally normal to low. Urine positive for albumin or protein.
Increased parathyroid hormone (PTH) level; decreased vitamin D levels (stages 4 or 5 CKD).
Stool may be Hemoccult-positive if GI bleeding occurs from uremia.
Other Diagnostic Tests
Structural abnormalities of kidney may be present on diagnostic exams.
Nonpharmacologic Therapy
Nutritional Management
Reduction in dietary protein intake has been shown to slow the progression of kidney disease.10 However, protein restriction must be balanced with the risk of malnutrition in patients with CKD. Patients with a GFR less than 25 mL/min/1.73 m2 received the most benefit from protein restriction;10 therefore, patients with a GFR above this level should not restrict protein intake. The NKF recommends that patients who have a GFR less than 25 mL/min/1.73 m2 who are not receiving dialysis, however, should restrict protein intake to 0.6 g/kg/day. If patients are not able to maintain adequate dietary energy intake, protein intake may be increased up to 0.75 g/kg/day.19 Malnutrition is common in patients with ESKD for various reasons, including decreased appetite, hypercatabolism, and nutrient losses through dialysis. For this reason, patients receiving dialysis should maintain protein intake of 1.2 g/kg/day to 1.3 g/kg/day.
Protein intake can have unique contributions to kidney damage in patients with DM. Dietary protein, particularly protein from animal sources, produces AGEs, which are an important cause of kidney damage in patients with DM.20 The NKF recommends that patients with DM with CKD stages 1 to 4 should limit protein intake to 0.8 g/kg/day to reduce proteinuria and stabilize kidney function.18
Pharmacologic Therapy
Intensive Blood Glucose Control (for Patients With Diabetes)
The target glycosylated hemoglobin level (HbA1c) should be less than 7.0% (0.07) for patients with DM to decrease the incidence of proteinuria and albuminuria in patients with and without documented DKD.18 This generally involves intensive insulin therapy, the administration of insulin three or more times daily to maintain preprandial blood glucose levels between 70 and 120 g/dL (3.9–6.7 mmol/L) and postprandial blood glucose levels less than 180 g/dL (10 mmol/L). This strategy has been proven to be effective in delaying the development and progression of DKD in patients with type 121 and type 2 DM.18 Continued benefits of intensive insulin therapy have been demonstrated up to 8 years in patients with type 1 DM.21 A decrease in HbA1c levels by 0.9% (0.009) has been shown to decrease the relative risk for microalbuminuria by 30% in patients with type 2 DM.22
Optimal Blood Pressure Control
Reductions in blood pressure are associated with a decrease in proteinuria, leading to a decrease in the rate of progression of kidney disease. The NKF recommends a goal blood pressure of less than 130/80 mm Hg in patients with stages 1 through 4 CKD.23
In patients with stage 5 CKD who are receiving hemodi-alysis, cardiovascular mortality is affected by blood pressure levels both before and after hemodialysis.24 Elevated blood pressure levels after hemodialysis increases cardiovascular risk. Both systolic blood pressure greater than 180 mm Hg and diastolic blood pressure greater than 90 mm Hg are independently associated with an increased risk of cardiovascular mortality (relative risk 1.96 and 1.73, respectively).24 Likewise, low blood pressure levels either before or after hemodialysis are also ass ociated with increased cardiovascular mortality. A systolic blood pressure less than 110 mm Hg before hemodialysis is associated with a four-fold increase in cardiovascular mortality; the same blood pressure at the end of hemodialysis is associated with a 2.62 relative risk.24 Therefore, the NKF recommends achieving a goal blood pressure less than 140/90 mm Hg before hemodialysis and less than 130/80 mm Hg after hemodialysis.25 These goals are controversial, however. One recent study demonstrated an increased risk of mortality for patients who achieved the target blood pressure recommended by the guidelines (hazards ratio 1.9).26
Because hypertension and kidney dysfunction are linked, blood pressure control can be more difficult to attain in patients with CKD compared to patients with normal kidney function. All antihypertensive agents have similar effects on reducing blood pressure. However, three or more agents are generally required to achieve the blood pressure goal of less than 130/80 mm Hg in CKD patients.23
Reduction in Proteinuria
The ability of antihypertensive agents to preserve kidney function differs. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) decrease glomerular capillary pressure and volume because of their effects on angiotensin II. This, in turn, reduces the amount of protein filtered through the glomerulus, independent of the reduction in blood pressure,27 which ultimately decreases the progression of CKD. The ability of ACEIs and ARBs to reduce proteinuria is greater than that of other antihypertensives, up to 35% to 40%,23 making ACEIs and ARBs the antihypertensive agents of choice for all patients with CKD, unless contraindicated. All patients with documented proteinuria should receive an ACE-I or ARB, regardless of blood pressure.23 Because diabetes is associated with an early onset of microalbuminuria, all patients with diabetes should also receive an ACE-I or ARB, regardless of blood pressure.23 When initiating ACE-I or ARB therapy, the dose should be titrated to the maximum tolerated dose, even if the blood pressure is less than 130/80 mm Hg. Figure 26–2 depicts an algorithm for the treatment of hypertension in patients with CKD. Patients who do not achieve adequate reductions in blood pressure or protein excretion may benefit from combination therapy with an ACE-I and an ARB.23 However, the benefits of combination therapy have been questioned by recent studies. Several large clinical trials have demonstrated that combination therapy with an ACE-I and ARB has been demonstrated to reduce proteinuria more than maximal doses of either agent alone.28,29 However, one study discovered that progression of kidney disease was worsened with combination therapy compared to either agent alone.28
FIGURE 26–2. Hypertension management algorithm for patients with CKD. Dosage adjustments should be made every 2 to 4 weeks as needed. The dose of one agent should be maximized before another is added. (ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; B P, blood pressure; CrCl, creatinine clearance; K, potassium; Scr, serum creatinine.) (From Joy MS, Kshirsagar A, Franceschini N. Chronic kidney disease: Progression-modifying therapies. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: McGraw-Hill; 2008: 752, with permission.)
The nondihydropyridine calcium channel blockers (CCBs) have been shown to also decrease protein excretion in patients with and without diabetes,30 but the reduction in proteinuria appears to be related to the reductions in blood pressure. The maximal effect of nondihydropyridine CCBs on proteinuria is seen with a blood pressure reduction to less than 130/80 mm Hg and no additional benefit is seen with increased doses. Dihydropyridine CCBs, however, do not have the same effects on protein excretion. In fact, dihydropyridine CCBs worsen protein excretion, despite similar reductions in blood pressure as nondihydropyridine CCBs.30
Other Interventions to Limit Progression of CKD
Hyperlipidemia Treatment
Hyperlipidemia plays a role in the development of cardiovascular disease (CVD) in patients with CKD. The primary goal of treatment of dyslipidemias is to decrease the risk of atherosclerotic CVD. A secondary goal in patients with CKD is to reduce proteinuria and decline in kidney function. Treatment of hyperlipidemia in patients with CKD has been demonstrated to slow the decline in GFR by 1.9 mL/min per year of treatment with antihyperlipidemic agents.31
The NKF suggests that CKD should be classified as a coronary heart disease (CHD) risk equivalent and the goal LDL-C level should be below 100 mg/dL (2.59 mmol/L) in all patients with CKD.25,32 The most frequently used agents for the treatment of dyslipidemias in patients with CKD are the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (“statins”) and the fibric acid derivatives. However, other treatments have been studied in patients with CKD and should be considered if first-line therapies are contraindicated.
Another important consideration in treating lipid disorders in patients with CKD is management of proteinuria. Protein excretion in the nephrotic range (greater than 3 g/day) is associated with an increase in both total and LDL-C levels.33 Triglyceride levels can also be elevated in patients with severe proteinuria. Results from clinical trials suggest that the use of ACEIs to reduce proteinuria can decrease TC levels.34 While the use of ACEIs is unlikely to decrease cholesterol to goal levels, reducing proteinuria can aid in cholesterol reduction, particularly in patients with nephrotic syndrome or severe proteinuria. Conversely, treatment of hyperlipidemia can reduce protein excretion and subsequent progression of CKD.4
Smoking Cessation
While the effects of smoking on the development and progression of CKD are well established, as discussed previously, t he effect of smoking cessation on CKD progression has not been studied. Data are emerging that suggest that smoking cessation may be a practical approach to slow the progression of CKD. Smoking cessation has been shown to reduce the risk of myocardial infarction by 50% to 70%, regardless of previous nicotine exposure.15 However, smoking cessation does not reverse existing kidney dysfunction in former smokers.
Anemia Treatment
Anemia decreases oxygen delivery to the renal tubules, promoting the release of inflammatory and vasoactive cytokines, which contribute to the progression of CKD. Treatment of anemia in patients with CKD reduces the cardiovascular effects of anemia and has been demonstrated to decrease morbidity and mortality by as much as 20%.35 Studies have demonstrated that treatment of anemia may slow the progression of CKD.36 The management of anemia will be discussed later.
Outcome Evaluation
Monitor SCr and potassium levels and blood pressure within 1 week after initiating ACE-I or ARB therapy. Discontinue the medication and switch to another agent if a sudden increase in SCr greater than 30% occurs, hyperkalemia develops, or the patient becomes hypotensive. Titrate the dose of the ACE-I or ARB every 1 to 3 months to the maximum tolerable dose. If blood pressure is not reduced to less than 130/80 mm Hg, add another agent to the regimen. Refer the patient to a nephrologist to manage complications associated with CKD. As CKD progresses to stage 4, begin discussion to prepare the patient for renal replacement therapy (RRT).
Patient Encounter, Part 1
A 62-year-old obese Caucasian female with a history of diabetes and hypertension presents to clinic for routine follow-up. Her fasting blood sugars have been elevated recently, averaging 180 to 250 mg/dL (10–13.9 mmol/L).
PMH: Diabetes mellitus for 8 years, not currently controlled; hypertension for 5 years, not currently controlled; hyperlipidemia, currently managed by diet therapy
FH: Mother is alive at age 87 with coronary artery disease; father is deceased from diabetes; she has no siblings
SH: She does not work; she smokes one pack of cigarettes per day, but denies alcohol or illicit drug use; she is sedentary
Meds: Furosemide 20 mg orally daily; nifedipine XL 30 mg orally daily; glyburide 10 mg orally daily
ROS: Unremarkable
PE:
VS: BP 145/92 mm Hg, P 82 bpm, T 36.9°C (98.4°F), ht 5′4′ (163 cm), wt 86.4 kg (190 lb)
CV: RRR, normal S1, S2; no murmurs, rubs or gallops; lungs clear
Abd: Obese; no organomegaly, bruits or tenderness, (+) bowel sounds; heme (−) stool
Exts: Trace pedal edema bilaterally; decreased sensation in feet to light touch; no lesions
Labs (Fasting): Sodium 145 mEq/L (145 mmol/L); potassium 3.2 mEq/L (3.2 mmol/L); chloride 112 mEq/L (112 mmol/L); carbon dioxide 26 mEq/L (26 mmol/L); blood urea nitrogen (BUN) 20 mg/dL (7.14 mmol/L urea); serum creatinine (SCr) 1.4 mg/dL (124 μmol/L); glucose 240 mg/dL (13.32 mmol/L); total cholesterol 196 mg/dL (5.07 mmol/L); low-density lipoprotein cholesterol (LDL-C) 112 mg/dL (2.90 mmol/L); high-density lipoprotein cholesterol (HDL-C) 28 mg/dL (0.72 mmol/L); triglycerides 280 mg/dL (3.16 mmol/L); hemoglobinA1C (HbA1C) 10% (0.1); urine microalbumin 270 mg/dL (2.7 g/L)
What risk factors does the patient have for the development of CKD?
What signs and symptoms are consistent with CKD?
How would you classify her CKD?
Identify your treatment goals for the patient.
What lifestyle modifications would you recommend for this patient with CKD?
What pharmacologic alternatives are available for this patient for treatment of CKD?
What other interventions are appropriate to minimize the progression of CKD?
CONSEQUENCES OF CKD AND ESKD
Impaired Sodium and Water Homeostasis
Sodium and water balance are primarily regulated by the kidney. Reductions in the number of functioning nephrons decrease glomerular filtration and subsequent reabsorption of sodium and water, leading to edema.
Pathophysiology
Sodium and water balance can be maintained despite wide variations in intake with normal kidney function. The fractional excretion of sodium (FENa) is approximately 1% to 3% with normal kidney function, allowing sodium balance to be maintained with a sodium intake of 120 to 150 mEq (120–150 mmol) per day. Urine osmolality can range from 50–1,200 mOsm/L (50 to 1,200 mmol/L) with normal kidney function, allowing for water balance to be maintained with a wide range of fluid intake. As the number of functioning nephrons decreases, the remaining nephrons increase sodium excretion and FENa may increase up to 10% to 20%.37 This produces an osmotic diuresis which impairs the ability of the kidneys to concentrate and dilute urine and the urine becomes fixed at an osmolality close to that of the plasma, approximately 300 mOsm/L (300 mmol/L). The inability of the kidney to concentrate the urine results in nocturia in patients with CKD, usually presenting as early as stage 3 CKD.
Clinical Presentation and Diagnosis of Impaired Sodium and Water Homeostasis
General
Alterations in sodium and water balance in CKD manifests as increased edema.
Symptoms
Nocturia can present in stage 3 CKD.
Edema generally presents in stage 4 CKD or later.
Signs
Cardiovascular: Worsening hypertension, edema
Genitourinary: Change in urine volume and consistency
Laboratory Tests
Increased blood pressure
Sodium levels remain within the normal range
Urine osmolality is generally fixed at 300 mOsm/L (300 mmol/L)
As the number of functioning nephrons continues to decline, the sodium load overwhelms the remaining nephrons and total sodium excretion is decreased, despite the increase in sodium excretion by the functioning nephrons. Sodium retention causes fluid retention that increases intravascular volume and raises systemic blood pressure. Severe volume overload can lead to pulmonary edema.
Treatment
Nonpharmacologic Therapy
The kidney is unable to adjust to abrupt changes in sodium intake in patients with severe CKD. Therefore, patients should be advised to refrain from adding salt to their diet, but should not restrict sodium intake. Changes in sodium intake should occur slowly over a period of several days to allow adequate time for the kidney to adjust urinary sodium content. Sodium restriction produces a negative sodium balance, which causes fluid excretion to restore sodium balance. The resulting volume contraction can decrease perfusion of the kidney and hasten the decline in GFR. Saline-containing IV solutions should be used cautiously in patients with CKD because the salt load may precipitate volume overload.
Fluid restriction is generally unnecessary as long as sodium intake is controlled. The thirst mechanism remains intact in CKD to maintain total body water and plasma osmolality near normal levels. Fluid intake should be maintained at the rate of urine output to replace urine losses, usually fixed at approximately 2 L/day as urine concentrating ability is lost. Significant increases in free water intake orally or IV can precipitate volume overload and hyponatremia. Patients with stage 5 CKD require RRT to maintain normal volume status. Fluid intake is often limited in patients receiving hemodialysis to prevent fluid overload between dialysis sessions.
Pharmacologic Therapy
Diuretic therapy is often necessary to prevent volume overload in patients with CKD in those who still produce urine. Loop diuretics are most frequently used to increase sodium and water excretion. Thiazide diuretics are ineffective when used alone in patients with a GFR less than 30 mL/min/1.73 m2.23,38 As CKD progresses, higher doses, as much as 80 to 1,000 mg/day of furosemide, or continuous infusion of loop diuretics may be needed, or combination therapy with loop and thiazide diuretics to increase sodium and water excretion.23,38
Outcome Evaluation
Monitor edema after initiation of diuretic therapy. Monitor fluid intake to ensure obligatory losses are being met and avoid dehydration. If adequate diuresis is not attained with a single agent, consider combination therapy with another diuretic.
Impaired Potassium Homeostasis
Potassium balance is also primarily regulated by the kidney via the distal tubular cells. Reduction in the number of functioning nephrons decreases the overall tubular secretion of potassium, leading to hyperkalemia. Hyperkalemia is estimated to affect more than 50% of patients with stage 5 CKD.39
Pathophysiology
The distal tubules secrete 90% to 95% of the daily dietary intake of potassium. The fractional excretion of potassium (FEK) is approximately 25% with normal kidney function.40 The GI tract excretes the remaining 5% to 10% of dietary potassium intake. Following a large potassium load, extracellular potassium is shifted intracellularly to maintain stable extracellular levels.
As the number of functioning nephrons decreases, both the distal tubular secretion and GI excretion are increased in the functioning nephrons because of aldosterone stimulation. Functioning nephrons increase FEK up to 100% and GI excretion increases as much as 30% to 70% in CKD,41 as a result of aldosterone secretion in response to increased potassium levels.41 This maintains serum potassium concentrations within the normal range through stages 1 to 4 CKD. Hyperkalemia begins to develop when GFR falls below 20% of normal, when the number of functioning nephrons and renal potassium secretion is so low that the capacity of the GI tract to excrete potassium has been exceeded.41
Medications can increase the risk of hyperkalemia in patients with CKD, including ACE-I and ARBs, used for the treatment of proteinuria and hypertension. Potassium-sparing diuretics, used for the treatment of edema and chronic heart failure, can also exacerbate the development of hyperkalemia, and should be used with caution in patients with stage 3 CKD or higher.
Treatment
Nonpharmacologic Therapy
Patients with CKD should avoid abrupt increases in dietary intake of potassium because the kidney is unable to increase potassium excretion with an acute potassium load, particularly in latter stages of the disease. Hyperkalemia resulting from an acute increase in potassium intake can be more severe and prolonged. Patients who develop hyperkalemia should restrict dietary intake of potassium to 50 to 80 mEq (50–80 mmol) per day. Potassium concentrations can also be altered in the dialysate for patients receiving hemodialysis and peritoneal dialysis to manage hyperkalemia. Because GI excretion of potassium plays a large role in potassium homeostasis in patients with stage 5 CKD, a good bowel regimen is essential to minimize constipation, which can occur in 40% of patients receiving hemodialysis.40 Severe hyperkalemia is most effectively managed by hemodialysis.
Pharmacologic Therapy
Patients with acute hyperkalemia usually require other therapies to manage hyperkalemia until dialysis can be initiated. Patients who present with hyperkalemia-induced cardiac abnormalities, which manifest as peaked T waves, a widened QRS complex or loss of P waves, should receive calcium gluconate or chloride (1 g IV) to reverse the cardiac effects. Temporary measures can be employed to shift extracellular potassium into the intracellular compartment to stabilize cellular membrane effects of excessive serum potassium levels. Such measures include the use of regular insulin (5–10 units IV) and dextrose (5–50% IV), or nebulized albuterol (salbutamol) (10–20 mg). Sodium bicarbonate should not be used to shift extracellular potassium intracellularly in patients with CKD unless severe metabolic acidosis (pH less than 7.2) is present. These measures will decrease serum potassium levels within 30 to 60 minutes after treatment, but potassium must still be removed from the body. Shifting potassium to the intracellular compartment, however, decreases potassium removal by dialysis. Often, multiple dialysis sessions are required to remove potassium that is redistributed from the intracellular space back into the serum.
Clinical Presentation and Diagnosis of Hyperkalemia
General
Hyperkalemia is generally asymptomatic in patients with CKD until serum potassium levels are greater than 5.5 mEq/L (5.5 mmol/L), when cardiac abnormalities present
Symptoms
Mild hyperkalemia is generally not associated with overt symptoms
Symptoms generally appear in stage 4 or 5 CKD
Signs
Cardiovascular: ECG changes (peaked T waves, widened QRS complex, loss of P wave)
Laboratory Tests
Increased serum potassium levels
Sodium polystyrene sulfonate (SPS, 15–30 gorally or rectally), a sodium-potassium exchange resin, promotes potassium excretion from the GI tract. The onset of action is within 2 hours after administration of SPS, but the maximum effect on potassium levels may not be seen for up to 6 hours, which limits the utility in patients with severe hyperkalemia. Of note, loop diuretics are often used to decrease potassium levels in patients with normal or mildly decreased kidney function, but are not useful in patients with stage 5 CKD to decrease potassium concentrations. Fludrocortisone is a mineralocorticoid that mimics the effects of aldosterone and increases potassium excretion in the distal tubules and through the GI tract. However, fludrocortisone causes significant sodium and water retention, which exacerbates edema and hypertension, and may not be tolerated by many CKD patients.
Outcome Evaluation
Monitor ECG continuously in patients with cardiac abnormalities until serum potassium levels drop below 5 mEq/L (5 mmol/L) or cardiac abnormalities resolve. Evaluate serum potassium and glucose levels within 1 hour in patients who receive insulin and dextrose therapy. Evaluate serum potassium levels within 2 to 4 hours after treatment with SPS or diuretics. Repeat doses of diuretics or SPS if necessary until serum potassium levels fall below 5 mEq/L (5 mmol/L). Monitor blood pressure and serum potassium levels in 1 week in patients who receive fludrocortisone.
Anemia of CKD
The progenitor cells of the kidney produce 90% of the hormone erythropoietin (EPO), which stimulates red blood cell (RBC) production. Reduction in the number of functioning nephrons decreases renal production of EPO, which is the primary cause of anemia in patients with CKD. The development of anemia of CKD results in decreased oxygen delivery and utilization, leading to increased cardiac output and left ventricular hypertrophy (LVH), which increase the cardiovascular risk and mortality in patients with CKD.
Epidemiology and Etiology
Current NKF guidelines define anemia as a hemoglobin (Hgb) level less than 13.5 g/dL (135 g/L or 8.37 mmol/L) in males and less than 12 g/dL (120 g/L or 7.4 mmol/L) in females.42 A number of factors can contribute to the development of anemia, including deficiencies in vitamin B12 or folate, hemolysis, bleeding, or bone marrow suppression. Many of these can be detected by alterations in RBC indices, which should be included in the evaluation for anemia. A complete blood cell count is also helpful in evaluating anemia to determine overall bone marrow function.
The prevalence of anemia correlates with the degree of kidney dysfunction. More than 26% of patients with a GFR greater than 60 mL/min/1.73 m2 are estimated to have Hgb levels less than 12 g/dL (120 g/L or 7.4 mmol/L), and the number increases to 75% in patients with a GFR less than 15 mL/min/1.73 m2.43 The risk of developing anemia also increases as GFR declines, doubling for patients with stage 3 CKD, increasing to 3.8-fold in patients with stage 4 CKD, and to 10.5-fold for patients with stage 5 CKD, compared to stages 1 and 2 CKD.43
Pathophysiology
The primary cause of anemia in patients with CKD is a decrease in EPO production. With normal kidney function, as Hgb, hematocrit (Hct), and tissue oxygenation decrease, the plasma concentration of EPO increases exponentially. As the number of functioning nephrons decrease, EPO production also decreases. Thus, as Hgb, Hct, and tissue oxygenation decrease in patients with CKD, plasma EPO levels remain constant within the normal range, but low relative to the degree of hypoxia present. The result is a normochromic, normocytic anemia.
Several other factors also contribute to the development of anemia in patients with CKD. Uremia, the accumulation of toxins that results from declining kidney function, decreases the lifespan of RBCs from a normal of 120 days to as low as 60 days in patients with stage 5 CKD. Iron deficiency and blood loss from regular laboratory testing and hemodialysis also contribute to the development of anemia in patients with CKD.
Patient Encounter, Part 2
The patient returns to your clinic 2 years later with complaints of “feeling tired all of the time.” She had been trying to exercise more, but has not had enough energy to exercise for the past 6 months or so. She also complains that she feels cold all of the time, despite increasing the temperature in her house.
Current Meds: Furosemide 80 mg orally daily; lisinopril 40 mg orally daily; metoprolol tartarate 50 mg orally twice daily; insulin glargine 25 units subcutaneously at bedtime; insulin lispro subcutaneously per sliding scale with meals
ROS: Slightly pale skin color; fatigue daily in the afternoon; otherwise unremarkable
PE:
VS: BP 135/85 mm Hg, P 72 bpm, T 35.9°C (96.6°F); wt 79.5 kg (175 lb)
Chest: RRR, normal S1, S2 present.
Abd: Obese; no organomegaly, bruits or tenderness, (+) bowel sounds; heme (−) stool
Exts: 1+ pedal edema bilaterally; decreased sensation in feet; small lesion on left ankle that appears to be healing slowly
Labs: Sodium 142 mEq/L (142 mmol/L); potassium 4.8 mEq/L (4.8 mmol/L); chloride 103 mEq/L (103 mmol/L); carbon dioxide 20 mEq/L (20 mmol/L); BUN 58 mg/dL (20.71 mmol/L urea); SCr 3.2 mg/dL (283 μmol/L); glucose 130 mg/dL (7.28 mmol/L); white blood cell (WBC) count 4.8 × 103 cells/m3 (4.8 × 109/L); red blood cell (RBC) count 2.5 × 106 cells/m3 (2.5 × 1012/L); hemoglobin (Hgb) 8.0 g/dL (80 g/L or 4.96 mmol/L); hematocrit (Hct) 25% (0.25); platelets 250 × 103 cells/m3 (250 × 109/L); HbA1C 7.5% (0.075)
What signs and symptoms are consistent with anemia of CKD?
What additional information could you request to determine other causes of anemia in this patient?
Treatment
General Approach to Therapy
Studies have demonstrated that initiation of treatment for anemia before stage 5 CKD decreases mortality in patients with ESKD receiving dialysis, particularly in the elderly.44 The treatment of anemia can decrease morbidity, increase exercise capacity and tolerance, and slow the progression of CKD if target Hgb levels are achieved.45
Patients with CKD should be evaluated for anemia when the GFR falls below 60 mL/min or if the SCr rises above 2 mg/dL (177 mmol/L). If the Hgb is less than 11 g/dL (110 g/L or 6.8 mmol/L), an anemia workup should be performed. The workup for anemia should rule out other potential causes for anemia (see Chap. 63). Abnormalities found during the anemia workup should be corrected before initiating erythropoiesis-stimulating agents (ESAs), particularly iron deficiency, as iron is an essential component of RBC production. If Hgb is still below the goal level when all other causes of anemia have been corrected, EPO deficiency should be assumed. EPO levels are not routinely measured and have little clinical significance in monitoring progression and treatment of anemia in patients with CKD.
Clinical Presentation and Diagnosis of Anemia of CKD
General
Anemia of CKD generally presents with fatigue and decreased quality of life.
Symptoms
Anemia of CKD is associated with symptoms of cold intolerance, shortness of breath, and decreased exercise capacity.
Signs
Cardiovascular: Left ventricular hypertrophy, ECG changes, congestive heart failure
Neurologic: Impaired mental cognition
Genitourinary: Sexual dysfunction
Laboratory Tests
Decreased RBC count, Hgb, and Hct
Decreased serum iron level, TIBC, serum ferritin, and TSAT
Decreased erythropoietin levels relative to the degree of hypoxia that is present
Generally, treatment for anemia of CKD requires a combination of ESA and iron supplementation. The goal of treatment is to maintain Hgb levels between 11 g/dL (110 g/L or 6.8 mmol/L) and 12 g/dL (120 g/L or 7.4 mmol/L).46 The goals for iron supplementation are:
• Serum ferritin levels
• 100 to 500 ng/mL (225–1,123.5 pmol/L) for patients not receiving hemodialysis
• 200 to 500 ng/mL (449.4–123.5 pmol/L) for patients receiving hemodialysis
• Transferrin saturation (TSAT): greater than 20% (0.2).42
The approach to the management of anemia of CKD with ESA and iron supplementation is illustrated in Figures 26–3 and 26–4.
Nonpharmacologic Therapy
Sufficient dietary iron intake must be maintained in patients with anemia of CKD. Approximately 1 to 2 mg of iron is absorbed daily from the diet. This small amount is generally not adequate to preserve adequate iron stores to promote RBC production. RBC transfusions have been used in the past as the primary means to maintain Hgb and Hct levels in patients with anemia of CKD. This treatment is still utilized today in patients with severe anemia or contraindications to ESAs, but is considered a third-line therapy for anemia of CKD.
Pharmacologic Therapy
The first-line treatment for anemia of CKD involves replacement of erythropoietin with ESAs. Erythropoietin-stimulating agents are synthetic formulations of EPO produced by recombinant human DNA technology. Use of ESAs increases the iron demand for RBC production and iron deficiency is common, requiring iron supplementation to correct and maintain adequate iron stores to promote RBC production. Androgens were used extensively before the availability of ESAs but are no longer recommended for the treatment of anemia42 primarily because of toxicity, namely, hepatotoxicity.
Erythropoiesis-Stimulating Agents. Erythropoietin is a growth factor that acts on erythroblasts formed from stem cells in the bone marrow, stimulating proliferation and differentiation into normoblasts, then reticulocytes, which are released into the bloodstream to eventually mature into erythrocytes (mature RBCs). The ESAs currently available in the United States are:
• Epoetin alfa (distributed as Epogen by Amgen, Inc., Thousand Oaks, CA; and Procrit by Ortho Biotech, Johnson & Johnson, Raritan, NJ)
• Darbepoetin alfa (Aranesp by Amgen, Inc.)
Epoetin α and epoetin β, which is available outside the United States, have the same biological activity as endogenous EPO. Darbepoetin alfa differs from epoetin alfa by the addition of carbohydrate side chains that increase the half-life of darbepoetin alfa compared to epoetin alfa and endogenous EPO, allowing for less frequent dosing than that of epoetin alfa. All ESAs are equivalent in their efficacy and have a similar adverse-effect profile.
FIGURE 26–3. Guidelines for erythropoietic therapy in the management of anemia of CKD. (Hgb, hemoglobin; SC, subcutaneous; TSat; transferrin saturation.) (Adapted from Hudson JQ. Chronic kidney disease: Management of complications. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: McGraw-Hill; 2008: 775, with permission.)
FIGURE 26–4. Guidelines for iron therapy in the management of anemia of CKD. (CKD, chronic kidney disease; HD, hemodialysis; Hgb, hemoglobin; PD, peritoneal dialysis; TSat, transferrin saturation.) (Adapted from Hudson, JQ. Chronic kidney disease: Management of complications. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: McGraw-Hill, 2008: 774, with permission.)
The most common adverse effect seen with ESA is increased blood pressure, which can occur in up to 23% of patients.42 Antihypertensive agents may be required to control blood pressure in patients receiving ESAs. Caution should be used when initiating an ESA in patients with very high blood pressures (greater than 180/100 mm Hg). If blood pressures are refractory to antihypertensive agents, ESAs may need to be withheld.
Subcutaneous (SC) administration of ESA produces a more predictable and sustained response than IV administration, and is therefore the preferred route of administration for both agents. IV administration is often utilized in patients who have established IV access or are receiving hemodialysis. Starting doses of ESAs depend on the patient’s Hgb level, the target Hgb level, the rate of Hgb increase, and clinical circumstances.42 The initial increase in Hgb should be 1 to 2 g/dL (10–12 g/L or 0.62–1.24 mmol/L) per month. The recommended starting dose of epoetin alfa is 50 to 100 units/kg/dose administered SC or IV 2 to 3 times weekly; the starting dose of darbepoetin alfa is 0.45 mcg/kg administered SC or IV once weekly (Table 26–3).
Two recent clinical trials evaluated the target level of Hgb in patients receiving ESAs. Both studies indicated that targeting Hgb levels greater than 13 g/dL (130 g/L or 8.07 mmol/L) resulted in more cardiovascular complications or death, compared to target Hgb levels less than 11 g/dL (110 g/L or 6.82 mmol/L). The effect of achieving the higher Hgb target on quality of life differed between the two studies.47,48 A secondary analysis of one study indicated that the inability to achieve the target Hgb level was associated with an increased risk of cardiovascular outcomes and death, regardless of the target Hgb level.49 Further studies are needed to evaluate the appropriate target level for Hgb. Nonetheless, based on the findings of these studies, the FDA recommended a black box warning be added to the product information for all ESAs indicating the maximum target Hgb should be between 10 and 12 g/dL (100 and 120 g/L or 6.21 and 7.45 mmol/L) for patients who are receiving ESAs.
Table 26–3 Estimated Starting Doses of Darbepoetin Alfa Based on Previous Epoetin Alfa Dose
Iron Supplementation. Use of ESAs can lead to iron deficiency if iron stores are not adequately maintained. If serum ferritin and TSAT fall below the goal levels, iron supplementation is required. Oral iron supplements are less costly than IV supplements and are generally the first-line treatment for iron supplementation for patients with CKD not receiving hemodialysis.42 When administering iron by the oral route, 200 mg of elemental iron should be delivered daily to maintain adequate iron stores.
Oral iron supplementation is generally not effective in maintaining adequate iron stores in patients receiving ESAs because of poor absorption and an increased need for iron with ESA therapy, making the IV route necessary for iron supplementation. The IV iron products currently available are:
• Iron dextran (distributed as INFeD by Watson Pharmaceuticals, Inc., Morristown, NJ, and Dexferrum by American Reagent, Inc., Shirley, NY)
• Sodium ferric gluconate (Ferrlecit by Watson Pharmaceuticals, Inc., Corona, CA)
• Iron sucrose (Venofer by American Reagent, Inc., Shirley, NY)
Initiation of IV iron should be based on evaluation of iron stores. A serum ferritin level less than 100 ng/mL (225 pmol/L) in conjunction with a TSAT level less than 20% (0.2) indicates absolute iron deficiency and is a clear indication for the need for iron replacement.42 Serum ferritin is an acute phase reactant, which may become elevated with inflammation and stress. Thus, when serum ferritin is normal or elevated in conjunction with TSAT levels less than 20%, treatment should be based on the clinical picture of the patient. Iron supplementation may be indicated if Hgb levels are below the goal level. One clinical trial evaluated the efficacy of IV iron supplementation in patients with high serum ferritin levels (500–1,200 ng/mL [1,123.5–2,696.4 pmol/L]) and low TSAT levels (less than 25% [0.25]). A significant increase in Hgb was noted in patients who received IV supplementation compared to those who did not. Furthermore, more patients achieved an increase in Hgb and the response rate was faster. The authors concluded that serum ferritin alone is not a good marker for iron deficiency.50
When replacing iron stores IV in patients receiving ESA therapy, the general approach to treatment is to give a total of 1 g of IV iron, administered in smaller, sequential doses. Table 26–4 lists the FDA-approved doses of the IV iron products. Because iron stores deplete quickly in patients who do not receive iron supplementation, maintenance doses are often used, particularly in patients receiving hemodialysis. Maintenance doses consist of smaller doses of iron administered weekly or with each dialysis session (e.g., iron dextran or iron sucrose 20–100 mg/week; sodium ferric gluconate 62.5–125 mg/week).
IV iron preparations are equally effective in increasing iron stores. Iron dextran has been associated with side effects, including anaphylactic reactions and delayed reactions, such as arthralgias and myalgias. A test dose of 25 mg iron dextran should be administered 30 minutes before the full dose to monitor for potential anaphylactic reactions. However, patients should be monitored closely when receiving iron dextran, as anaphylactic reactions can occur in patients who safely received prior doses of iron dextran. For this reason, use of iron dextran has decreased dramatically in CKD patients in favor of the newer iron preparations, sodium ferric gluconate and iron sucrose, which are associated with fewer severe reactions. The most common side effects seen with these preparations include hypotension, flushing, nausea, and injection site reactions. A test dose is not required prior to the administration of either sodium ferric gluconate or iron sucrose. Long-term use of IV iron may increase oxidative stress, inflammation, and renal and cardiovascular injury.51
Outcome Evaluation
Evaluate Hgb every 1 to 2 weeks when ESA therapy is initiated or the dose is adjusted until Hgb is between 11 g/dL (110 g/L or 6.8 mmol/L) and 12 g/dL (120 g/L or 7.4 mmol/L). Once goal Hgb is attained, evaluate Hgb every 2 to 4 weeks thereafter. While the patient is receiving ESA therapy, monitor iron stores monthly in patients who are not receiving iron supplements or every 3 months in patients who are receiving iron supplements. When the goal Hgb is reached, monitor iron stores every 3 months.
Secondary Hyperparathyroidism and Bone and Mineral Metabolism Disorders
Epidemiology and Etiology
Increases in parathyroid hormone (PTH) occur early as kidney function begins to decline. The actions of PTH on bone turnover lead to bone and mineral metabolism disorders (BMMD). As many as 75% to 100% of patients with stage 3 CKD have BMMD.52 The type of bone disease can vary based on the degree of bone turnover. High bone turnover is the most common cause of bone abnormalities in patients with CKD, present in as many as 75% of patients receiving dialysis,52 and is generally mediated by high levels of PTH. Adynamic bone disease, characterized by low bone turnover, is less common, although the prevalence appears to be increasing,52 which may be related to more aggressive treatment of hyperparathyroidism. The development of BMMD can dramatically affect morbidity in patients with CKD.
Table 26–4 Intravenous Iron
Patient Encounter, Part 3
The patient returns to your clinic in one week and states that her symptoms have not changed. She is asking about the results from her laboratory studies.
Labs: WBC 4.5 × 103 cells/m3 (4.5 × 109/L); RBC 2.3 × 106 cells/m3 (2.3 × 1012/L); Hgb 8.1 g/dL (81 g/L or 5 mmol/L); Hct 24% (0.24); mean corpuscular volume (MCV) 88 fL; mean corpuscular hemoglobin concentration (MCHC) 35 g/dL (350 g/L); iron 35 mcg/dL (6.26 μmol/L); total iron binding capacity (TIBC) 450 mcg/dL (80.55 μmol/L); ferritin 75 ng/mL (168 pmol/L); transferrin saturation (TSAT) 15% (0.15); stool guaiac negative × 3
What treatment would you recommend for this patient for treatment of anemia?
How would you evaluate the effectiveness of treatment of anemia?
Pathophysiology
As kidney function declines in patients with CKD, decreased phosphorus excretion disrupts the balance of calcium and phosphorus homeostasis. Decreased vitamin D activation in the kidney also decreases calcium absorption from the GI tract. The parathyroid glands release PTH in response to decreased serum calcium and increased serum phosphorus levels. The actions of PTH include the following:
• Increasing calcium resorption from bone
• Increasing calcium reabsorption from the proximal tubules in the kidney
• Decreasing phosphorus reabsorption in the proximal tubules in the kidney
• Stimulating activation of vitamin D by 1-α-hydroxylase to calcitriol (1,25-dihydroxyvitmin D3) to promote calcium absorption in the GI tract and increased calcium mobilization from bone
All of these actions are directed at increasing serum calcium levels and decreasing serum phosphorus levels, although the activity of calcitriol also increases phosphorus absorption in the GI tract and mobilization from the bone, which can worsen hyperphosphatemia. Calcitriol also decreases PTH levels through a negative feedback loop. These measures are sufficient to correct serum calcium levels in the earlier stages of CKD.
As kidney function continues to decline and the GFR falls less than 40 mL/min/1.73 m2, phosphorus excretion continues to decrease and calcitriol production decreases,53 causing PTH levels to begin to rise significantly, leading to secondary hyperparathyroidism (sHPT). The excessive production of PTH leads to hyperplasia of the parathyroid glands, which decreases the sensitivity of the parathyroid glands to serum calcium levels and calcitriol feedback, further promoting sHPT.
The most dramatic consequence of sHPT is alterations in bone turnover and the development of BMMD. Other complications of CKD can also promote BMMD. Metabolic acidosis decreases bone formation and excessive aluminum levels cause aluminum uptake into bone in place of calcium, weakening the bone structure. The pathogenesis of sHPT and BMMD are depicted in Figure 26–5.
The increased serum phosphorus binds to calcium in the serum, which leads to deposition of hydroxyapatite crystals throughout the body. The calcium-phosphorus (Ca-P) product reflects serum solubility. A Ca-P product greater than 75 mg2/dL2 (5.81 mmol2/L2) promotes crystal deposition in the joints and eye, leading to arthritis and conjunctivitis, respectively. Soft tissue deposition primarily affects the coronary arteries of the heart, lungs, and vascular tissue53 and is associated with a Ca-P product greater than 55 mg2/dL2 (4.44 mmol 2/L2).54 The Ca-P product has been associated with a 40% increase in mortality54and is a risk factor for calcification of vascular and soft tissues.52
Metabolic acidosis, a common complication of CKD, also contributes to BMMD by altering the solubility of hydroxyapatite, promoting bone dissolution. Additionally, metabolic acidosis inhibits the activity of osteoblasts to decrease bone formation, while stimulating osteoclasts to promote bone resorption. Finally, metabolic acidosis can worsen sHPT by reducing the sensitivity of the parathyroid gland to serum calcium levels.55
Treatment
General Approach
Diagnosis and management of bone disease in CKD is based on corrected serum levels of calcium and phosphorus, the Ca-P (using corrected calcium levels), and intact PTH levels (iPTH).56 The target levels of each vary with the stage of CKD and are listed in Table 26–5. The primary target for treatment is control of serum phosphorus levels, as this is the initial parameter that disrupts homeostasis. However, serum phosphorus can be difficult to control, particularly in the latter stages of CKD. Management of sHPT often requires supplemental treatment in addition to phosphorus management.
FIGURE 26–5. Pathogenesis of secondary hyperparathyroidism and bone and mineral disorder in patients with CKD. *These adaptations are lost as kidney failure progresses. ([Ca] × [PO4], calcium-phosphorus product; PTH, parathyroid hormone. (From Hudson JQ. Chronic kidney disease: Management of complications.) In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: McGraw-Hill, 2008:767, with permission.)
Clinical Presentation and Diagnosis of sHPT and ROD
General
Onset of sHPT and ROD is subtle and may not be associated with symptoms.
Symptoms
sHPT and ROD are usually asymptomatic in early disease. Calcification in the joints can be associated with decreased range of motion.
Conjunctival calcifications are associated with a gritty sensation in the eyes, redness, and inflammation.
Signs
Cardiovascular: Increased stroke index, heart rate, and diastolic and mean arterial pressures
Musculoskeletal: Bone pain, muscle weakness
Dermatologic: Pruritus
Laboratory Tests
Increased serum phosphorus levels
Low to normal serum calcium levels
Increased Ca-P product
Increased PTH levels
Decreased vitamin D levels
Diagnostic Tests
Radiographic studies show calcium-phosphate deposits in joints and/or cardiovascular system
Bone biopsy of the iliac crest
Nonpharmacologic Therapy
The first-line treatment for the management of hyperphosphatemia is dietary phosphorus restriction to 800 to 1,000 mg/day in patients with stage 3 CKD or higher who have phosphorus levels at the upper limit of the normal range or elevated iPTH levels.56 Foods high in phosphorus are also high in protein, which can make it difficult to restrict phosphorus intake while maintaining adequate protein intake to avoid malnutrition. Hemodialysis and peritoneal dialysis can remove up to 2 to 3 g of phosphorus per week. However, this is insufficient to control hyperphosphatemia, and pharmacologic therapy is necessary in addition to dialysis treatment.
Other nonpharmacologic strategies to manage sHPT and BMMD in patients with CKD include restriction of aluminum exposure and parathyroidectomy. Ingestion of aluminum-containing antacids and other aluminum-containing products should be avoided in patients with stage 4 CKD or higher (GFR less than 30 mL/min/1.73 m2) because of the risk of aluminum toxicity and potential uptake into the bone. Purification techniques for dialysate solutions also minimize the risk of exposure to aluminum.
Parathyroidectomy is a treatment of last resort for sHPT, but should be con sidered in patients with persistently elevated iPTH levels above 800 pg/mL (800 ng/L) that is refractory to medical therapy to lower serum calcium and/or phosphorus levels.56 A portion or all of the parathyroid tissue may be removed, and in some cases a portion of the parathyroid tissue may be transplanted into another site, usually the forearm. Bone turnover can be disrupted in patients undergoing parathyroidectomy whereby bone production outweighs bone resorption. The syndrome, known as “hungry bone syndrome,” is characterized by excessive uptake of calcium, phosphorus, and magnesium for bone production, leading to hypocalcemia, hypophosphatemia, and hypomagnesemia. Serum ionized calcium levels should be monitored frequently (every 4–6 hours for the first 48–72 hours) in patients receiving a parathyroidectomy. Calcium supplementation is usually necessary, administered IV initially, then orally (with vitamin D supplementation) once normal calcium levels are attained for several weeks to months after the procedure.
Pharmacologic Therapy
Phosphate-Binding Agents. When serum phosphorus levels cannot be controlled by restriction of dietary intake, phosphate-binding agents are used to bind dietary phosphate in the GI tract to form an insoluble complex that is excreted in the feces. Phosphorus absorption is decreased, thereby decreasing serum phosphorus levels. The drugs used for binding dietary phosphate are listed in Table 26–6. These agents should be administered with each meal and can be tailored to the amount of phosphorus that is typically ingested during each meal. For example, patients can take a smaller dose with smaller meals or snacks, and a larger dose with larger meals.
Table 26–5 Target Levels for Calcium, Phosphorus, Ca-P, and Intact PTH
Calcium-based phosphate binders, including calcium carbonate and calcium acetate, are effective in decreasing serum phosphate levels, as well as in increasing serum calcium levels. Calcium acetate binds more phosphorus than the carbonate salt, making it a more potent agent for binding dietary phosphate. Calcium citrate is usually not used as a phosphate-binding agent because the citrate salt can increase aluminum absorption. The calcium-containing phosphate binders also aid in the correction of metabolic acidosis, another complication of kidney failure. Caution should be used with these agents if serum calcium levels are near the upper end of the normal range or are elevated because of the risk of increasing the Ca-P product and potentiating vascular and soft tissue calcifications. The dose of calcium-based phosphate binders should not provide more than 1,500 mg of elemental calcium per day, and the total elemental calcium intake per day should not exceed 2,000 mg, including medication and dietary intake.56The most common adverse effects of calcium-containing phosphate binders are constipation and hypercalcemia.
Aluminum- and magnesium-containing phosphate-binding agents are not recommended for chronic use in patients with CKD to minimize the risk of aluminum and magnesium accumulation. Aluminum-containing agents may be used for a short course of therapy (less than 4 weeks) if phosphorus levels are significantly elevated greater than 7 mg/dL (2.26 mmol/L), but should be replaced by other phosphate-binding agents after no more than 4 weeks. Excessive aluminum levels lead to aluminum intoxication, causing neurotoxicity that can manifest as encephalopathy or dementia. Other consequences of aluminum intoxication include anemia and bone disease as aluminum is taken up in place of iron in RBCs and calcium in skeletal bones. In addition to the risk of magnesium accumulation, the use of magnesium-containing agents is also limited by the GI side effects, primarily diarrhea.
Phosphate-binding agents that do not contain calcium, magnesium, or aluminum include sevelamer hydrochloride, sevelamer carbonate, and lanthanum carbonate. These agents are particularly useful in patients with hyperphosphatemia who have elevated serum calcium levels or who have vascular or soft tissue calcifications. Sevelamer is a cationic polymer that is not systemically absorbed and binds to phosphate in the GI tract, and prevents absorption and promotes excretion of phosphate through the GI tract via the feces. Sevelamer has an added benefit of reducing LDL-C by up to 30% and increasing HDL-C levels.56 The most common side effects of sevelamer are GI complaints, including nausea, constipation, and diarrhea. The cost of sevelamer is significantly higher compared to calcium-containing phosphate binders, which often makes sevelamer a second-line agent for controlling phosphorus levels. However, recent studies have demonstrated that sevelamer decreases mortality in patients receiving hemodialysis compared to calcium-containing phosphate binders, primarily by decreasing the occurrence of calcifications in the coronary arteries.57,58
Lanthanum is a naturally occurring trivalent rare earth element (atomic number 57). Lanthanum carbonate quickly dissociates in the acidic environment of the stomach, where the lanthanum ion binds to dietary phosphorus, forming an insoluble compound that is excreted in the feces. Lanthanum has been shown to remove more than 97% of dietary phosphorus from the GI tract.59 Side effects of lanthanum include nausea, peripheral edema, and myalgias.
Vitamin D Therapy. Exogenous vitamin D compounds that mimic the activity of calcitriol act directly on the parathyroid gland to decrease PTH secretion. This is particularly useful when reduction of serum phosphorus levels does not sufficiently reduce PTH levels. The most active form of vitamin D is calcitriol (1,25-dihydroxyvitamin D). The effects of calcitriol are mediated by upregulation of the vitamin D receptor in the parathyroid gland, which decreases parathyroid gland hyperplasia and PTH synthesis and secretion. However, vitamin D receptor upregulation also occurs in the intestines, which increases calcium and phosphorus absorption, increasing the risk of hypercalcemia and hyperphosphatemia. It is important that serum calcium and phosphorus levels are within the normal range for the stage of CKD and the Ca-P product is less than 55 mg2/dL2 (4.44 mmol 2/L2) prior to starting calcitriol therapy.
Vitamin D supplementation can be used to lower serum PTH levels in patients with CKD. Ergocalciferol has been shown to be effective in lowering PTH secretion in patients with stage 3 CKD.61 However, as CKD progresses to stages 4 and 5, the kidney loses the ability to produce 1α-hydroxylase, which is responsible for renal activation of vitamin D. In these later stages of CKD, activated vitamin D analogs must be used to decrease PTH secretion. Calcitriol (1,25-dihydroxyvitamin D3) is available commercially as an oral formulation (Rocaltrol by Roche Laboratories, Inc., Nutley, NJ) and an injectable formulation (Calcijex by Abbott Laboratories, North Chicago, IL). This analog has the same biologic activity as endogenous calcitriol. Other vitamin D analogs available in the United States include paricalcitol (19-nor-1,25-dihydroxyvitamin D2, Zemplar by Abbott Laboratories, North Chicago, IL and doxercalciferol (1-α-hydroxyvitamin D2, Hectorol by Genzyme Corp., Cambridge, MA), both of which are also available in oral and injectable formations. Alfacalcidiol (1-α-hydroxyvitamin D3) is only available outside the United States. Paricalcitol has less effect on vitamin D receptors in the intestines, decreasing the effects on intestinal calcium and phosphorus absorption, while retaining the effects on parathyroid gland hyperplasia and PTH synthesis and secretion.60 This makes paricalcitol more useful in patients with an elevated Ca-P product. Doxercalciferol, on the other hand, has similar effects as calcitriol on vitamin D receptors in the parathyroid glands and intestines. Like calcitriol, calcium and phosphorus levels and the Ca-P product should be within the normal range for the stage of CKD prior to starting doxercalciferol. Recommendations for vitamin D analog therapy depend on the stage of CKD (Table 26–7).56
Table 26–6 Phosphate-Binding Agents Used in the Treatment of Hyperphosphatemia in CKD
It is important to monitor vitamin D therapy aggressively to assure that PTH levels are not oversuppressed. Oversuppression of PTH levels can induce adynamic bone disease, which manifests as decreased osteoblast and osteoclast activity, decreased bone formation, and low bone turnover.
Calcimimetics
Cinacalcet is a calcimimetic that increases the sensitivity of receptors on the parathyroid gland to serum calcium levels to reduce PTH secretion. In addition to lowering PTH levels, cinacalcet has been shown to reduce serum calcium levels by approximately 5% and serum phosphorus levels by 2.6% to 8.4%.62 This makes cinacalcet beneficial to use in patients with elevated PTH levels who have an increased Ca-P product and cannot use vitamin D therapy. Because the effects of cinacalcet on PTH can reduce serum calcium levels and result in hypocalcemia, cinacalcet should not be used if serum calcium levels are below 8.4 mg/dL (2.1 mmol/L). Cincalcet should also be used with caution in patients with seizure disorders because low serum calcium levels can lower the seizure threshold.62
Reversal of Metabolic Acidosis
Studies have demonstrated that reversal of metabolic acidosis can improve bone disease associated with CKD.55 Serum bicarbonate levels should be maintained at 22 mEq/L (22 mmol/L) in patients with bone disease associated with CKD.56 The treatment of metabolic acidosis is described later.
Outcome Evaluation
Monitor serum calcium and phosphorus levels regularly in patients receiving phosphate-binding agents. When initiating therapy, monitor serum levels every 1 to 4 weeks, depending on the severity of hyperphosphatemia. Titrate doses of phosphate binders to achieve the target levels of serum calcium and phosphorus and the Ca-P product (Table 26–5). Once target levels are achieved, monitor serum calcium and phosphorus levels every 1 to 3 months. Monitor intact PTH levels monthly while initiating vitamin D therapy, then every 3 months once stable iPTH levels are achieved. When starting or increasing the dose of cinacalcet, monitor serum calcium and phosphorus levels within 1 week and iPTH levels should be monitored within 1 to 4 weeks. Once target levels are achieved, decrease monitoring to every 3 months.
Metabolic Acidosis
Epidemiology and Etiology
Approximately 80% of patients with a GFR less than 20 to 30 mL/min/1.73 m2 develop metabolic acidosis.55 Metabolic acidosis can increase protein catabolism and decrease albumin synthesis, which promote muscle wasting, and alter bone metabolism. Other consequences associated with metabolic acidosis in CKD include worsening cardiac disease, impaired glucose tolerance, altered growth hormone and thyroid function, and inflammation.55
Table 26–7 Dosing Recommendations for Vitamin D in Patients with CKD
Patient Encounter, Part 4
The patient returns to your clinic 1 year later for routine follow-up. She has no complaints at this time.
Current Meds: Furosemide 80 mg orally daily; lisinopril 40 mg orally daily; metoprolol 75 mg orally twice daily; insulin glargine 28 units subcutaneously at bedtime; insulin lispro subcutaneously per sliding scale with meals; darbepoetin 60 mcg subcutaneously weekly
ROS: Unremarkable
PE:
VS: BP 128/75 mm Hg, P 68 bpm, T 36.5°C (97.9°F); wt 77.3 kg (170 lb)
Chest: RRR, normal S1, S2 present
Abd: Obese; no organomegaly, bruits, tenderness, (+) bowel sounds; heme (-) stool
Exts: 2+ edema bilaterally; decreased sensation to light touch in feet; no lesions
Labs: Sodium 144 mEq/L (144 mmol/L); potassium 5.0 mEq/L (5.0 mmol/L); chloride 105 mEq/L (105 mmol/L); carbon dioxide 18 mEq/L (18 mmol/L); BUN 75 mg/dL (26.78 mmol/L urea); SCr 4.8 mg/dL (424 μmol/L); glucose 115 mg/dL (6.38 mmol/L); calcium 8.6 mg/dL (2.15 mmol/L); phosphate 7.8 mg/dL (2.52 mmol/L); albumin 3.0 mg/dL (30 g/L); intact parathyroid hormone (iPTH) 538 pg/mL (538 ng/L or 57.6 pmol/L); WBC 6.0 × 103 cells/mm3(6.0 × 109/L); RBC 3.5 × 106 cells/mm3 (3.5 × 1012/L); Hgb 10.5 g/dL (6.51 mmol/L); Hct 32% (0.32); platelets 350 × 103 cells/mm3 (350 × 109/L)
What signs are consistent with secondary hyperparathyroidism (sHPT)?
How would you determine whether treatment is necessary for this patient?
What treatment would you recommend for sHPT?
Pathophysiology
The kidney plays a key role in the management of acid–base homeostasis in the body by regulating excretion of hydrogen ions. With normal kidney function, bicarbonate that is freely filtered through the glomerulus is completely reabsorbed via the renal tubules. Hydrogenions are generated at a rate of 1 mEq/kg (1 mmol/kg) per day during metabolism of ingested food and are excreted at the same rate by the kidney via buffers in the urine created by ammonia generation and phosphate excretion. As a result, the pH of body fluids is maintained within a very narrow range.
As kidney function declines, bicarbonate reabsorption is maintained, but hydrogen excretion is decreased because the ability of the kidney to generate ammonia is impaired. The positive hydrogen balance leads to metabolic acidosis, which is characterized by a serum bicarbonate level of 15 to 20 mEq/L (15–20 mmol/L). This picture is generally seen when the GFR declines below 20 to 30 mL/min/1.73 m2.55
Treatment
Serum electrolytes should be monitored in patients with CKD for the development of metabolic acidosis. Metabolic acidosis in patients with CKD is generally characterized by an elevated anion gap greater than 17 mEq/L (17 mmol/L), due to the accumulation of phosphate, sulfate, and other organic anions.
Nonpharmacologic Therapy
Treatment of metabolic acidosis in CKD requires pharmacologic therapy. Other disorders that may contribute to metabolic acidosis should also be addressed. Altering bicarbonate levels in the dialysate fluid in patients receiving dialysis may assist with the treatment of metabolic acidosis, although pharmacologic therapy may still be required.
Pharmacologic Therapy
Pharmacologic therapy with sodium bicarbonate or citrate/citric acid preparations may be needed in patients with stage 3 CKD or higher to replenish body stores of bicarbonate. Calcium carbonate and calcium acetate, used to bind phosphorus in sHPT, also aid in increasing serum bicarbonate levels, in conjunction with other agents.
Sodium bicarbonate tablets are administered in increments of 325 and 650 mg tablets. A 650 mg tablet of sodium bicarbonate contains 7.7 mEq (7.7 mmol) each of sodium and bicarbonate. Sodium retention associated with sodium bicarbonate can cause volume overload, which can exacerbate hypertension and chronic heart failure. Patient tolerability of sodium bicarbonate is low because of carbon dioxide production in the GI tract that occurs during dissolution.
Solutions that contain sodium citrate/citric acid (Shohl’s solution and Bicitra) provide 1 mEq/L (1 mmol/L) each of sodium and bicarbonate. Polycitra is a sodium/potassium citrate solution that provides 2 mEq/L (2 mmol/L) of bicarbonate, but contains 1 mEq/L (1 mmol/L) each of sodium and potassium, which can promote hyperkalemia in patients with severe CKD. The citrate portion of these preparations is metabolized in the liver to bicarbonate, while the citric acid portion is metabolized to CO2 and water, increasing tolerability compared to sodium bicarbonate. Sodium retention is also decreased with these preparations. However, these products are liquid preparations, which may not be palatable to some patients. Citrate can also promote aluminum intoxication by augmenting aluminum absorption in the GI tract.
When determining the dose of bicarbonate replacement, the goal for therapy is to achieve a normal serum bicarbonate level of 24 mEq/L (24 mmol/L). The dose is usually determined by calculating the base deficit: [0.5 L/kg × (body weight)] × [(normal CO2) - (measured CO2)]. Because of the risk of volume overload resulting from the sodium load administered with bicarbonate replacement, the total base deficit should be administered over several days. Once the goal serum bicarbonate level is attained, a maintenance dose of bicarbonate is necessary and should be titrated to maintain serum bicarbonate levels.
Outcome Evaluation
Monitor serum electrolytes and arterial blood gases regularly. Correct metabolic acidosis slowly to prevent the development of metabolic alkalosis or other electrolyte abnormalities.
Other Therapeutic Considerations in CKD
Uremic Bleeding
Uremia can lead to a number of alterations in clotting ability, resulting in hemorrhage. Bleeding complications associated with CKD include ecchymoses, prolonged bleeding from mucous membranes and puncture sites used for blood collection and hemodialysis, GI bleeding, intramuscular bleeding, and others. Most bleeding complications associated with CKD are mild. However, serious bleeding events, including GI bleeds and intracranial hemorrhage, can occur.
Pathophysiology
Uremia alters a number of mechanisms that contribute to bleeding. Platelet function and aggregation are altered through decreased production of thromboxane.63 Platelet–vessel wall interactions are also altered in patients with uremia because of decreased activity of von Willebrand’s factor63 and are exacerbated by anemia in CKD patients. With a normal RBC count in the plasma, platelets skim the surface of the endothelial tissue in the blood vessels. In patients with anemia, RBC count is decreased and platelets circulate closer to the center of the vessels, which decreases the interaction with the vessel wall. The risk of bleeding is increased in patients receiving hemodialysis. Anticoagulants administered to prevent or treat clotting during hemodialysis or in vascular access sites, including heparin, warfarin, aspirin, and clopidogrel, exacerbate the risk of bleeding in these patients.
Treatment
Nonpharmacologic Therapy. The incidence and severity of bleeding associated with uremia has decreased since dialysis has become the mainstay of treatment for ESKD. Dialysis initiation improves platelet function and reduces bleeding time.63 Improved care of the patient with ESKD, with anemia treatment and improvement in nutritional status, are also likely contributors to decreased uremic bleeding.
Pharmacologic Therapy. Treatments used to decrease bleeding time in patients with uremic bleeding include cryoprecipitate, which contains various components important in platelet aggregation and clotting, such as von Willebrand’s factor and fibrinogen. Cryoprecipitate decreases bleeding time within 1 hour in 50% of patients. However, cost and the risk of infection have limited the use of cryoprecipitate.
Desmopressin (DDAVP) increases the release of factor VIII (von Willebrand’s factor) from endothelial tissue in the vessel wall. Bleeding time is promptly reduced, within 1 hour of administration, and is sustained for 4 to 8 hours.63 Doses used for uremic bleeding are 0.3 to 0.4 mcg/kg IV over 20 to 30 minutes, 0.3 mcg/kg subcutaneously, or 2 to 3 mcg/kg intranasally. Repeated doses can cause tachyphylaxis by depleting stores of von Willebrand’s factor. Side effects of DDAVP include flushing, dizziness, and headache.
Estrogens have also been used to decrease bleeding time. The onset of action is slower than that of DDAVP, but more sustained, and it depends on the route of administration. IV doses of 0.6 mg/kg/day for 4 to 5 days decreases bleeding time within 6 hours of administration, and produces an effect that lasts up to 2 weeks after stopping therapy. The onset of action with oral doses of 50 mg/kg daily is within 2 days of treatment and is sustained for 4 to 5 days after stopping therapy. Transdermal patches providing 50 to 100 mcg/day have also been shown to be effective in decreasing bleeding time.63 Side effects of estrogen use include hot flashes in both females and males, fluid retention, and hypertension.
Pruritus
Pruritus can affect 25% to 86% of patients with advanced stages of CKD, and is not related to the cause of kidney failure.64 Pruritus can be significant and has been linked to mortality in patients receiving hemodialysis.64
Pathophysiology
The cause of pruritus is unknown, although several mechanisms have been proposed. Vitamin A is known to accumulate in the skin and serum of patients with CKD, but a definite correlation with pruritus has not been established. Histamine may also play a role in the development of pruritus, which may be linked to mast cell proliferation in patients receiving hemodialysis. Hyperparathy-roidism has also been suggested as a contributor to pruritus, despite the fact that serum PTH levels do not correlate with itching. Accumulation of divalent ions, specifically magnesium and aluminum, may also play a role in pruritus in patients with CKD. Other theories that have been proposed include inadequate dialysis, dry skin, peripheral neuropathy, and opiate accumulation.64
Treatment
Nonpharmacologic Therapy. Pruritus associated with CKD is difficult to alleviate. It is important to evaluate other potential dermatologic causes of pruritus to maximize the potential for relief. Adequate dialysis is generally the first line of treatment in patients with pruritus. However, this has not been shown to decrease the incidence of pruritus significantly. Maintaining proper nutritional intake, especially with regard to dietary phosphorus and protein intake, may lessen the degree or occurrence of pruritus. Patients who do not attain relief from other measures may benefit from ultraviolet B phototherapy.
Pharmacologic Therapy. Topical emollients have been used as treatment for pruritus in patients with dry skin, but are often not effective in relieving pruritus associated with CKD. Antihistamines, such as hydroxyzine 25 to 50 mg or diphenhydramine 25 to 50 mg orally or IV, are used as first-line oral agents used to treat pruritus. Cholestyramine has also been used at doses of 5 g twice daily. Oral activated charcoal has also been used in doses of 1 to 1.5 g four times daily with some demonstrated efficacy. Other therapies that are often used in combination with other agents include oral ondansetron or naltrexone and topical capsaicin. Each has been reported to have efficacy in the treatment of pruritus associated with CKD.64
Vitamin Replacement
Water-soluble vitamins removed by hemodialysis (HD) contribute to malnutrition and vitamin deficiency syndromes. Patients receiving HD often require replacement of water-soluble vitamins to prevent adverse effects. The vitamins that may require replacement are ascorbic acid, thiamine, biotin, folic acid, riboflavin, and pyridoxine. Patients receiving HD should receive a multivitamin B complex with vitamin C supplement, but should not take supplements that include fat-soluble vitamins, such as vitamins A, E, or K, which can accumulate in patients with kidney failure.
RENAL REPLACEMENT THERAPY
Patients who progress to ESKD require RRT. The modalities that are used for RRT are dialysis, including HD and peritoneal dialysis (PD), and kidney transplantation. The United States Renal Data Service (USRDS) reported that the number of patients with ESKD was 506,256, with 110,854 new cases being diagnosed in 2006.2 The most common form of RRT is dialysis, accounting for 65% of all patients with ESKD.2 The principles and complications associated with dialysis are discussed below. Chapter 55 discusses the principles of kidney transplantation.
Indications for Dialysis
Planning for dialysis should begin when GFR falls less than 30 mL/min/1.73 m2 (stage 4 CKD),1 when progression to ESKD is inevitable, to allow time to educate the patient and family on the treatment modalities and establish the appropriate access for the modality of choice. Ideally, initiation of dialysis should be done at a point when the patient is ready to undergo treatment, rather than when the patient is in emergent need of dialysis.
Initiation of dialysis is dependent on the patient’s clinical status. Symptoms that may indicate the need for dialysis include persistent anorexia, nausea, vomiting, fatigue, and pruritus. Other criteria that indicate the need for dialysis include declining nutritional status, declining serum albumin levels, uncontrolled hypertension, and volume overload, which may manifest as chronic heart failure, and electrolyte abnormalities, particularly hyperkalemia. Blood urea nitrogen (BUN) and SCr levels may be used as a guide for the initiation of dialysis, but should not be the absolute indicator. Dialysis is initiated in most patients when the GFR falls below 15 mL/min/1.73 m2.1 Patients should determine which modality of dialysis to use based on their own preferences. Advantages and disadvantages of hemodialysis and peritoneal dialysis are listed in Tables 26–8 and 26–9, respectively.
The goals of dialysis are to remove toxic metabolites to decrease uremic symptoms, correct electrolyte abnormalities, restore acid–base status, and maintain volume status to ultimately improve quality of life and decrease the morbidity and mortality associated with ESKD.
Hemodialysis
Principles of Hemodialysis
Hemodialysis (HD) involves the exposure of blood to a semipermeable membrane (dialyzer) against which a physiologic solution (dialysate) is flowing (Fig. 26–6). The dialyzer is composed of thousands of capillary fibers made up of the semipermeable membrane, which are enclosed in the dialyzer, to increase the surface area of blood exposure to maximize the efficiency of removing substances. The dialysate is composed of purified water and electrolytes, and is run through the dialyzer countercurrent to the blood on the other side of the semipermeable membrane. The process allows for the removal of several substances from the bloodstream, including water, urea, creatinine, electrolytes, uremic toxins, and drugs. Although the dialysate is not sterilized, the membrane prevents bacteria from entering into the bloodstream. However, if the membrane ruptures during hemodialysis, infection becomes a major concern for the patient.
Table 26–8 Advantages and Disadvantages of Hemodialysis
|
Advantages |
|
1. Higher solute clearance allows intermittent treatment |
|
2. Parameters of adequacy of dialysis are better defined and therefore underdialysis can be detected early |
|
3. The technique’s failure rate is low |
|
4. Even though intermittent heparinization is required, hemostasis parameters are better corrected with hemodialysis than peritoneal dialysis |
|
5. In-center hemodialysis enables closer monitoring of the patient |
|
Disadvantages |
|
1. Requires multiple visits each week to the hemodialysis center, which translates into loss of control by the patient |
|
2. Dysequilibrium, dialysis, hypotension, and muscle cramps are common. May require months before patient adjusts to hemodialysis |
|
3. Infections in hemodialysis patients may be related to the choice of membranes, the complement-activating membranes being more deleterious |
|
4. Vascular access is frequently associated with infection and thrombosis |
|
5. Decline of residual renal function is more rapid compared to peritoneal dialysis |
From Foote EF, Manley HJ. Hemodialysis and peritoneal dialysis. In: DiPiro JT, Talbert RL, Yee GC, et al., (eds.) Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York: McGraw-Hill; 2008: O104, with permission.
Table 26–9 Advantages and Disadvantages of Peritoneal Dialysis
|
Advantages |
|
1. More hemodynamic stability (blood pressure) due to slow ultrafiltration rate |
|
2. Increased clearance of larger solutes, which may explain good clinical status in spite of lower urea clearance |
|
3. Better preservation of residual renal function |
|
4. Convenient intraperitoneal route of administration of drugs such as antibiotics and insulin |
|
5. Suitable for elderly and very young patients who may not tolerate hemodialysis well |
|
6. Freedom from the “machine” gives the patient a sense of independence (for continuous ambulatory peritoneal dialysis) |
|
7. Less blood loss and iron deficiency, resulting in easier management of anemia or reduced requirements for erythropoietin and parenteral iron |
|
8. No systemic heparinization requirement |
|
9. Subcutaneous versus IV erythropoietin or darbepoetin is usual, which may reduce overall doses and be more physiologic |
|
Disadvantages |
|
1. Protein and amino acid losses through the peritoneum and reduced appetite owing to continuous glucose load and sense of abdominal fullness predispose to malnutrition |
|
2. Risk of peritonitis |
|
3. Catheter malfunction, and exit site and tunnel infection |
|
4. Inadequate ultrafiltration and solute dialysis in patients with a large body size, unless large volumes and frequent exchanges are employed |
|
5. Patient burnout and high rate of technique failure |
|
6. Risk of obesity with excessive glucose absorption |
|
7. Mechanical problems such as hernias, dialysate leaks, hemorrhoids, or back pain may occur |
|
8. Extensive abdominal surgery may preclude peritoneal dialysis |
|
9. No convenient access for IV iron administration |
From Foote EF, Manley HJ. Hemodialysis and peritoneal dialysis. In: DiPiro JT, Talbert RL, Yee GC, et al., (eds.) Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York: McGraw-Hill; 2008: O105, with permission.
Patient Encounter, Part 5
The patient presents to clinic several years later and complains that she “feels lousy.” She states that she doesn’t feel like eating and has lost 9 kg (20 lb) in the last 6 months.
Current Meds: Furosemide 80 mg orally twice daily; metolazone 5 mg orally twice daily; lisinopril 40 mg orally daily; metoprolol 75 mg orally twice daily; insulin glargine 30 units subcutaneously at bedtime; insulin lispro subcutaneously per sliding scale with meals; darbepoetin 100 mcg subcutaneously weekly; iron polysaccharide 150 mg orally daily; sevelamer 800 mg orally three times a day with meals; calcitriol 0.25 mcg orally daily; sodium bicarbonate 1,300 mg orally three times a day
ROS: Unremarkable
PE:
VS: BP 160/85 mm Hg, P 70 bpm, T 36.8°C (98.2°F), wt 68.2 kg (150 lb)
Chest: RRR, normal S1, S3, and S4 both present; slight pericardial friction rub
Exts: 3+ bilateral lower extremity edema which is present half-way up her calf
Labs: Sodium 142 mEq/L (142 mmol/L); potassium 5.8 mEq/L (5.8 mmol/L); chloride 102 mEq/L (102 mmol/L); carbon dioxide 16 mEq/L (16 mmol/L); BUN 85 mg/dL (30.35 mmol/L urea); SCr 9.5 mg/dL (840 μmol/L); glucose 112 mg/dL (6.22 mmol/L); calcium 8.2 mg/dL (2.05 mmol/L); phosphate 5.8 mg/dL (1.87 mmol/L); iPTH 438 pg/mL (438 ng/L or 46.9 pmol/L); WBC 5.3 × 103 cells/mm3 (5.3 × 109/L); RBC 3.2 × 106 cells/mm3 (3.2 × 1012/L); Hgb 9.8 g/dL (98 g/L or 6.08 mmol/L); Hct 29% (0.29); platelets 390 × 103 cells/mm3 (390 × 109/L)
What indications does the patient have for dialysis?
What alternatives for renal replacement therapy exist for the patient?
What are the advantages and disadvantages of each modality for renal replacement?
Three types of membranes used for dialysis are classified by the size of the pores and the ability to remove solutes from the bloodstream.
• Conventional (standard) membranes have small pores, which limit solute removal to relatively small molecules, such as creatinine and urea.
• High-efficiency membranes also have small pores, but have a higher surface area that increases removal of small molecules, such as water, urea, and creatinine from the blood.
FIGURE 26–6. In hemodialysis, the patient’s blood is pumped to the dialyzer at a rate of 300 to 600 mL/min. An anticoagulant (usually heparin) is administered to prevent clotting in the dialyzer. The dialyate is pumped at a rate of 500 to 1,000 mL/min through the dialyzer countercurrent to the flow of blood. The rate of fluid removal from the patient is controlled by adjusting the pressure in the dialysate compartment. (From Foote EF, Manley HJ. Hemodialysis and peritoneal dialysis. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: McGraw-Hill, 2008: O106, with permission.)
• High-flux membranes have larger pores that allow for the removal of substances with higher molecular-weight, including some drugs, such as vancomycin, than conventional membranes.
Three primary processes are utilized for the removal of substances from the blood.
• Diffusion is the movement of a solute across the dialyzer membrane from an area of higher concentration (usually the blood) to a lower concentration (usually the dialysate). This process is the primary means for small molecules, such as electrolytes, to be removed from the bloodstream. At times, solutes can be added to the dialysate that are diffused into the bloodstream. Changing the composition of the dialysate allows for control of the amount of electrolytes that are being removed.
• Ultrafiltration is the movement of solvent (plasma water) across the dialyzer membrane by applying hydrostatic or osmotic pressure, and is the primary means for removing water from the bloodstream. Changing the hydrostatic pressure applied to the dialyzer or the osmotic concentration of the dialysate allows for control of the amount of water being removed.
• Convection is the movement of dissolved solutes across the dialyzer membrane by “dragging” the solutes along a pressure gradient with a fluid transport and is the primary means for larger molecules to be removed from the bloodstream, such as urea. Changing the pore size of the dialyzer membrane alters the efficiency of convection and allows for control of the amount of water removed in relation to the amount of solute being removed.
Vascular Access
Long-term permanent access to the bloodstream is a key component of HD. There are three primary techniques used to obtain permanent vascular access in patients receiving HD, including arteriovenous fistulas (AVF), arteriovenous grafts (AVG) and catheters. An AVF is the preferred access method because it has the longest survival rate and the fewest complications.65 An AVF is made by creating an anastomosis between an artery and a vein, usually in the forearm of the nondominant arm (Fig. 26–7). An AVG results in a similar access site, but uses a synthetic graft, usually made of polytetrafluoroethylene, to connect the artery and vein in the forearm (Fig. 26–7). The advantages of the AVG is that it is able to be used within 2 to 3 weeks, compared to 2 to 3 months for an AVF. However, AVGs are complicated by stenosis, thrombosis, and infections, which lead to a shorter survival time of the graft. Double-lumen venous catheters, placed in the femoral, subclavian, or jugular vein, are often used as temporary access while waiting for the AVF or AVG to mature. The catheters are tunneled beneath the skin to an exit site to reduce the risk of infection. Venous catheters can also be used as permanent access in patients in whom arteriovenous access cannot be established.
Complications of Hemodialysis
Complications associated with HD include hypotension, muscle cramping, thrombosis, and infection.
Hypotension
Hypotension is the most common complication seen during hemodialysis. It has been reported to occur with approximately 10% to 30% of dialysis sessions, but may be as frequent as 50% of sessions in some patients.66
Pathophysiology. Hypotension associated with hemodia-lysis manifests as a symptomatic sudden drop of more than 30 mm Hg in mean arterial or systolic pressure or a systolic pressure drop to less than 90 mm Hg during the dialysis session. The primary cause is fluid removal from the bloodstream. Ultrafiltration removes fluid from the plasma, which promotes redistribution of fluids from extracellular spaces into the plasma. However, decreased serum albumin levels and removal of solutes from the bloodstream decrease the osmotic pressure of the plasma relative to the extracellular spaces, slowing redistribution during hemodialysis.67 The decreased plasma volume causes hypotension. Other factors that can contribute to hypotension include antihypertensive medications prior to HD, a target “dry weight” (the target weight after HD session is complete) that is too low, diastolic or autonomic dysfunction, low dialysate calcium or sodium, high dialysate temperature, or ingesting meals prior to HD.
FIGURE 26–7. The predominant types of vascular access for chronic dialysis patients are (A) the arteriovenous fistula and (B) the synthetic arteriovenous forearm graft. The first primary arteriovenous fistula is usually created by the surgical anastamosis of the cephalic vein with the radial artery. The flow of blood from the higher-pressure arterial system results in hypertrophy of the vein. The most common AV graft (depicted in green) is between the brachial artery and the basilic or cephalic vein. The flow of blood may be diminished in the radial and ulnar arteries because it preferentially flows into the low pressure graft. (From Foote EF, Manley HJ. Hemodialysis and peritoneal dialysis. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: McGraw-Hill, 2008: O106, with permission.)
Risk factors that may increase the potential for hypotension include elderly age, diabetes, autonomic neuropathy, uremia, and cardiac disease.66 The symptoms associated with hypotension during dialysis include dizziness, nausea, vomiting, sweating, and chest pain.
Treatment. Nonpharmacologic management of acute hypotension that occurs during dialysis involves placing the patient in the Trendelenburg position (with the head lower than the feet) and decreasing the ultrafiltration rate. Pharmacologic management of acute hypotension during dialysis includes administration of normal saline (100–200 mL), hypertonic saline (23.4%, 10–20 mL), or mannitol (12.5 g) to restore intravascular volume.
Preventive measures for patients who may be prone to hypotension include accurate determination of the “dry weight” and maintaining a constant ultrafiltration rate. Midodrine is an α-adrenergic agonist that is effective in reducing hypotension in patients with autonomic dysfunction that is taken with each dialysis session or as chronic therapy. Midodrine can be administered at doses of 2.5 to 10 mg prior to HD or 5 mg twice daily for chronic hypotension. Side effects of midodrine include pruritus and paresthesias.
Patient Encounter, Part 6
The patient presents to the dialysis clinic 3 months later for her scheduled hemodialysis session. One hour into the session, she begins to complain of feeling dizzy and faint.
PE:
VS: BP 80/50 mm Hg (was 142/88 mm Hg at the start of hemodialysis), P 92 bpm; T 35.1°C (95.1°F); wt 65.9 kg (145 lb)
Chest: RRR, normal S1, S2 present
What are the potential causes of her hypotension?
What are the treatment alternatives for hypotension in the patient?
What are potential alternatives to avoid hypotension in future dialysis sessions?
Hypotension may be related to alterations in levocarnitine levels during dialysis. Patients who have low levels of levocarnitine may benefit from supplementation. Levocarnitine is administered as doses of 20 mg/kg IV at the end of each dialysis session. However, levocarnitine should not be used as a first-line agent for the treatment of hypotension because of the significant cost associated with the treatment. Patients receiving levocarnitine should be evaluated every 3 months for response to therapy.68 Other preventive measures that have not been well studied include caffeine, sertraline, or fludrocortisone.
Muscle Cramps
Pathophysiology. Muscle cramps can occur with up to 20% of dialysis sessions.69 The cause is often related to excessive ultrafiltration, which causes hypoperfusion of the muscles. Other contributing factors to the development of muscle cramps include hypotension and electrolyte and acid-base imbalances that occur during hemodialysis sessions.
Treatment. Nonpharmacologic treatments of muscle cramping that occurs during hemodialysis include decreasing the ultrafiltration rate and accurately determining the “dry weight.” Pharmacologic measures include vitamin E, which is administered at doses of 400 IU daily. Other options that are not as well studied include oxazepam and prazosin.
Thrombosis
Thrombosis associated with hemodialysis most commonly occurs in patients with venous catheter access for dialysis and is a common cause of catheter failure. However, thrombosis can occur in synthetic grafts and less frequently in AV fistulas.
Nonpharmacologic management of thrombosis in a hemodialysis catheter involves saline flushes. Smaller clots may be managed by balloon angioplasty to mechanically open the catheter. In severe cases in whom clots cannot be removed by either mechanical or pharmacologic therapy, the catheter may require replacement.
Pharmacologic management of thrombosis includes local administration of thrombolytic agents. Alteplase (2 mg per port) and reteplase (0.5 unit per port) are the two most commonly used agents today. Urokinase has been used in the past, but after its reintroduction to the U.S. market, the larger dosed vial size makes it less cost effective than the newer agents.
Infection
Infections are an important cause of morbidity and mortality in patients receiving hemodialysis. The cause of infection is usually related to organisms found on the skin, namely Staphylococcus epidermidisand S. aureus. Other organisms have also been found to cause access-related infections. The greatest risk to patients receiving hemodialysis is the development of bacteremia. As with thrombosis, venous catheters are most commonly infected, followed by synthetic AV grafts, and finally AV fistulas.
Blood cultures should be obtained for any patient receiving hemodialysis who develops a fever. Nonpharmacologic management of infections involves preventive measures with sterile technique, proper disinfection, and minimizing the use and duration of venous catheters for hemodialysis access.
Pharmacologic management of infections should cover the Gram-positive organisms that most frequently cause access-related infections. Patients who have positive blood cultures should receive treatment tailored to the organism isolated. Preventive measures for access-related infections include mupirocin at the exit site and povidone-iodine ointment. The recommendations of the NKF for treatment of infections associated with hemodialysis are listed in Table 26–10.
Peritoneal Dialysis
Principles of PD
PD utilizes similar principles as hemodialysis in that blood is exposed to a semipermeable membrane against which a physiologic solution is placed. In the case of PD, however, the semipermeable membrane is the peritoneal membrane, and a sterile dialysate is instilled into the peritoneal cavity. The peritoneal membrane is composed of a continuous single layer of mesothelial cells that covers the abdominal and pelvic walls on one side of the peritoneal cavity, and the visceral organs, including the GI tract, liver, spleen, and diaphragm on the other side. The mesothelial cells are covered by microvilli that increase the surface area of the peritoneal membrane to approximate body surface area (1–2 m2). Blood vessels that supply the abdominal organs, muscle, and mesentery serve as the blood component of the system.
The gaps between the mesothelial cells allow for large solutes to pass through into the bloodstream. Both the interstitium and endothelial cells of the blood vessels provide resistance to limit the solute size that is removed from the blood. Diffusion is the most important component of solute transport in PD, which is enhanced by the large surface area and volume of dialysate, as well as contact time with the peritoneal membrane. Ultrafiltration is achieved in PD by creating an osmotic pressure gradient between the dialysate and the blood. Traditionally, glucose has been used to create the osmotic gradient, but the solutions are not biocompatible with the peritoneal membrane, resulting in cytotoxicity of the cells. More recently, polymeric glucose derivatives, such as icodextrin, have been used to create a colloid-driven osmosis that results in ultrafiltration and convection of solute removal.
In PD, prewarmed dialysate is instilled into the peritoneal cavity where it “dwells” for a specified length of time (usually one to several hours, depending on the type of PD) to adequately clear metabolic waste products and excess fluids and electrolytes. At the end of the dwell time, the dialysate is drained and replaced with fresh dialysate. The continuous nature of PD provides for a more physiologic removal of waste products from the bloodstream, which mimics endogenous kidney function by decreasing the fluctuations seen in serum concentrations of the waste products. Similarly, water is removed at a more constant rate, lessening the fluctuations in intravascular fluid balance and providing for more hemodynamic stability.
There are several types of PD that are used:
Table 26–10 Management of Hemodialysis Access Infections
• Continuous ambulatory peritoneal dialysis (CAPD) is the most common. The patient exchanges 1 to 3 L of dialysate every 4 to 6 hours throughout the day with a longer dwell time overnight.
• Automated peritoneal dialysis (APD) procedures involve the use of a cycler machine that performs sequential exchanges overnight while the patient is sleeping.
• Continuous cycling PD (CCPD) performs three to five exchanges throughout the night. The final exchange remains in the peritoneal cavity to dwell for the duration of the day.
• Nightly intermittent PD (NIPD) performs six to eight exchanges throughout the night. The final exchange of dialysate is drained in the morning and the peritoneal cavity remains empty throughout the day.
• Nocturnal tidal PD (NTPD) is similar to NIPD, with the exception that only a portion of the dialysate is exchanged throughout the night. The final exchange is drained in the morning and the peritoneal cavity remains empty throughout the day.
Peritoneal Access
Access to the peritoneal cavity requires placement of an indwelling catheter with the distal end of the catheter resting in the peritoneal cavity. The central portion of the catheter is generally tunneled under the abdominal wall and subcutaneous tissue where it is held in place by cuffs that provide stability and mechanical support to the catheter. The proximal portion of the catheter exits the abdomen near the umbilicus (Fig. 26–8). There are several types of indwelling catheters available; the most common is the Tenckhoff catheter. Placement and handling of the catheter during PD exchanges requires a sterile environment to minimize the risk of infectious complications.
FIGURE 26–8. Diagram of the placement of a peritoneal dialysis catheter through the abdominal wall into the peritoneal cavity. (From Foote EF, Manley HJ. Hemodialysis and peritoneal dialysis. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: McGraw-Hill, 2008: O110, with permission.)
Complications of Peritoneal Dialysis
Complications associated with PD include mechanical problems related to the PD catheter, metabolic problems associated with the components of the dialysate fluid, damage to the peritoneal membrane, and infections (Table 26–11). Strategies to manage infectious complications of PD are discussed below.
Peritonitis
Peritonitis is a leading cause of morbidity in PD patients, which often leads to loss of the catheter and subsequent change to HD as the treatment modality. However, recent advances with connectors used during instillation and drainage of dialysate and delivery systems have dramatically decreased the incidence of peritonitis. Peritonitis can be caused by chemical irritation or microorganisms.
Pathophysiology. Gram-positive organisms, namely S. epider-midis, are the most common cause of peritonitis. Other pathologic organisms include S. aureus, streptococcal species, enterococcus species, Gram-negative organisms including Escherichia coli and Pseudomonas species, and fungal organisms. Peritonitis should be presumed if cloudy fluid is drained from the peritoneal cavity and the fluid should be evaluated by cultures. Antibiotic treatment should be initiated immediately, until cell counts and cultures prove otherwise.70 Patients with peritonitis may also complain of abdominal pain, although pain may be absent in some cases.
Treatment. The International Society of Peritoneal Dialysis (ISPD) revised the recommendations for the treatment of PD-related infections in 2005.70 Drug selection for empiric treatment of peritonitis should cover both Gram-positive and Gram-negative organisms specific to the dialysis center and be based on the protocols and sensitivity patterns of organisms known to cause peritonitis, as well as the history of infections in the patient. First-generation cephalosporins, such as cefazolin, or vancomycin are recommended for empiric coverage of Gram-positive organisms. Appropriate coverage for Gram-negative organisms includes third- or fourth-generation cephalosporins, such as ceftazidime or cefepime, or aminoglycosides. Alternatives for Gram-negative coverage include oral fluoroquinolones. An example of an appropriate empiric treatment for peritonitis includes cefazolin in combination with ceftazidime, cefepime, or an aminoglycoside. If the patient has a cephalosporin allergy, vancomycin in combination with an aminoglycoside is an alternative empiric treatment.70
Table 26–11 Common Complications During Peritoneal Dialysis
|
Mechanical Complications |
|
Kinking in catheter |
|
Catheter migration |
|
Catheter adherence to peritoneal tissue |
|
Excessive movement of catheter at exit site |
|
Peritoneal Damage |
|
Alterations in permeability of the peritoneal membrane |
|
Pain |
|
Impingement of the catheter tip on visceral organs Instillation pain |
|
• Rapid inflow of dialysate |
|
• Acidic pH of dialysate |
|
• Chemical irritation from dialysate additives (e.g., antibiotics) |
|
• Low dialysate temperature |
|
Infections |
|
Peritonitis |
|
Metabolic Complications |
|
Exacerbation of diabetes mellitus from glucose load Fluid overload |
|
• Exacerbation of chronic heart failure |
|
• Edema |
|
• Pulmonary congestion |
|
Electrolyte abnormalities |
|
Malnutrition |
|
• Albumin and amino acid loss |
|
• Muscle wasting |
|
• Increased adipose tissue |
|
• Fibrin formation in dialysate |
The preferred route of administration is intraperitoneal (IP) rather than IV to achieve maximum concentrations at the site of infection. Antibiotics can be administered IP intermittently as a single large dose in one exchange per day or continuously as multiple smaller doses with each exchange. Intermittent administration requires at least 6 hours of dwell time in the peritoneal cavity to allow for adequate systemic absorption and provides adequate levels to cover the 24-hour period. However, continuous administration is better suited for PD modalities that require more frequent exchanges (less than 6-hour dwell time). The reader should refer to the ISPD guidelines for dosing recommendations for IP antibiotics in CAPD and automated PD patients.70 The dose of the antibiotics should be increased by 25% for patients with residual kidney function who are able to produce more than 100 mL urine output per day.
Once the organism has been identified and sensitivities are known, drug selection should be adjusted to reflect the susceptibilities of the organism. Streptococcal, staphylococ-cal, and enterococcal species sensitive to β-lactam antibiotics should be treated with continuous IP dosing to increase efficacy and minimize resistance.70 Peritonitis caused by S. aureus or P. aeruginosa are often associated with catheter-related infections, which are difficult to treat and often require removal of the catheter. Rifampin 600 mg orally daily (in a single or divided dose) may be added to IP vancomycin for the treatment of methicillin-resistant S. aureus (MRSA), but should be limited to duration of 1 week to minimize the development of resistance. Two antibiotics are required for treatment of P. aeruginosa peritonitis.70 If multiple organisms are cultured, treatment should cover all of the organisms, including anaerobic organisms, and the patient should be evaluated for other intra-abdominal pathologies.70
Peritonitis caused by fungal organisms is associated with mortality in 25% of patients,70 which can be reduced by removing the catheter after fungal organisms are identified. Empiric treatment should include IP amphotericin B and flucytosine.70 Although IP amphotericin administration is associated with chemical irritation and pain, penetration of amphotericin into the peritoneal cavity is poor with IV administration. Fluconazole, voriconazole, or caspofungin may be suitable alternatives, depending on culture results.
Catheter-Related Infections
Catheter-related infections generally occur at the exit site or the portion of the catheter that is tunneled in the subcutaneous tissue. Previous infections increase the risk and incidence of catheter-related infections.
Pathophysiology. The major pathologic organisms responsible for causing catheter-related infections are S. aureus and P. aeruginosa. These organisms also cause the most serious catheter-related infections. S. epidermidis is found in less than 20% of catheter-related infections. Other organisms include diphtheroids, anaerobic bacteria, Legionella, and fungi.70
Exit-site infections present with purulent drainage at the site. Erythema may or may not be present with an exit-site infection. Tunnel infections are generally an extension of the exit-site infection and rarely occur alone. Symptoms of a tunnel infection may include tenderness, edema, and erythema over the tunnel pathway, but are often asymptomatic. Ultrasound can be used to detect tunnel infections in asymptomatic patients. Exit-site infections caused by S. aureus and P. aeruginosa often spread to tunnel infections and are the most common causes of catheter-infection–related peritonitis.
Treatment. Exit-site infections may be treated immediately with empiric coverage, or treatment may be delayed until cultures return. Empiric treatment of catheter-related infections should cover S. aureus. Coverage for P. aeruginosa should also be included if the patient has a history of infections with this organism.70 Cultures and sensitivity testing are particularly important in tailoring antibiotic therapy for catheter-related infections to ensure eradication of the organism and prevent recurrence or related peritonitis.
Less severe infections may be treated with topical antibiotic cream, although this practice is controversial. Oral antibiotics are also effective for treatment of catheter-related infections. Empiric or routine use of vancomycin for Gram-positive infections should be avoided unless the infection is caused by MRSA. Rifampin may be added to therapy for severe infections or slowly-resolving S. aureus infections, but monotherapy is not recommended.70 Oral fluoroquinolones are used as first-line agents to treat P. aeruginosa, which can be difficult to treat and require prolonged treatment. If the infection is slow to resolve or if it recurs, IP ceftazidime or a second agent should be added.70Treatment of catheter-related infections should be continued until the exit site appears normal with no erythema or drainage. Generally, at least 2 weeks of therapy or longer are required to ensure complete eradication of the organism and prevent future recurrence, which is common with S. aureus and P. aeruginosa. Infections that do not resolve may require replacement of the PD catheter. Catheter-related infections that present in conjunction with or progress to peritonitis with the same organism require removal of the PD catheter until the peritonitis is resolved.70
Prophylaxis of Peritonitis and Catheter-Related Infections
Prevention of peritonitis and catheter-related infections starts when the catheter is placed. The exit site should be properly cared for until it is well healed before it can be used for PD. Patients should receive proper instructions for care of the catheter during this time period, which can last up to 2 weeks. Patients should also be instructed on the proper techniques to use for dialysate exchanges to minimize the risk of infections during exchanges, which is the most common cause of peritonitis.
Intranasal S. aureus increases the risk of S. aureus exit-site infections, tunnel infections, peritonitis, and subsequent catheter loss.70 Several measures have been used to decrease the risk of peritonitis caused by S. aureus, including mupirocin cream applied daily around the exit site, intranasal mupirocin cream twice daily for 5 days each month, or rifampin 300 mg orally twice daily for 5 days, repeated every 3 months.70 Mupirocin use is preferred over rifampin to prevent the development of resistance to rifampin, although mupirocin resistance has also been reported.70 Other measures that have been used to decrease both S. aureus and P. aeruginosa infections include gentamicin cream applied twice daily and ciprofloxacin otic solution applied daily to the exit site.70
Outcome Evaluation
Clinical improvement should be seen within 48 hours of initiating treatment for peritonitis or catheter-related infections. Perform daily inspections of peritoneal fluid or the exit site to determine clinical improvement. Peritoneal fluid should become clear with improvement of peritonitis and erythema, and discharge should remit with improvement of catheter-related infections. If no improvement is seen within 48 hours, obtain additional cultures and cell counts to determine the appropriate alterations in therapy.
Abbreviations Introduced in This Chapter
Patient Care and Monitoring
1. Assess the patient to determine if the patient should be evaluated for CKD. Does the patient have any risk factors for CKD?
2. Review any available laboratory data to determine the staging of CKD.
3. Obtain a thorough medical and medication history from the patient. Does the patient have any concomitant diseases, such as diabetes or hypertension, that should be treated to prevent the progression of CKD?
4. Determine if an ACE-I or ARB is appropriate for the patient. Does the patient have proteinuria?
5. Develop a plan to assess and optimize treatment of CKD.
6. Determine if the patient requires medical treatment for electrolyte imbalances. Does the patient have edema? Does the patient have an arrhythmia?
7. Educate the patient on dietary changes to manage electrolyte imbalances associated with CKD.
8. Assess the patient for the presence of anemia. Do the laboratory tests suggest the patient requires medical treatment?
9. Develop a plan to assess and optimize treatment for anemia.
10. Determine if the patient requires medical intervention to prevent the development of or treatment for sHPT.
11. Develop a plan to assess and optimize treatment for sHPT.
12. Establish if the patient requires RRT.
13. Evaluate the patient for complications associated with dialysis. Does the patient develop hypotension or cramps during hemodialysis? Does the patient have symptoms consistent with peritonitis or a catheter infection?
14. Develop a plan to assess and optimize treatment for complications associated with dialysis.
15. Stress the importance of adherence with the treatments for CKD and associated complications, including lifestyle modifications and medications. Recommend a therapeutic regimen that is easy for the patient to accomplish.
16. Provide patient education with regard to CKD and the associated complications, lifestyle modifications, and drug therapy:
• What causes CKD and what things to avoid.
• Possible complications of CKD and symptoms associated with the complications.
• When to take medications.
• What potential adverse effects may occur.
• Which drugs may interact with therapy.
• Warning signs to report to the physician (edema, irregular heart beat, fatigue, unusual bleeding).
Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.
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