Joanna Q. Hudson and Lori D. Wazny
KEY CONCEPTS
Chronic kidney disease (CKD) is classified based on the cause of kidney disease, assessment of glomerular filtration rate, and extent of proteinuria.
Frequent complications of advanced CKD include altered sodium and water balance, hyperkalemia, metabolic acidosis, anemia, CKD-related mineral and bone disorder (CKD-MBD), and cardiovascular disease.
Reduction of kidney mass, development of glomerular hypertension, and intratubular proteinuria are key mechanisms responsible for the progression of CKD.
Anemia of CKD is primarily caused by a deficiency in the production of endogenous erythropoietin by the kidney with iron deficiency as a contributing factor.
CKD-MBD includes abnormalities in parathyroid hormone (PTH), calcium, phosphorus, the calcium–phosphorus product, vitamin D, bone turnover, and soft-tissue calcifications and contributes to extravascular calcifications.
Guidelines by the National Kidney Foundation Kidney Disease/Dialysis Outcomes Quality Initiative (NKF-KDOQI) and Kidney Disease: Improving Global Outcomes (KDIGO) provide information to assist healthcare providers in clinical decisions and the design of appropriate therapy to manage CKD progression and the associated complications.
Patient education plays a critical role in the appropriate management of patients with CKD and related complications. A multidisciplinary team structure is a rational approach to provide this education and effectively design and implement the extensive nonpharmacologic and pharmacologic interventions required.
Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are key pharmacologic treatments of CKD because of their effects on renal hemodynamics and reduction of blood pressure, which help to limit kidney disease progression.
Management of anemia includes administration of erythropoietic-stimulating agents (ESAs) (epoetin alfa, darbepoetin alfa) and regular iron supplementation (oral or IV administration) to maintain hemoglobin and prevent the need for blood transfusions. There is evidence indicating a higher risk of cardiovascular events when hemoglobin is targeted to greater than 11 g/dL (110 g/L; 6.83 mmol/L).
Management of CKD-MBD includes dietary phosphorus restriction, phosphate-binding agents, vitamin D supplementation, and calcimimetic therapy.
Chronic kidney disease (CKD) is defined as abnormalities in kidney structure or function, present for 3 months or longer, with implications for health.1 Structural abnormalities include albuminuria of more than 30 mg/day, presence of hematuria or red cell casts in urine sediment, electrolyte and other abnormalities due to tubular disorders, abnormalities detected by histology, structural abnormalities detected by imaging, or history of kidney transplantation. An abnormality in kidney function is usually indicated by a decrease in glomerular filtration rate (GFR).
CKD is classified by cause of kidney disease, GFR category, and albuminuria level based on new recommendations from the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines for evaluation and management of CKD.1 This is referred to as CGA staging (cause, GFR, albuminuria). Tables 29-1 and 29-2 outline the GFR and albuminuria categories. Table 29-1 also shows the corresponding staging terminology by the Kidney Disease Outcomes Quality Initiative (KDOQI).2 For the purpose of this chapter, the KDOQI terminology for staging will be used since currently most studies and recommendations refer to the KDOQI staging system. When the GFR remains below 15 mL/min/1.73 m2 (0.14 mL/s/m2) renal replacement therapy, either dialysis (see Chap. 30) or transplantation (see Chap. 70), is indicated. The patient with stage 5 CKD requiring chronic dialysis or renal transplantation is said to have end-stage renal disease (ESRD). In this chapter, ESRD refers specifically to patients who are receiving chronic dialysis and transplantation and is covered in Chapters 30 and 70.
TABLE 29-1 GFR Categories1,2
TABLE 29-2 Quantifi cation of Proteinuria by Different Methods
The prognosis of CKD can vary and is dependent on the following factors: (a) cause of kidney disease; (b) GFR at time of diagnosis; (c) degree of albuminuria; and (d) presence of other comorbid conditions. Patients with any of the following should be referred to a nephrologist for evaluation and collaborative management: GFR less than 30 mL/min/1.73 m2 (0.29 mL/s/m2), persistent and significant albuminuria, progression of CKD (e.g., drop in GFR category), presence of urinary red cell casts not readily explained, CKD and hypertension refractory to treatment (e.g., ≥4 antihypertensive agents), persistent abnormalities of serum potassium, recurrent or extensive nephrolithiasis, or hereditary kidney disease.1
Often complications of CKD are unrecognized or are inappropriately managed, and for many patients this contributes to significant morbidity, premature mortality, or a poor prognosis by the time they reach ESRD. Frequent complications of advanced CKD include altered sodium and water balance, hyperkalemia, metabolic acidosis, anemia, CKD-related mineral and bone disorder (CKD-MBD), and cardiovascular disease (CVD). This chapter covers the pathophysiology and treatment of anemia and CKD-MBD with other complications briefly discussed at the end of the chapter. The reader is referred to Chapters 34, 36, and 37 for a more detailed discussion of sodium and water balance, hyperkalemia, and metabolic acidosis. Table 29-3 lists other complications of advanced CKD not covered in detail in this chapter.
TABLE 29-3 Other Complications of Chronic Kidney Disease
EPIDEMIOLOGY
Drawing from National Health and Nutrition Examination Survey (NHANES) data, the prevalence of CKD (not including the ESRD population) in the United States is estimated to affect over 25 million people, 13% of the U.S. population.3 CKD is more likely in individuals over 60 years of age and in those with diabetes, hypertension, and CVD. In the National Kidney Foundation’s Kidney Early Evaluation Program (KEEP), over 32,000 of the 124,041 participants (25%) had CKD.4 The 2012 report of the United States Renal Data System (USRDS) indicates that in 2010, the latest year for which data are available, approximately 114,083 new cases of ESRD were reported (incidence) and the number of individuals with ESRD (prevalence) as of the end of 2010 was just over 593,086, including 413,725 patients on dialysis and 179,361 with a functioning kidney after transplantation.3 Incidence rates of ESRD are higher in African Americans (3.4 times greater) and Native Americans (0.5 times greater) compared with whites and 1.5 times greater in Hispanics than in non-Hispanics.3 In patients 75 years of age and older, the incidence and prevalence rates have increased since the year 2000 by 12% and 44%, respectively. Total Medicare costs for ESRD in 2010 were approximately $32.9 billion, an 8% increase from the previous year, which accounted for approximately 6% of the total Medicare budget.3
Mortality in the CKD population is 59% higher than in non-CKD patients when adjusted for age, gender, race, comorbidity, and prior hospitalizations.3 The mortality rate in the ESRD population increases substantially with age and is much greater than age-matched individuals in the general population for every age group. In fact, ESRD patients have a mortality rate 6 to 8 times higher than age-matched individuals without kidney disease.3 Associated predictors of mortality and hospitalization in hemodialysis patients include decreased serum albumin, elevated phosphorus, low hemoglobin (Hb) level, catheter use for dialysis access, and the presence of comorbidities, such as diabetes and CVD.3,5 The association of mortality with these factors highlights the need to address complications as soon as they are detected, ideally prior to development of ESRD.
The prevalence of secondary complications at specific stages of CKD is difficult to ascertain because of limited data and use of various definitions. Data from the KEEP study targeting a higher-risk population reported that anemia (defined as a Hb of <13.5 g/dL [<135 g/L; <8.38 mmol/L] in men and <12 g/dL [<120 g/L; <7.45 mmol/L] in women) was present in over 20% of individuals with CKD with a much higher prevalence (approximately 60%) in those with stage 4 or 5 CKD.4 Forty-five percent of CKD KEEP participants with an available parathyroid hormone (PTH) level had an elevated value. Other evaluations have reported elevated PTH (>65 pg/mL, [>65 ng/L; >7 pmol/L]) in 56% of individuals with an estimated GFR (eGFR) less than 60 mL/min/1.73 m2.6
Although the number of patients with ESRD is substantial, it is projected that by the year 2020 the prevalence will significantly increase, with the majority of cases attributable to diabetes. CKD is one of the public health priorities for the nation and is one of the disease prevention and health promotion focus areas in Healthy People 2020.7 The CKD goals are as follows: (a) reduce the proportion of the U.S. population with CKD, (b) increase the proportion of persons with CKD who know they have impaired kidney function, (c) increase the proportion of persons with diabetes and CKD who receive recommended medical evaluation, (d) increase the proportion of persons with diabetes and CKD who receive recommended medical treatment with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers, (e) improve cardiovascular care in persons with CKD, (f) reduce the death rate among people with CKD, (g) reduce the rate of new cases of ESRD, (h) reduce kidney failure due to diabetes, (i) increase the proportion of CKD patients receiving care from a nephrologist at least 12 months before the start of renal replacement therapy, and (j) reduce deaths in persons with ESRD.
ETIOLOGY OF CKD
Susceptibility Factors
CKD susceptibility factors include advanced age, low income or education, and racial/ethnic minority status, as well as reduced kidney mass, low birth weight, family history of CKD, inflammation, and dyslipidemia.8–11 Although most of these susceptibility factors are not amenable to pharmacologic or lifestyle interventions, they are useful for identifying individuals at high risk of CKD.
Initiation Factors
Initiation factors are conditions that directly result in kidney damage and are modifiable by pharmacologic therapy. Diabetes mellitus continues to be the leading cause of CKD and ultimately of ESRD in the United States and Canada, accounting for 45% of new ESRD cases in 2010.3 Hypertension is the second leading cause of ESRD and it accounts for approximately 29% of new cases of ESRD.3Glomerulonephritis, which includes a wide variety of lesions caused by immunologic, vascular, and other idiopathic diseases (see Chap. 32), is the third leading cause of ESRD. Other diseases and conditions causing CKD are polycystic kidney disease, Wegener’s granulomatosis, vascular diseases, and human immunodeficiency virus (HIV) nephropathy.
Progression Factors
Progression risk factors are those associated with further decline in kidney function. Persistence of the underlying initiation factors (e.g., diabetes mellitus, hypertension, glomerulonephritis) themselves may serve as the most important predictor of progressive CKD. Other factors associated with progression include those that may be consequent to the underlying kidney disease (e.g., hypertension, proteinuria) or independent of underlying kidney disease (e.g., smoking, obesity).
Diabetes Mellitus
Without treatment, nearly 80% of patients with type 1 diabetes and microalbuminuria will develop overt nephropathy and nearly 50% of those with type 1 diabetes, nephropathy, and hypertension will develop stage 5 CKD within 10 years.12,13 In contrast, only 20% to 40% of those with type 2 diabetes for more than 15 years will demonstrate progressive disease.12 A recent evaluation of participants in the Diabetes Control and Complications Trial (DCCT) and the Epidemiology of Diabetes Interventions and Complications (EDIC) studies suggests the historical estimates of diabetes with CKD may be inflated, since only 17% to 25% of the type 1 diabetic participants developed diabetes with CKD after 30 years.14 It is not clear whether the lower incidence represents an improvement in overall care or simply is a by-product of enrollment in these studies. Progression of diabetes with CKD likely has multiple determinants including both hypertensive and glycemic control and therefore occurs at a variable rate.
Hypertension
Hypertension is both a cause of CKD and a result of CKD. Early treatment of hypertension and achievement of target blood pressure has been demonstrated to slow the rate of progression of CKD. The KDIGO guidelines for the management of blood pressure in CKD recommend the goal is to control blood pressure at all stages of CKD regardless of the underlying cause.15
Proteinuria
The importance of proteinuria in the progression of CKD has been well documented.16 Proteinuria is also a strong risk factor for cardiovascular mortality and morbidity.17 In diabetes with CKD, an albumin excretion rate higher than 30 mg per 24 hours strongly predicted the development of progression of CKD.18 In the Modification of Diet in Renal Disease (MDRD) study, the baseline level of proteinuria also predicted progression of CKD in nondiabetic kidney disease.19 The joint role of blood pressure and proteinuria on the progression of CKD was investigated in a meta-analysis that compared the efficacy of antihypertensive regimens for patients with predominantly nondiabetic kidney disease.20 Patients with higher systolic blood pressures and proteinuria greater than 1 g/day had a significantly greater risk for progression of CKD.
Smoking
Smoking is associated with an acute reduction in GFR and an increase in urinary albumin excretion, heart rate, and blood pressure, likely secondary to nicotine exposure.21 Data also suggest that smoking may promote initiation and progression of CKD in patients with type 1 and type 2 diabetes.22,23 The “cigarette pack years” was an independent predictive factor for CKD progression among diabetic subjects.24 In addition, smoking has been associated with the diagnosis of CKD in those with hypertension, especially among black patients, and with the development of stage 5 CKD.21,25 Smoking has also been identified as a risk factor for CKD progression in patients with IgA nephropathy, polycystic kidney disease, and systemic lupus erythematosus.22,26
Obesity
Population data from Kaiser Permanente revealed an increased risk of stage 5 CKD in overweight and obese subjects.27 The risk of stage 5 CKD was directly related to the magnitude of obesity and remained even after adjustment for diabetes and hypertension. Another study showed that a BMI ≥25 kg/m2 at age 20 years is associated with a threefold increase in risk of CKD compared with a BMI lower than 25 kg/m2. Obesity (BMI ≥30 kg/m2) among men and morbid obesity (BMI ≥35 kg/m2) among women were associated with threefold to fourfold increases in risk.28 This finding has been supported by results of a meta-analysis where the presence of kidney disease was associated with higher BMI and obesity led to more progressive loss of kidney function.29 Observational studies have also shown obesity to be an independent risk factor for onset of CKD.30 The available data suggest the need to include weight reduction as part of the treatment of progressive kidney disease.
PATHOPHYSIOLOGY
Chronic Kidney Disease
Progression of CKD to ESRD occurs over years to decades in the majority of people, with the precise mechanism of kidney damage dependent on the etiology of the disease. As evidenced by the variety of initiation and progression factors, kidney damage can result from an array of heterogeneous causes. Diabetes with CKD is characterized by glomerular mesangial expansion. In hypertensive nephrosclerosis, the kidney’s arterioles have arteriolar hyalinosis while with polycystic kidney disease renal cysts develop. While the initial structural damage depends on the primary disease affecting the kidney, the majority of progressive nephropathies share a final common pathway to irreversible renal parenchymal damage and ESRD (Fig. 29-1).31 The key elements of this pathway are (a) loss of nephron mass, (b) glomerular capillary hypertension, and (c) proteinuria.
FIGURE 29-1 Proposed mechanisms for progression of kidney disease.
Exposure to any of the initiation risk factors can result in loss of nephron mass. The remaining nephrons hypertrophy to compensate for the loss of nephron mass and kidney function.31 Initially, this compensatory hypertrophy may be adaptive; however, over time it can lead to the development of intraglomerular hypertension, possibly mediated by angiotensin II.32 Angiotensin II is a potent vasoconstrictor of both afferent and efferent arterioles, but it preferentially affects the efferent arterioles, leading to increased pressure within the glomerular capillaries and consequent increased filtration fraction. The development of intraglomerular hypertension usually correlates with the development of systemic arterial hypertension. High intraglomerular capillary pressure impairs the size-selective function of the glomerular permeability barrier, resulting in increased urinary excretion of albumin and proteinuria.32Angiotensin II may also mediate CKD progression through nonhemodynamic effects.
Proteinuria alone may promote progressive loss of nephrons as a result of direct cellular damage.31 Filtered proteins such as albumin, transferrin, complement factors, immunoglobulins, cytokines, and angiotensin II are toxic to kidney tubular cells. Numerous studies have demonstrated that the presence of these proteins in the renal tubule leads to increased production of inflammatory and vasoactive cytokines such as endothelin and monocyte chemoattractant protein-1 (MCP-1).33 Proteinuria is also associated with the activation of complement components on the apical membrane of proximal tubules. Accumulating evidence now suggests that intratubular complement activation may be the key mechanism of damage in the progressive proteinuric nephropathies.33 These events ultimately lead to scarring of the interstitium, progressive loss of structural nephron units, and a reduction in GFR.
Anemia of Chronic Kidney Disease
The primary cause of anemia in CKD patients is a decrease in production of erythropoietin, the glycoprotein hormone necessary for erythropoiesis (red blood cell production), by interstitial fibroblasts in the renal cortex of the kidney where approximately 90% of production occurs. In individuals with normal kidney function, plasma concentrations of erythropoietin increase exponentially in response to hypoxia; however, this response is lost as kidney disease progresses to stage 3 CKD and beyond. The result is a normochromic (normal colored red cell), normocytic (normal size red cell) anemia.34
Iron deficiency is common in individuals with stage 5 CKD due to decreased GI absorption of iron, inflammation, frequent blood testing, blood loss from hemodialysis, and increased iron demands from erythropoietic-stimulating agent (ESA) therapy, making it the leading cause of resistance to ESAs.35 Frequent iron supplementation is necessary to prevent and correct iron deficiency in both the ESRD and CKD populations. Hepcidin is a hormone produced by the liver that is responsible for regulation of iron. This hormone directly inhibits the protein ferroportin that transports iron out of storage cells. When iron stores are high, hepcidin production is increased to block the transfer of iron from enterocytes to the plasma. Conversely, hepcidin production is decreased when iron stores are low. Hepcidin production is also induced by inflammation or infection. As a result, the increase in hepcidin in inflammatory conditions may lead to a sequestering of iron and ineffective red blood cell production (e.g., iron-restricted erythropoiesis). The fact that hepcidin plays such a role in iron regulation has prompted the development of hepcidin antagonists to potentially alter iron transport. At this time there is no agent that is commercially available.36
Additional factors contributing to the development of anemia of CKD are the decreased red cell life span (from the normal of 120 days to approximately 60 days in individuals with stage 5 CKD) and vitamin B12 and folate deficiencies. A schematic of the process of red blood cell production is shown in Figure 29-2 that includes factors that impair this process in individuals with CKD.35
FIGURE 29-2 The process of red blood cell production (erythropoiesis) in the bone marrow requires erythropoietin and iron. This process is impaired due to factors that occur in advanced CKD such as accumulation of uremic toxins and inflammation (shown in rectangles and ovals). (BFU-E, burst-forming unit erythroid; CFU-E, colony-forming unit erythroid; RBC, red blood cells.) (Reprinted from reference 35. Copyright © 2009, with permission from Elsevier.)
Anemia in the CKD population has been associated with decreased quality of life, increased hospitalizations, and CVD.37 ESAs have been shown to reduce these morbidities; however, there is now increasing evidence that treatment of anemia to achieve Hb targets above 11 g/dL (110 g/L; 6.83 mmol/L) may lead to increased risk of cardiovascular events and death.38–41 Thus, treatment approaches have shifted to less aggressive use of ESAs and more conservative Hb goals in the CKD population.42
CKD-Related Mineral and Bone Disorder
Disorders of mineral and bone metabolism are common in the CKD population and include abnormalities in PTH, calcium, phosphorus, the calcium–phosphorus product (Ca × P product), vitamin D, and bone turnover, as well as soft-tissue calcifications. Historically these abnormalities have been described as characteristics of secondary hyperparathyroidism (sHPT) and renal osteodystrophy (ROD). The more recently adopted term CKD-MBD encompasses the abnormalities in mineral and bone metabolism as well as associated calcifications.43
The pathophysiology of CKD-MBD is complex (Fig. 29-3). Calcium and phosphorus homeostasis is mediated through the effects of PTH, the precursor form of vitamin D known as 25-hydroxyvitamin D (25OHD), active vitamin D or 1,25-dihydroxyvitamin D (calcitriol), and fibroblast growth factor-23 (FGF-23) on bone, the GI tract, kidney, and the parathyroid gland. As kidney function declines, there is a decrease in phosphorus elimination, which results in hyperphosphatemia and a reciprocal decrease in serum calcium concentration. Hypocalcemia is the primary stimulus for secretion of PTH by the parathyroid glands. PTH secretion is suppressed by the interaction of ionized calcium with the calcium-sensing receptor on the chief cells of the parathyroid gland. Hyperphosphatemia also increases PTH synthesis and release through its direct effects on the parathyroid gland and production of prepro-PTH messenger RNA.44 In an attempt to normalize ionized calcium, PTH decreases phosphorus reabsorption and increases calcium reabsorption by the proximal tubules of the kidney (at least until the GFR falls to less than approximately 30 mL/min/1.73 m2 [0.29 mL/s/m2]) and also increases calcium mobilization from bone. FGF-23 production in bone also increases and this growth factor promotes phosphate excretion by the kidney. The result is a resetting of the calcium and phosphorus homeostasis set point, at least in the early stages of CKD; however, this occurs at the expense of an elevated PTH (“the trade-off hypothesis”). With advanced kidney disease, the kidney fails to respond to PTH or to FGF-23. The increase in PTH is most notable when GFR is less than 60 mL/min/1.73 m2 (0.58 mL/s/m2) (stage 3 CKD) and worsens as kidney function further declines.44
FIGURE 29-3 Pathophysiology of CKD-MBD. (a These adaptations are lost as kidney disease progresses.)
The most active form of vitamin D (1,25-dihydroxyvitamin D3 or calcitriol) promotes increased intestinal absorption of calcium and phosphorus, which helps to normalize ionized calcium. Calcitriol also works directly on the parathyroid gland to suppress PTH production. The enzyme 1-α-hydroxylase is responsible for the final hydroxylation and conversion of the vitamin D precursor, 25OHD, to the active form in the kidney. As kidney disease progresses, the process is impaired due to decreased delivery of 25OHD to the kidney as GFR declines and loss of 1-α-hydroxylase activity. The resultant vitamin D deficiency leads to reduced intestinal calcium and phosphorus absorption and worsening hyperparathyroidism. Increases in FGF-23, which facilitate excretion of phosphorus, also promote calcitriol deficiency.45 Calcitriol deficiency is observed at all levels of GFR, but is more prevalent in individuals with stage 4 or 5 CKD.46 Deficiency in 25OHD (levels of <30 ng/mL [<75 nmol/L]) is also common in individuals with CKD due to decreased dermal synthesis of vitamin D, decreased exposure to sunlight, and reduced dietary intake of vitamin D and is a contributing factor to development of hyperparathyroidism.46
The abnormalities of CKD-MBD lead to bone abnormalities and other associated consequences. The continuous high rate of production of PTH by the parathyroid glands promotes parathyroid hyperplasia. Nodular tissue demonstrates more rapid growth potential and appears to be associated with fewer vitamin D and calcium-sensing receptors, resulting in resistance to the effects of calcium and vitamin D therapy.44 Bone abnormalities are found almost universally in ESRD patients and in the majority of those with stage 3 to 5 CKD.43 The bone abnormalities include osteitis fibrosa cystica (high bone turnover disease), osteomalacia (low bone turnover disease), and adynamic bone disease. Osteitis fibrosa cystica is most common and is characterized by areas of peritrabecular fibrosis. Bone marrow fibrosis and decreased erythropoiesis are also consequences of severe osteitis fibrosa cystica. Osteomalacia was historically noted in hemodialysis patients with aluminum toxicity, a finding less common today due to the decreased use of aluminum-containing phosphate binders and changes in the processing of dialysate solutions to decrease aluminum content. Adynamic lesions are characterized by low amounts of fibrosis or osteoid tissue and low bone formation rates. Multiple risk factors for the development of this bone disease have been identified: high concentrations of dialysate calcium along with high doses of calcium-containing phosphate binders, aggressive management with vitamin D therapy, diabetes, and aluminum toxicity.43 Symptoms of CKD-MBD are often not evident until after significant skeletal damage has developed; consequently, prevention is the key to minimize the consequences of long-term complications. When symptoms such as bone pain and skeletal fractures occur, the disease is not easily amenable to treatment.
The morbidity and mortality of CKD patients is increased in individuals with PTH levels >495 pg/mL (>495 ng/L; >53 pmol/L).47 Elevations of serum phosphorus, even within the upper limits of the normal range, have been associated with increased risk of cardiovascular events and/or mortality (all-cause or cardiovascular mortality) in patients with stage 3 to 5 CKD.48 The incidence of calciphylaxis (also known as calcific uremic arteriolopathy [CUA]), which refers to rapid calcification of subcutaneous (SubQ) tissue, in patients with advanced kidney disease has increased over the last decade and has been associated with CKD-MBD and an elevated Ca × P product, although a direct cause and effect relationship has not been established.49 Intake of calcium from calcium-based binders may also contribute to coronary artery calcification (CAC).43 These data underscore the need to consider all the consequences of elevated PTH, calcium, and phosphorus, not just their effects on bone.
CLINICAL PRESENTATION Stage 4 or 5 Chronic Kidney Disease
Symptoms
• Uremic symptoms (fatigue, weakness, shortness of breath, mental confusion, nausea and vomiting, bleeding, and loss of appetite), as well as itching, cold intolerance, weight gain (from accumulation of fluid), and peripheral neuropathies are common in patients with stage 5 disease.
Signs
• Edema, changes in urine output (volume and consistency), “foaming” of urine (indicative of proteinuria), and abdominal distension.
Laboratory Tests
• Decreased : eGFR, bicarbonate (metabolic acidosis), Hb/hematocrit (Hct; anemia), iron indices (iron deficiency), vitamin D levels, albumin (malnutrition), glucose (may result from decreased degradation of insulin with impaired kidney function or poor oral intake), and calcium (in early stages of CKD).
• Increased : serum creatinine, cystatin C, blood urea nitrogen, potassium, phosphorus, PTH, FGF-23, ACR, PCR, blood pressure (hypertension is a common cause and result of CKD), glucose (uncontrolled diabetes is a cause of CKD), low-density lipoprotein and triglycerides, and calcium (in ESRD).
• Other : may be hemoccult-positive if GI bleeding occurs secondary to uremia.
Other Diagnostic Tests
• Urine sediment abnormalities (hematuria, red blood cell and white blood cell casts, renal tubular epithelial cells)
• Pathologic abnormalities indicating glomerular, vascular, tubulointerstitial disease, or cystic and congenital diseases
• Structural abnormalities such as polycystic kidneys, renal masses, renal artery stenosis, cortical scarring due to infarcts and pyelonephritis, or small kidneys (common in more severe CKD) detected by imaging studies (e.g. ultrasound, computed tomography, magnetic resonance imaging, angiography)
CLINICAL PRESENTATION
Chronic Kidney Disease
CKD is often asymptomatic, which is a reason many patients are not diagnosed with the disease until they reach stage 5 CKD and are at or near the point of requiring renal replacement therapy. This problem has prompted automated reporting by clinical labs of the eGFR as determined by the MDRD equation or Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI equation) for the purpose of identifying individuals with CKD earlier (see eChap. 17). Clinicians must understand how to interpret the eGFR and values for urine albumin excretion to appropriately stage individuals with CKD (Tables 29-1 and 29-2). eChapter 17 provides a detailed discussion of the methods available for detection of urinary albumin and protein.
The albumin-to-creatinine ratio (ACR) is recommended as the preferred measurement for testing of urinary protein because it is relatively standardized and albumin is the most important protein lost in the urine in the majority of patients with CKD.1 Some data suggest, however, that ACR is a poor predictor of 24-hour total protein loss compared with the protein-to-creatinine ratio (PCR) and it is not a better predictor of renal outcomes and mortality in patients with CKD.1 Hence, there may be clinical reasons for a specialist to use PCR instead of ACR to quantify and monitor significant levels of proteinuria (e.g., patients with monoclonal gammopathies). For measurement of both ACR and PCR, an early morning urine sample is preferred since it correlates the best with 24-hour protein excretion and has relatively low intraindividual variability. A random urine sample is acceptable if an early morning urine sample is not available. Conditions that may transiently increase the ACR include menstrual blood, urinary tract infection, exercise, and those conditions that increase vascular permeability (e.g., sepsis).
Twenty-four-hour urine collection for protein remains the standard reference, but this urine collection process is prone to errors, particularly in the outpatient setting or in hospitalized patients who do not have a urinary catheter. Inaccuracies, such as missed collection of a urine sample during the 24-hour period, may contribute to underestimation of true proteinuria.
The subjective and objective findings of CKD that may be present in an individual are dependent on the severity of disease and are more likely to be observed in stage 4 or 5 CKD. Damage to the kidney has detrimental consequences for many other organ systems, particularly once patients develop ESRD. Anemia, CKD-MBD, malnutrition, and fluid and electrolyte abnormalities become more common as kidney function deteriorates. Secondary complications may even be recognized prior to making the diagnosis of CKD and presence of such complications warrants further workup.
Because patients are often asymptomatic, CKD should be suspected in individuals with conditions such as diabetes, hypertension, genitourinary abnormalities, and autoimmune diseases. In addition, individuals of older age and those with a family history of kidney disease should be considered for CKD screening. Recommended screening studies include serum creatinine and assessment of GFR, urinalysis, and/or imaging studies of the kidneys. Abnormal elevations of serum creatinine, reflecting decreases in GFR, or presence of urinary or imaging study abnormalities are indications for a full evaluation of CKD. The rate of GFR loss can vary in CKD because of differences in the underlying disease process and the extent of kidney damage, treatment responsiveness, and compliance with therapies.
DIAGNOSTIC CONSIDERATIONS FOR SECONDARY COMPLICATIONS
As two of the most common complications of CKD, anemia and CKD-MBD should be diagnosed early in the course of CKD.
Anemia of Chronic Kidney Disease
Signs and symptoms of anemia of CKD include fatigue, shortness of breath, cold intolerance, chest pain, tingling in the extremities, tachycardia, headaches, and general malaise. Despite associations of development of LVH with worsening anemia, there are no prospective studies demonstrating that early and aggressive treatment improves cardiovascular end points or reduces LVH in the CKD population. Improvements in quality of life have been observed with increases in Hb, but such improvements must be weighed against reported risks associated with using ESAs to achieve near-normal Hb levels in the CKD population.50
Since individuals with anemia of CKD may be asymptomatic, laboratory evaluation is commonly the initial approach to diagnosing anemia of CKD. According to the KDOQI guidelines for anemia management, the Hb should be measured in all individuals with CKD regardless of stage.51 KDIGO recommends measuring Hb concentrations annually in stage 3 CKD patients, biannually in stage 4 to 5 CKD patients, and at least every 3 months in dialysis patients.42 The diagnosis of anemia is made and further workup of anemia is required when the Hb is less than 13 g/dL (130 g/L; 8.07 mmol/L) for adult males and less than 12 g/dL (120 g/L; 7.45 mmol/L) for adult females using the KDIGO definition.42 Iron deficiency is the primary cause of resistance to treatment of anemia with ESAs; therefore, assessment of the iron status is necessary. The iron indices transferrin saturation (TSat) and serum ferritin provide information on iron immediately available for use in the bone marrow for red blood cell production (TSat) and storage iron (serum ferritin). The TSat is calculated as follows: (serum iron/TIBC) × 100, where TIBC is the total iron-binding capacity. If the TSat and serum ferritin values are below the desired threshold (see Treatment section later in this chapter), iron supplementation is warranted.
Additional workup should be done to evaluate other causes of anemia such as blood loss, deficiencies in vitamin B12 or folate, or other disease states that contribute to anemia, including human immunodeficiency virus infection and malignancies. Red blood cell indices (mean corpuscular volume, mean corpuscular Hb concentration), white blood cell count, differential and platelet count, and absolute reticulocyte count should also be assessed. A stool guaiac test should be performed to rule out GI bleeding. Measurement of serum erythropoietin concentrations is not generally useful since levels may fall into what is considered a “normal” range, but are insufficient relative to the degree of decline in Hb.
CKD-Related Mineral and Bone Disorder
Patients with CKD-MBD are generally asymptomatic until bone manifestations such as prolonged high bone turnover develop or the patient experiences calcifications. Biochemical or imaging abnormalities typically precede clinical manifestations. The biochemical abnormalities of CKD-MBD that should be evaluated in patients with stage 3 CKD include serum phosphorus, calcium, Ca × P product, and PTH. The recommended frequencies of monitoring calcium, phosphorus, and PTH by CKD stage based on the KDOQI and KDIGO guidelines are shown in Table 29-4.43,52 The KDIGO guidelines also recommend monitoring bone-specific alkaline phosphatase annually in stage 4 and 5 CKD patients. The frequency of monitoring these parameters may increase once a diagnosis of CKD-MDB is made, and further information is needed to assess the patient’s response to treatment and to guide decisions about changes in therapy.
TABLE 29-4 Recommended Frequency of Monitoring Calcium, Phosphorus, PTH, and 25OHD by Stage of CKD (KDOQI and KDIGO Guidelines)43,52
In addition to monitoring for biochemical abnormalities that define CKD-MBD, evaluation of bone architecture is also necessary in some cases. The gold standard test for diagnosing bone manifestations of CKD-MBD is a bone biopsy for histologic analysis; however, this is an invasive test that is not easily performed. KDOQI and KDIGO guidelines recommend bone biopsy only in patients in whom the etiology of symptoms is not clear or in individuals with more unique biochemical abnormalities.43,52 This includes patients experiencing unexplained fractures, persistent hypercalcemia, and possible aluminum toxicity. If aluminum concentrations are elevated (60 to 200 mcg/L [2.2 to 7.4 μmol/L]), a deferoxamine test should be done. KDIGO also suggests a bone biopsy be considered in CKD patients prior to beginning treatment with bisphosphonates since adynamic bone disease is a contraindication to the use of these agents. Bone biopsy findings are described on the basis of turnover rate, mineralization, and volume. Bone mineral density testing is not generally recommended in patients with advanced CKD since this test has not been shown to predict fracture risk and does not indicate the type of ROD.43
Abnormalities in mineral metabolism are highly associated with vascular and soft-tissue calcifications, known risk factors for mortality; therefore, diagnostic testing for calcifications should be considered in the evaluation for CKD-MBD. Electron-beam computed tomography (EBCT) is a noninvasive and sensitive method available for detecting cardiovascular calcifications and has been used clinically and in studies in the CKD population. Other methods advocated include lateral abdominal radiographs to detect vascular calcification and echocardiogram to detect valvular calcification. KDIGO suggests these tests are reasonable alternatives to EBCT based on the sensitivity to detect calcifications and lower cost.43
TREATMENT
General Approach to Patient Care
Individuals with CKD should be evaluated frequently to assess the rate of progression of CKD, to diagnose secondary complications and comorbid conditions, and to receive treatment for these complications prior to development of ESRD. Historically, the common complications of anemia and CKD-MBD have not been diagnosed or appropriately managed in the earlier stages of CKD. Late referral to a nephrologist may in part account for this poor management; however, even in ideal clinical environments such as nephrology clinics, these secondary complications may not be recognized in the early stages of CKD.
Management of CKD should be based on the most current consensus guidelines and the best clinical practices such as those developed by the National Kidney Foundation Kidney Disease/Dialysis Outcomes Quality Initiative (NKF-KDOQI), KDIGO, and other relevant professional associations.1,2 The KDOQI and KDIGO guidelines and recommendations were developed based on evidence, when available, and the recommendations of an expert group of individuals. With this in mind, these recommendations should not replace clinical judgment, but should provide a basis on which treatment decisions can be made in the context of both evidence and opinion. The secondary complications of CKD that are addressed in the currently available KDOQI guidelines include anemia of CKD, bone metabolism and disease, CVD in dialysis patients, dyslipidemias, hypertension, and nutrition. KDIGO clinical practice guidelines pertinent to CKD address evaluation and management of CKD, blood pressure MBD, anemia, lipid management, hepatitis C in CKD, and glomerulonephritis.
Appropriate management of CKD ideally involves a multidisciplinary approach to address the nonpharmacologic and pharmacologic interventions, dietary education, and social/financial concerns. The typical team in outpatient dialysis facilities includes physicians (nephrologists), nurses, dietitians, and social workers as mandated by the U.S. government. In some clinical settings pharmacists are also active members of the care team. ESRD patients are prescribed an average of 10 to 12 medications, which increases the potential for drug-related problems (DRPs).3,53 Pharmacists involved with the CKD population have identified DRPs (e.g., inappropriate dose or indication for a medication, adverse drug reactions) that commonly occur in the CKD population and have demonstrated that clinical pharmacy services reduce such problems and improve patient’s quality of life.53 Patients with CKD who have access to an interdisciplinary team as opposed to a nephrologist alone have been shown to have increased Hb values, were more likely to receive ACEI, iron supplementation, and bicarbonate therapies, had a slower decline in eGFR (1.2 mL/min/1.73 m2 vs. 2.5 mL/min/1.73 m2), and had decreased mortality.54–56Interdisciplinary teams in these published studies consisted of nephrologists, nephrology nurses, dietitians, social workers, pharmacists, and diabetes educators.
Pharmacists must be prepared to provide Medication Therapy Management (MTM) for individuals with CKD since this population receives medications and care in the community settings. Drug-dosing guidelines based on the degree of kidney function should be followed, and a complete medication history of prescription and nonprescription medications, as well as herbals and nutritional supplements, should be obtained and routinely updated. Recommendations on drug dosing in patients with CKD are also available from a KDIGO conference that addressed this topic.57 Appropriate measures should also be taken for hospitalized patients to decrease the risk of nephrotoxicity from radiocontrast agents and antibiotics such as aminoglycosides, as well as from nonsteroidal antiinflammatory drugs and ACEIs (see Chap. 31).
A summary of nonpharmacologic and pharmacologic recommendations that apply to all individuals with CKD is listed in Table 29-5.
TABLE 29-5 Recommendations for Individuals with CKD1,15
Desired Outcome
The overall goal of therapy in individuals with CKD is to delay or prevent progression of the disease, thereby minimizing the development or severity of associated complications and ultimately limiting the progression to ESRD when hemodialysis, peritoneal dialysis, or kidney transplantation is required. Once a patient is diagnosed with CKD, implementation of therapy to address the primary cause (e.g., diabetes, hypertension, or glomerulonephritis) is a priority. Patients who reach stage 4 CKD almost inevitably experience progression to ESRD, and thus at some time in the near future will require dialysis or transplantation to sustain life. It is during stage 4 CKD that planning for renal replacement therapy (hemodialysis or peritoneal dialysis) should begin, including patient education about dialysis modalities and options for transplantation (see Chaps. 30 and 70). With ESRD the primary goal is to sustain a good quality of life and prevent adverse outcomes by aggressively managing complications of CKD.
Desired Outcomes
The overall goal of therapy in individuals with CKD is to delay or prevent progression of the disease, thereby minimizing the development or severity of associated complications and ultimately limiting the progression to ESRD when hemodialysis, peritoneal dialysis, or kidney transplantation is required.
The desired outcomes of anemia management are to increase oxygen-carrying capacity, improve the patient’s quality of life, and decrease the need for blood transfusions.
The overall goal for management of CKD-MBD is to “normalize” the biochemical parameters and prevent the detrimental consequences, including bone manifestations, cardiovascular and extravascular calcifications, and the associated morbidity and mortality.
Nonpharmacologic Therapy
Diet Meta-analyses to determine the effect of protein restriction on the progression of CKD suggest only a relatively small benefit from dietary protein restriction.58–60 Protein restriction to 0.8 g/kg/day is recommended only in patients with an eGFR less than 30 mL/min/1.73 m2 with appropriate monitoring by a dietitian to avoid malnutrition. High sodium intake can increase blood pressure and proteinuria, blunt the response to renin–angiotensin system blockade, and induce glomerular hyperfiltration; therefore, decreasing salt intake to less than 2 g or 90 mEq (mmol) per day of sodium (corresponding to 5 g sodium chloride) is recommended, particularly in patients with hypertension or proteinuria.1
Smoking Cessation and Exercise Smoking cessation is encouraged to slow progression of CKD and to reduce the risk of CVD.1 Clinicians should educate patients regarding the risks and institute appropriate therapeutic options, both nonpharmacologic and pharmacologic, for smoking cessation. These options are discussed in further detail in Chapter 49. People with CKD are encouraged to exercise at least 30 minutes five times per week and achieve a healthy body weight to maintain a BMI of 20 to 25 kg/m2.1
Pharmacologic Therapy
Diabetes with CKD Figure 29-4 provides an algorithm for the management of diabetes in patients with CKD. ACEI and/or an angiotensin receptor blocker (ARB) should be used as first-line therapy if the urine albumin excretion or equivalent test (Table 29-2) is >30 mg/24 h. The dose is usually increased until albuminuria is reduced by 30% to 50% or side effects such as a significant drop in eGFR or elevation in serum potassium occur (Table 29-6).
FIGURE 29-4 Diabetes with CKD algorithm. Strategy for screening and treatment of diabetes with CKD based on urine albumin excretion, target blood pressure, and eGFR. (Data from National Kidney Foundation. KDOQI clinical practice guidelines and clinical practice recommendations for diabetes and chronic kidney disease. Am J Kidney Dis 2007;49(Suppl 2):S1–S180; reference 1.)
TABLE 29-6 ACEI and ARB Drug Monitoring in CKD
Evidence from clinical trials has confirmed the beneficial effects of ACEIs on kidney function for patients with diabetes, and both ACEIs and ARBs remain the mainstay of therapy.61,62 These studies showed benefits of ACEI in individuals with both type 1 and type 2 diabetes with varying degrees of kidney damage. A meta-analysis that pooled several of the small and large randomized controlled studies showed beneficial effects of ACEI therapy on diabetes with CKD.63 Progression to proteinuria was reduced by 65% for patients with diabetes mellitus and microalbuminuria, and progression of CKD (doubling of serum creatinine) was reduced by 40% for both diabetics and nondiabetics with macroalbuminuria.
ARBs have also been shown to slow the progression of diabetes in patients with CKD.64–66 Currently, both ACEIs and ARBs reduce the rate of progression in type 2 diabetes, whereas only ACEIs have been adequately evaluated for patients with type 1 diabetes. However, in practice these agents are used interchangeably. Chapter 3 includes a thorough discussion of dose, dose titration, monitoring, and adverse effects of ACEI and ARB. Alternative drug treatments to reduce proteinuria are discussed below.
Figure 29-4 provides the current glycosylated hemoglobin (HgbA1C) target in this patient population. However, it should be noted that HgbA1C measurements are based on an assumed red blood cell life span of 90 days. In CKD, the red blood cell life span is decreased, so HgbA1C values may be falsely low.1 The HgbA1C should be interpreted along with the patient’s home blood glucose readings before making a determination of diabetic control. It is also important to note that patients with stage 3 and 4 CKD are at higher risk of developing hypoglycemia because the kidney metabolizes insulin. When GFR decreases, the degradation of endogenous or injected insulin is decreased and patients may require reduced doses of oral or injectable hypoglycemics. As a result, patients with eGFR <30 mL/min/1.73 m2 should be educated on how to recognize and treat hypoglycemic episodes. Dose adjustments or avoidance of renally eliminated hypoglycemics is necessary. A thorough review of dosing, monitoring, and goals of therapies to treat diabetes mellitus is provided in Chapter 57.
Hypertension Figure 29-5 provides an algorithm for the recommended blood pressure goals based on the degree of albuminuria present and the choice of antihypertensive agent for CKD patients without diabetes mellitus. Previous guidelines suggested a target blood pressure of less than 130/80 mm Hg for all patients with CKD. A meta-analysis of 2,272 subjects with nondiabetic kidney disease concluded that no benefits in renal or cardiovascular outcomes or mortality were achieved in patients treated to a goal blood pressure of 125 to 130/75 to 80 mm Hg as compared with 140/90 mm Hg.67 Subjects with proteinuria greater than 300 mg/day did benefit from the lower blood pressure target. The ongoing Systolic Blood Pressure Intervention Trial (SPRINT) may provide the evidence needed to determine whether an even lower blood pressure goal of 120 mm Hg systolic pressure is desirable in patients with nephrotic range proteinuria.68 The KDIGO guidelines recommend a target blood pressure of ≤140/90 mm Hg if urine albumin excretion or equivalent (Table 29-2) is <30 mg/24 h.15
FIGURE 29-5 Treatment of hypertension in chronic kidney disease patients, nondialysis ND-CKD without diabetes mellitus. Strategy for treatment of hypertension based on urine albumin excretion and target blood pressure. (Data from reference 1.)
In patients with a urine albumin excretion >30 mg/24 h or equivalent (Table 29-2), the target blood pressure is ≤130/80 mm Hg and first-line therapy with an ACEI or ARB is recommended.15 If this fails to achieve the target blood pressure, then thiazide diuretics may offer additional reduction of proteinuria in combination with an ARB.69,70 It has been widely quoted that thiazide diuretics are not effective for blood pressure control when creatinine clearance is less than 30 mL/min (0.5 mL/s), but there is limited evidence to support this statement.71 While salt and water excretion may initially account for their antihypertensive effect, long-term lowering of blood pressure appears to involve vasodilation that is not affected by reduced kidney function. While there is some controversy, a switch to a loop diuretic should be considered in patients with stage 4 or 5 CKD with inadequate blood pressure control while receiving a regimen that included a thiazide diuretic. The choice of additional antihypertensive agents should be based on concomitant disease states and other compelling indications as discussed in Chapter 3. At this time, there is insufficient evidence to recommend the combination of an ACEI plus an ARB to prevent progression of CKD.1 Patients and clinicians should be aware that targeting a blood pressure of less than 130/80 mm Hg will often require three or more drugs.
Proteinuria The antiproteinuric effect of ACEIs and ARBs is a class effect and not specific to any one agent.63,72 For patients with hypertension, the primary goal is to achieve the target blood pressure while a secondary goal is to control proteinuria. For normotensive patients, the ACEI/ARB dose should be titrated to reduce the degree of proteinuria. Patients with hypertension and proteinuria may experience adverse effects associated with blood pressure lowering, and drug doses should be titrated to achieve the maximum reduction of proteinuria without reducing blood pressure to a level associated with adverse events including further decline in kidney function. Specific dosing recommendations for ACEIs and ARBs have not been established; consequently, the lowest recommended dose should be initiated for the management of hypertension. In addition, one needs to consider the presence of other concomitant diseases and past history of treatment, as well as any adverse effects demonstrated with particular agents. If patients exhibit adverse effects such as cough with an ACEI, a switch to an ARB may be appropriate.
Clinical Controversy…
Early studies suggested that a combination of ACEI and ARB may have additional benefit; however, recent data suggest that the combination may be associated with a higher incidence of adverse outcomes including frequent hyperkalemia and need for acute dialysis. CKD guidelines state that there is insufficient evidence to recommend this combination to prevent progression of CKD. A trial to evaluate combination therapy in patients with diabetes and CKD is ongoing and will provide further information on this topic.
The lack of response of some patients to ACEI or ARB therapy may be due to aldosterone escape in renin–angiotensin–aldosterone system (RAAS) blockade. Combination therapy with both ACEIs and ARBs has been investigated based on the rationale that further aldosterone blockade may improve outcomes.73–75 In summary, these studies demonstrate a greater reduction in proteinuria, with some studies demonstrating a trend to higher serum potassium and serum creatinine concentrations. Unfortunately, none of these studies were of sufficient duration to determine if the reduction in proteinuria translates to preservation of kidney function. The ONTARGET study raised concerns with the use of an ACEI plus an ARB. This study randomized 25,620 patients with established atherosclerotic vascular disease or diabetes with end-organ damage to telmisartan, ramipril, or a combination of the two drugs.76 The composite outcome of dialysis, renal transplantation, doubling of serum creatinine, or death occurred more frequently in patients receiving combination treatment than in either of the two other groups, despite a lower degree of albuminuria and less progression to microalbuminuria or macroalbuminuria. These findings have led some to advise against the combination of these two agents; however, critics of the study have argued that these findings cannot be extrapolated to individuals with proteinuric kidney disease as only 4% of patients in the study had overt proteinuria.77 Combination therapy with an ACEI and an ARB likely does have a role for patients with diabetes and CKD with macroalbuminuria and is being evaluated more closely in an ongoing randomized double-blind multicenter clinical trial of Veterans Administration patients (VA NEPHRON D).78
The concept of aldosterone escape has led to the search for other methods to suppress the RAAS in an effort to improve renal outcomes. A Cochrane systematic review examined the addition of an aldosterone antagonist (e.g., spironolactone, eplerenone) to an ACEI, ARB, or ACEI plus ARB mainly in patients with diabetes and CKD.79 Significant decreases in proteinuria were observed; however, there was also a significant increase in the risk of hyperkalemia (relative risk [RR] 3.06, 95% CI 1.26 to 7.41). At this time, long-term effects on renal outcomes, mortality, and safety are unknown.
Aliskiren, a direct renin inhibitor, has been shown to reduce proteinuria when used in combination with an ARB or a diuretic.80,81 While short-term benefits have been demonstrated, there are concerns regarding the use of aliskiren in combination with an ACEI or ARB. The ALTITUDE trial compared placebo or aliskiren 300 mg/day added to an ACEI or ARB in patients with diabetes who had either an increased urine albumin or an eGFR of 30 to 60 mL/min/1.73 m2 and established CVD.82 This trial was stopped early due to safety concerns that included an increase in hyperkalemia and hypotension in the aliskiren combination group with no benefit in the primary composite cardiovascular and renal outcomes. The FDA subsequently issued a warning that aliskiren in combination with an ACEI or ARB is contraindicated in patients with diabetes and that the use of aliskiren with an ACEI or ARB in patients with an eGFR <60 mL/min/1.73 m2 should be avoided.83
Some CCBs decrease glomerular injury without negatively changing renal hemodynamics.84 The postulated mechanisms for this decrease in renal injury include suppression of glomerular hypertrophy, inhibition of platelet aggregation, and decrease in salt accumulation. Although the data regarding dihydropyridine CCBs do not suggest any beneficial effects beyond those attributable to reducing blood pressure, there is some suggestion that the nondihydropyridine agents (diltiazem and verapamil) have beneficial effects on proteinuria, although not as profoundly as ACEIs.85 These agents have been used to reduce proteinuria when used in combination with an ACEI or ARB despite the fact that data are limited to support this strategy. In general, nondihydropyridine CCBs are used as second-line antiproteinuric drugs when an ACEI or ARB is contraindicated or not tolerated. There are also trials to support use of CCBs that also affect T-type calcium channels (e.g., benidipine, clinidipine); however, these agents are not currently available in the United States.86 Kidney diseases that cause glomerulonephritis are associated with significant proteinuria. A thorough review of the types and additional treatments for glomerulonephritis is provided in Chapter 32.
Personalized Pharmacotherapy
The clearance of all ACEIs (with the exception of fosinopril) is reduced in CKD; therefore, it is necessary to initiate therapy at lower initial doses and subsequently titrate the dose to achieve the optimal therapeutic effects such as decreased proteinuria and lowering of blood pressure. The antiproteinuric effects of ACEIs/ARBs are not necessarily attained at the same doses as the antihypertensive effects. Thus, individualization of therapy is required for patients who have reached their blood pressure goals yet require further reductions in urinary protein excretion.
Evaluation of Therapeutic Outcomes
A monitoring plan for ACEI and ARB therapy in the CKD population is outlined in Table 29-6 with some recommendations based on the KDOQI guidelines on hypertension in CKD.87 Frequency of lab and urine testing based on stage of CKD and degree of albuminuria as defined by KDIGO is shown in Table 29-7. The monitoring necessary for patients with hypertension and diabetes is the same in the CKD population as it is in the non-CKD population, and readers should refer to the appropriate chapters in this textbook for further information.
TABLE 29-7 Recommended Outcome Measure Monitoring Intervals for Patients with CKD1
Anemia of Chronic Kidney Disease
Desired Outcome
The desired outcomes of anemia management are to increase oxygen-carrying capacity, decrease signs and symptoms of anemia, improve the patient’s quality of life, and decrease the need for blood transfusions. Achievement of these goals requires a combination of an ESA and iron supplementation to promote and maintain erythropoiesis. Hb is the preferred monitoring parameter for red blood cell production because, unlike Hct, its concentration is not affected by blood storage conditions and instrumentation used for analysis. Table 29-8 lists the Hb and iron indices for nondialysis and dialysis-dependent CKD patients as suggested by KDOQI and KDIGO guidelines.
TABLE 29-8 Suggested Hb and Iron Indices in Adults with Anemia of Chronic Kidney Disease: KDOQI and KDIGO Guidelines42,103
Target Hemoglobin and Use of ESAs
Initiation of ESA therapy should be considered in all CKD patients when Hb is between 9 and 10 g/dL (90 and 100 g/L; 5.59 and 6.21 mmol/L) and in nondialysis patients when the following additional criteria are met: (a) the rate of Hb decline indicates the likelihood of requiring a RBC transfusion and (b) reducing the risk of alloimmunization and/or other RBC-transfusion-related risks is a goal. According to the labeling for the available ESAs, the ESA dose should be decreased or interrupted when Hb is above 10 g/dL (100 g/L; 6.21 mmol/L) in CKD patients not receiving dialysis or above 11 g/dL (110 g/L; 6.83 mmol/L) in patients receiving dialysis. This is in contrast to the KDOQI and more recent KDIGO recommendations. On November 1, 2011, Centers for Medicare and Medicaid Services (CMS) removed the requirement that dialysis providers maintain Hb levels above 10 g/dL (100 g/L; 6.21 mmol/L) because no lower level of Hb was proven safe for patients treated with an ESA.88 This change took effect in payment year 2013.
The target range for Hb in the CKD population is a topic of much debate. Observational studies and USRDS data have shown decreased hospitalizations, lower mortality, and improved quality of life with Hb levels above 11 g/dL (110 g/L; 6.83 mmol/L).89,90 While these data support a higher Hb, targeting Hb levels above 13 g/dL (130 g/L; 8.07 mmol/L) with ESA therapy has resulted in increased risk of mortality and cardiovascular events compared with patients maintained in the 11 to 12 g/dL (110 to 120 g/L; 6.83 to 7.45 mmol/L) range. These conclusions were based on clinical trials (CHOIR and CREATE trials) that included individuals with early stage CKD and from previous data reported in the hemodialysis population (Normal Hematocrit Cardiac Trial [NHCT]).38–41 A summary of these key trials is shown in Table 29-9. An increased risk of all-cause mortality with ESA treatment was also reported in a meta-analysis of nine randomized controlled trials that included over 5,100 CKD patients treated to Hb targets in the range of 12 to 16 g/dL (120 to 160 g/L; 7.45 to 9.93 mmol/L).91 There was also a higher risk of dialysis access thrombosis and uncontrolled blood pressure in the higher Hb group. Subsequent analysis of the CHOIR trial has also shown an association between targeting a higher Hb and increased rate of progression of CKD.92
TABLE 29-9 Trials Evaluating ESAs and Target Hb/Hct
Results from the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) (Table 29-9) also failed to support a higher Hb.93 Despite the association between anemia and reduction in hospitalization and cardiovascular events that prompted many to expect positive outcomes from this study, individuals treated to the higher Hb target did not have a reduction in the primary end points. In addition, there was also an almost twofold increase in the risk of stroke (5% in the treatment group vs. 2.6% in the placebo group), a finding that was not associated with baseline characteristics of the patients or other potential risk factors.94 Those patients with a history of cancer in the higher Hb group also had a higher risk of death, a finding that requires additional investigation.
Clinical Controversy…
The higher risk of mortality and cardiovascular events in CKD patients treated to achieve a higher Hb with an ESA has led to an update in targets for Hb. There are discrepancies, however, in the FDA-approved labeling for ESAs and the KDIGO and KDOQI guidelines in terms of when to initiate therapy and the target Hb. There are also practitioners who advocate that for patients without specific cardiovascular risk factors (e.g., atherosclerosis), a Hb of 11 to 12 g/dL (120 to 130 g/L) or greater achieved with low-dose ESA is reasonable. Healthcare providers must weigh the risks and benefits of ESA use in individual patients and consider the reimbursement structure for ESAs and iron in the practice environment when making decisions about anemia management.
The association of poor outcomes with the dose of ESA used in the aforementioned studies has raised concern. Subsequent analysis of the CHOIR study showed that high-dose ESA use was associated with greater risk of death.95Those individuals able to achieve the target Hb in the CHOIR study did not have worse outcomes. Further analysis of the NHCT data also showed a reduction in mortality by 60% for those individuals who responded to epoetin therapy compared with nonresponders.96 Such findings have led to discussion of whether hyporesponsiveness to ESAs due to other conditions such as inflammation may explain the higher event rates in this group of individuals. The overall negative cardiovascular outcomes observed with higher Hb targets in the randomized trials have prompted much discussion about the potential causes, including not only ESA dose and Hb target but also the rate of rise in Hb and the variability in Hb over time (e.g., degree of fluctuation in Hb).97
Since the CHOIR and CREATE trials in 2006 and evaluation of subsequent reports calling into question the safety of ESAs, there have been several FDA advisories and changes made to ESA product labeling for more conservative use of ESAs. The most recent was in June 2011 when the FDA notified healthcare professionals of modified recommendations.98 ESA manufacturers revised the precautions, black box warning, and dosing sections of ESA product labeling. The labeling for all ESAs warns that dosing ESAs to target Hb levels greater than 11 g/dL (110 g/L; 6.83 mmol/L) for CKD patients increases the risk for death, serious cardiovascular reactions, and stroke.99–102 Practitioners are advised to consider ESAs in patients with CKD only when the Hb is below 10 g/dL (100 g/L; 6.21 mmol/L) and to individualize therapy to use the lowest ESA dose necessary to decrease the need for red blood cell transfusions.
Of note, recommendations in the revised product labeling differ from the target of 11 to 12 g/dL (110 to 120 g/L; 6.83 to 7.45 mmol/L) recommended in the KDOQI guidelines for management of anemia of CKD and from the previous labeling that recommended a target of 10 to 12 g/dL (100 to 120 g/L; 6.21 to 7.45 mmol/L) in ESA-treated patients with CKD.103 KDIGO anemia guidelines from 2012 are shown in Table 29-8. It is important to consider that in making the recommendations regarding Hb targets listed in Table 29-8, the KDIGO expert panel considered the quality of the evidence to be low or very low. Clinicians should always take into account trends in Hb when adjusting ESA doses. Before making treatment decisions, prescribers must weigh the risks of ESA use and higher Hb values against the benefit of fewer blood transfusions and ensure that patients understand these risks and benefits.
Iron Status
Iron supplementation is required by most CKD patients receiving an ESA because of the increased iron demand that results from stimulation of red blood cell production. As CKD worsens, a progressive decline in Hb despite ESA therapy may be observed. Iron indices that should be monitored include the TSat, an indicator of iron immediately available for delivery to the bone marrow, and serum ferritin, an indirect measure of storage iron. The content of hemoglobin in reticulocytes (CHr) is also recommended as a parameter to assess iron status in hemodialysis patients, although it is not commonly used in clinical practice. Transferrin is the carrier protein for iron and, as a protein, may be affected by nutritional status. Serum ferritin is an acute-phase reactant, meaning it may be elevated under certain inflammatory conditions and give a false indication of storage iron. Previous versions of the KDOQI anemia guidelines recommended an upper level for TSat of 50% (0.50) and serum ferritin of 800 ng/mL (800 mcg/L; 1,800 pmol/L) to reduce the risk of iron overload. No upper level for these iron indices has been established in the current recommendations; however, the guidelines state that there is insufficient evidence to recommend routine administration of IV iron if the patient’s serum ferritin level is greater than 500 ng/mL (500 mcg/L; 1,100 pmol/L).51 KDIGO guidelines do not suggest stringent iron indices, but do recommend that iron supplementation be administered if TSat is ≤30% (≤0.30) and serum ferritin is ≤500 ng/mL (≤500 mcg/L; ≤1,100 pmol/L) if the goal is to increase the Hb or decrease the ESA dose (Table 29-8).42 Since ferritin is an acute-phase reactant, the decision of whether to give IV iron in conditions of elevated ferritin must be based on objective parameters such as TSat and Hb in addition to the clinical condition of the patient (e.g., infection, inflammation).
Iron supplementation is required for absolute iron deficiency, when whole-body iron stores are low, but may also be required in individuals with functional iron deficiency. In the latter condition the individual with anemia may have a low TSat, but a serum ferritin at or above goal. In this situation iron stores fail to release iron rapidly enough to satisfy the demands for erythropoiesis. It has been shown that anemic hemodialysis patients with a TSat less than 25% (0.25) and serum ferritin between 200 and 1,200 ng/mL (200 and 1,200 mcg/L; 450 and 2,700 pmol/L) had an improved response to ESAs when they also received a 1 g course of IV iron.104
Nonpharmacologic Therapy
Nonpharmacologic therapy for anemia of CKD includes maintaining adequate dietary intake of iron as well as folate and B12. Patients on hemodialysis or peritoneal dialysis should be routinely supplemented with water-soluble vitamins (vitamins B, C, and folic acid) as these vitamins are often depleted with dialysis therapy. A relatively small amount of dietary iron, approximately 1 to 2 mg (or approximately 10%), is absorbed each day, primarily in the duodenum. Although there is some debate as to whether GI absorption of iron is significantly altered in patients with severe CKD, it is clear that oral intake from dietary sources alone is insufficient to meet the increased iron requirements from initiation of ESA therapy.
Pharmacologic Therapy
Pharmacologic therapy for anemia of CKD is based on a foundation of ESA therapy to correct erythropoietin deficiency and iron supplementation to correct and prevent iron deficiency caused by ongoing blood loss and increased iron demands associated with the initiation of erythropoietic therapy. Iron supplementation is first-line therapy for anemia of CKD if iron deficiency is diagnosed, and for some patients the target Hb may be achieved without concomitant ESA therapy. For most individuals with advanced CKD, however, combined therapy with iron and an ESA is required.
Iron Supplementation Iron supplements provide the elemental iron required for production of Hb and its subsequent incorporation in red blood cells, the net result of which is an increase in the transportation of oxygen to tissues.
Therapeutic Options Options for iron supplementation include oral and IV therapy. Oral iron preparations include ferrous salts (ferrous sulfate, ferrous fumarate, and ferrous gluconate), polysaccharide iron complex, and a heme iron polypeptide formulation. Numerous nonprescription products are available and differ in their content of elemental iron. Approximately 10% of orally administered iron is absorbed in the duodenum and upper jejunum. Absorption of iron is decreased by food and achlorhydria. The heme form of oral iron binds to a different receptor in the GI tract than nonheme iron, is absorbed to a greater extent, and may be better tolerated.105 Some oral iron formulations also include ascorbic acid to enhance iron absorption. Serum iron concentrations and the area under the curve are not useful to assess efficacy due to the complex regulation of iron uptake by erythrocytes and incorporation as iron stores following administration.106
IV iron preparations are colloids that consist of an iron-containing core that is surrounded by a carbohydrate shell to stabilize the iron complex. Available agents differ in the size of the core and the composition of the surrounding carbohydrate. These differences affect the rate of dissociation of iron from the complex to phagocytes within the reticuloendothelial system where iron is either stored or released to the extracellular carrier protein transferrin, which transports iron to the bone marrow for red blood cell production.
Five IV iron products are currently available in the United States (see Table 29-10): two composed of iron dextran (INFeD®, molecular weight [MW] 96 kDa; and Dexferrum®, MW 265 kDa), sodium ferric gluconate (Ferrlecit®and Nulecit®, MW 350 kDa), iron sucrose (Venofer®, MW 43 kDa), and ferumoxytol (Feraheme®, MW 750 kDa).107–112
TABLE 29-10 IV Iron Preparations107–111
Either oral or IV administration of iron is recommended in stage 3 to 4 CKD patients and those receiving peritoneal dialysis. Oral iron supplementation is more convenient for those patients who do not have regular IV access; however, at some point they are likely to require IV iron supplementation to meet iron needs and correct absolute iron deficiency, especially if they are receiving an ESA. In HD patients with ESRD, GI absorption of iron is often inadequate to meet the increase in iron demand from ESA therapy and chronic blood loss. KDOQI guidelines recommend IV iron as the preferred route of administration in the HD population.51 Parenteral iron improves the responsiveness to ESA therapy and thus lower doses can be used to maintain the target Hb in hemodialysis patients.
Iron administration in patients with functional iron deficiency is questionable. A trial of IV iron therapy may be warranted if the Hb is less than desired.104
Adverse Effects Adverse effects of oral iron are primarily GI in nature and include constipation, nausea, and abdominal cramping. These adverse effects are more likely as the dose is escalated and may be present in more than 50% of patients receiving 200 mg of elemental iron per day. These unfavorable effects often discourage patients from taking these medications on a chronic basis. Some of these GI side effects can be minimized if oral iron products are taken with food; however, food may decrease absorption of oral iron.
Adverse effects of IV iron include allergic reactions, hypotension, dizziness, dyspnea, headaches, lower back pain, arthralgia, syncope, and arthritis. Some of these reactions, in particular hypotension, can be minimized by decreasing the dose or rate of infusion of iron. The most concerning potential consequence of IV iron administration is anaphylaxis. Anaphylactic reactions to iron dextran have been reported in up to 1.8% of patients, with serious reactions including respiratory complications and cardiovascular collapse occurring in approximately 0.6% to 0.7% of patients.42 Such reactions are believed to be partly a response to antibody formation to the dextran component. Adverse reactions have been reported more frequently in those receiving Dexferrum compared with INFeD.42
Sodium ferric gluconate, iron sucrose, and ferumoxytol have a better safety record than either of the iron dextran products, based on their history of use in Europe over the last 4 decades (sodium ferric gluconate and iron sucrose) and data in the United States since these products were approved. A comparison of adverse event rates reported to the FDA for IV iron products revealed that ferumoxytol had higher rates of adverse events than sodium ferric gluconate or iron sucrose.113 Serious adverse events including anaphylactic-type reactions and cardiac arrest prompted a change in the product labeling postmarketing.110 As a superparamagnetic oxide, ferumoxytol may affect the diagnostic ability of magnetic resonance imaging studies; therefore, these imaging studies should be done prior to administration of ferumoxytol when possible. These effects may persist for up to 3 months following administration of ferumoxytol. Ferumoxytol will not interfere with x-ray, computed tomography, positron emission tomography, single photon emission computed tomography, ultrasonography, or nuclear medicine imaging.110
Administration of IV iron also introduces a risk of iron overload. Deposition of excess iron may affect several organ systems, leading to hepatic, pancreatic, and cardiac dysfunction. Bone marrow biopsy provides the most definitive diagnosis of iron overload, but because it is an extremely invasive procedure, it is not widely employed in most clinical settings. Maintaining serum ferritin and TSat values that demonstrate efficacy in preventing iron deficiency, yet are safe, is the most reasonable approach to minimize the risk of iron toxicity. The challenge is in defining these upper limits, particularly for serum ferritin, which may be elevated in inflammatory conditions and not reflective of true iron stores in such situations. If symptomatic overload does occur, deferoxamine (Desferal), deferiprone (Ferriprox), or phlebotomy may be necessary.
Dosing and Administration If oral therapy is initiated, the recommended dose is 200 mg of elemental iron per day. With numerous oral agents to choose from, the best option is one that provides adequate elemental iron with the fewest number of dosage units required per day. KDIGO guidelines suggest a 1-to 3-month trial of oral therapy in the nondialysis CKD population.42 For the hemodialysis population, administration of 1 g of IV iron is recommended to initially replete patients with an absolute iron deficiency. Typical repletion dosing regimens for IV iron are 100 mg as iron sucrose or iron dextran over 10 dialysis sessions, or 125 mg of sodium ferric gluconate over 8 dialysis sessions (see Table 29-10). Ferumoxytol is administered as 510 mg at a rate not to exceed 30 mg/s (1 mL/s) with a second dose given within 3 to 8 days, a higher dose and administration rate compared with other available IV iron formulations.110 Without ongoing iron supplementation, many patients quickly become iron deficient. To prevent iron deficiency, maintenance doses of IV iron are administered in hemodialysis patients (e.g., iron sucrose or iron dextran 25 to 100 mg/wk; sodium ferric gluconate 62.5 to 125 mg/wk) based on evidence of improved Hb and lower ESA doses with these regimens.42,51
Administration of a 25 mg test dose is required for all iron dextran products. This test dose should be administered over at least 30 seconds for InFeD and 5 minutes for Dexferrum.107,108 It is recommended that a period of ≥1 hour lapse before administering the remainder of the dose. Patients receiving any of the non-dextran IV iron agents should be closely observed for signs of hypersensitivity during and for at least 30 minutes after administration.109–111 KDIGO guidelines advocate monitoring for 60 minutes following an infusion of any available IV iron product, with a stronger emphasis on this recommendation for iron dextran products.42
The safety and efficacy of high-dose IV iron regimens have been evaluated. Iron dextran has been safely administered to dialysis patients in total-dose infusions ranging from 400 mg to 2 g and to patients with stage 3 or 4 CKD at doses of up to 500 mg.114,115 Sodium ferric gluconate has been safely administered at doses of 250 mg infused over 1 hour (4.2 mg/min).116 Iron sucrose at doses of up to 500 mg administered over 3 hours on consecutive days has been successful in maintaining iron stores without causing serious adverse events.117 Higher-dose regimens for iron sucrose have been approved in patients with early stage CKD and peritoneal dialysis patients (see Table 29-10), populations in whom administration of higher doses is more convenient as these patients are seen less frequently by healthcare providers than the hemodialysis population.111 As a general practice, if IV iron doses higher than those currently approved are used in practice, they should be administered over at least 2 to 4 hours depending on the dose due to the risk of hypersensitivity reactions, hypotension, dizziness, and nausea.
Although there are conflicting reports, most clinicians believe that exposure to iron may contribute to the risk of bacterial infection because iron is used by microorganisms for metabolic functions. The association of IV iron with oxidative stress, acceleration of atherosclerosis, and other cardiovascular conditions has also been suggested.118 These potential long-term risks of IV iron therapy are not clearly defined, and there are no data confirming unequivocally that aggressive use of IV iron in CKD patients treated with ESA therapy increases patient morbidity or mortality. KDIGO guidelines suggest that IV iron be avoided in patients with active systemic infections.42
Erythropoietic-Stimulating Agent Therapy
Since FDA approval of epoetin alfa in 1989, ESA therapy has become an integral part of the care for patients with CKD. ESAs available in the United States include epoetin alfa (distributed as Epogen and Procrit), and darbepoetin alfa (Aranesp).99–101 Peginesatide, a synthetic, pegylated peptide that has no amino acid sequence homology to erythropoietin, was available in March 2012 and approved for use in dialysis patients, but was withdrawn from the market in early 2013 due to reports of serious adverse events.102
Pharmacology and Mechanism of Action Epoetin alfa is a glycoprotein manufactured by recombinant DNA technology that has the same amino acid sequence as endogenous erythropoietin. Darbepoetin alfa has two additional N-linked carbohydrate chains that decrease the affinity for the erythropoietin receptor, but yield a longer duration of activity compared with erythropoietin. All ESAs have the same biologic activity as endogenous erythropoietin in that they bind to and activate the erythropoietin receptor to stimulate erythropoiesis.
Pharmacokinetics and Pharmacodynamics All available ESAs may be administered by either the IV or the SubQ route. Although bioavailability is less with SubQ than with IV administration, the prolonged absorption phase leads to an extended half-life (see Table 29-11). The prolonged half-life with SubQ administration leads to a more sustained physiologic stimulation of erythroid precursors. Trials have shown that the same target Hb can be achieved and maintained at SubQ epoetin doses 15% to 30% lower than IV doses.51,119 The prolonged half-life of darbepoetin offers the advantage of less-frequent dosing, starting at once a week or once every other week. This is of particular benefit in stage 4 and 5 CKD patients who are not yet receiving dialysis and those receiving peritoneal dialysis since these patients are not in a clinical setting as frequently as hemodialysis patients and do not have regular IV access.
TABLE 29-11 Erythropoietic-Stimulating Agents99–101
The pharmacodynamics of ESAs is important to consider when evaluating response to therapy. With initiation of ESA therapy or a change in dose, the Hb may begin to rise as the result of demargination of reticulocytes; however, it takes approximately 10 days before erythrocyte progenitor cells mature and are released into the circulation. The Hb continues to increase until the life span of the cells stimulated by ESA therapy is reached (mean 2 months; range 1 to 4 months in patients with ESRD). At this point a new steady state is achieved (i.e., the rate at which red blood cells are being produced equals the rate at which they are leaving the circulation). For this reason it is important to evaluate the Hb response over several weeks.
Efficacy Patients will generally respond to ESA therapy in a dose-related fashion. The most common causes of resistance are iron deficiency, acute illness, catheter insertion, hypoalbuminemia, elevated C-reactive protein, chronic bleeding, aluminum toxicity, malnutrition, hyperparathyroidism, cancer and chemotherapy, HIV, inflammation, and infection.51 Deficiencies in folate and vitamin B12 should also be considered as potential causes of resistance to ESA therapy, as both are essential for optimal erythropoiesis.
Adverse Effects Hypertension is the most common adverse event reported with ESAs and may be associated with the rate of rise in Hb.51 Protocols established in some clinical settings recommend withholding ESA therapy if blood pressure is above a defined threshold. KDOQI guidelines for anemia do not recommend withholding ESA therapy for elevated blood pressure, but instead advocate more judicious use of antihypertensive agents and dialysis to control blood pressure; however, according to FDA-approved product labeling, ESAs should not be used in those with uncontrolled blood pressure.99–101Seizures have occurred in patients treated with epoetin, particularly within the first 90 days of starting therapy. Vascular access thrombosis may also be more frequent during ESA therapy.42 The potential for these adverse effects calls for close monitoring of the rate of rise in Hb, changes in blood pressure, and neurologic symptoms following initiation of therapy or a change in ESA dose.
Antibody-associated pure red cell aplasia (PRCA) was reported in the late 1990s and early in 2000, but there have been very few cases since that time. An evaluation for PRCA should be considered for patients receiving ESA therapy for more than 8 weeks who develop either a rapid decrease in Hb level (rate of 0.5 to 1 g/dL/wk [5 to 10 g/L/wk; 0.31 to 0.62 mmol/L/wk]) or require one to two blood transfusions per week, and have an absolute reticulocyte count of less than 10,000/μL (10 × 109/L) with a normal platelet and white blood cell count.42 Discontinuation of ESA therapy is recommended in antibody-mediated PRCA because antibodies are cross-reactive and continued exposure may lead to anaphylactic reactions. Immunosuppressive therapy has been effective in up to 50% of patients with PRCA.120 No cases of PRCA were reported with peginesatide in initial clinical trials and there is evidence that peginesatide stimulates erythropoiesis in conditions of PRCA or hyporesponsiveness due to antierythropoietin antibodies.121
Drug–Drug Interactions No significant drug interactions have been reported with the available ESAs.
Dosing and Administration Recommended starting doses of ESA are listed in Table 29-11. Less frequent dosing of epoetin alfa (e.g., every 1 to 2 weeks) is effective and may be preferred for stage 3 and 4 CKD patients since these patients are seen in the outpatient clinical setting on a relatively infrequent basis.122 Subcutaneous dosing is also more convenient in this population and in peritoneal dialysis patients who do not have regular IV access. Conversion tables for patients who are to be switched from epoetin alfa (units per week) to darbepoetin alfa (micrograms per week) are available in the labeling information for darbepoetin.101
When starting an ESA, Hb levels should be monitored at least weekly until stable and then at least monthly. Dose adjustments should be made based on Hb response with consideration of data on risks associated with higher Hb levels and rate of rise in Hb. An acceptable rate of increase in Hb is 1 to 2 g/dL (10 to 20 g/L; 0.62 to 1.24 mmol/L) per month. As a general rule, ESA doses should not be increased more frequently than every 4 weeks, although decreases in dose may occur more frequently in response to a rapid rate of rise in Hb. Based on labeling for ESAs, the dose should be reduced by at least 25% if the Hb increases by more than 1 g/dL (10 g/L; 0.62 mmol/L) in a 2-week period. The dose should be reduced or temporarily discontinued if the Hb level approaches or exceeds 11 g/dL (110 g/L; 6.83 mmol/L) in dialysis patients (all ESAs) or 10 g/dL (100 g/L; 6.21 mmol/L) in patients with CKD not requiring dialysis. KDIGO recommendations advocate a decrease in dose as opposed to withholding the ESA when a decrease in Hb concentration is desired.42 A 25% increase in dose may be considered if the Hb has not increased by 1 g/dL (10 g/L; 0.62 mmol/L) after 4 weeks of ESA treatment and if no causes of resistance to the ESA have been identified. For patients who do not respond adequately over a 12-week escalation period, an increase in ESA dose is unlikely to improve response and may increase risks. Initial hyporesponsiveness to ESAs should be considered when there is no increase in Hb from baseline after the first month of appropriate weight-based dosing. Acquired ESA hyporesponsiveness may be suspected when patients previously on a stable ESA dose require two increases in ESA doses up to 50% beyond the stable dose.42 In these situations repeat escalations in ESA dose beyond double the initial weight-based dose should be avoided. The lowest dose of ESA should be used to maintain a Hb level sufficient to reduce the need for RBC transfusions.99–101 Figure 29-6 provides an approach to management of anemia using ESAs and iron therapy in patients with CKD.
FIGURE 29-6 Algorithm for management of anemia using iron and ESA therapy.42
Transfusions and Adjunct Therapies Red blood cell transfusions carry many risks and therefore should only be used in select situations, such as acute management of symptomatic anemia, following significant acute blood loss, and prior to surgical procedures that carry a high risk of blood loss, with the goal of preventing inadequate tissue oxygenation or cardiac failure. L-Carnitine supplementation and vitamin C were previously suggested as adjunctive treatments of anemia associated with kidney disease, but are not recommended because of the lack of evidence supporting improved anemia management with these therapies.42
Personalized Pharmacotherapy
Despite the fact that anemia is common in the CKD population and treatment guidelines are available, management cannot be standardized for all patients. The labeling changes for ESAs do not recommend a specific Hb target for all patients, but rather an individualized approach that considers risks of using ESAs, the rate of increase in Hb, the likelihood of requiring a blood transfusion, and other clinical conditions. For example, a lower ESA dose may be rational for a patient with a history of CVD, thromboembolism, or uncontrolled high blood pressure. The decision to withhold ESA therapy should be considered in patients with a history of malignancy (particularly active malignancy when cure is expected) or stroke. Conservative use of ESAs and lower Hb goals may also be desired in a patient with a high likelihood of a transplant where exposure to blood transfusions increases the risk of developing antibodies to multiple human leukocyte antigens and decreases their success in finding an appropriate donor match. While risks of targeting a Hb above 11 g/dL (110 g/L; 6.83 mmol/L) have been demonstrated, the precise Hb range to target and when to start therapy may also depend more on other factors including the patient-perceived quality of life. Improvements in patient-reported fatigue, energy level, sense of vitality, and physical functioning with anemia treatment have been demonstrated.123 Patients should be informed of the risks of ESA therapy, but also the potential benefits from the patient perspective. This is one rationale for having ESAs under the REMS program.
The concerns for patient safety, the need for more stringent control of Hb levels, and cost of ESA therapy have also led to development of anemia management clinics. Pharmacist-managed clinics have shown Hb values within the target range and lower ESA usage compared with physician-based care and may be an ideal environment for an individualized approach to manage anemia of CKD.124
Evaluation of Therapeutic Outcomes
Iron status should be assessed at least every 3 months in patients receiving a stable ESA regimen or for those hemodialysis patients not treated with an ESA to detect iron deficiency as a cause for anemia.42,51Iron status should be monitored more frequently (e.g., every month) when initiating or increasing the ESA dose, following a course of IV iron, or when other factors put the patient at risk for iron loss (e.g., bleeding). For all ESAs, the initial dose and subsequent adjustments should be determined by the patient’s Hb level and the observed rate of increase in Hb. In patients with anemia not treated with an ESA, Hb levels should be monitored at least every 3 months in stage 3 to 5 CKD patients not requiring hemodialysis and at least monthly in hemodialysis patients.42 Hb should be monitored at least monthly (weekly preferred) in patients started on ESA therapy until the Hb is stable. Once Hb is stable, the recommended frequency of monitoring is monthly in dialysis patients and every 3 months in nondialysis CKD patients (see Fig. 29-6).
CKD-Related Mineral and Bone Disorder
Desired Outcome
The overall goal for management of CKD-MBD is to “normalize” the biochemical parameters and prevent the detrimental consequences, including bone manifestations, cardiovascular and extravascular calcifications, and the associated morbidity and mortality. Unfortunately, prospective trials to evaluate the effect of controlling CKD-MBD on these outcomes are limited. At present there are two guidance documents—KDOQI and KDIGO—that clinicians can use in their decision-making process.43,52 The KDOQI clinical practice guidelines for bone metabolism and disease have been available since 2003 and provide recommendations for the workup and treatment of CKD-MBD.52 In 2009 the KDIGO clinical practice guidelines for CKD-MDB were published.43 It should be noted that many of the recommendations in both documents are based on opinion or limited evidence given the lack of randomized controlled studies to evaluate treatment outcomes.
The KDOQI-recommended targets for calcium, phosphorus, Ca × P product, and PTH based on the stage of CKD are shown in Table 29-12.52 There are no substantial differences between KDOQI and KDIGO with regard to recommendations for serum calcium (corrected for serum albumin) and phosphorus. Both KDOQI and KDIGO recommend maintaining serum phosphorus within the normal range for stage 3 to 4 CKD patients and lowering phosphorus toward the normal range for dialysis patients. KDIGO recommends that the corrected serum calcium be maintained within the normal range for all CKD patients; however, KDOQI recommends a more conservative range in stage 5 CKD patients based on an increased risk of soft-tissue and vascular calcifications. The most appropriate strategy is to evaluate trends in corrected calcium to predict if hypercalcemia is a concern that warrants changes in therapy.
TABLE 29-12 Guidelines for Calcium, Phosphorus, Calcium–Phosphorus Product, and Parathyroid Hormone43,52
Evaluation of PTH Clinicians involved in the care of patients with CKD should know which PTH assays are available in their facilities. PTH is secreted from the parathyroid gland as intact PTH, an 84-amino-acid peptide chain (1 to 84 PTH) that is biologically active, and as smaller carboxy-terminal PTH fragments.125 Circulating levels of these fragments (e.g., 7 to 84 PTH) may increase substantially in patients with CKD and actively antagonize the effects to 1 to 84 PTH. The available immunoradiometric assays measure not only the intact PTH molecule but also fragments, which may lead to overestimation of biologically active PTH. While correction factors have been proposed, they cannot be uniformly applied to all commercially available assays that measure different types and amounts of PTH fragments and give inconsistent results. Because of the variability in PTH measurement, KDIGO did not specify a particular PTH target, but rather advocated looking at trends in serum PTH to make treatment decisions. For the dialysis population, KDIGO recommends a PTH range of two to nine times the upper limit of the normal range for the assay (corresponds to a PTH of approximately 130 to 600 pg/mL or 130 to 600 ng/L [14 to 64 pmol/L]).43 This approach proposed by KDIGO is advocated to control hyperparathyroidism, yet prevent oversuppression of PTH and reduce the risk of adynamic bone disease.
Nonpharmacologic Therapy
Dietary Phosphorus Restriction Dietary phosphorus restriction should be a first-line intervention for management of hyperphosphatemia and CKD-MBD and should be initiated for most patients with stage 3 to 5 CKD. The KDOQI guidelines recommend phosphorus restriction to 800 to 1,000 mg/day when the upper levels of serum phosphorus are reached.52 This recommendation also applies to patients with PTH levels above the recommended range given the evidence that lowering phosphorus ingestion directly decreases PTH synthesis and secretion.126 The challenge with dietary restriction of phosphorus is providing enough protein to prevent malnutrition, a common problem in the ESRD population because foods high in phosphorus are generally high in protein. Examples of foods or beverages that contain high amounts of phosphorus include meats, dairy products, dried beans, nuts, colas, peanut butter, and beer. Nutritional goals must be evaluated on an individual basis, preferably by a dietitian specializing in the care of CKD patients. Dialysis patients require a higher protein intake (1.2 to 1.3 g/kg/day), making restriction of phosphorus even more challenging.
One of the most common obstacles to dietary phosphorus restriction is patient nonadherence because of the poor palatability of the allowed foods. Regular counseling by a dietitian is necessary to design a realistic diet that works with the patient’s lifestyle.
Dialysis Hemodialysis and peritoneal dialysis lower serum phosphorus and calcium, the extent of which is dependent on concentration of each in the dialysate and the duration of dialysis. The dialysate calcium concentration in hemodialysis or peritoneal dialysis should be between 2.5 and 3 mEq/L (1.25 and 1.5 mmol/L).43,52 Removal of phosphorus does occur with peritoneal dialysis and hemodialysis (approximately 2 to 3 g/wk, dependent on the dialysis prescription); however, dialysis alone does not usually control hyperphosphatemia. Patients on daily hemodialysis or nocturnal hemodialysis who typically have longer and/or more frequent dialysis sessions may have better phosphorus control and require fewer phosphate-binding agents due to increased phosphorus removal.127
Parathyroidectomy Parathyroidectomy is a therapeutic option for patients with severe CKD-MBD who do not respond to pharmacologic therapy. Surgery is recommended for those patients with persistently elevated PTH (PTH >800 pg/mL [>800 ng/L; >86 pmol/L]) associated with hypercalcemia and/or hyperphosphatemia who are refractory to medical therapy.52 Surgical approaches include either subtotal parathyroidectomy or total parathyroidectomy with autotransplantation of parathyroid tissue to an accessible site, such as the forearm. Postoperative hypocalcemia, hypophosphatemia, and hypomagnesemia may occur because of a marked increase in bone production in relation to bone absorption (“hungry bone syndrome”). Following surgery frequent monitoring of calcium and phosphorus is necessary. Treatment with supplemental calcium and vitamin D may be required for weeks or months.
Pharmacologic Therapy
Phosphate-Binding Agents Patients with CKD, especially those with ESRD, typically require phosphate-binding agents in addition to dietary interventions to control serum phosphorus.
Pharmacology and Mechanism of Action Drugs that bind dietary phosphorous in the GI tract form insoluble phosphate compounds that are excreted in feces, thus reducing dietary phosphorus absorption. A variety of phosphate-binding agents are available, including elemental calcium-, lanthanum-, aluminum-, and magnesium-containing compounds, and the nonelemental agent sevelamer carbonate (Table 29-13). Patients must be instructed to take these agents with meals to maximize the binding of phosphorus in the GI tract.
TABLE 29-13 Phosphate-Binding Agents for Treatment of Hyperphosphatemia in CKD Patients
Efficacy Oral calcium compounds are well established as first-line agents for control of both serum phosphorus and calcium concentrations, at least in the early stages of CKD when hypocalcemia is more common. Calcium carbonate and calcium acetate are the primary preparations used; calcium citrate is also available but is used less frequently since the citrate component increases aluminum absorption, although this problem is much less likely today as exposure to sources of aluminum has been reduced in CKD patients. Calcium carbonate is marketed in a variety of dosage forms and is relatively inexpensive. Unfortunately, many calcium carbonate products are considered food supplements and thus do not meet United States Pharmacopeia (USP) disintegration and dissolution requirements. In general, nationally advertised brands do meet these requirements, but it is difficult to determine whether private labels or house brands conform to these standards. Variability in gastric pH may also affect disintegration or dissolution, and thus phosphate-binding efficacy. Calcium carbonate is more soluble in an acidic medium and therefore should be administered prior to meals when stomach acidity is highest. In addition, acid-suppressing agents such as ranitidine and proton pump inhibitors may reduce the phosphate-binding activity of calcium carbonate by increasing gastric pH. Calcium acetate binds approximately twice as much phosphorus as calcium carbonate at comparable doses of elemental calcium.52 Increased binding potency limits GI calcium absorption; however, calcium acetate is more soluble and therefore better absorbed than calcium carbonate in an alkaline pH, which may explain the similar incidence of hypercalcemia with these agents. For patients with hypocalcemia, calcium carbonate or calcium acetate may also be given as a calcium supplement taken between meals to promote calcium absorption.
Although calcium-containing phosphate-binding agents continue to be used as first-line therapy, their chronic use may increase the risk for vascular and tissue calcification. KDOQI guidelines recommend that the total dose of elemental calcium provided by calcium-containing binders should not exceed 1,500 mg/day and the total daily intake of elemental calcium from all sources should not exceed 2,000 mg.52KDIGO guidelines are less specific and suggest restricting the dose of calcium-containing binders only if hypercalcemia is present or if arterial calcification or adynamic bone disease is evident.43 Both of these recommendations regarding calcium intake are based primarily on opinion.
Sevelamer is a nonabsorbable, nonelemental hydrogel phosphate-binding agent that effectively lowers phosphorus and has also been shown to significantly lower LDL and increase HDL cholesterol.43 Once-daily dosing of sevelamer carbonate powder has also been shown to significantly decrease phosphorus levels, although this regimen was not as effective as three times daily dosing.128 Whether sevelamer lowers the risk of calcification compared with calcium-containing binders is an issue of some debate.43,129,130 KDOQI guidelines suggest using a non–calcium-containing binder in dialysis patients with severe vascular or soft-tissue calcifications, although these are opinion-based recommendations.52 KDIGO recommends that binder choice be made considering the stage of CKD and the risk of calcifications.43
Clinical Controversy…
Hyperphosphatemia and vascular calcifications are associated with higher mortality. There is evidence that calcium-containing phosphate binders promote progression of vascular calcification; however, not all studies support this finding and recent evidence suggests this effect may occur with non–calcium-containing binders as well. The effect of binder choice on mortality is also controversial. There is evidence of a survival benefit with sevelamer in hemodialysis patients, but this is not a uniform finding. Currently, KDIGO guidelines recommend that calcium-based phosphate binders be restricted in patients with hypercalcemia, vascular calcifications, and/or adynamic bone disease; however, more evidence is needed to help guide selection of phosphate binders.
Lanthanum carbonate is a phosphate binder approved for patients with ESRD and has demonstrated efficacy in controlling phosphorus and maintaining PTH in the target range with less risk of hypercalcemia than calcium-containing binders.43 The initial daily dose of 1,500 mg (administered in divided doses with meals) is often titrated to a range of 1,500 to 3,000 mg to maintain target phosphorus. The poor GI absorption, which limits systemic effects, and high binding capacity with phosphorus make this an attractive phosphate-binding agent, particularly when calcium-containing binders are not recommended due to hypercalcemia. Lanthanum is available as a chewable tablet, which may be appealing for some patients. Lanthanum carbonate (2,250 to 3,000 mg/day) was as effective in lowering serum phosphorus as sevelamer hydrochloride (4,800 to 6,400 mg/day) in hemodialysis patients.131
Aluminum salts were widely used in the 1980s as phosphate-binding agents because of their high binding potency. They should no longer be used as first-line agents, but rather reserved for acute treatment of severe hyperphosphatemia or used at low doses in combination with either calcium-containing binding agents or sevelamer in cases of hyperphosphatemia that is not responding to therapy with a single agent. According to KDOQI guidelines, the duration of aluminum therapy should be limited to 4 weeks if these agents are used at all.52
Magnesium-containing antacids are also effective phosphate binders and may decrease the amount of calcium-containing binders necessary for control of phosphorus; however, their use is limited by the frequent occurrence of GI side effects (i.e., diarrhea) and the potential for magnesium accumulation.
Clinical trials of niacin and niacin derivatives have been conducted to evaluate their potential use as phosphate-binding agents. While significant reductions in serum phosphorus have been observed with these agents in patients with stage 2 to 3 CKD and in hemodialysis patients, flushing reactions will likely limit their use in clinical practice.132
Adverse Effects Adverse effects of all available phosphate binders are generally limited to GI side effects, including constipation, diarrhea, nausea, vomiting, and abdominal pain. The risk of hypercalcemia may necessitate restriction of calcium-containing binder use and/or a reduction in dietary intake. Aluminum binders have been associated with CNS toxicity and the worsening of anemia, whereas magnesium binder use may lead to hypermagnesemia and hyperkalemia; therefore, aluminum and magnesium are not recommended for regular use in patients with kidney disease.
Drug–Drug and Drug–Food Interactions Calcium-containing phosphate-binding agents interfere with the absorption of several oral medications that are commonly prescribed for CKD patients, including iron, zinc, and quinolone antibiotics. No drug interaction studies have been performed with sevelamer carbonate; however, studies with sevelamer hydrochloride have not shown interactions with digoxin, warfarin, metoprolol, enalapril, or iron. Coadministration with ciprofloxacin did, however, result in a 50% decrease in bioavailability of the antibiotic. This information is included in the labeling for sevelamer carbonate.133 Potential interactions between sevelamer and cyclosporine (decreased bioavailability of cyclosporine) and altered phosphorus binding in the presence of agents that increase gastric pH (e.g., omeprazole) have been reported.134,135 Coadministration of lanthanum with tetracyclines, fluoroquinolones, levothyroxine, or drugs known to bind with cationic antacids may result in decreased bioavailability of these agents. The bioavailability of warfarin, digoxin, and metoprolol was not affected by coadministration of lanthanum.136 In general, it is rational to separate the administration time of oral medications for which a reduction in bioavailability has a clinically significant effect (e.g., quinolones) from phosphate binders by at least 1 hour before or 3 hours after administration of the phosphate binder. This is a key patient-counseling recommendation as patients are often switched from one phosphate binder to another, and it is easier for them to remember this general concept regarding phosphate binders and other medications. Many phosphate binders are marketed as antacids or calcium supplements, and often CKD patients do not know why they have been prescribed these agents. Regular patient counseling is essential to improve adherence and minimize the potential for drug interactions.
Dosing and Administration Initial dosing regimens for phosphate-binding agents and suggested dose titration schemes are shown in Table 29-13. Doses should be titrated to achieve the recommended serum phosphorus concentrations based on the patient’s stage of CKD. The daily dose of elemental calcium should be limited in individuals with elevated calcium levels.
Vitamin D Therapy There are several vitamin D compounds available in the United States (see Table 29-14). Ergocalciferol (D2) and cholecalciferol (D3) must be converted to the active form in the kidney while vitamin D analogs do not require this conversion step.
TABLE 29-14 Vitamin D Agents
Pharmacology and Mechanism of Action Calcitriol (1,25-dihydroxyvitamin D3) suppresses PTH secretion by stimulating absorption of serum calcium by intestinal cells and through direct activity on the parathyroid gland to decrease PTH synthesis. As a result, the serum calcium concentration is raised and the parathyroid glands decrease the rate of formation and secretion of PTH. The set point for calcium (i.e., the calcium concentration at which PTH secretion is decreased by 50%), which is generally raised in CKD-MBD, is lowered when active vitamin D therapy is initiated. This indicates that a lower ionized calcium concentration is effective at suppressing secretion of PTH. All of these actions are mediated by the interaction of vitamin D with vitamin D receptors, which are located in many organs, including the parathyroid gland, GI tract, and kidney. Calcitriol also upregulates vitamin D receptors, which ultimately may reduce parathyroid hyperplasia. Unfortunately, the enhanced GI absorption of calcium and phosphorus with calcitriol therapy frequently leads to hypercalcemia and hyperphosphatemia and an increase in the Ca × P product, which is associated with soft-tissue and vascular calcifications.52
The unique interactions of vitamin D with the vitamin D receptors have led to the development of vitamin D analogs that vary in their affinity for the vitamin D receptors. Paricalcitol and doxercalciferol retain activity with vitamin D receptors on the parathyroid gland to effectively lower PTH, but have less risk of hypercalcemia and hyperphosphatemia. Paricalcitol differs from calcitriol by the absence of the exocyclic carbon 19 and the fact that it is a vitamin D2 derivative (19-nor-1,25-dihydroxyvitamin D2). Doxercalciferol is a prohormone that is activated by CYP27 in the liver to form the major active D2metabolite 1,25-dihydroxyvitamin D2. These analogs are available in IV and oral forms.
D2 and D3 bind with vitamin D–binding protein in the circulation and are delivered to the liver where they are converted to 25OHD, by the 25-hydroxylase enzyme. The 25OHD form is converted to the biologically active form 1,25-dihydroxyvitamin D (either D2 or D3 depending on the parent compound) by the 1-α-hydroxylase enzyme. This conversion occurs primarily in the kidney, but this enzyme is also present in extrarenal tissues. It is not clear whether active vitamin D produced in extrarenal tissue exerts its effects only locally or contributes to the overall endocrine functions of active vitamin D. It is 25OHD (the precursor form of active vitamin D) that is measured clinically to diagnose vitamin D deficiency. Supplementation with nutritional vitamin D is recommended for patients with low vitamin D levels (defined as a 25OHD less than 30 ng/mL [75 nmol/L]). This recommendation primarily applies to patients with stage 3 and 4 CKD who may have greater ability to convert 25OHD to the active form by hydroxylation in the kidney.
Pharmacokinetics Oral absorption of calcitriol occurs rapidly; therefore, both oral and IV therapies are reasonable options for treatment of CKD-MBD. The half-life of active calcitriol ranges from 15 to 38 hours in patients with ESRD.137 The half-life of paricalcitol when administered IV or orally is approximately 14 to 20 hours.138 The mean half-life of doxercalciferol after oral administration is approximately 32 to 37 hours with a range of up to 96 hours. These agents are extensively bound to plasma proteins and not removed by dialysis.
Efficacy Calcitriol, paricalcitol, and doxercalciferol are all effective in lowering PTH in patients with CKD; however, the trade-off is the undesired effect of raising calcium and phosphorus concentrations due to increased intestinal absorption. Although these effects are less likely with the newer analogs (paricalcitol and doxercalciferol), elevated calcium concentrations have been observed with these agents as well. Although comparisons between vitamin D analogs are relatively limited, the incidence of hyperphosphatemia with paricalcitol was lower than with doxercalciferol when administered at high doses to hemodialysis patients.139 A more rapid suppression of PTH was also observed in paricalcitol-treated patients compared with those who received calcitriol.140 The more clinically significant finding from this study was the decrease in incidence of hypercalcemia and elevated Ca × P product in the paricalcitol-treated patients.
Nontraditional effects of vitamin D, including a potential survival benefit, have also been reported in both CKD and ESRD patients.48,141 It must be noted that these are observational studies and that prospective, randomized controlled trials are required to better understand survival benefits associated with vitamin D therapy. When the effect of paricalcitol on left ventricular mass was evaluated in patients with CKD and mild to moderate left ventricular hypertrophy, there was no improvement in left ventricular mass after 48 weeks of therapy.142 Antiproteinuric effects of paricalcitol have also been reported in patients with stage 4 and 5 CKD.143 A significant reduction in the urinary ACR was observed in CKD patients with type 2 diabetes receiving 2 mg of oral paricalcitol daily compared with placebo. These findings are of interest when considering other potential effects of vitamin D beyond suppression of PTH.
A review and meta-analysis of available studies in CKD patients (including dialysis) found that nutritional vitamin D supplementation with D2 and D3 led to improvement in 25OHD levels and decreased PTH without significant hypercalcemia or hyperphosphatemia.144 There were few randomized studies included in this analysis and no study evaluated objective measures of bone disease or mortality. In ESRD patients nutritional vitamin D resulted in increased levels of 1,25-dihydroxyvitamin D, which suggests a potential role of extrarenal pathways of vitamin D activation.145
Adverse Effects Although all agents are effective in suppressing PTH levels, they may cause hypercalcemia and hyperphosphatemia, an effect that is most likely with calcitriol. Monitoring of PTH, calcium, and phosphorus is necessary to evaluate these effects and make changes in drug therapy.
Drug–Drug and Drug–Food Interactions Cholestyramine may reduce the absorption of orally administered calcitriol and doxercalciferol. In vitro data suggest that paricalcitol is metabolized by the hepatic enzyme CYP3A4 and has the potential to interact with other agents that are metabolized by this enzyme. When ketoconazole, a CYP3A4 inhibitor, was given concomitantly, paricalcitol serum concentrations doubled.146 Caution is also advised when CYP3A4 inhibitors are given to those receiving doxercalciferol since hydroxylation of this precursor agent may be inhibited. There is also a warning in the product labeling to avoid concomitant use of magnesium-containing antacids and doxercalciferol to prevent development of hypermagnesemia.147
Dosing and Administration Because deficiency in the vitamin D precursor, 25OHD, is common in patients with CKD, measuring 25OHD levels in patients with stage 3 or 4 CKD who have PTH values above the upper recommended ranges is reasonable (see Table 29-12). If the 25OHD level is less than 30 ng/mL (75 nmol/L), nutritional vitamin D (e.g., D2 or D3) is recommended. The dose and duration of treatment are dependent on the severity of the deficiency. To prevent vitamin D insufficiency, doses of 600 to 800 units/day of D2 are recommended. Calcitriol, doxercalciferol, or paricalcitol should be administered when PTH remains elevated despite the achievement of adequate 25OHD levels. Based on evidence of extrarenal pathways of conversion of vitamin D to the active form, there may be some basis for supplementation of nutritional vitamin D in the ESRD population, although most of these patients require an active vitamin D sterol (calcitriol, doxercalciferol, or paricalcitol).
Administration of calcitriol by either the oral or the IV route may be based on daily dosing (usually 0.25 to 1 mcg/day) or pulse dosing (0.5 to 2 mcg two to three times per week). Logistically, IV dosing is more practical in hemodialysis patients, whereas oral therapy is more practical for nondialysis CKD and peritoneal dialysis patients. Recommended doses of doxercalciferol and paricalcitol are shown in Table 29-14. Prior to starting therapy, the serum calcium and phosphorus should be within the normal range to minimize the risk of hypercalcemia and an elevated Ca × P product. This does not mean that vitamin D therapy should be withheld or discontinued in all patients with a Ca × P product greater than 55 mg2/dL2 (4.4 mmol2/L2) unless they are well above this threshold. Rather, use of agents with a lower risk of hypercalcemia and hyperphosphatemia and more prudent use of phosphate binders to lower calcium and phosphorus may be necessary in such patients. Dose adjustments of vitamin D should be made every 2 to 4 weeks based on PTH concentrations and trends in calcium and phosphorus.
Calcimimetics
Pharmacology and Mechanism of Action Cinacalcet hydrochloride (Sensipar) is a calcimimetic agent approved for treatment of sHPT in patients with CKD on dialysis. This compound acts by increasing the sensitivity of the calcium-sensing receptor located on the surface of the chief cells of the parathyroid gland to extracellular calcium, subsequently reducing PTH secretion. Cinacalcet does not increase intestinal calcium and phosphorus absorption. In fact, the reduction in PTH with cinacalcet is associated with a decrease in serum calcium.43
Pharmacokinetics The maximum plasma concentration of cinacalcet is achieved in approximately 2 to 6 hours following oral administration. The half-life is approximately 30 to 40 hours. Cinacalcet has a large volume of distribution (approximately 1,000 L) and is 93% to 97% bound to plasma proteins, both characteristics indicating that removal by dialysis is negligible. It is metabolized by the liver, specifically by the cytochrome P450 isoenzymes CYP3A4, CYP2D6, and CYP1A2.148
Efficacy In clinical trials conducted predominantly in dialysis patients, cinacalcet significantly decreased PTH and the Ca × P product, regardless of the severity of sHPT.43 Studies in CKD patients not on dialysis showed effective lowering of PTH, but a high incidence of hypocalcemia and hyperphosphatemia; thus, this agent is not approved in the nondialysis CKD population. Cinacalcet may be used as a single agent to control hyperparathyroidism in ESRD patients; however, combined therapy with vitamin D is an effective approach to achieve target PTH, calcium, and phosphorus as demonstrated in clinical trials.43 The effect of cinacalcet on vascular calcification has also been evaluated. The ADVANCE Study assessed the effect of cinacalcet plus low-dose active vitamin D versus flexible dosing of active vitamin D on progression of CAC in hemodialysis patients.149 This study showed that the increase in CAC scores was less in cinacalcet-treated patients, although changes were not significant for all scores evaluated. A decrease in all-cause and cardiovascular mortality was also suggested by results of an observational study in hemodialysis patients prescribed cinacalcet in addition to vitamin D compared with those on vitamin D alone.150 While these findings were promising, they were not supported by the EVOLVE trial (the Evaluation of Cinacalcet Therapy to Lower Cardiovascular Events), a prospective study designed to evaluate whether treatment with cinacalcet reduced the risk of all-cause mortality and cardiovascular events in HD patients.151 Although patients in the cinacalcet group had fewer events, the results were not statistically significant.
Adverse Effects The most frequently reported adverse events with cinacalcet were nausea and vomiting. Cinacalcet lowers serum calcium and may cause hypocalcemia; therefore, this agent should not be started if the serum calcium is less than the lower limit of normal, approximately 8.4 mg/dL (2.10 mmol/L). Serum calcium should be measured within 1 week after initiation or following a dose adjustment of cinacalcet. Once the maintenance dose is established, serum calcium should be measured approximately monthly. Potential manifestations of hypocalcemia include paresthesia, myalgia, cramping, tetany, and convulsions.
Drug–Drug and Drug–Food Interactions Because cinacalcet is partially metabolized by cytochrome P450 CYP3A4, there is potential for drug interactions with agents that inhibit this pathway. Coadministration of cinacalcet and ketoconazole, a strong inhibitor of CYP3A4, resulted in an increase in the area under the curve and maximum concentration of 2.3 and 2.2 times, respectively. Cinacalcet is also a potent inhibitor of the enzyme CYP2D6. As a result, dose adjustments of concomitant medications that are predominantly metabolized by this enzyme and have a narrow therapeutic index, such as flecainide, thioridazine, vinblastine, and most tricyclic antidepressants (e.g., amitriptyline), may be necessary.148 Concurrent administration of cinacalcet with amitriptyline increased amitriptyline and nortriptyline (active metabolite) exposure by approximately 20% in CYP2D6-extensive metabolizers.148
Several agents commonly used in the CKD population have been evaluated for interactions with cinacalcet. Coadministration of calcium carbonate, sevelamer, and pantoprazole did not affect the pharmacokinetics of cinacalcet. Coadministration of cinacalcet with warfarin also did not affect the pharmacokinetics of warfarin.148
Food has been shown to increase absorption of cinacalcet by up to 81% compared with fasting; therefore, this medication should be taken with meals to achieve the maximal effect.
Dosing and Administration The recommended starting dose of cinacalcet is 30 mg once daily. Calcium and phosphorus should be measured within 1 week and PTH should be measured within 1 to 4 weeks after starting cinacalcet or adjusting the dose. The dose should be titrated every 2 to 4 weeks to a maximum dose of 180 mg once daily to achieve the desired PTH levels and to maintain near-normal serum calcium concentrations. Patients with hepatic disease may require lower doses, as studies have shown a decrease in metabolism of cinacalcet in this patient population. Cinacalcet is available as a film-coated tablet containing 30, 60, or 90 mg.
Personalized Pharmacotherapy
Management of PTH, phosphorus, and calcium is important in preventing CKD-MBD and cardiovascular and extravascular calcifications. Patients with CKD-MBD usually require a combination of dietary intervention, phosphate-binding medications, vitamin D, and calcimimetic therapy (for ESRD patients) to achieve these goals. KDOQI clinical practice guidelines for bone metabolism and disease suggest specific target ranges for calcium, phosphorus, Ca × P product, and PTH defined based on opinion and evidence when available. Given the lack of randomized controlled trials to support specific target levels for calcium, phosphorus, and PTH, the KDIGO recommendations for target levels and treatment approaches are much more general. Despite the fact that protocols for management of CKD-MBD exist that follow KDOQI or KDIGO, individualization of therapy is necessary and the evidence supporting specific targets is not robust.
When individualizing therapy for a patient, clinicians will also have to take into account the recent changes in the bundling system of payment for outpatient dialysis centers. The financial reimbursement a dialysis unit receives per dialysis session includes IV vitamin D therapy and in 2016 will also include the oral vitamin D agents, cinacalcet, and phosphate binders. There are concerns in the nephrology community about the effect the new system would have on treatment for CKD-MBD. Dialysis providers may advocate changing patients from more expensive, noncalcemic phosphate binders (e.g., sevelamer carbonate and lanthanum carbonate) to less expensive calcium-containing binders. Calcitriol, which is more likely to cause hypercalcemia and hyperphosphatemia, may be used more in the ESRD population since both the IV and oral forms are less expensive than paricalcitol and doxercalciferol. It is also anticipated that the use of cinacalcet may be reduced because of the cost of this oral calcimimetic. These changes in prescribing to reduce cost burden on dialysis facilities could potentially increase the incidence of hypercalcemia, calcifications, and morbidity in the ESRD population.
OTHER COMPLICATIONS OF CKD
Cardiovascular Disease
Patients with CKD are at increased risk of CVD independent of the etiology of their kidney disease.152 As a predominant comorbidity, cardiovascular disorders and their sequelae are the leading cause of death in the ESRD population.3 Higher mortality and risk of cardiovascular events has also been observed in individuals with stage 3 to 5 CKD.3 In addition to traditional cardiac risk factors such as hypertension and hyperlipidemia, diabetes, tobacco use, and physical inactivity, patients with kidney disease have other unique risk factors. Among these are hyperhomocysteinemia, elevated levels of C-reactive protein, increased oxidant stress, and hemodynamic overload.153
Screening for the presence of cardiovascular risk factors is a high priority in this population. Individuals with stage 4 CKD should be assessed for cardiovascular risk factors. Modifiable cardiovascular risk factors such as hypertension, diabetes mellitus, hyperlipidemia, and smoking should be aggressively managed.152 The KDOQI CVD guidelines recommend that all patients starting dialysis be assessed for cardiomyopathy, coronary artery, valvular heart, cerebrovascular, and peripheral vascular disease. They should also be screened for traditional (e.g., hypertension) and nontraditional cardiovascular risk factors.153 Recommendations for management of coronary artery disease, acute coronary syndromes, valvular heart disease, cardiomyopathy, dysrhythmias, cerebrovascular disease, and peripheral vascular disease are also included in the KDOQI guidelines as are differences in management of these disorders in dialysis patients compared with the general population. Guidelines for management of cardiovascular risk factors are also included.
Hyperlipidemia
CKD with or without nephrotic syndrome is frequently accompanied by abnormalities in lipoprotein metabolism. It is well established that dyslipidemias cause atherosclerotic CVD, and there are many compelling reasons to treat these disorders. A clear association between hypercholesterolemia, hypertriglyceridemia, and other lipoprotein changes in patients with CKD and CVD has not been demonstrated in large prospective studies because individuals with kidney disease are usually excluded from these trials. A low or declining serum cholesterol in patients with ESRD is associated with higher mortality, a paradoxical effect.153 These findings beg the question of whether aggressive lipid lowering is warranted in this population.
Although the concentrations of LDL are not uniformly increased in patients with kidney disease, these patients appear to produce small, dense LDL particles that are more susceptible to oxidation and more atherogenic than larger LDL subfractions. Other lipoprotein abnormalities include changes in apoprotein content of lipoprotein molecules, low HDL, increased triglycerides, and increased very-low-density and intermediate-density lipoproteins.154 For patients with CKD and a urinary protein excretion greater than 3 g/day, the major lipid abnormalities are elevation of plasma total and LDL cholesterol, with or without low HDL cholesterol (<35 mg/dL [<0.91 mmol/L]), and elevated triglycerides. Treatment of proteinuria resolves the hyperlipidemia in most patients with nephrotic syndrome.
Management of dyslipidemia in patients with CKD has been guided by recommendations from the National Cholesterol Education Program and the KDOQI guidelines for dyslipidemia.154,155 Based on evidence of risk reduction and the benefits of lipid-lowering therapy in the general population, the consensus was that CKD patients should be treated aggressively to an LDL cholesterol goal below 100 mg/dL (2.59 mmol/L).154,155 However, the KDIGO guidelines for lipid management in CKD published in 2013 do not support this goal since clinical trials have not proven the strategy of targeting a specific LDL level to be beneficial.156 KDIGO recommends that a lipid profile be done for all adults with CKD to include LDL, HDL, and triglycerides.154,156 Follow up lipid levels are not recommended unless the information may alter management (e.g., assessing adherence to therapy or assessing cardiovascular risk in a patient <50 years of age and not currently on a statin). Patients should also be evaluated for other conditions that are known to cause dyslipidemias (e.g., liver disease).
KDIGO acknowledges that reduction in the risk of adverse cardiovascular events in patients with CKD has only been demonstrated with regimens that include a statin or statin plus ezetimibe combination and recommendations focus on these agents for individuals at risk of cardiovascular events.
Statins in CKD
Statins have been shown to decrease mortality and cardiovascular events in patients with early stage CKD; however, data are not as compelling in the ESRD population.157 Although observational studies in hemodialysis patients receiving statins indicated a significant benefit, findings from prospective studies have not been encouraging.158,159 Results from a 4-year study evaluating the effect of atorvastatin therapy on cardiac mortality in more than 1,200 hemodialysis patients with type 2 diabetes showed no significant benefit in the composite end point compared with the placebo group.158 In fact, there was a significantly greater RR of fatal stroke in the atorvastatin-treated patients. These findings do not support initiation of statin therapy in ESRD patients, especially those with type 2 diabetes. The AURORA trial assessed the impact of rosuvastatin 10 mg daily or placebo on the primary end points of death from cardiovascular causes, nonfatal MI, or nonfatal stroke.159 Despite a 43% reduction in cholesterol in the rosuvastatin group, there was no difference in the primary end points. The recently published Study of Heart and Renal Protection (SHARP) trial evaluated the effects of combined simvastatin (20 mg) and ezetimibe (10 mg) compared with placebo on time to first major vascular event (nonfatal MI or cardiac death, any stroke, or revascularization) in patients with no history of MI or coronary revascularization and included patients with CKD (6,247) and ESRD (3,023).160 In patients receiving combined therapy during the 4.9-year followup period, there was a 17% reduction in the RR of major vascular events compared with the placebo group. A 32% reduction in LDL (from 103 to 70 mg/dL [2.66 to 1.81 mmol/L]) was achieved in a population assessed as two-third compliant with therapy. While overall these results are positive, the study was not powered to evaluate whether the observed effect was significant in the ESRD patients as a separate group.
Based on the available evidence, the KDIGO guidelines for lipid management in CKD recommend treatment with a statin in adults aged 50 and older with stage 1 to 5 CKD (not on dialysis). The statin/ezetimibe combination may also be an option in patients in this age group in stage 3 to 5 CKD (not on dialysis). KDIGO only recommends statins in adults aged 18 to 49 years with stage 1 to 5 CKD (not on dialysis) who have one or more of the following: known coronary disease, diabetes mellitus, prior ischemic stroke, and an estimated 10-year incidence of coronary death or nonfatal myocardial infarction >10%. It is not recommended that statins or statin/ezetimibe be initiated in patients with stage 5 CKD on dialysis; however, therapy with these agents may be continued if patients were receiving these medications at the time of dialysis initiation.156 Due to the risk of adverse events with statins and absence of safety data in patients with stage 3 to 5 CKD, KDIGO recommends using statins at doses shown to be beneficial in randomized studies conducted in this population (e.g., atorvastatin 20 mg, fluvastatin 80 mg, rosuvastatin 10 mg, simvastatin 20 mg).156
Nutritional Status
Protein–energy malnutrition is very common among patients with advanced CKD (stages 4 and 5).161 Causes of malnutrition in these patients include inadequate food intake secondary to anorexia, altered taste sensation, and the unpalatability of prescribed diets. Other factors in the ESRD population, such as the effect of the dialysis procedure on removal of nutrients, hypercatabolism induced by other inflammatory conditions, and blood loss, are also contributory. Protein restriction as an intervention to potentially delay progression of kidney disease in patients with stage 4 CKD may also lead to protein malnutrition by the time a patient reaches ESRD; therefore, the risks versus the benefits of this intervention must be considered on an individual basis as hypoalbuminemia and malnutrition have a strong association with mortality in chronic dialysis patients.
Patients with ESRD have increased nutritional needs relative to the general population, based on the effect of the disease state and the dialysis procedures on nutritional status. The recommended dietary protein intake in chronic hemodialysis patients is 1.2 g/kg body weight per day.161 The recommended intake for chronic peritoneal dialysis patients is at least 1.2 to 1.3 g/kg body weight per day, based on the increased protein loss that occurs with this dialysis modality. The recommended total daily energy intake in both hemodialysis and peritoneal dialysis patients is 35 kcal/kg (147 kJ/kg) body weight per day. For peritoneal dialysis patients, this includes intake from both diet and the glucose absorbed from peritoneal dialysate. For patients older than 60 years of age, this criterion differs, because increasing age is generally associated with reduced physical activity and lean body mass. Daily energy intake for these patients is 30 to 35 kcal/kg (126 to 147 kJ/kg) body weight per day. Nutritional support should be considered for those patients who cannot achieve these goals with oral intake alone. Another option for nutritional supplementation in patients on hemodialysis includes interdialytic parenteral nutrition.
Vitamin requirements for ESRD patients receiving dialysis differ from those of a healthy person because of dietary modifications, kidney dysfunction, and dialysis therapy. The plasma concentrations of vitamins A and E are elevated in ESRD, whereas those of the water-soluble vitamins (B1, B2, B6, B12, niacin, pantothenic acid, folic acid, biotin, and vitamin C) tend to be low in large part because many are dialyzable. The goal for vitamin supplementation should be to prevent subclinical and frank deficiency. Special vitamin supplements have been formulated for the dialysis population, which primarily include vitamins B and C and folic acid.
BOTTOM LINE
The number of patients with and at risk for CKD is increasing, with a substantial rise in the population with stage 5 CKD expected in the next decade. Although efforts to delay progression of CKD including prudent use of ACEIs and ARBs are paramount, measures to diagnose and manage the associated secondary complications and comorbid conditions early in the course of the disease are also essential. Common complications of stage 4 and 5 CKD include anemia and CKD-MBD. Cardiovascular complications are also prevalent in the population with CKD, and are the leading cause of mortality in patients with ESRD. Patient education plays a critical role in the appropriate management of CKD and related complications.
A multidisciplinary team structure is a rational approach to providing this education and effectively designing and implementing the required extensive nonpharmacologic and pharmacologic interventions. Pharmacists are among the healthcare providers who contribute substantially to this team as shown by their activities in MTM, improving patient adherence with drug therapy, and providing more cost-effective medication use in dialysis facilities. There are many opportunities for pharmacists to become involved in both the outpatient dialysis or ambulatory care settings and the inpatient environment to improve the management of patients with CKD and the associated complications.
ABBREVIATIONS
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