16. Kidney Disease - Joanna Q. Hudson, PharmD, BCPS, FASN

16-1. Acute Kidney Injury


Acute renal failure, now increasingly referred to as acute kidney injury (AKI), is defined as rapid (hours to days) deterioration of kidney function resulting in azotemia (retention of nitrogenous waste products such as urea) and failure of the kidney to maintain fluid, electrolyte, and acid-base homeostasis.

A reduced urine output is frequently seen: oliguria (urine output < 400 mL/d), anuria (urine output < 50 mL/d), and nonoliguria (urine output > 400 mL/d).

The classification system proposed to distinguish between mild or severe and early or late cases of AKI is known as RIFLE: Risk of kidney dysfunction, Injury to the kidney, Failure or Loss of kidney function, and End-stage renal disease (ESRD):

• Risk: A 1.5-fold increase in the serum creatinine or a decrease of the glomerular filtration rate (GFR) by 25 percent or urine output < 0.5 mL/kg/h for 6 hours

• Injury: A twofold increase in the serum creatinine or a decrease of GFR by 50% or urine output < 0.5 mL/kg/h for 12 hours

• Failure: A threefold increase in the serum creatinine, a decrease of GFR by 75% or urine output of < 0.5 mL/kg/h for 24 hours, or anuria for 12 hours

• Loss: Complete loss of kidney function (e.g., need for renal replacement therapy) for more than 4 weeks

• ESRD: Complete loss of kidney function (e.g., need for renal replacement therapy) for more than 3 months

A modification of RIFLE that includes slightly adapted diagnostic criteria and a staging system was proposed by the Acute Kidney Injury Network. The classification or staging system corresponds to risk (stage 1), injury (stage 2), and failure (stage 3) of the RIFLE criteria. Loss and ESRD were removed from the staging system and defined as outcomes.


Incidence and prevalence

• Community-acquired AKI accounts for 1% of hospital admissions.

• Hospital-acquired AKI occurs in 5-7% of hospitalized patients.


• The best prognosis is when renal replacement therapy is not required.

• The mortality rate is 40-50% for patients who require renal replacement therapy.

• The mortality rate is > 50% for patients with multiple organ failure.

Types and Classifications

AKI is classified according to the area of the kidney affected:

• Prerenal AKI is characterized by a decrease in perfusion to the kidney with or without systemic arterial hypotension. It is the most common type of AKI and is usually reversible.

• Intrinsic or intra renal AKI is the result of structural damage to the parenchymal tissue of the kidney. It is divided into vascular, glomerular, interstitial, and tubular disorders (most common).

• Postrenal AKI is an obstruction of urine flow occurring at any level of the urinary outflow tracts.

Clinical Presentation

• Decreased urine output

• Signs of hypovolemia (prerenal causes), such as tachycardia, decreased venous and arterial pressure, and orthostasis

• Unique color and composition of urine: cola-colored urine (suggesting bleeding) and foaming (indicating proteinuria)

• Symptoms of uremia (a clinical syndrome resulting from azotemia), including weakness, shortness of breath, fatigue, mental status changes, nausea and vomiting, bleeding, loss of appetite, and edema

• Flank pain

• Increased weight (suggesting fluid accumulation)

• Increased blood pressure (suggesting fluid accumulation)

• Signs and symptoms of electrolyte abnormalities (hyperkalemia) and metabolic acidosis (see Chapter 17 on fluids and electrolytes)

• Bladder distention or prostate enlargement (postrenal causes)

• Other findings specific to the cause of AKI (see section on pathophysiology)

Pathophysiology and Etiologies

Prerenal AKI

Prerenal AKI is caused by conditions that decrease glomerular hydrostatic pressure, leading to a decrease in GFR (see discussion on etiologies). Hypoperfusion leads to increased sodium and water reabsorption by the kidney and stimulates compensatory mechanisms.

The following compensatory mechanisms increase glomerular hydrostatic pressure and GFR:

• Vasodilation of the afferent arteriole (mediated primarily by prostaglandins)

• Vasoconstriction of the efferent arteriole (mediated primarily by angiotensin II)

Alterations in afferent and efferent arteriolar tone can affect compensatory mechanisms. Nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) inhibitors can prevent compensatory vasodilation of the afferent arteriole. Angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and renin inhibitors can prevent compensatory vasoconstriction of the efferent arteriole.

Etiologies of prerenal AKI are as follows:

• Intravascular volume depletion related to excessive diuresis, vomiting, excessive gastrointestinal (GI) fluid loss, and bleeding

• Severe hypotension

• Decreased effective blood volume (volume sensed by arterial baroreceptors) as occurs with congestive heart failure, cirrhosis, nephrotic syndrome, and hepatorenal syndrome

• Systemic vasodilatation as occurs with sepsis, liver failure, and anaphylaxis

• Large-vessel renal vascular disease, including renal artery thrombosis or embolism and renal artery stenosis

• Medications (see

Table 16-1).

Intrinsic acute renal failure

The primary anatomic sites of the kidney are prone to structural damage from prolonged ischemia and direct toxicity because of the high metabolic activity and concentrating ability of the kidney.

Etiologies by anatomic site are as follows:

• Vascular: Inflammation and emboli

• Glomerular (glomerulonephritis): Systemic lupus erythematosus and medications (see Table 16-1)

• Interstitial: Ischemia, allergic interstitial nephritis, infections, and medications (see Table 16-1)

• Tubular—accounts for 90% of intrinsic cases: Intrarenal vasoconstriction, direct tubular toxicity, and intratubular obstruction; prolonged ischemia from prerenal causes; and toxins

• Endogenous: Myoglobin, hemoglobin, and uric acid

• Exogenous: Medications (see Table 16-1; aminoglycosides are common nephrotoxins leading to nonoliguric AKI after 5-7 days of therapy); radiocontrast-induced AKI; other causes such as ethylene glycol and pesticides

Postrenal acute kidney disease

This disease is an obstruction of urinary flow at any level from the urinary collecting system to the urethra. It must involve both kidneys (or one kidney in a patient with a single functioning kidney).

Etiologies by anatomic site are as follows:

• Renal pelves or tubules: Crystal deposition

• Ureteral: Tumor, stricture, and stones

• Bladder neck obstruction: Prostatic hypertrophy and bladder carcinoma

• Medications: See Table 16-1.

[Table 16-1. Drug-Induced Causes of Kidney Disease]

Diagnostic Criteria

Table 16-2 shows the diagnostic tests and the findings associated with AKI. A diagnosis requires the following steps:

• Evaluate physical findings: Assess for signs and symptoms listed in clinical presentation.

• Take medication history (including OTC medication and herbals): Identify potentially nephrotoxic agents (Table 16-1).

• Estimate GFR: Normal is 100-125 mL/min/1.73 m2.

• Consider limitations in using serum creatinine as a marker of kidney function (e.g., conditions of poor muscle mass) and in using equations to estimate GFR in patients with unstable kidney function.

• Other assessment equations and methods (e.g., Jelliffe equation) are available to estimate GFR in patients with unstable kidney function.

Creatinine clearance

Creatinine clearance (CrCl) is measured using urine collection methods:


where UCr

= urinary creatinine concentration (mg/dL)



= volume of urine (mL)



= serum creatinine concentration (mg/dL)



= time period of urine collection (minutes)


[Table 16-2. Laboratory Findings to Differentiate Prerenal and Intrinsic Kidney Disease]

CrCl is estimated using the Cockcroft-Gault equation (assumes stable kidney function): 000018

where BW = body weight in kg. Ideal body weight is recommended if patient's body weight is more than 30% above the ideal body weight. Multiply the result of the Cockcroft-Gault equation by 0.85 for females.

Blood tests

• Elevated: Blood urea nitrogen (BUN), serum creatinine, and electrolytes (potassium and phosphorus)

• Decreased: Calcium (consider albumin concentration) and bicarbonate


• An elevated specific gravity and osmolality are indicative of prerenal causes and stimulation of sodium and water retention.

• Proteinuria includes microalbuminuria (> 30 mg/d), overt proteinuria (> 300 mg/d), and nephrotic range proteinuria (> 3 g/d).

• Hematuria is indicated by red blood cells.

• Glucose and ketones may be present.

• Urine sediment consisting of granular casts and cellular debris suggests structural damage.

• White blood cells suggest inflammation.

• Eosinophils are associated with acute allergic interstitial nephritis.

• Consider whether fluids or diuretics were previously administered when interpreting urinalysis.

Urine chemistries

Evaluate urine sodium, potassium, chloride, creatinine, and urinary anion gap.

Fractional excretion of sodium (FENa) is useful to differentiate prerenal AKI from acute intrinsic kidney injury. A low value (< 1%) suggests retention of sodium and water (prerenal etiology) versus intrinsic cause.


where UNa

= urine sodium



= urine creatinine



= plasma creatinine



= plasma sodium


Other tests

Radiographic procedures include ultrasound, plain film radiograph, radioisotope scan, and computed tomography.

Renal biopsy is indicated for patients without cause of AKI identified by other diagnostic tests.

Treatment Principles and Goals


Risk factors must be identified:

• Volume depletion

• Exposure to nephrotoxic medications

• Preexisting kidney or hepatic disease

Surgical procedures can be a risk factor. Consider baseline kidney function, age, cardiovascular status, and volume status.

Diagnostic tests requiring radiocontrast media can put patients at risk. Risk factors for contrast nephropathy are diabetes, heart failure, age > 75, and an estimated GFR < 60 mL/min/1.73 m2. In addition to being given hydration, high-risk patients should receive oral acetylcysteine (Mucomyst) 600 mg twice daily for 2 days beginning the day before exposure to radiocontrast dye. Bicarbonate may also be added to the hydration fluid.

Treatment Goals

• Correct underlying causes of AKI (e.g., discontinue nephrotoxic agents, correct fluid status, treat underlying infection, and address cause of urinary tract obstructions).

• Return to baseline kidney function or highest kidney function possible.

• Prevent development of chronic kidney disease and the need for chronic renal replacement therapies (dialysis or transplantation).

• Avoid nephrotoxic agents or take measures to reduce exposure if possible.

• Adjust doses of medications on the basis of kidney function.

• Avoid agents contraindicated in patients with kidney disease, such as metformin (Glucophage).

• Address complications of AKI, such as electrolyte abnormalities (hyperkalemia), fluid overload, metabolic acidosis (see Chapter 17 on fluids and electrolytes), hyperphosphatemia (see Section 16-2 on chronic kidney disease).

Strategies for treatment

• Address underlying cause of AKI.

• Provide supportive care with diuretic therapy (loop diuretics) and replacement fluids as needed to maintain hemodynamic stability.

Drug Therapy


Select diuretics are shown in

Table 16-3.

Mechanism of action

Loop diuretics are delivered to the tubular lumen of the kidney by proximal tubular cells and cause inhibition of sodium and chloride reabsorption in the thick ascending limb of the loop of Henle to promote water excretion.

Osmotic diuretics are freely filtered into the tubular lumen in the proximal tubule and increase the osmolarity of the glomerular filtrate, which inhibits tubular reabsorption of water and electrolytes and increases urinary output.

Thiazide and thiazide-like diuretics inhibit the Na+-Cl- cotransport in the early distal convoluted tubules. They are generally used in combination with loop diuretics for resistant edema and fluid overload, particularly metolazone, which is effective at GFRs < 30 mL/min. Other thiazide diuretics are generally not effective when GFR is < 30 mL/min.

Adverse drug events

Loop diuretics

Adverse drug events are as follows:

• Hypokalemia, hypomagnesemia, hyponatremia, hypovolemia, hyperuricemia, and hyperglycemia

• Hypercalciuria

• Orthostatic hypotension and dehydration

• Metabolic alkalosis (partly attributable to extracellular fluid volume contraction)

• Ototoxicity

• Diarrhea and nausea

Furosemide, bumetanide, and torsemide have a sulfonamide substituent (potential for hypersensitivity reactions). Ethacrynic acid is generally reserved for patients allergic to sulfa compounds.

[Table 16-3. Diuretics as Drug Therapy for AKI by Drug Classification]

Osmotic diuretics

The following adverse drug events may occur:

• Acute expansion of extracellular fluid volume and increased risk of pulmonary edema

• Acute rise in serum K+, nausea and vomiting, headache, blurred vision, and rash

Thiazide and thiazide-like diuretics

Adverse drug events include the following:

• Hypokalemia, hyponatremia, and hypercalcemia

• Hypovolemia and orthostatic hypotension

• Hyperglycemia, hypochloremic alkalosis, and hyperlipidemia

• Hypersensitivity reactions from sulfonamide substituents

• Chest pain (metolazone; more common with Mykrox, which is more rapidly and extensively absorbed than Zaroxolyn)

Drug-drug and drug-disease interactions

• Loop diuretics and aminoglycosides have an increased potential for ototoxicity.

• Diuretics and other nephrotoxins have an increased risk of nephrotoxicity if hypovolemia occurs.

• Diuretics and lithium used concomitantly may result in decreased renal clearance of lithium. Monitor lithium concentrations more closely.

• For diuretics and digoxin, hypokalemia from diuretic use may increase risk of toxicity with digoxin. Monitor potassium and digoxin.

• Loop and thiazide diuretics may increase gout attacks because of hyperuricemia.

• For thiazide diuretics and diabetes, hyperglycemia may result from thiazides. Increase glucose monitoring.

• The following conditions decrease secretion of the diuretic to its site of action in the renal tubule:

• Proteinuria (diuretic binds to protein and is not available at its site of action)

• Decreased renal blood flow

• Competitive inhibition of transport system (NSAIDs, probenecid, and cephalosporins)

Parameters to monitor

• Blood pressure (sitting and standing), pulse, urine output, fluid intake, serum creatinine, serum electrolytes, blood urea nitrogen, bicarbonate, calcium, glucose, and uric acid

• In the case of osmotic diuretics, serum osmolality (310-320 mOsm/kg); assess urine output after initial test dose (goal urine flow is at least 30-50 mL/h)


Loop diuretics

• Oral bioavailability: Furosemide (60%), bumetanide (85%), and torsemide (85%)

• Oral:intravenous dose ratios: Furosemide (1.5), bumetanide (1), and torsemide (1)

• Equivalent doses: 1 mg bumetanide = 20 mg torsemide = 40 mg furosemide

• Elimination route: Furosemide (primarily renal), bumetanide (hepatic and renal), torsemide (primarily hepatic), and ethacrynic acid (hepatic and renal)

Thiazide and thiazide-like diuretics

Metolazone absorption differs between brands. Mykrox (available outside the United States) is more rapidly and extensively absorbed than Zaroxolyn.

Other factors

Patients with kidney disease generally require larger doses of diuretics to achieve adequate concentrations of the drug at the site of action in the kidney.

The brands of metolazone (Zaroxolyn and Mykrox) are not bioequivalent and should not be interchanged.


The use of dopamine in AKI is controversial because benefits have not consistently been demonstrated.

Nondrug Therapy

Fluid management

Fluid intake and output should be evaluated and adjustments made to maintain hemodynamic stability (consider sensible and insensible losses).

Fluid selection (e.g., crystalloids, colloids, or normal saline) and rate of correction depend on the clinical condition of the patient.

Nutritional therapy

A high-calorie diet is generally required (patient-specific).

Restriction of sodium, potassium, and phosphorus should be considered.

Renal replacement therapies

Renal replacement therapies are procedures by which the blood is artificially cleared of waste and some essential metabolic products to augment the function of failed or failing kidneys. They include hemodialysis and hemofiltration, in which the semipermeable membrane is a dialyzer, and peritoneal dialysis, in which the peritoneal cavity serves as this membrane. Procedures may be intermittent or continuous. Hemodialysis and hemofiltration are the most common modalities for patients with AKI. Kidney transplantation is also considered a form of renal replacement therapy.

The potential for drug removal by dialysis must be considered.

Indications for renal replacement therapy

Any of the following refractory to more conservative measures are indications for renal replacement therapy:

• Acidosis

• Electrolyte abnormalities (hyperkalemia)

• Intoxication (drug-induced kidney failure), if drug can be removed by dialysis

• Volume overload

• Uremia (BUN >100 mg/dL) or uremic symptoms (pericarditis, encephalopathy, bleeding, dyscrasia, nausea, vomiting, and pruritus)

16-2. Chronic Kidney Disease


Chronic kidney disease (CKD) is kidney damage with or without a decrease in GFR or a GFR < 60 mL/min/1.73 m2 for ≥ 3 months. Kidney damage is defined as pathologic abnormalities or markers of damage, including abnormalities in blood or urine tests or in imaging studies.

CKD is classified into five stages on the basis of kidney damage and GFR (

Table 16-4). End-stage renal disease occurs when patients require renal replacement therapy (either dialysis or transplantation) to sustain life.

Epidemiology of Chronic Kidney Disease

Incidence and prevalence

Approximately 26 million American adults have CKD. The number of patients with CKD continues to increase, with a 50% increase in the number of patients with ESRD expected by 2020. The incidence of CKD is approximately four times higher in the African American population. The incidence is greatest in individuals age 45-64.

Approximately 500,000 patients are being treated for ESRD (including patients receiving hemodialysis, peritoneal dialysis, and transplantation).


Life expectancy is four to five times shorter in dialysis patients than in the general population. The primary causes of death in the ESRD population are cardiovascular diseases and infection. Comorbidities, estimated GFR, and albumin at initiation of dialysis are strong predictors of mortality in the dialysis population.

Clinical Presentation

• Changes in urine output (may not occur in earlier stages of CKD)

• Foaming of urine, which indicates proteinuria (

Table 16-5):

• Microalbuminuria: Albumin in the urine in amounts of 30-300 mg/d

[Table 16-4. Stages of Chronic Kidney Disease]

[Table 16-5. Definitions of Proteinuria and Albuminuria]

• Albuminuria: Albumin in the urine in amounts > 300 mg/d

• Clinical proteinuria: Total protein (in addition to albumin) in the urine in amounts > 300 mg/d

• Increased blood pressure (hypertension is a common etiology and result of CKD)

• Signs and symptoms of hyperglycemia and glucosuria (diabetes is a common etiology)

• Signs and symptoms associated with fluid and electrolyte abnormalities (e.g., hyperkalemia and fluid overload; see Chapter 17 on fluids and electrolytes)

• Development of secondary complications of CKD:

• Anemia: Decreased hemoglobin and hematocrit, iron deficiency common

• CKD mineral and bone disorder: Increased serum phosphorus, decreased serum calcium (at risk for hypercalcemia as kidney disease progresses), increased intact parathyroid hormone (iPTH), and vitamin D deficiency

• Metabolic acidosis: Decreased serum bicarbonate and increased anion gap

• Malnutrition: Decreased albumin and prealbumin (see Chapter 19 on nutrition)

• Signs of uremia (see Section 16-1) in later stages of CKD (stages 4 and 5 CKD)

Pathophysiology of Progressive Kidney Disease and Selected Secondary Complications

Progressive kidney disease

Progressive loss of nephron function results in adaptive changes in remaining nephrons to increase single nephron glomerular filtration pressure. Over time, the compensatory increase in single nephron GFR leads to hypertrophy from sustained increases in pressure and loss of individual nephron function.

Proteinuria, one of the initial diagnostic signs, may also contribute to the progressive decline in kidney function. Loss of kidney function is usually irreversible.

Etiology of progressive kidney disease

Each of the following may result in damage to the kidney that leads, over time, to a decrease in functioning nephrons and in total GFR:

• Diabetes (accounts for primary cause in 44% of patients with ESRD)

• Hypertension (accounts for primary cause in 26% of patients with ESRD)

• Glomerulonephritis

• Cystic kidney disease

• HIV (human immunodeficiency virus) nephropathy

• Other contributing factors (smoking, obesity, genetic factors, and gender differences)

Anemia of chronic kidney disease

The primary etiology is a decrease in production of the hormone erythropoietin by the kidney as kidney disease progresses. More than 90% of erythropoietin production occurs in the kidney and approximately 10% in the liver.

CKD results in a normochromic, normocytic anemia. Red blood cell lifespan is also decreased from 120 days to approximately 60 days in patients with kidney failure. Other contributors include iron deficiency and blood loss (e.g., from uremic bleeding, dialysis).

CKD Mineral and Bone Disorder

As kidney function declines, phosphorus elimination decreases. Hyperphosphatemia causes a reciprocal decrease in serum calcium concentrations (hypocalcemia). Hypocalcemia stimulates the release of iPTH by the parathyroid glands.

Conversion of the vitamin D precursor to the active form (1,25-dihydroxyvitamin D3) occurs in the kidney. As kidney disease progresses, there is a decline in the 1α-hydroxylase enzyme that promotes the final hydroxylation step in the kidney, resulting in a deficiency in active vitamin D. Deficiencies in the precursor form of vitamin D have also been observed in stages 3 and 4 CKD. Active vitamin D (1,25-dihydroxyvitamin D3) promotes increased intestinal absorption of calcium and suppresses production of parathyroid hormone by the parathyroid gland; therefore, vitamin D deficiency leads to worsening secondary hyperparathyroidism.

Increased iPTH promotes the following:

• Decreased phosphorus reabsorption within the kidney

• Increased calcium reabsorption by the kidney

• Increased calcium mobilization from bone

As kidney disease progresses, the following occur:

• Hyperphosphatemia and subsequent hypocalcemia progressively worsen, and secondary hyperparathyroidism becomes more severe.

• The renal effects of PTH on phosphorus and calcium are no longer maintained, and PTH predominantly stimulates calcium resorption from bone.

• Decreased production of active vitamin D worsens hypocalcemia and secondary hyperparathyroidism.

• In more severe CKD (stages 4 and 5), patients are prone to develop hypercalcemia, in part because of the use of calcium-containing phosphate binders.

• Patients with stage 5 CKD are at risk for calcifications and calciphylaxis.

• Uncontrolled secondary hyperparathyroidism leads to hyperplasia of the parathyroid gland and renal osteodystrophy (from sustained effects of iPTH on bone).

Metabolic acidosis

• Decreased excretion of acid by the kidney

• Accumulation of endogenous acids attributable to impaired kidney function (e.g., phosphates and sulfates)

Diagnostic Criteria

Progressive kidney disease

There is a progressive increase in serum creatinine: > 1.1-1.2 mg/dL for females and > 1.2-1.3 mg/dL for males. Consider factors that may alter serum creatinine, such as decreased muscle mass and nutritional status.

There is a decreased GFR (see Table 16-4 for CKD classifications). Consider the assessment method used:

• Measured creatinine clearance (see discussion of diagnostic criteria for acute kidney injury in Section 16-1)

• Cockcroft-Gault equation (see discussion of diagnostic criteria for acute kidney injury in Section 16-1)

• Modification of diet in renal disease abbreviated equation


186 × (serum creatinine)- 1.154


× (age in years)-0.203


× 1.210(if patient is black)


× 0.742(if patient is female)


• Schwartz equation (children)


   where k = 0.55 for children aged 1-13 years

• Microalbuminuria, albuminuria, or clinical proteinuria (Table 16-5)

• Abnormal serum chemistries:

• Increased serum creatinine and BUN

• Increased potassium, decreased serum bicarbonate, increased phosphorus, and decreased calcium (indicative of secondary complications)

• Development of secondary complications (e.g., anemia, CKD mineral and bone disorder, and fluid and electrolyte abnormalities)

Anemia of chronic kidney disease

Testing for anemia is recommended in all patients with CKD. Guidelines for anemia management in patients with CKD recommend further evaluation for anemia when hemoglobin is < 12 g/dL in females and < 13.5 g/dL in males.

For iron deficiency, evaluate red blood cell indices and iron indices to identify iron deficiency as a contributing factor; iron deficiency manifests as a microcytic anemia.

• Red blood cell count: < 4.2 × 106 cells per mm2

• Mean corpuscular volume: < 80 femoliters

• Serum iron: < 50 mg/dL

• Total iron binding capacity: < 250 mg/dL

• Transferrin saturation (TSat): < 16%

• Serum ferritin: < 12 ng/mL

Transferrin saturation and serum ferritin should be maintained at higher values for CKD patients receiving erythropoietin therapy (TSat > 20% and serum ferritin >100 ng/mL for CKD patients not on dialysis and for peritoneal dialysis patients; and TSat > 20% and serum ferritin >200 ng/mL for hemodialysis patients).

Evaluate for folate and vitamin B12 deficiencies (manifests as a macrocytic anemia), sources of blood loss (e.g., GI bleeding), and confounding disease states (e.g., cancer and HIV).

CKD Mineral and Bone Disorder

• Serum phosphorus: > 4.6 mg/dL (> 5.5 mg/dL in stage 5 CKD)

• Calcium abnormalities:

• Hypocalcemia: Corrected serum calcium < 8.5 mg/dL

• Hypercalcemia (a concern in stages 4 and 5 CKD): Corrected calcium = measured serum calcium + 0.8 × (normal serum albumin - measured serum albumin); normal serum albumin = 4.0 g/dL

• Elevated calcium × phosphorus product: > 55 mg2/dL2 (elevated product increases risk for metastatic calcifications)

• Intact parathyroid hormone: > 70 pg/mL (stage 3 CKD), > 110 pg/mL (stage 4 CKD), and > 300 pg/mL (stage 5 CKD)

• Radiographic evidence of bone abnormalities (e.g., osteitis fibrosa cystica)

Metabolic acidosis

Serum bicarbonate (HCO3-) is < 20 mEq/L.

Typically have an increased anion gap: anion gap = [Na+] - ([Cl-] + [HCO3-]).

Signs and symptoms of chronic metabolic acidosis that develop as CKD progresses are generally not of the same magnitude as those of acute metabolic acidosis (e.g., hyperventilation, cardiovascular and central nervous system manifestations).

Treatment Principles and Goals

Progressive kidney disease

Treatment principles

• Control underlying cause of progressive CKD (e.g., diabetes and hypertension; see Chapters 8 and 13, respectively).

• Meet blood pressure goal: < 130/80 mm Hg for patients with evidence of kidney disease and/or diabetes.

• Prevent or minimize microalbuminuria or proteinuria.

• Slow the rate of progression of CKD (by achieving diabetes and hypertension goals and minimizing proteinuria).

• Prevent drug-induced causes of kidney disease:

• Avoid chronic use of combinations of analgesics.

• Minimize use of agents known to cause AKI (patients can develop an acute-on-chronic kidney disease).

• Manage secondary complications of CKD (anemia, mineral and bone disorders, and electrolyte abnormalities).

• Control hyperlipidemia.

• Address cardiovascular risk factors (cardiovascular disease is the leading cause of death in the CKD population).

• Adjust drug doses on the basis of kidney function.

• Avoid medications contraindicated in patients with reduced kidney function. For example, metformin (Glucophage) is contraindicated in patients with elevated serum creatinine (> 1.5 mg/dL for men and > 1.4 mg/dL for women) because of the increased risk of lactic acidosis.

• Prepare patient for renal replacement therapy (i.e., dialysis and transplantation) as needed.

• Start dialysis if stable GFR < 15 mL/min/1.73 m2 and based on other indications (see Section 16-2 on indications for renal replacement therapy).

• Recommend smoking cessation.

Treatment strategies

• Diuretics for fluid balance and management of hypertension (diuretic selection based on kidney function)

• Antihypertensives with diet and lifestyle modifications for control of blood pressure (see Chapter 8 on hypertension)

• Antidiabetic agents with diet and lifestyle modifications for control of blood glucose (see Chapter 13 on diabetes)

• ACEIs and ARBs to delay progression of kidney disease (recommended for patients with diabetes and individuals with hypertension and proteinuria; see Table 16-5)

• Protein restriction to 0.6-0.8 g/kg/d:

• Consider for patients with > 1 g/d proteinuria despite optimal blood pressure control with a regimen that includes an ACEI or ARB.

• Be cautious about maintaining adequate caloric intake and avoid malnutrition.

• Do not implement for patients < 80% of their ideal body weight or with > 10 g/d proteinuria.

• Renal replacement therapy:

• Consider plans for dialysis therapy (hemodialysis or peritoneal dialysis) during stage 4 CKD (when GFR < 30 mL/min) (see Section 16-2 for general description of dialysis).

• Evaluate candidacy for kidney transplantation.

Anemia of chronic kidney disease

Target hemoglobin is 11-12 g/dL, and target hematocrit is 33-36% (based on the Kidney Disease Outcome Quality Initiative Guidelines). Note: The FDA labeling for all erythropoietic stimulating agents states the goal hemoglobin as 10-12 g/dL.

Iron indices are transferrin saturation > 20% and serum ferritin > 100 ng/mL for CKD patients not on dialysis and for peritoneal dialysis patients. The goal for serum ferritin in hemodialysis patients is > 200 ng/mL). Note: Ferritin is an acute phase reactant and may be elevated during conditions of infection or inflammation.

Treatment strategies

Erythropoietic stimulating agents

Erythropoietic stimulating agents (ESAs) stimulate red blood cell production in the bone marrow.

ESAs may be administered subcutaneously (SC) or intravenously (IV). SC is generally preferred for patients not on hemodialysis (i.e., peritoneal dialysis and early stage CKD patients who do not have IV access).

Epoetin alfa (Epogen and Procrit): Initial doses are 50-100 units/kg IV or SC three times per week.

Darbepoetin alfa (Aranesp): Initial dose is 0.45 mcg/kg IV or SC administered once weekly. Alternatively, for patients not on dialysis, an initial dose of 0.75 mcg/kg may be administered SC every two weeks.

Dose conversion is from epoetin alfa (units/week) to darbepoetin alfa (mcg/week)(

Table 16-6).

The darbepoetin package insert states that for patients receiving epoetin alfa 2-3 times per week, darbepoetin alfa should be administered weekly. For patients receiving epoetin alfa once per week, darbepoetin alfa should be administered once every two weeks. In this situation, the weekly epoetin dose should be multiplied by 2 and that dose should be used in Table 16-6 to determine the appropriate darbepoetin dose.

For dose titration, allow at least 2-4 weeks before making a change in the dose of epoetin alfa or darbepoetin alfa based on the change in hemoglobin or hematocrit. If a change in hemoglobin is < 1 g/dL

[Table 16-6. Estimated Starting Doses of Darbepoetin Alfa Based on Previous Epoetin Alfa Dose]

in a 4-week period and iron stores are adequate, increase the ESA dose by 25%. If a change in hemoglobin is > 1 g/dL in a 2-week period, or the hemoglobin is approaching 12 g/dL, reduce the ESA dose by 25%.

Iron supplementation

Iron supplementation prevents iron deficiency as a cause of resistance to therapy with erythropoietic stimulating agents. Iron deficiency should be corrected prior to making changes in the dose of the erythropoietic stimulating agent.

Oral iron supplementation is limited by poor absorption and is often inadequate to achieve goal iron indices. It may be reasonable for stages 3 and 4 CKD patients and the peritoneal dialysis population (patients without IV access). The recommended dose is 200 mg elemental iron per day.

Intravenous iron supplementation is preferred for treatment of absolute iron deficiency and in hemodialysis patients with regular intravenous access. One may administer a full course of iron, typically a total dose of 1 g divided over 8-10 hemodialysis sessions (100 mg per dose for iron sucrose [Venofer] and iron dextran [InFeD and Dexferrum] or 125 mg per dose for sodium ferric gluconate [Ferrlecit]). Weekly doses of 25-125 mg may be administered as maintenance doses of iron in hemodialysis patients.

• Iron sucrose: The 100 mg dose may be diluted in 100 mL of 0.9% NaCl (sodium chloride) administered IV over at least 15 minutes or administered undiluted over 2-5 minutes.

• Iron dextran: The 100 mg dose may be administered over 2 minutes IV push. One must administer a 25 mg test dose because of the risk of anaphylactic reactions.

• Sodium ferric gluconate: The 125-mg dose may be diluted in 100 mL of 0.9% NaCl and administered IV over 1 hour or administered undiluted as an IV injection at a rate up to 12.5 mg/min. Dosing in pediatric patients is 1.5 mg/kg in 25 mL of 0.9% NaCl over 60 minutes (maximum dose 125 mg).

IV iron regimens differ in peritoneal dialysis patients and patients with CKD not requiring dialysis. A total dose of 1 g is recommended for iron-deficient patients, administered in divided doses. Iron sucrose has an approved regimen in these populations.

The approved dosing regimen for iron sucrose in nondialysis CKD patients is 200 mg over 2-5 minutes on five different occasions within a 14-day period. Peritoneal dialysis patients should receive 300 mg in 0.9% NaCl administered IV over 1.5 hours, followed by a second infusion of 300 mg 14 days later and then by a 400 mg dose administered over 2.5 hours 14 days later.

Ferumoxytol (Feraheme) is an IV form of iron approved in 2009 for treatment of iron deficiency anemia in adults with chronic kidney disease. The approved dose is 510 mg (17 mL) as a single dose, followed by a second 510 mg dose 3-8 days after the initial dose.

Blood transfusions may be required for more severe anemia or when blood loss is a major contributing factor.

CKD Mineral and Bone Disorder

• Goal serum phosphorus is 2.7-4.6 mg/dL for stages 3 and 4 CKD and 3.5-5.5 mg/dL for stage 5 CKD.

• Goal serum corrected calcium is approximately 8.5-10 mg/dL (normal range) for stages 3 and 4 CKD and 8.4-9.5 mg/dL for stage 5 CKD (recommend a lower range in stage 5 CKD because of risk of hypercalcemia and calcifications).

• Calcium × phosphorus product is < 55 mg2/dL2.

• Goal iPTH is as follows:

• Stage 3 CKD: iPTH 35-70 pg/mL

• Stage 4 CKD: iPTH 70-110 pg/mL

• Stage 5 CKD: iPTH 150-300 pg/mL

Treatment strategies

• Follow a dietary phosphorus restriction of 800-1,000 mg/d phosphorus (consult with dietitian).

• Use phosphate binding agents—elemental (calcium, lanthanum, aluminum, and magnesium) and nonelemental (sevelemer):

• Titrate doses on the basis of phosphorus and calcium × phosphorus product.

• Limit use of calcium-containing phosphate binders if hypercalcemia occurs.

• Aluminum is not a first-line agent; prescribe it only if needed for short-term use (< 30 days) to minimize the risk of accumulation.

• Remove phosphorus by dialysis for ESRD patients. Continue phosphorus restriction and use of phosphate binding agents with dialysis.

• Maintain goal calcium and phosphorus concentrations.

• Provide vitamin D supplementation depending on the stage of CKD. Supplementation with the active form (calcitriol) or a vitamin D analog (doxercalciferol or paricalcitol) may be necessary in more severe stages of CKD (stages 4 and 5). Supplementation with a vitamin D precursor (e.g., ergocalciferol) may be sufficient in earlier stages.

• Use a calcimimetic agent (cinacalcet [Sensipar]) to help control iPTH in ESRD patients. Initial dose is 30 mg po daily. The dose of cinacalcet should be titrated no more frequently than every 2-4 weeks through sequential doses of 60, 90, 120, and 180 mg once daily to target iPTH (150-300 pg/mL).

• Control metabolic acidosis (which causes bone demineralization if not controlled).

Metabolic acidosis

• Serum bicarbonate: 22-26 mEq/L

• pH: 7.35-7.45

Treatment strategies

• Administration of sodium bicarbonate or other alkali preparation: Gradual correction (over days to weeks) is usually appropriate for asymptomatic patients with mild to moderate acidosis (serum bicarbonate 12-20 mEq/L and pH 7.2-7.4).

• Dialysis: Bicarbonate or lactate contained within the dialysate solution diffuses from dialysate to plasma and effectively treats metabolic acidosis.


Progressive kidney disease

• Patients at high risk for CKD (e.g., patients with diabetes or hypertension) or patients diagnosed with CKD should have the following monitored regularly:

• Serum creatinine: Consider limitations.

• Estimated GFR: Assess rate of progression (mL/min per year).

• Proteinuria: Monitor annually in patients with type 1 diabetes with diabetes duration of ≥ 5 years and at diagnosis for patients with type 2 diabetes.

• Serum electrolytes: Assess levels.

• Blood pressure: Assess in individuals with hypertension.

• Blood glucose: Assess in individuals with diabetes.

• Drug regimens: Evaluate and adjust on the basis of kidney function.

Anemia of chronic kidney disease

• Monitor hemoglobin and hematocrit every 1-2 weeks after initiation of erythropoietic therapy or following a dose change and every 2-4 weeks once stable target hemoglobin and hematocrit are achieved.

• Monitor iron indices (transferrin saturation and serum ferritin).

• Evaluate patient for signs and symptoms of anemia.

CKD Mineral and Bone Disorder

• Phosphorus

• Calcium

• Parathyroid hormone

• Vitamin D (measure precursor levels, 25 hydroxyvitamin D, in patients with stages 3 and 4 CKD)

Metabolic acidosis

• Serum bicarbonate

• Potassium

Drug Therapy

Progressive kidney disease

• ACEIs and ARBs (see Chapter 8 on hypertension and Chapter 13 on diabetes)

• Antihypertensive agents (see Chapter 8 on hypertension)

• Antidiabetic agents (see Chapter 13 on diabetes)


Anemia is treated with erythropoietic stimulating agents (

Table 16-7).

Mechanism of action

These agents stimulate the division and differentiation of erythroid progenitor cells and induce the release of reticulocytes from the bone marrow into the bloodstream, where they mature into erythrocytes.

Adverse drug events

Adverse drug events include the following:

• Hypertension

• Red blood cell aplasia

• Seizures (rare)

• Polycythemia

• Thrombocytosis

Drug-drug and drug-disease interactions

Causes of resistance to erythropoietic therapy are as follows:

• Iron deficiency

• Secondary hyperparathyroidism

• Inflammatory conditions

• Aluminum accumulation

• Other disease states causing anemia (e.g., cancer and HIV)

Parameters to monitor

The following should be monitored:

• Hemoglobin and hematocrit

• Iron indices

• Blood pressure

[Table 16-7. Erythropoietic Stimulating Agents]


Erythropoietic stimulating agents have the following half-lives:

• Epoetin alfa: Approximately 8.5 hours IV and 24 hours SC

• Darbepoetin alfa: Approximately 25 hours IV and 48 hours SC

The effect on hematologic parameters is observed over approximately 7 days to 6 weeks.

Steady-state conditions depend on the lifespan of red blood cells and the rate of red blood cell production.

Strengths and dosage forms

Epoetin alfa is supplied as single-dose, preservative-free solution (in vials of 2,000, 3,000, 4,000, 10,000, and 40,000 units/mL) and as a multidose, preserved solution (in vials of 10,000- and 20,000 units/mL).

Darbepoetin alfa is available in two solutions. A polysorbate solution and an albumin solution are supplied as single-dose vials (of 25, 40, 60, 100, 200, 300, and 500 mg/mL and of 150 mg/0.75 mL); as single-dose prefilled syringes; and as prefilled autoinjectors (syringes and autoinjectors available in doses of 25, 40, 60, 100, 150, 200, 300, and 500mcg). They contain no preservatives.

Iron supplementation

Iron supplements are described in

Table 16-8.

Mechanism of action

Supplies a source of elemental iron necessary for the function of hemoglobin, myoglobin, and specific enzyme systems, and allows transport of oxygen via hemoglobin.

Patient instructions and counseling

• Oral iron may cause stools to be dark in color.

• Take between meals to increase absorption.

• Oral iron may be taken with food if GI upset occurs.

• Do not take with dairy products or antacids.

Adverse drug events

• Oral iron may cause stomach cramping, constipation, nausea, vomiting, and dark stools.

• In the case of intravenous iron, anaphylactic reactions have occurred with iron dextran (InFed and Dexferrum); administer a 25 mg test dose prior to administration of the full dose. A reduced incidence of hypersensitivity reactions exists with sodium ferric gluconate (Ferrlecit), iron sucrose (Venofer), and ferumoxytol (Feraheme). For all preparations, observe patients for diaphoresis,

[Table 16-8. Iron Supplements]

   nausea, vomiting, lower back pain, dyspnea, and hypotension.

• Iron overload may be treated with deferoxamine (Desferal).

Drug-drug and drug-disease interactions

GI absorption of oral iron is decreased when given with antacids, quinolones, and tetracycline and increased when administered with vitamin C.

Intravenous iron has a potential to increase risk of infection. Administration to patients with severe systemic infections is controversial.

Parameters to monitor

• Ferritin and transferrin saturation.

• Hemoglobin and hematocrit.

• Monitor for anaphylactic or hypersensitivity reactions after IV administration.

Strengths and dosage forms

• Ferumoxytol (Feraheme) is supplied in 17 mL single-dose vials containing 30 mg of elemental iron per milliliter.

• Iron dextran (InFeD and Dexferrum) is supplied in 2 mL single-dose vials containing 50 mg of elemental iron per milliliter.

• Iron sucrose (Venofer) is supplied in 5 mL single-dose vials containing 100 mg elemental iron (20 mg/mL).

• Sodium ferric gluconate (Ferrlecit) is supplied as colorless glass ampules containing 62.5 mg elemental iron in 5 mL (12.5 mg/mL).

CKD Mineral and Bone Disorder

Phosphate binding agents are used to treat this disorder (

Table 16-9).

Mechanism of action

These agents combine with dietary phosphate in the GI tract to form an insoluble complex that is excreted in the feces.

Patient instructions and counseling

• Take with meals and snacks.

• Do not take with oral iron salts or certain antibiotics (quinolones, tetracyclines).

• Aluminum and magnesium products are generally for short-term use because of concern of accumulation in patients with kidney disease.

• Use in conjunction with dietary phosphorus restriction.

Adverse drug events

• Calcium products can result in hypercalcemia, nausea, vomiting, abdominal pain, and constipation.

• Sevelamer hydrochloride (Renagel) and sevelamer carbonate (Renvela) can result in decreased LDL (low-density lipoprotein) cholesterol, increased HDL (high-density lipoprotein) cholesterol (may be a beneficial effect), nausea, and vomiting. Note: Sevelamer carbonate (Renvela) has less risk of lowering serum bicarbonate levels than does sevelamer hydrochloride (Renagel). The new formulation will eventually replace Renagel.

[Table 16-9. Phosphate Binding Agents]

• Lanthanum carbonate (Fosrenol) may cause nausea, vomiting, diarrhea, abdominal pain, and constipation.

• Aluminum may cause constipation, aluminum toxicity, chalky taste, cramps, nausea, and vomiting.

• Magnesium products may cause diarrhea, hypermagnesemia, cramps, and muscle weakness.

• All products may cause hypophosphatemia.

Drug-drug and drug-disease interactions

Calcium, lanthanum, aluminum, and magnesium are elemental compounds that may bind with antibiotics (quinolones and tetracyclines) in the GI tract, thus decreasing their absorption.

Sevelamer hydrochloride (Renagel) may contribute to metabolic acidosis and decreased LDL cholesterol. There is less risk of metabolic acidosis with sevelamer carbonate (Renvela).

Parameters to monitor

• Phosphorus, calcium, and iPTH

• Aluminum and magnesium (if receiving aluminum or magnesium-containing products)

• For sevelamer (Renvela and Renagel), serum bicarbonate and LDL cholesterol

Vitamin D therapy

Vitamin D therapy is described in

Table 16-10.

Mechanism of action (active vitamin D)

This therapy increases intestinal absorption of calcium, increases tubular reabsorption of calcium by the kidney (in patients with sufficient kidney function), suppresses synthesis of parathyroid hormone, and increases intestinal phosphorus absorption.

Patient instructions and counseling

• Use in conjunction with dietary phosphorus restriction and phosphate binding agents; therapy may need to be temporarily discontinued if calcium and phosphorus are elevated.

• Notify health care provider of any of the following signs of hypercalcemia: weakness, headache, decreased appetite, and lethargy.

Adverse drug events

• Hypercalcemia: Decreased incidence with vitamin D analogs (paricalcitol, doxercalciferol)

• Hyperphosphatemia: Decreased incidence with vitamin D analogs

• Adynamic bone disease: Caused by oversuppression of PTH

Drug-drug and drug-disease interactions

• Cholestyramine may decrease intestinal absorption of oral products.

• Magnesium absorption may be increased with concomitant administration.

[Table 16-10. Vitamin D Therapy]

Parameters to monitor

• iPTH

• Calcium

• Phosphorus

• Calcium × phosphorus product (vitamin D therapy may need to be temporarily discontinued or the dose decreased if the calcium × phosphorus product is elevated)

• Alkaline phosphatase

• Signs of vitamin D intoxication and hypercalcemia (e.g., weakness, headache, somnolence, nausea, vomiting, bone pain, and polyuria)


• Calcitriol (Calcijex):

• Half-life 3-8 hours; protein binding 99.9%

• Paricalcitol (Zemplar):

• Half-life: Healthy subjects 4-6 hours (oral); Stage 3 and 4 CKD 17-20 hours (oral); Stage 5 CKD 14-15 hours (IV)

• Protein binding: > 99%

• Doxercalciferol (Hectorol):

• Half-life of active metabolite: 32-37 hours

Ergocalciferol requires hydroxylation within the liver to form calcifediol and a second hydroxylation within the kidney to form active vitamin D.

Doxercalciferol requires conversion to its active form 1α, 25-dihydroxyvitamin D2 in the liver.

Strengths and dosage forms

• Calcitriol (Calcijex): 1 mcg/mL ampules

• Calcitriol (Rocaltrol): 0.25 and 0.5 mcg capsules and 1 mcg/mL oral solution

• Paricalcitol (Zemplar): IV—2 and 5 mcg/mL vials; po—1, 2, and 4 mcg capsules

• Doxercalciferol: IV—2 mcg/mL ampules; po—0.5 and 2.5 mcg capsules

Calcimimetics: Cinacalcet (Sensipar)

Cinacalcet is approved for patients with stage 5 CKD who are on dialysis. It is used in conjunction with phosphate binder therapy and vitamin D. The dose range is 30-180 mg/d; initial dose is 30 mg titrated every 2-4 weeks on the basis of iPTH levels. Do not start therapy if corrected serum calcium is < 8.4 mg/dL.

Mechanism of action

Cinacalcet binds with the calcium-sensing receptor on the parathyroid gland and increases sensitivity of the receptor to extracellular calcium, thereby decreasing the stimulus for PTH secretion.

Patient instructions and counseling

• Cinacalcet should be taken with food or shortly after a meal.

• Tablets should be taken whole and should not be divided.

Adverse drug events

• Hypocalcemia (use with caution in patients with seizure disorder)

• Nausea and vomiting

• Diarrhea

• Myalgias

Drug-drug and drug-disease interactions

Cinacalcet is metabolized by multiple cytochrome P450 (CYP) enzymes, primarily CYP3A4, CYP2D6, and CYP1A2. Adjustments in dose may be required for patients taking agents that inhibit metabolism of cinacalcet (e.g., ketoconazole). Dose reductions of drugs with a narrow therapeutic range and with a metabolism dependent on these enzymes may also be required (e.g., tricyclic antidepressants, flecainide, and thioridazine).

Parameters to monitor

Serum calcium and serum phosphorus should be measured within 1 week and iPTH should be measured 1-4 weeks after initiation or dose adjustment of cinacalcet. The dose of cinacalcet should be titrated no more frequently than every 2-4 weeks through sequential doses of 60, 90, 120, and 180 mg once daily to target iPTH (150-300 pg/mL).


• The maximum concentration is achieved in approximately 2-6 hours following administration and is increased with food.

• Half-life is 30-40 hours.

• Volume of distribution is approximately 1,000 L.

• Cinacalcet is approximately 93-97% bound to plasma proteins.

• Cinacalcet is metabolized primarily by CYP3A4, CYP2D6, and CYP1A2.

Strengths and dosage forms

Cinacalcet is available in 30-, 60-, and 90-mg tablets.

Metabolic acidosis

See Chapter 17 on critical care.

Vitamin supplementation (specific to the dialysis population)

Water-soluble vitamins for dialysis patients are described in

Table 16-11.

Mechanism of action

Vitamin supplementation replaces water-soluble vitamins lost during dialysis without providing supratherapeutic amounts of fat-soluble vitamins.

Patient instructions and counseling

• Take daily to replace water-soluble vitamins.

• Hemodialysis patients should take after dialysis.

Adverse drug events

• General: Nausea, headache, pruritus, and flushing (depending on specific vitamin)

• Vitamin B6 (pyridoxine): Neuropathy and increased aspartate transaminase

• Vitamin C (ascorbic acid): Hyperoxaluria, dizziness, diarrhea, fatigue, and nausea

• Folic acid: Headache, rash, and pruritus

Drug-drug and drug-disease interactions

Folic acid may decrease phenytoin concentrations by increasing the metabolism.

Nondrug Therapy

• Preparation for renal replacement therapy when patients reach stage 4 CKD:

• Choice of chronic dialysis (hemodialysis or peritoneal dialysis) if patient is a candidate for both modalities and discussion of transplantation

• Placement of dialysis access (fistula or graft for hemodialysis, catheter for peritoneal dialysis)

[Table 16-11. Water-Soluble Vitamin Supplements for Dialysis Patients]

• Patient education regarding choice of renal replacement therapy and complications of CKD


• Risks and benefits of protein restriction (0.6-0.8 g/kg/d) should be considered in patients with stage 4 CKD.

• Increased protein requirements should be considered for patients on dialysis (approximately 1.2 g/kg/d) and even greater requirements for peritoneal dialysis patients because of increased protein loss with the dialysis procedure.

• Nutritional supplementation should be taken as needed.

• Counseling by a renal dietitian may be beneficial to tailor a diet based on the stage of CKD.

Renal replacement therapies


The intermittent hemodialysis procedure is generally performed three times per week for 3-5 hours for patients with stage 5 kidney disease (end-stage renal disease). It requires a viable permanent access site (graft or fistula) or a temporary site for patients requiring immediate dialysis or experiencing failed permanent access sites. Fistulas are the preferred access for chronic hemodialysis.

Complications include infection, hypotension during dialysis, clotting, and dialyzer reactions. Drug removal by hemodialysis is most likely to occur for drugs with small molecular weight, low protein binding, and small volume of distribution.

Peritoneal dialysis

Peritoneal dialysis requires insertion of a catheter into the peritoneum. Types include continuous ambulatory peritoneal dialysis and automated peritoneal dialysis (which includes continuous cycling, nocturnal tidal, and nightly intermittent peritoneal dialysis).

Several complications are possible:

• Peritonitis

• Most common gram-positive organisms are Staphylococcus epidermidis and Staphylococcus aureus.

• Most common gram-negative organisms are Enterobacteriacae and Pseudomonas aeruginosa.

• Empiric therapy should include gram-positive coverage (first-generation cephalosporin or vancomycin if MRSA [methicillin-resistant Staphylococcus aureus] is prevalent) and gram-negative coverage (e.g., ceftazidime and aminoglycoside).

• Intraperitoneal administration of antibiotics is recommended.

• Hyperglycemia from glucose content of dialysate solution

• Malnutrition from increased protein loss


See Chapter 20 for information on transplantation.

16-3. Key Points

Acute Kidney Injury

• Prevention of kidney dysfunction in high-risk patients is the most effective strategy to address AKI.

• Conditions that put patients at increased risk of AKI include decreased perfusion of the kidney (attributable to dehydration or poor effective circulating volume such as with congestive heart failure) and administration of potentially nephrotoxic agents, particularly under conditions of decreased perfusion.

• Nephrotoxic agents should be avoided when possible in patients at risk for AKI.

• Immediate recognition and treatment of AKI may prevent irreversible kidney damage.

• Goals of treatment for patients with AKI are achievement of baseline kidney function and prevention of both chronic kidney disease and the need for chronic renal replacement therapy.

• Diuretics are often used in patients with AKI to maintain fluid balance and hemodynamic stability.

• A review of medications is frequently necessary to ensure appropriate dose adjustments based on kidney function (see Appendix B for drugs in renal failure).

Chronic Kidney Disease

• Chronic kidney disease is classified in stages 1 through 5 on the basis of estimated glomerular filtration rate and evidence of pathological abnormalities or markers of kidney damage, including abnormalities in blood or urine tests or in imaging studies.

• Screening for microalbuminuria and proteinuria is important for identifying patients with kidney disease and monitoring progression of the disease.

• Therapy to delay progression of kidney disease includes control of diabetes and hypertension, initiation of therapy with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and protein restriction if indicated.

• Common secondary complications of CKD include anemia, fluid and electrolyte abnormalities, hyperphosphatemia, secondary hyperparathyroidism, and malnutrition.

• Management of anemia includes administration of erythropoietic stimulating agents (epoetin alfa [Epogen and Procrit] and darbepoetin alfa [Aranesp]) and iron supplementation with oral iron (multiple preparations) or intravenous iron (sodium ferric gluconate [Ferrlecit], iron sucrose [Venofer], ferumoxytol [Feraheme], or iron dextran [InFeD and Dexferrum]) to achieve target hemoglobin (11-12 g/dL), while preventing iron deficiency.

• Hyperphosphatemia is managed by dietary phosphorus restriction; use of phosphate binding agents (calcium-containing products, lanthanum carbonate [Fosrenol], or sevelemer carbonate [Renvela]); and dialysis.

• Management of secondary hyperparathyroidism includes control of serum calcium and phosphorus and administration of vitamin D therapy—including vitamin D precursors in early CKD based on kidney function (ergocalciferol [Drisdol and Calciferol])—and active vitamin D therapy for more severe kidney disease (calcitriol [Calcijex and Rocaltrol], paricalcitol [Zemplar], or doxercalciferol [Hectorol]). The calcimimetic agent cinacalcet (Sensipar) is indicated for management of secondary hyperparathyroidism in patients with stage 5 CKD who are on dialysis and is used in conjunction with phosphate binders and vitamin D.

• Nutritional requirements must be reevaluated on the basis of severity of kidney disease (e.g., protein restriction to delay progression of CKD versus increased protein requirements for patients on dialysis).

16-4. Questions


R. T. is a 45-year-old female admitted to the hospital after fainting at work. Her past medical history includes type 2 diabetes and rheumatoid arthritis. Her only complaint is that she has had difficulty over the past 5 days keeping down anything she eats or drinks. She has also noticed a decrease in urination over the past 24 hours. Regular medications include aspirin 325 mg qd, ibuprofen 600 mg qd for arthritis, metformin 500 mg qd, glyburide 5 mg qd, and Tylenol prn for headache. Laboratory values in the emergency department showed a serum creatinine of 2.0 mg/dL and BUN of 56 mg/dL, consistent with acute kidney injury. Her lab tests from 1 month ago at a regular checkup were normal. The most likely etiology of R. T.'s acute kidney injury is

A. dehydration from poor oral intake.

B. trauma from fainting.

C. age-related decreases in kidney function.

D. kidney failure caused by diabetes.

E. obstruction of urine outflow.



Which of the following medications may have contributed to R. T.'s acute kidney injury?

A. Aspirin

B. Ibuprofen

C. Metformin

D. Glyburide

E. Tylenol



Which of the following diuretics may retain its effectiveness at a glomerular filtration rate < 30 mL/min?

A. Hydrochlorothiazide

B. Chlorothiazide

C. Metolazone

D. Spironolactone

E. Aldactone



Which of the following fluid and electrolyte abnormalities typically occur in patients with severe kidney dysfunction (i.e., creatinine clearance < 15 mL/min)?

I. Metabolic alkalosis

II. Hyperkalemia

III. Hyperphosphatemia

A. I only

B. III only

C. I and II only

D. II and III only

E. I, II, and III



Which set of laboratory values is most consistent with a patient in acute intrinsic kidney disease?

A. Urinary granular casts absent, FENa < 1, urinary osmolality 600 mOsm/kg

B. Urinary granular casts absent, FENa > 1, urinary osmolality 600 mOsm/kg

C. Urinary granular casts present, FENa < 1, urinary osmolality 300 mOsm/kg

D. Urinary granular casts present, FENa > 1, urinary osmolality 300 mOsm/kg

E. Acute intrinsic kidney failure can only be diagnosed by biopsy.



Which of the following diuretics would be most appropriate for the initial treatment of a patient with acute kidney injury?

I. Metolazone

II. Spironolactone

III. Furosemide

A. I only

B. III only

C. I and II only

D. II and III only

E. I, II, and III



A patient with nephrotoxicity caused by tobramycin would likely present with an increase in serum creatinine

A. immediately after starting therapy and with nonoliguria.

B. immediately after starting therapy and with oliguria.

C. 5-7 days after starting therapy and with oliguria.

D. 5-7 days after starting therapy and with nonoliguria.

E. within 24 hours with excessive diuresis.



Lisinopril may cause hemodynamically mediated kidney disease by preventing which of the following compensatory mechanisms by the kidney?

A. Vasodilation of the afferent arteriole

B. Vasoconstriction of the afferent arteriole

C. Vasodilation of the efferent arteriole

D. Vasoconstriction of the efferent arteriole

E. Vasodilation of both the afferent and the efferent arterioles



The estimated creatinine clearance for a 47-year-old male patient with an ideal body weight of 176 pounds (slightly less than actual body weight) and a serum creatinine of 2.2 mg/dL is

A. 32 mL/min.

B. 40 mL/min.

C. 47 mL/min.

D. 93 mL/min.

E. 120 mL/min.



D. K. is a 53-year-old black female (body weight = 65 kg) with hypertension and hypercholesterolemia who is seen in the outpatient nephrology clinic for evaluation of kidney disease progression. Her current blood pressure is 156/82 mm Hg, SCr is 2.6 mg/dL (stable for the past 4 months), BUN is 44 mg/dL, and urinary protein is 800 mg/d. Her medications are enalapril 20 mg/d × 1 year and simvastatin 20 mg qd × 2 years. On the basis of D. K.'s estimated creatinine clearance, she would be classified in which of the following stages of chronic kidney disease?

A. Stage 1

B. Stage 2

C. Stage 3

D. Stage 4

E. Stage 5



The recommended target blood pressure for D. K. is

A. < 110/70 mm Hg.

B. < 130/90 mm Hg.

C. < 130/80 mm Hg.

D. < 140/95 mm Hg.

E. < 140/90 mm Hg.



Which of the following would be most beneficial in a patient with type 1 diabetes and microalbuminuria to delay progression of CKD?

I. Angiotensin-converting enzyme inhibitor

II. Angiotensin receptor blocker

III. Loop diuretic

A. I only

B. III only

C. I and II only

D. II and III only

E. I, II, and III



Epoetin alfa and darbepoetin alfa stimulate erythropoiesis by which of the following?

A. Prevention of excessive red blood cell destruction

B. Prevention of degradation of bone marrow stem cells

C. Differentiation of peritubular interstitial cells of the kidney

D. Increase in size of red blood cells produced in the bone marrow

E. Differentiation of erythroid progenitor stem cells in the bone marrow



When administered intravenously, darbepoetin alfa has a terminal half-life approximately __________ that of epoetin alfa.

A. equal to

B. twofold longer than

C. twofold shorter than

D. threefold longer than

E. threefold shorter than



One of the most commonly reported adverse reactions with epoetin alfa and darbepoetin alfa is

A. nausea.

B. hypertension.

C. constipation.

D. anemia.

E. anaphylaxis.



At least _________ should be allowed to lapse before a change in dose of epoetin alfa or darbepoetin alfa is made on the basis of a change in hemoglobin and hematocrit.

A. 1 week

B. 2-4 weeks

C. 6-8 weeks

D. 2 months

E. 4 months



R. A. is a 42-year-old 70-kg male on hemodialysis tiw who receives epoetin alfa for treatment of anemia. He has been stable on an epoetin dose of 4,000 units intravenously tiw with an average hemoglobin of 11 g/dL (hematocrit of 33%). Over the past 3 months, his hematocrit has dropped to 28%. Iron indices reveal the following: serum ferritin 78 ng/mL and transferrin saturation 12%. The best initial treatment for R. A. is to

A. increase the dose of epoetin alfa to maintain a hemoglobin of 11-12 g/dL (hematocrit of 33-36%).

B. withhold epoetin alfa therapy until hemoglobin increases to 12 g/dL.

C. administer intravenous iron (sodium ferric gluconate) at a maintenance dose of 125 mg per week.

D. administer a 1 g total dose of intravenous iron in divided doses.

E. begin oral ferrous sulfate 325 mg tid.



In the gastrointestinal tract, calcitriol

A. promotes absorption of calcium and inhibits absorption of phosphorus.

B. promotes absorption of phosphorus and inhibits absorption of calcium.

C. promotes absorption of both calcium and phosphorus.

D. promotes decreased binding of calcium and phosphorus.

E. promotes increased elimination of calcium and phosphorus.



J. T. is a 63-year-old female with stage 5 CKD (end-stage kidney disease) receiving peritoneal dialysis. Her most recent laboratory analysis reveals the following: BUN 58 mg/dL, SCr 5.2 mg/dL, phosphorus 7.4 mg/dL, calcium 9.0 mg/dL, albumin 2.5 g/dL, and iPTH 542 pg/mL. In addition to dietary restriction of phosphorus, which of the following agents is best for initial management of J. T.'s hyperphosphatemia?

I. Sevelamer carbonate

II. Lanthanum carbonate

III. Calcium carbonate

A. I only

B. III only

C. I and II only

D. II and III only

E. I, II, and III



J. T. should be instructed to take her phosphate binder

A. with meals to enhance systemic absorption of phosphorus.

B. with meals to minimize systemic absorption of phosphorus.

C. between meals to avoid food-drug interactions.

D. between meals to minimize GI side effects.

E. There are no specific instructions to follow with regard to meals.



Which of the following agents is appropriate for a patient with stage 5 CKD and secondary hyperparathyroidism requiring treatment to reduce iPTH?

I. Calcitriol

II. Paricalcitol

III. Ergocalciferol

A. I only

B. III only

C. I and II only

D. II and III only

E. I, II, and III



Cinacalcet is a calcimimetic that works by which of the following mechanisms?

A. It decreases the sensitivity of the calcium-sensing receptors on the parathyroid gland to calcium, which prevents secretion of PTH.

B. It increases the sensitivity of the calcium-sensing receptors on the parathyroid gland to calcium, which prevents secretion of PTH.

C. It stimulates the breakdown of iPTH and prevents the effects of PTH on bone turnover.

D. It inhibits the breakdown of iPTH to provide a negative feedback system and suppress PTH synthesis.

E. It increases calcium concentrations, which suppresses secretion of PTH from the parathyroid gland.



A drug with which of the following characteristics is most likely to be removed by hemodialysis (Vd = volume of distribution)?

A. fu 0.05, Vd 0.2 L/kg

B. fu 0.05, Vd 0.6 L/kg

C. fu 0.30, Vd 0.6 L/kg

D. fu 0.95, Vd 0.2 L/kg

E. fu 0.95, Vd 6 L/kg



The best antibiotic selection for empiric treatment of peritonitis in a peritoneal dialysis patient is

A. cefazolin + vancomycin.

B. cefazolin + ceftazidime.

C. vancomycin alone.

D. cefazolin alone.

E. gentamicin alone.



Which of the following supplements should be recommended daily in a patient with stage 5 CKD requiring chronic hemodialysis?

A. Multivitamin

B. Nephrocaps

C. Vitamin A

D. Nephrocaps + vitamin A

E. Folic acid only


16-5. Answers


A. Dehydration is the most likely cause of AKI in R. T. because she has had a decrease in oral intake over the past 5 days. Dehydration would be classified as a prerenal cause of AKI. Fainting was likely a result of dehydration and not the cause of her decline in kidney function. A serum creatinine of 2.0 mg/dL would not be considered normal in a 45 year old, eliminating age as a rationale for kidney disease. Diabetes would be more likely to cause a chronic decrease in her kidney function as opposed to an acute change (lab tests from 1 month ago were normal, ruling out evidence of chronic kidney disease). She has had some urine output in the past 24 hours, which rules out obstruction.



B. NSAIDs are associated with hemodynamic changes (in particular, they prevent the compensatory vasodilation of the afferent arteriole that occurs in conditions of prerenal acute kidney disease). Metformin is not a cause of AKI in this case but would need to be discontinued at this time because of the risk of lactic acidosis in a patient with decreased kidney function (serum creatinine > 1.4 mg/dL in females and > 1.5 mg/dL in males).



C. There is some evidence that metolazone is beneficial in patients with kidney disease and a GFR < 30 mL/min. This is not the case with other thiazide or thiazide-like diuretics or with potassium-sparing diuretics. Metolazone is frequently used in combination with loop diuretics for this reason.



D. Hyperkalemia and hyperphosphatemia are common electrolyte abnormalities observed as kidney function decreases. Metabolic acidosis is also common, but not metabolic alkalosis.



D. Acute intrinsic kidney disease is generally characterized by the presence of granular casts (indicating structural damage), a fractional excretion of sodium > 1, and a urine osmolality similar to that of plasma osmolality (indicating changes in concentrating ability of the kidney).



B. A patient with acute kidney disease generally requires aggressive diuresis (while avoiding dehydration). Furosemide is a loop diuretic that is more potent than a thiazide-like diuretic (metolazone) or a potassium-sparing diuretic (spironolactone) and would be a rational choice for initial therapy of AKI. Spironolactone may also cause hyperkalemia in a patient with AKI.



D. Aminoglycoside-induced nephrotoxicity is characterized by a delay in changes in serum creatinine (approximately 5-7 days) and relatively normal urine output (nonoliguria).



D. Angiotensin-converting enzyme inhibitors may contribute to development of AKI in patients with conditions resulting in prerenal kidney disease (e.g., conditions resulting in decreased perfusion of the kidney, hypovolemia, heart failure, liver disease, and so forth). ACEIs (and angiotensin receptor blockers) prevent the compensatory vasoconstriction of the efferent arteriole mediated by angiotensin II that occurs in an attempt to increase GFR.



C. Using the Cockcroft-Gault equation to estimate creatinine clearance, one finds that this patient has an estimated creatinine clearance of 47 mL/min. For females, multiply the calculated value by 0.85.


BW (kg) = 176 lbs/2.2 = 80 kg

SCr = 2.2 mg/dL



D. D. K.'s estimated creatinine clearance determined using the Cockcroft-Gault equation is 26 mL/min, classified as stage 4 CKD (GFR 15-29 mL/min/1.73 m2).


with the result multiplied by 0.85 for a female. Note: The estimated GFR determined using the Modification of Diet in Renal Disease equation is 25 mL/min/1.73m2.



C. The recommended blood pressure for D. K. is < 130/80 mm Hg because she has stage 4 CKD.



C. ACEIs and ARBs are advocated for patients with diabetes and microalbuminuria. The decreases in glomerular pressure caused by these agents that are detrimental in patients with AKI are beneficial in a chronic condition such as diabetes, in which sustained elevations in glomerular pressure result in worsening kidney disease over time.



E. Erythropoietic agents including epoetin alfa and darbepoetin alfa work in the bone marrow to stimulate differentiation of erythroid progenitor stem cells and result in an increase in red blood cell production (increase erythrocytes).



D. The half-life of darbepoetin alfa is three times longer than that of epoetin alfa, giving this agent the added benefit of reduced frequency of administration.



B. Hypertension is the most common adverse effect in patients receiving erythropoietic agents.



B. Stimulation of erythropoiesis by epoetin alfa and darbepoetin alfa occurs immediately; however, it will take at least 2-4 weeks before substantial changes in hemoglobin and hematocrit are observed as a result of any change in dose of erythropoietic therapy.



D. R. A. is iron deficient, as indicated by his low serum ferritin (< 100 ng/mL) and transferrin saturation (< 20%). No change in epoetin alfa should be made until the iron deficiency is corrected (this is the leading cause of resistance to epoetin alfa and darbepoetin alfa therapy). R. A. will require a full course of iron (1 g administered intravenously in divided doses with each dialysis session) as opposed to a maintenance dose, which should be administered once R. A. is iron replete. Sodium ferric gluconate may be administered in doses of 125 mg per dialysis session for eight sessions to give the total 1 g dose (iron sucrose would be administered in 100 mg increments over 10 hemodialysis sessions). Ferumoxytol would be administered as two 510 mg doses given 3-8 days apart. Absorption of oral iron is poor, making intravenous iron preferred in this hemodialysis patient.



C. Active vitamin D (calcitriol) promotes absorption of both calcium and phosphorus in the GI tract. This is one reason that therapy with calcitriol or a vitamin D analog may need to be withheld if the calcium × phosphorus product is elevated.



C. Sevelamer carbonate (Renvela) or lanthanum carbonate would be better options than a calcium-containing binder for initial management because J. T. has a corrected calcium of 10.2 mg/dL [corrected calcium = measured serum calcium + 0.8 × (normal serum albumin - measured serum albumin)] and a calcium × phosphorus product of 75 mg2/dL2. This elevated product increases the risk of metastatic calcifications. She requires a phosphorus binding agent without calcium to minimize calcium absorbed in the GI tract.



B. Phosphate binders should be taken with meals to minimize systemic absorption of phosphorus from the GI tract.



C. Calcitriol and paricalcitol are active forms of vitamin D that do not require conversion in the liver or kidney. Ergocalciferol is a vitamin D precursor that does require activation and would not be recommended for a patient with stage 5 CKD without the necessary activity of the enzyme in the kidney (1α-hydroxylase) responsible for final conversion to the active form.



B. The calcimimetic agent cinacalcet (Sensipar) works by binding with the calcium-sensing receptor on the parathyroid gland and increases the sensitivity of this receptor to calcium, thereby suppressing secretion of PTH.



D. Drug characteristics that make an agent more likely to be removed by dialysis include low protein binding, small volume of distribution, and low molecular weight. Among the choices given, the agent that best meets these criteria is choice D, which has a high fraction unbound in the plasma and a low volume of distribution.



B. Empiric therapy should include antibiotics with gram-positive and gram-negative coverage. Choice B is most appropriate.



B. Nephrocaps include water-soluble vitamins (vitamin B complex + vitamin C + folic acid) recommended for a patient with kidney failure. Supplementation with fat-soluble vitamins is not recommended in patients with kidney failure because of toxicities associated with accumulation.


16-6. References

Acute Kidney Injury and Drug-Induced Kidney Disease

Lameire N, Van Viesen W, Vanholder R. Acute renal failure. Lancet. 2005;365(9457):417-30.

Nolin TD, Himmelfarb J. Drug-induced kidney disease. In: DiPiro J, Talbert RL, eds. Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York: McGraw-Hill; 2008:795-810.

Ricci Z, Cruz D, Ronco C. The RIFLE criteria and mortality in acute kidney injury: A systematic review. Kidney International. 2008;73:538-46.

Wood AJJ. Diuretic therapy. N Engl J Med. 1998; 339:387-95.

Chronic Kidney Disease and Progression

Abosaif NY, Arije A, Atray NK, et al. K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Am J Kidney Dis. 2004;43(suppl 1):S1-290.

Chobanian AV, Bakris GL, Black HR, et al. and the National High Blood Pressure Education Program Coordinating Committee. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 report. JAMA. 2003;289: 2560-72.

Levey AS, Beto JA, Coronado BE, et al. Controlling the epidemic of cardiovascular disease in chronic renal disease: What do we know? What do we need to learn? Where do we go from here? Am J Kidney Dis. 1998;32:853-906.

National Kidney Foundation. NKF-K/DOQI clinical practice guidelines for chronic kidney disease: Evaluation, classification, and stratification. Am J Kidney Dis. 2002;39(suppl 1):S1-266.

U.S. Renal Data System. USRDS 2008 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Bethesda, Md.: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2008.


American Reagent Laboratories. Venofer (iron sucrose injection) package insert. Shirley, N.Y.: American Reagent Laboratories; 2007.

Amgen. Aranesp (darbepoetin alfa) package insert. Thousand Oaks, Calif.: Amgen; 2008.

Macdougall IC, Gray SJ, Elston O, et al. Pharmacokinetics of novel erythropoiesis stimulating protein compared with epoetin alfa in dialysis patients. J Am Soc Nephrol. 1999;10:2392-95.

National Kidney Foundation. K/DOQI clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease. Am J Kidney Dis. 2006 May;47(5 suppl 3):S1-145.

Watson Pharmaceuticals. Ferrlecit (sodium ferric gluconate complex in sucrose injection) package insert. Corona, Calif.: Watson Pharmaceuticals; 2006.

Hyperphosphatemia and Secondary Hyperparathyroidism

Amgen. Sensipar (cinacalcet HCl) tablets package insert. Thousand Oaks, Calif: Amgen; 2007.

Eknoyan G, Levin A, Levin NW. Bone metabolism and disease in chronic kidney disease. Am J Kidney Dis. 2003;42(4 suppl 3):S1-201.


National Kidney Foundation. K/DOQI clinical practice guidelines for nutrition in chronic renal failure. Am J Kidney Dis. 2000;35(suppl 2):S1-140.


Aronoff GR, Bennett WM, Berns JS, et al. Drug Prescribing in Renal Failure: Dosing Guidelines for Adults and Children. 5th ed. Philadelphia: American College of Physicians; 2007.

Ifudu O. Care of patients undergoing hemodialysis. N Engl J Med. 1998;339:1054-62.

National Kidney Foundation Kidney Disease Outcomes Quality Initiative. Clinical Practice Guidelines for Peritoneal Dialysis Adequacy: Update 2006. New York: National Kidney Foundation. Available at: