2304 PART 9 Disorders of the Kidney and Urinary Tract

can occasionally be seen in glomerulonephritis, vasculitis, or toxins/

medications that can affect the glomerulus as well as the tubulointerstitium (e.g., NSAIDs). AKI can also complicate cases of minimal change

disease, a cause of the nephrotic syndrome often associated with low

serum albumin concentrations (Chap. 309). If the dipstick is positive

for hemoglobin but few red blood cells are evident in the urine sediment, then rhabdomyolysis or hemolysis should be suspected.

Prerenal azotemia may present with hyaline casts or an unremarkable urine sediment examination. Postrenal AKI may also be associated with an unremarkable sediment, but hematuria and pyuria may

be seen depending on the cause of obstruction. AKI from ATN due

to ischemic injury, sepsis, or certain nephrotoxins has characteristic

urine sediment findings: pigmented “muddy brown” granular casts and

tubular epithelial cell casts. These findings may be absent in more than

20% of cases, however. Glomerulonephritis may lead to dysmorphic

red blood cells or red blood cell casts. Interstitial nephritis may lead to

white blood cell casts. The urine sediment findings overlap somewhat

in glomerulonephritis and interstitial nephritis, and a diagnosis is not

always possible on the basis of the urine sediment alone. Urine eosinophils have a limited role in differential diagnosis; they can be seen

in interstitial nephritis, pyelonephritis, cystitis, atheroembolic disease,

or glomerulonephritis. Crystalluria may be important diagnostically.

The finding of oxalate crystals in AKI should prompt an evaluation

for ethylene glycol toxicity. Abundant uric acid crystals may be seen in

tumor lysis syndrome.

■ BLOOD LABORATORY FINDINGS

Certain forms of AKI are associated with characteristic patterns in the

rise and fall of SCr. Prerenal azotemia typically leads to modest rises

in SCr that return to baseline with improvement in hemodynamic

status. Contrast nephropathy leads to a rise in SCr within 24–48 h,

peak within 3–5 days, and resolution within 5–7 days. In comparison,

atheroembolic disease usually manifests with more subacute rises in

SCr, although severe AKI with rapid increases in SCr can occur in this

setting. With many of the epithelial cell toxins such as aminoglycoside

antibiotics and cisplatin, the rise in SCr is characteristically delayed for

3–5 days to 2 weeks after initial exposure.

A complete blood count may provide diagnostic clues. Anemia is

common in AKI and is usually multifactorial in origin. It is not related

to an effect of AKI solely on production of red blood cells because this

effect in isolation takes longer to manifest. Myeloma can be diagnosed

with serum immunoelectrophoresis or free light chain assay, and it can

often be suspected if the blood anion gap is low due to unmeasured

cationic proteins. Peripheral eosinophilia can accompany interstitial

nephritis, atheroembolic disease, polyarteritis nodosa, and ChurgStrauss vasculitis. Severe anemia in the absence of bleeding may reflect

hemolysis, multiple myeloma, or thrombotic microangiopathy (e.g.,

hemolytic uremic syndrome [HUS] or TTP). Other laboratory findings

of thrombotic microangiopathy include thrombocytopenia, schistocytes on peripheral blood smear, elevated lactate dehydrogenase level,

and low haptoglobin content. Evaluation of patients suspected of having TTP or HUS includes measurement of levels of the von Willebrand

factor cleaving protease (ADAMTS13) and testing for Shiga toxin–

producing Escherichia coli. “Atypical HUS” constitutes the majority of

adult cases of HUS; genetic testing is important because it is estimated

that 60–70% of atypical HUS patients have mutations in genes encoding proteins that regulate the alternative complement pathway.

AKI often leads to hyperkalemia, hyperphosphatemia, and hypocalcemia. Marked hyperphosphatemia with accompanying hypocalcemia

may suggest rhabdomyolysis or tumor lysis syndrome. Serum creatine

kinase and uric acid levels are often elevated in rhabdomyolysis, while

tumor lysis syndrome can be associated with normal or marginally

elevated creatine kinase and markedly elevated serum uric acid. The

anion gap may be increased with any cause of uremia due to retention of anions such as phosphate, hippurate, sulfate, and urate. The

co-occurrence of an increased anion gap and an osmolal gap may

suggest ethylene glycol poisoning, which may also cause oxalate

crystalluria and oxalate deposition in kidney tissue. Low anion gap

may provide a clue to the diagnosis of multiple myeloma due to the

presence of unmeasured cationic proteins. Laboratory blood tests

helpful for the diagnosis of glomerulonephritis and vasculitis include

depressed complement levels and high titers of antinuclear antibodies

(ANAs), antineutrophil cytoplasmic antibodies (ANCAs), antiglomerular basement membrane (anti-GBM) antibodies, and cryoglobulins.

Anti-phospholiase A2 receptor antibodies will point to a diagnosis of

membranous nephropathy.

■ RENAL FAILURE INDICES

Several indices have been used to help differentiate prerenal azotemia

from intrinsic AKI when the tubules are malfunctioning. The low

Urinary sediment in AKI

Normal or few RBCs or

WBCs or hyaline casts

Prerenal

Postrenal

Arterial thrombosis

 or embolism

Preglomerular

 vasculitis

HUS or TTP

Scleroderma crisis

RBCs

RBC casts

GN

Vasculitis

Malignant

 hypertension

Thrombotic

 microangiopathy

Interstitial

 nephritis

GN

Pyelonephritis

Allograft

 rejection

Malignant

 infiltration of the

 kidney

ATN

Tubulointerstitial

 nephritis

Acute cellular

 allograft rejection

Myoglobinuria

Hemoglobinuria

ATN

GN

Vasculitis

Tubulo-

 interstitial

 nephritis

Allergic

 interstitial

 nephritis

Atheroembolic

 disease

Pyelonephritis

Cystitis

Glomerulo-

 nephritis

Acute uric acid

 nephropathy

Calcium oxalate

 (ethylene glycol

 intoxication)

Drugs or toxins

 (acyclovir,

 indinavir,

 sulfadiazine,

 amoxicillin)

Abnormal

WBCs

 WBC casts

Renal tubular

epithelial

(RTE) cells

RTE casts

Pigmented casts

Granular casts Eosinophiluria Crystalluria

FIGURE 310-6 Interpretation of urinary sediment findings in acute kidney injury (AKI). ATN, acute tubular necrosis; GN, glomerulonephritis; HUS, hemolytic-uremic

syndrome; RBCs, red blood cells; RTE, renal tubular epithelial; TTP, thrombotic thrombocytopenic purpura; WBCs, white blood cells. (Adapted from L Yang, JV Bonventre:

Diagnosis and clinical evaluation of acute kidney injury. In Comprehensive Nephrology, 4th ed. J Floege et al [eds]. Philadelphia, Elsevier, 2010.)

2305Acute Kidney Injury CHAPTER 310

tubular flow rate and increased renal medullary recycling of urea seen

in prerenal azotemia may cause a disproportionate elevation of the

BUN compared to creatinine. Other causes of disproportionate BUN

elevation need to be kept in mind, however, including upper gastrointestinal bleeding, hyperalimentation, increased tissue catabolism, and

glucocorticoid use.

The FeNa is the fraction of the filtered sodium load that is not

reabsorbed by the tubules, and is a measure of both the kidney’s ability

to reabsorb sodium as well as endogenously and exogenously administered factors that affect tubular reabsorption. As such, it depends on

sodium intake, effective intravascular volume, GFR, diuretic intake,

and intact tubular reabsorptive mechanisms. With prerenal azotemia,

the FeNa may be <1%, suggesting avid tubular sodium reabsorption.

In patients with CKD, a FeNa significantly >1% can be present despite

a superimposed prerenal state. The FeNa may also be >1% despite

hypovolemia due to treatment with diuretics. Low FeNa is often seen

early in glomerulonephritis and other disorders and, hence, should

not be taken as prima facie evidence of prerenal azotemia. Low FeNa

is therefore suggestive of, but not synonymous with, effective intravascular volume depletion, and should not be used as the sole guide for

volume management. The response of urine output to crystalloid or

colloid fluid administration may be both diagnostic and therapeutic in

prerenal azotemia. In ischemic AKI, the FeNa is frequently >1% because

of tubular injury and resultant impaired ability to reabsorb sodium.

Several causes of ischemia-associated and nephrotoxin-associated AKI

can present with FeNa <1%, however, including sepsis (often early in

the course), rhabdomyolysis, and contrast nephropathy.

The ability of the kidney to produce a concentrated urine is

dependent upon many factors and relies on good tubular function

in multiple regions of the kidney. In the patient not taking diuretics

and with good baseline kidney function, urine osmolality may be

>500 mOsm/kg in prerenal azotemia, consistent with an intact medullary concentration gradient and elevated serum vasopressin levels

causing water reabsorption by passive diffusion from the collecting

duct into a concentrated medullary interstitium, resulting in concentrated urine. In elderly patients and those with CKD, however, baseline

concentrating defects may exist, making urinary osmolality unreliable

in many instances. Loss of concentrating ability is common in most

forms of AKI that affect the tubules and interstitium, resulting in urine

osmolality <350 mOsm/kg, but this finding is not specific.

■ RADIOLOGIC EVALUATION

Postrenal AKI should always be considered in the differential diagnosis of AKI because treatment is usually successful if instituted early.

Simple bladder catheterization can rule out urethral obstruction.

Imaging of the urinary tract with renal ultrasound or CT scan should

be undertaken to investigate obstruction in individuals with AKI

unless an alternate diagnosis is apparent. Findings of obstruction

include dilation of the collecting system and hydroureteronephrosis.

Obstruction can be present without radiologic abnormalities in the

setting of volume depletion, retroperitoneal fibrosis, encasement

with tumor, and also early in the course of obstruction. If a high

clinical index of suspicion for obstruction persists despite normal

imaging, antegrade or retrograde pyelography should be performed.

Imaging may also provide additional helpful information about kidney size and echogenicity to assist in the distinction between acute

versus CKD. In CKD, kidneys are usually smaller unless the patient

has diabetic nephropathy, HIV-associated nephropathy, or infiltrative diseases. Normal-sized kidneys are expected in AKI. Enlarged

kidneys in a patient with AKI suggest the possibility of acute interstitial nephritis or infiltrative diseases. As described previously,

vascular imaging may be useful if venous or arterial obstruction is

suspected, but the risks of contrast administration should be kept in

mind. MRI with gadolinium-based contrast agents (GBCAs) should

be avoided if possible in severe AKI due to the possibility of inducing nephrogenic system fibrosis, a rare but serious complication

seen most commonly in patients with end-stage renal disease. The

recommendations regarding use of GBCAs in subjects with CKD

remain controversial.

■ KIDNEY BIOPSY

If the cause of AKI is not apparent based on the clinical context,

physical examination, laboratory studies, and radiologic evaluation,

kidney biopsy should be considered. The kidney biopsy can provide

definitive diagnostic and prognostic information about acute kidney

disease and CKD. The procedure is most often used in AKI when

prerenal azotemia, postrenal AKI, and ischemic or nephrotoxic AKI

have been deemed unlikely, and other possible diagnoses are being

considered such as glomerulonephritis, vasculitis, interstitial nephritis,

myeloma kidney, HUS and TTP, and allograft dysfunction. Kidney

biopsy is associated with a risk of bleeding, which can be severe and

organ- or life-threatening in patients with thrombocytopenia or coagulopathy, but the diagnostic and prognostic information obtained can

be invaluable.

■ NOVEL BIOMARKERS

BUN and creatinine are functional biomarkers of glomerular filtration rather than tissue injury biomarkers and, therefore, may be

suboptimal for the diagnosis of actual parenchymal kidney damage.

BUN and creatinine are also relatively slow to rise after kidney injury.

Several urine and blood biomarkers have been investigated and show

promise for earlier and accurate diagnosis of AKI and for predicting AKI prognosis. In cases of oliguric AKI, the urinary flow rate in

response to bolus intravenous furosemide 1.0–1.5 mg/kg can be used

a prognostic test: urine output <200 mL over 2 h after intravenous

furosemide may identify patients at higher risk of progression to more

severe AKI, and the need for renal replacement therapy. The severity

or risk of progressive AKI may also be reflected in findings on urine

microscopy. In one study involving review of fresh urine sediments by

board-certified nephrologists, a greater number of renal tubular epithelial

cells and/or granular casts in the urine sediment was associated with both

the severity and worsening of AKI. Protein biomarkers of kidney injury

have also been identified in animal models of AKI and have been used

in humans and found to be particularly useful in toxicity identification.

Kidney injury molecule-1 (KIM-1) is a type 1 transmembrane protein that

is abundantly expressed in proximal tubular cells injured by ischemia or

multiple, distinct nephrotoxins, such as cisplatin. KIM-1 is not expressed

in appreciable quantities in the absence of tubular injury or in extrarenal

tissues. KIM-1 can be detected after ischemic or nephrotoxic injury in

the urine and plasma. Neutrophil gelatinase associated lipocalin (NGAL,

also known as lipocalin-2 or siderocalin) is another biomarker of AKI.

NGAL was first discovered as a protein in granules of human neutrophils.

NGAL can bind to iron siderophore complexes and may have tissueprotective effects in the proximal tubule. NGAL is highly upregulated

after inflammation and kidney injury and can be detected in the plasma

and urine within 2 h of cardiopulmonary bypass–associated AKI. Soluble

urokinase plasminogen activator receptor (suPAR) is a signaling glycoprotein expressed in multiple cell types and thought to be involved in

the pathogenesis of certain kidney diseases; suPAR has been measured

in the plasma and found to predict the subsequent development of AKI.

In 2014, the U.S. Food and Drug Administration (FDA) approved the

marketing of a test based on the combination of the urinary concentrations of two cell-cycle arrest biomarkers, insulin-like growth factor

binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinase-2

(TIMP-2) as predictive biomarkers for higher risk of the development

of moderate to severe AKI in critically ill patients. In 2018 the FDA also

qualified a panel of urinary markers including KIM-1, NGAL, N-acetylbeta-D-glucosaminidase, osteopontin, cystatin-C, and clusterin for the

detection of kidney tubular injury in phase 1 trials in healthy volunteers. The optimal use of AKI biomarkers in clinical settings is an area

of ongoing investigation.

COMPLICATIONS OF AKI

The kidney plays a central role in homeostatic control of volume status,

blood pressure, plasma electrolyte composition, and acid-base balance,

and for excretion of nitrogenous and other waste products. Complications associated with AKI are, therefore, protean, and depend on the

severity of AKI and other associated conditions. Mild to moderate AKI

may be entirely asymptomatic, particularly early in the course.

2306 PART 9 Disorders of the Kidney and Urinary Tract

■ UREMIA

Buildup of nitrogenous waste products, manifested as an elevated

BUN concentration, is a hallmark of AKI. BUN itself poses little direct

toxicity at levels <100 mg/dL. At higher concentrations, mental status

changes and bleeding complications can arise. Other toxins normally

cleared by the kidney may be responsible for the symptom complex

known as uremia. Few of the many possible uremic toxins have been

definitively identified. The correlation of BUN and SCr concentrations

with uremic symptoms is extremely variable, due in part to differences

in urea and creatinine generation rates across individuals.

■ HYPERVOLEMIA AND HYPOVOLEMIA

Expansion of extracellular fluid volume is a major complication of

oliguric and anuric AKI, due to impaired salt and water excretion. The

result can be weight gain, dependent edema, increased jugular venous

pressure, and pulmonary edema; the latter can be life threatening. Pulmonary edema can also occur from volume overload and hemorrhage

in pulmonary renal syndromes. AKI may also induce or exacerbate

acute lung injury characterized by increased vascular permeability and

inflammatory cell infiltration in lung parenchyma. Recovery from AKI

is often heralded by an increase in urine output. This “polyuric” phase

of recovery may be due to an osmotic diuresis from retained urea and

other waste products as well as delayed recovery of tubular reabsorptive

functions.

■ HYPONATREMIA

Abnormalities in plasma electrolyte composition can be mild or life

threatening. The dysfunctional kidney has limited ability to regulate

electrolyte balance. Administration of excessive hypotonic crystalloid or isotonic dextrose solutions can result in hypoosmolality and

hyponatremia, which, if severe, can cause neurologic abnormalities,

including seizures.

■ HYPERKALEMIA

An important complication of AKI is hyperkalemia. Marked hyperkalemia is particularly common in rhabdomyolysis, hemolysis, and

tumor lysis syndrome due to release of intracellular potassium from

damaged cells. Muscle weakness may be a symptom of hyperkalemia.

Potassium affects the cellular membrane potential of cardiac and neuromuscular tissues. The more serious complication of hyperkalemia

is due to effects on cardiac conduction, leading to potentially fatal

arrhythmias.

■ ACIDOSIS

Metabolic acidosis, usually accompanied by an elevation in the anion

gap, is common in AKI, and can further complicate acid-base and

potassium balance in individuals with other causes of acidosis, including sepsis, diabetic ketoacidosis, or respiratory acidosis.

■ HYPERPHOSPHATEMIA AND HYPOCALCEMIA

AKI can lead to hyperphosphatemia, particularly in highly catabolic

patients or those with AKI from rhabdomyolysis, hemolysis, and

tumor lysis syndrome. Metastatic deposition of calcium phosphate can

lead to hypocalcemia. AKI-associated hypocalcemia may also arise

from derangements in the vitamin D–parathyroid hormone–fibroblast

growth factor-23 axis. Hypocalcemia is often asymptomatic but can

lead to perioral paresthesias, muscle cramps, seizures, carpopedal

spasms, and prolongation of the QT interval on electrocardiography.

Calcium levels should be corrected for the degree of hypoalbuminemia,

if present, or ionized calcium levels should be followed. Mild, asymptomatic hypocalcemia does not require treatment.

■ BLEEDING

Hematologic complications of AKI include anemia and bleeding, both

of which are exacerbated by coexisting disease processes such as sepsis, liver disease, and disseminated intravascular coagulation. Direct

hematologic effects from AKI-related uremia include decreased erythropoiesis and platelet dysfunction.

■ INFECTIONS

Infections are a common precipitant of AKI and also a dreaded complication of AKI. Impaired host immunity has been described in ESKD

and may be operative in severe AKI.

■ CARDIAC COMPLICATIONS

The major cardiac complications of AKI are arrhythmias, pericarditis,

and pericardial effusion. In addition, volume overload and uremia

may lead to cardiac injury and impaired cardiac function. In animal

studies cellular apoptosis and capillary vascular congestion as well as

mitochondrial dysfunction have been described in the heart after renal

ischemia reperfusion.

■ MALNUTRITION

AKI is often a severely hypercatabolic state, and therefore malnutrition

is a major complication.

■ PREVENTION AND TREATMENT OF AKI

The management of individuals with and at risk for AKI varies according to the underlying cause (Table 310-3). Common to all are several

principles. Optimization of hemodynamics, correction of fluid and

electrolyte imbalances, discontinuation of nephrotoxic medications,

and dose adjustment of administered medications are all critical.

Common causes of AKI such as sepsis and ischemic ATN do not yet

have specific therapies once injury is established, but meticulous clinical attention is needed to support the patient until (if) AKI resolves.

The kidney possesses remarkable capacity to repair itself after even

severe, dialysis-requiring AKI, when baseline renal function was intact.

However, many patients with AKI, particularly when superimposed

on preexisting CKD, undergo maladaptive repair processes and do

not recover fully and may remain dialysis dependent. It has become

increasingly apparent that AKI predisposes to accelerated progression

of CKD, and CKD is an important risk factor for AKI.

Prerenal Azotemia Prevention and treatment of prerenal azotemia

require optimization of renal perfusion. The composition of replacement fluids should be targeted to the type of fluid lost. Severe acute

blood loss should be treated with packed red blood cells. In AKI,

oliguria alone is not an indication for fluid administration. Intravascular hypovolemia should be the only indication. Optimal fluid composition is not well defined. Crystalloid solutions are less expensive

than albumin-containing solutions, and albumin does not provide a

survival benefit compared to crystalloid. Albumin may decrease fluid

requirements but does not reduce the need for renal replacement therapy. Buffered crystalloid solutions (e.g., Ringer’s Lactate, Hartmann’s

solution, Plasma-Lyte) are recommended for patients with AKI who

are not hypochloremic; 0.9% saline is recommended for hypovolemic

hypochloremic patients if the serum chloride concentration is closely

monitored. Excessive chloride administration from 0.9% saline may

lead to hyperchloremic metabolic acidosis and may impair GFR.

Hydroxyethyl starch solutions increase the risk of severe AKI and are

contraindicated. Bicarbonate-containing solutions (e.g., dextrose water

with 150 mEq sodium bicarbonate) can be used if metabolic acidosis

is a concern.

Optimization of cardiac function in AKI may require use of inotropic agents, preload- and afterload-reducing agents, antiarrhythmic

drugs, and mechanical aids such as ventricular assist devices. Invasive

hemodynamic monitoring to guide therapy may be necessary.

Cirrhosis and Hepatorenal Syndrome Fluid management in

individuals with cirrhosis, ascites, and AKI is challenging because of

the frequent difficulty in ascertaining intravascular volume status.

Administration of intravenous fluids as a volume challenge may be

required diagnostically as well as therapeutically. Excessive volume

administration may, however, result in worsening ascites and pulmonary compromise in the setting of hepatorenal syndrome or AKI due

to superimposed spontaneous bacterial peritonitis. Peritonitis should

be ruled out by culture of ascitic fluid. Albumin may prevent AKI in

those treated with antibiotics for spontaneous bacterial peritonitis. The

definitive treatment of the hepatorenal syndrome is orthotopic liver

2307Acute Kidney Injury CHAPTER 310

transplantation. Bridge therapies that have shown promise include

terlipressin (a vasopressin analog), with albumin, or, when terlipressin

is not available, combination therapy with octreotide (a somatostatin

analog) and midodrine (an α1

-adrenergic agonist), in combination

with intravenous albumin (25–50 g, maximum 100 g/d).

Intrinsic AKI Several agents have been tested and have failed to

show benefit in the treatment of acute tubular injury. These include

atrial natriuretic peptide, low-dose dopamine, endothelin antagonists,

erythropoietin, loop diuretics, calcium channel blockers, α-adrenergic

receptor blockers, prostaglandin analogs, antioxidants, antibodies

against leukocyte adhesion molecules, and insulin-like growth factor,

among many others. Most studies have enrolled patients with severe

and well-established AKI, and treatment may have been initiated too

late. Kidney injury biomarkers described previously may provide an

opportunity to test agents earlier in the course of AKI.

AKI due to acute glomerulonephritis or vasculitis may respond to

immunosuppressive agents and/or plasmapheresis (Chap. 309). Allergic interstitial nephritis due to medications requires discontinuation

of the offending agent. Glucocorticoids have been used but not tested

in randomized trials, in cases where AKI persists or worsens despite

discontinuation of the suspected medication. AKI due to scleroderma

(scleroderma renal crisis) should be treated with ACE inhibitors. Idiopathic TTP is a medical emergency and should be treated promptly

with plasma exchange. Pharmacologic blockade of complement activation may be effective in atypical HUS.

Early and aggressive volume repletion is mandatory in patients

with rhabdomyolysis, who may initially require 10 L of fluid per day.

Alkaline fluids (e.g., 75 mmol/L sodium bicarbonate added to 0.45%

saline) may be beneficial in preventing tubular injury and cast formation, but carry the risk of worsening hypocalcemia. Diuretics may

be used if fluid repletion is adequate but unsuccessful in achieving

urinary flow rates of 200–300 mL/h. There is no specific therapy for

established AKI in rhabdomyolysis, other than dialysis in severe cases

or general supportive care to maintain fluid and electrolyte balance

and tissue perfusion. Careful attention must be focused on calcium and

phosphate status because of precipitation in damaged tissue and release

when the tissue heals.

Postrenal AKI Prompt recognition and relief of urinary tract

obstruction can forestall the development of permanent structural

damage induced by urinary stasis. The site of obstruction defines

the treatment approach. Transurethral or suprapubic bladder catheterization may be all that is needed initially for urethral strictures or

functional bladder impairment. Ureteric obstruction may be treated

by percutaneous nephrostomy tube placement or ureteral stent placement. Relief of obstruction is usually followed by an appropriate diuresis for several days. In rare cases, severe polyuria persists due to tubular

dysfunction and may require continued administration of intravenous

fluids and electrolytes for a period of time.

■ SUPPORTIVE MEASURES FOR AKI

Volume Management Hypervolemia in oliguric or anuric AKI

may be life threatening due to acute pulmonary edema, especially

because many patients have coexisting pulmonary disease, and AKI

likely increases pulmonary vascular permeability. Fluid and sodium

should be restricted, and diuretics may be used to increase the urinary flow rate. There is no evidence that increasing urine output

itself improves the natural history of AKI, but diuretics may help to

avoid the need for dialysis in some cases. In severe cases of volume

overload, furosemide may be given as a bolus (200 mg) followed by

an intravenous drip (10–40 mg/h), with or without a thiazide diuretic.

In decompensated heart failure, stepped diuretic therapy was found

to be superior to ultrafiltration in preserving renal function. Diuretic

therapy should be stopped if there is no response. Dopamine in low

doses may transiently increase salt and water excretion by the kidney

in prerenal states, but clinical trials have failed to show any benefit in

patients with intrinsic AKI. Because of the risk of arrhythmias and

potential bowel ischemia, the risks of dopamine outweigh the benefits

if used specifically for the treatment or prevention of AKI.

Electrolyte and Acid-Base Abnormalities The treatment of

dysnatremias and hyperkalemia is described in Chap. 53. Metabolic acidosis is generally not treated unless severe (pH <7.20 and

serum bicarbonate <15 mmol/L). Acidosis can be treated with oral

TABLE 310-3 Management of Acute Kidney Injury

General Issues

1. Optimization of systemic and renal hemodynamics through volume

resuscitation and judicious use of vasopressors

2. Elimination of nephrotoxic agents (e.g., ACE inhibitors, ARBs, NSAIDs,

aminoglycosides) if possible

3. Initiation of renal replacement therapy when indicated

Specific Issues

1. Nephrotoxin-specific

a. Rhabdomyolysis: aggressive intravenous fluids; consider forced alkaline

diuresis

b. Tumor lysis syndrome: aggressive intravenous fluids and allopurinol or

rasburicase

2. Volume overload

a. Salt and water restriction

b. Diuretics

c. Ultrafiltration

3. Hyponatremia

a. Restriction of enteral free water intake, minimization of hypotonic

intravenous solutions including those containing dextrose

b. Hypertonic saline is rarely necessary in AKI. Vasopressin antagonists are

generally not needed.

4. Hyperkalemia

a. Restriction of dietary potassium intake

b. Discontinuation of potassium-sparing diuretics, ACE inhibitors, ARBs,

NSAIDs

c. Loop diuretics to promote urinary potassium loss

d. Potassium binding ion-exchange resin (sodium polystyrene sulfonate)

e. Insulin (10 units regular) and glucose (50 mL of 50% dextrose) to promote

entry of potassium intracellularly

f. Inhaled beta-agonist therapy to promote entry of potassium intracellularly

g. Calcium gluconate or calcium chloride (1 g) to stabilize the myocardium

5. Metabolic acidosis

a. Sodium bicarbonate (if pH <7.2 to keep serum bicarbonate >15 mmol/L)

b. Administration of other bases, e.g., THAM

c. Renal replacement therapy

6. Hyperphosphatemia

a. Restriction of dietary phosphate intake

b. Phosphate binding agents (calcium acetate, sevelamer hydrochloride,

aluminum hydroxide—taken with meals)

7. Hypocalcemia

a. Calcium carbonate or calcium gluconate if symptomatic

8. Hypermagnesemia

a. Discontinue Mg2+ containing antacids

9. Hyperuricemia

a. Acute treatment is usually not required except in the setting of tumor lysis

syndrome (see above)

10. Nutrition

a. Sufficient protein and calorie intake (20–30 kcal/kg per day) to avoid

negative nitrogen balance. Nutrition should be provided via the enteral

route if possible.

11. Drug dosing

a. Careful attention to dosages and frequency of administration of drugs,

adjustment for degree of renal failure

b. Note that serum creatinine concentration may overestimate renal function

in the non–steady state characteristic of patients with AKI.

Abbreviations: ACE, angiotensin-converting enzyme; AKI, acute kidney infection;

ARBs, angiotensin receptor blockers; NSAIDs, nonsteroidal anti-inflammatory

drugs; THAM, tris (hydroxymethyl) aminomethane.

2308 PART 9 Disorders of the Kidney and Urinary Tract

or intravenous sodium bicarbonate (Chap. 55), but overcorrection

should be avoided because of the possibility of metabolic alkalosis,

hypocalcemia, hypokalemia, and volume overload. Hyperphosphatemia is common in AKI and can usually be treated by limiting intestinal

absorption of phosphate using phosphate binders (calcium carbonate,

calcium acetate, lanthanum, sevelamer, or aluminum hydroxide).

Symptomatic hypocalcemia should be treated with calcium gluconate

or calcium chloride. Ionized calcium should be monitored rather than

total calcium when hypoalbuminemia is present.

Malnutrition Increased catabolism with protein energy wasting is

common in severe AKI, particularly in the setting of multisystem organ

failure. Inadequate nutrition may lead to starvation ketoacidosis and

protein catabolism. Excessive nutrition may increase the generation

of nitrogenous waste and lead to worsening azotemia. Total parenteral nutrition requires large volumes of fluid administration and may

complicate efforts at volume control. According to the Kidney Disease

Improving Global Outcomes (KDIGO) guidelines, patients with AKI

should achieve a total energy intake of 20–30 kcal/kg per day. Protein

intake should vary depending on the severity of AKI: 0.8–1.0 g/kg per

day in noncatabolic AKI without the need for dialysis; 1.0–1.5 g/kg per

day in patients on dialysis; and up to a maximum of 1.7 g/kg per day

if hypercatabolic and receiving continuous renal replacement therapy.

Trace elements and water-soluble vitamins should also be supplemented in AKI patients treated with dialysis and continuous renal

replacement therapy.

Anemia The anemia seen in AKI is usually multifactorial and is not

improved by erythropoiesis-stimulating agents, due to their delayed

onset of action and the presence of bone marrow resistance in critically ill patients. Uremic bleeding may respond to desmopressin or

estrogens, but may require dialysis for treatment in the case of longstanding or severe uremia. Gastrointestinal prophylaxis with proton

pump inhibitors or histamine (H2

) receptor blockers is required. It is

important to recognize, however, that proton pump inhibitors have

been associated with AKI from interstitial nephritis, a relationship that

is increasingly being recognized. Venous thromboembolism prophylaxis is important and should be tailored to the clinical setting; lowmolecular-weight heparins and factor Xa inhibitors have unpredictable

pharmacokinetics in severe AKI and should generally be avoided if

possible.

Dialysis Indications and Modalities (See also Chap. 312)

Dialysis is indicated when medical management fails to control volume overload, hyperkalemia, or acidosis; in some toxic ingestions; and

when there are severe complications of uremia (asterixis, pericardial

rub or effusion, encephalopathy, uremic bleeding). Late initiation of

dialysis carries the risk of avoidable volume, electrolyte, and metabolic

complications of AKI. On the other hand, initiating dialysis too early

may unnecessarily expose individuals to intravenous lines and invasive

procedures, with the attendant risks of infection, bleeding, procedural

complications, and hypotension. In randomized controlled trials,

earlier versus later initiation of dialysis has not been demonstrated

to improve survival, and may increase the risk of adverse events. The

initiation of dialysis should not, however, await the development of a

life-threatening complication of renal failure. Many nephrologists initiate dialysis for AKI empirically when the BUN exceeds a certain value

(e.g., 100 mg/dL) in patients without clinical signs of recovery of kidney

function. The available modes for renal replacement therapy in AKI

require either access to the peritoneal cavity (for peritoneal dialysis)

or the large blood vessels (for hemodialysis, hemofiltration, and other

hybrid procedures). Small solutes are removed across a semipermeable

membrane down their concentration gradient (“diffusive” clearance)

and/or along with the movement of plasma water (“convective”

clearance). Hemodialysis can be used intermittently or continuously

and can be done through convective clearance, diffusive clearance,

or a combination of the two. Vascular access is through the femoral,

internal jugular, or subclavian veins. Hemodialysis is an intermittent

procedure that removes solutes through diffusive and convective clearance. Hemodialysis is typically performed 3–4 h per day, three to four

times per week, and is the most common form of renal replacement

therapy for AKI. One of the major complications of hemodialysis is

hypotension, particularly in the critically ill, which can perpetuate AKI

by causing ischemic injury to the recovering organ.

Continuous intravascular procedures were developed in the early

1980s to treat hemodynamically unstable patients without inducing

the rapid shifts of volume, osmolarity, and electrolytes characteristic

of intermittent hemodialysis. Continuous renal replacement therapy

(CRRT) can be performed by convective clearance (continuous venovenous hemofiltration [CVVH]), in which large volumes of plasma

water (and accompanying solutes) are forced across the semipermeable

membrane by means of hydrostatic pressure; the plasma water is then

replaced by a physiologic crystalloid solution. CRRT can also be performed by diffusive clearance (continuous venovenous hemodialysis

[CVVHD]), a technology similar to hemodialysis except at lower blood

flow and dialysate flow rates. A hybrid therapy combines both diffusive

and convective clearance (continuous venovenous hemodiafiltration

[CVVHDF]). To achieve some of the advantages of CRRT without the

need for 24-h staffing of the procedure, some physicians favor slow

low-efficiency dialysis (SLED) or extended daily dialysis (EDD). In this

therapy, blood flow and dialysate flow are higher than in CVVHD, but

the treatment time is reduced to ≤12 h. The choice of modality is often

dictated by the immediate availability of technology and the expertise

of medical staff.

The optimal dose of dialysis for AKI for any particular patient is

not clear. Daily intermittent hemodialysis and high-dose CRRT do

not confer a demonstrable survival or renal recovery advantage, but

care should be taken to avoid undertreatment. Studies have failed to

show that continuous therapies are superior to intermittent therapies

when measuring survival rates. If available, CRRT is often preferred

in patients with severe hemodynamic instability, cerebral edema, or

significant volume overload.

Peritoneal dialysis can be performed through a temporary intraperitoneal catheter. It is rarely used in the United States for AKI in

adults (although it was “rediscovered” during the COVID-19 pandemic owing to inadequate numbers of continuous and intermittent

hemodialysis machines). Peritoneal dialysis has enjoyed widespread

use internationally, particularly when hemodialysis technology is not

as readily available. Dialysate solution is instilled into and removed

from the peritoneal cavity at regular intervals in order to achieve

diffusive and convective clearance of solutes across the peritoneal

membrane; ultrafiltration of water is achieved by the presence of an

osmotic gradient across the peritoneal membrane achieved by high

concentrations of dextrose in the dialysate solution. Because of its

continuous nature, it is often better tolerated than intermittent procedures like hemodialysis in hypotensive patients. Peritoneal dialysis

may not be sufficient for hypercatabolic patients due to inherent limitations in dialysis efficacy.

OUTCOME AND PROGNOSIS

The development of AKI is associated with a significantly increased

risk of in-hospital and long-term mortality, longer length of stay, and

increased costs. AKI is also associated with an increased risk of later

cardiovascular disease events, though the mechanisms are not well

understood. Prerenal azotemia, with the exception of the cardiorenal

and hepatorenal syndromes, and postrenal azotemia carry a better

prognosis than most cases of intrinsic AKI. The kidneys may recover

even after severe, dialysis-requiring AKI. Survivors of an episode of

AKI requiring temporary dialysis, however, are at extremely high risk

for progressive CKD, and up to 10% may develop ESKD requiring

dialysis or transplantation. AKI and CKD are increasingly seen as

interrelated syndromes: CKD is a major risk factor for the development

of AKI, and AKI is a risk factor for the future development of CKD.

Measurement of albuminuria after an AKI episode can help predict

the risk of kidney disease progression and can serve as a valuable riskstratification tool. Postdischarge care after AKI under the supervision

of a nephrologist for aggressive secondary prevention of kidney disease

is prudent.

2309Chronic Kidney Disease CHAPTER 311

Chronic kidney disease (CKD) encompasses a spectrum of pathophysiologic processes associated with abnormal kidney function, often with

a progressive decline in glomerular filtration rate (GFR). The risk of

worsening CKD is closely linked to both the GFR and the amount of

albuminuria. Figure 311-1 provides a staging of CKD stratified by the

estimates for further progressive decline of GFR based on these two

parameters.

The dispiriting term end-stage renal disease represents a stage of

CKD where the accumulation of toxins, fluid, and electrolytes normally

excreted by the kidneys leads to death unless the toxins are removed

by renal replacement therapy, using dialysis or kidney transplantation.

These interventions are discussed in Chaps. 312 and 313. End-stage

renal disease will be supplanted in this chapter by the term stage 5 CKD.

■ PATHOPHYSIOLOGY OF CKD

The pathophysiology of CKD involves two broad mechanisms of damage: (1) specific initiating mechanisms particular to the underlying

311 Chronic Kidney Disease

Joanne M. Bargman, Karl Skorecki

etiology (e.g., genetic abnormalities in kidney development, immune

complex deposition, and inflammation in certain types of glomerulonephritis, or toxin exposure in certain diseases of the renal tubules

and interstitium), and (2) nonspecific mechanisms involving hyperfiltration and hypertrophy of the remaining viable nephrons, which

are common consequences of long-term reduction of renal mass,

irrespective of underlying etiology. The responses to reduction in

nephron number are mediated by vasoactive hormones, cytokines,

and growth factors. Eventually, the short-term adaptations of hyperfiltration and hypertrophy to maintain GFR become maladaptive as

the increased pressure and flow within the nephron predisposes to

distortion of glomerular architecture, abnormal podocyte function,

and disruption of the filtration barrier, leading to sclerosis and dropout

of the remaining nephrons (Fig. 311-2). Increased intrarenal activity of

the renin-angiotensin system (RAS) appears to contribute both to the

initial compensatory hyperfiltration and to the subsequent maladaptive

hypertrophy and sclerosis. This process explains why a reduction in

renal mass from an isolated insult may lead to a progressive decline

in renal function over many years and the efficacy of pharmacologic

approaches that attenuate this response (Fig. 311-3).

■ IDENTIFICATION OF RISK FACTORS

AND STAGING OF CKD

There has been significant recent progress in the identification of risk

factors that increase the risk for CKD, even in individuals with normal

GFR (Table 311-1).

Adults with such risk factors should be monitored at least every 2

years for albuminuria, decline in eGFR, and blood pressure abnormalities, so that a clinical management pathway can be planned.

Most recently identified risk factors for which there is now a consensus include a past episode of apparently recovered acute kidney injury

(AKI), tobacco use, and many forms of apparently resolved childhood

and adolescent kidney disease. There is also an increasing awareness of

the role of genetic risk factors, which account for 15–40% of adult-onset

CKD, with the percentage often depending on the contribution of

demographic structure and history to the genetic variation for any population. Many rare inherited forms of CKD follow a Mendelian inheritance pattern, often as part of a systemic syndrome, with the most

Mildly decreased

Mildly to moderately

decreased

Moderately to

severely decreased

Severely decreased

Kidney failure

Normal or high

Normal to

mildly

increased

<30 mg/g

<3 mg/mmol

30–300 mg/g

3–30 mg/mmol

>300 mg/g

>30 mg/mmol

Moderately

increased

Severely

increased

60–89

45–59

30–44

15–29

<15

G1 ≥90

G2

G4

G5

G3a

G3b

GFR categories (mL/min/1.73 m2)

description and range

Prognosis of CKD by GFR

and albuminuria categories:

KDIGO 2012

Persistent albuminuria categories

description and range

A1 A2 A3

FIGURE 311-1 Kidney Disease Improving Global Outcome (KDIGO) classification of chronic kidney disease (CKD). Gradation of color from green to red corresponds to

increasing risk and progression of CKD. GFR, glomerular filtration rate. (Reproduced with permission from KDIGO 2012 Clinical Practice Guideline for the Evaluation and

Management of Chronic Kidney Disease. Kidney Int Suppl 3:5, 2013.)

■ FURTHER READING

Bonventre JV, Yang L: Cellular pathophysiology of ischemic acute

kidney injury. J Clin Invest 121:4210, 2011.

Hoste EAJ et al: Global epidemiology and outcomes of acute kidney

injury. Nature Rev Nephrol 14:607, 2018.

Kidney Disease: Improving Global Outcomes (KDIGO) Acute

Kidney Injury Work Group: KDIGO Clinical Practice Guidelines

for Acute Kidney Injury. Kidney Int Supp 2:1, 2012.

STARRT-AKI Investigators for the Canadian Critical Care Trials

Group: Timing of initiation of renal-replacement therapy in acute

kidney injury. N Engl J Med 383:240, 2020.

2310 PART 9 Disorders of the Kidney and Urinary Tract

common in this category being autosomal dominant polycystic kidney

disease (ADPKD). In addition, it is now appreciated that many unique,

kindred-specific, site-specific copy number variants and microdeletions, as well as functional variants at >60 genetic loci known to harbor

systemic and kidney-only disease pathogenic mutations, also contribute to risk for pleiotropic presentations of CKD (Table 311-2). Many

of the genes with identified CKD-causing mutations are expressed in

the podocytes of the renal glomeruli or in the glomerular basement

membrane, but others are expressed in tubule segments with a primary

tubulointerstitial process and secondary glomerular injury. Given the

significant contribution of monogenic disease etiologies, consideration is now given to chromosomal microarray and genome or exome

sequencing for CKD of unknown cause in young adults, as noted below

under Evaluation and Management of Patients with CKD.

In addition, recent research in the genetics of predisposition to

common complex diseases has revealed DNA sequence variants at a

Distal

Af tubule ferent

arteriole

Efferent

arteriole

Normal

endothelium

Basement

membrane

Podocytes

Enlarged

arteriole

Damaged

endothelium

Sclerosis

Normal Glomerulus Hyperfiltering Glomerulus

FIGURE 311-2 Left: Schema of the normal glomerular architecture. Right: Secondary glomerular changes associated with a reduction in nephron number, including

enlargement of capillary lumens and focal adhesions, which are thought to occur consequent to compensatory hyperfiltration and hypertrophy in the remaining nephrons.

(From JR Ingelfinger: Is microanatomy destiny?. N Engl J Med 348:99, 2003. Copyright © 2003, Massachusetts Medical Society. Reprinted with permission from Massachusetts

Medical Society.)

Glomerulus

Increased

intraglomerular

pressure

Normal

kidney

Afferent

arteriole

Ang II

Afferent

arteriole

Distal tubule Distal tubule

Efferent

arteriolar

constricted

Efferent

arteriole

Tubule Tubule

Urinary protein

A B

Ang II

FIGURE 311-3 Schematic representation of the effect of intraglomerular hypertension on nephron survival.

2311Chronic Kidney Disease CHAPTER 311

number of genetic loci that are associated with common forms of CKD.

A striking example is the finding of allelic versions of the APOL1 gene,

of West African population ancestry, which contributes to the severalfold higher frequency of certain common etiologies of nondiabetic

CKD (e.g., focal segmental glomerulosclerosis) observed among African and Hispanic Americans, in major regions of continental Africa

and the global African diaspora. The prevalence in West African populations seems to have arisen as an evolutionary adaptation conferring

protection from tropical pathogens. As in other common diseases with

a heritable component, environmental triggers (e.g., a viral pathogen)

transform genetic risk into disease.

To stage CKD, it is necessary to estimate the GFR rather than relying

on serum creatinine concentration (Table 311-3). Many laboratories now

report an estimated GFR, or eGFR, using one of these equations. These

equations are valid only if the patient is in steady state, that is, the serum

creatinine is neither rising nor falling over days. The societal implications

of adjustment for a construct of race have been the subject of important

recent discourse, with the idea that more individually sound adjustments

without potentially negative racial categorizations be developed.

The normal annual mean decline in GFR with age from the peak

GFR (~120 mL/min per 1.73 m2

) attained during the third decade of

life is ~1 mL/min per year per 1.73 m2

, reaching a mean value of 70 mL/

min per 1.73 m2

 at age 70, with considerable interindividual variability.

Although reduced GFR is expected with aging, the lower GFR signifies

a true loss of kidney function with attendant consequences in terms

of risk of CKD complications and requirement for dose adjustment

of medications. The mean GFR is lower in women than in men. For

example, a woman in her eighties with a laboratory report of serum

creatinine in the normal range may have a GFR of <50 mL/min per 1.73 m2

.

Relatedly, even a mild elevation in serum creatinine concentration often

signifies a substantial reduction in GFR in older individuals.

Measurement of albuminuria is also helpful for monitoring

nephron injury and the response to therapy in many forms of

CKD, especially chronic glomerular diseases. The cumbersome

24-h urine collection has been replaced by measurement of urinary

albumin-to-creatinine ratio (UACR) in one and preferably several

spot first-morning urine samples as a measure pointing to glomerular injury. Even in patients with negative conventional urinary

dipstick tests for protein, persistent UACR >2.5 mg/mmol (male) or

>3.5 mg/mmol (female) on two to three occasions serves as a marker

not only for early detection of primary kidney disease but for systemic microvascular disease as well.

TABLE 311-2 Monogenic Risk Loci for Chronic Kidney Disease

Copy number variants

17q12

22q11.2

16p11.2

Single nucleotide variants at four most predominant genetic loci with mendelian

inheritance

Genes for autosomal dominant polycystic kidney disease

ADPKD1

ADPKD2

GANAB

DNAJBll

ALG9

Genes for type IV collagen-associated nephropathy

COL4A3

COL4A4

COL4A5

Genes for autosomal dominant tubulointerstitial kidney disease

UMOD

MUCl

REN

HNFlB

SEC6lAl

Genes with known common variants that confer increased risk with odds ratio

exceeding 2 with non-Mendelian inheritance patterns

APOL1

TABLE 311-1 Risk Factors for Chronic Kidney Disease (CKD) in

Adulthood by Categorya

Chronic Nonrenal (Systemic) Disease

Diabetes and metabolic syndrome

Autoinflammatory disease (e.g., lupus, vasculitis, cancer immunotherapy)

Infections (e.g., HIV, HBV, HCV)

Absence of infection (JCV)

Nephrotoxic exposure (including many antineoplastic therapies)

Hypertension (risk, cause, or consequence)

Demographic, Anthropomorphic, Ancestry, Geographic

Age

Sex

Population ancestry

Family history

 Region-specific CKD risk of uncertain etiology (e.g., Central America,

Sri Lanka, and indigenous peoples of Australia and New Zealand)

Childhood and Adolescent States and Diseases

Premature and SGA birth

Increased BMI

Persistent asymptomatic microscopic hematuria

Elevated blood pressure

Childhood kidney disease (even resolved)

Treated childhood cancer

Adult Onset

Prior acute kidney injury

Preeclampsia

Kidney donation (or other acquired nephrectomy)

Genetic

Monogenic Mendelian inheritance

Polygenic complex inheritance

Viral Infection

HIV infection (HIVAN)

SARS-CoV-2 (COVAN)

Lifestyle

Smoking

Diet

Physical activity

a

Not biomarkers.

Abbreviations: BMI, body mass index; COVAN, COVID-19–associated nephropathy;

HBV, hepatitis B virus; HCV, hepatitis C virus; HIVAN, HIV-associated nephropathy;

JCV, JC virus; SGA, small for gestational age.

TABLE 311-3 Recommended Equations for Estimation of Glomerular

Filtration Rate (GFR) Using Serum Creatinine Concentration (SCR),

Age, Sex, Race, and Body Weight

1. Equation from the Modification of Diet in Renal Disease Study

Estimated GFR (mL/min per 1.73 m2

) = 1.86 × (SCr)

−1.154 × (age)−0.203

Multiply by 0.742 for women

Multiply by 1.21 for African ancestry (currently under review)

2. CKD-EPI Equation

GFR = 141 × min(SCr/κ, 1)α × max(SCr/κ, 1)–1.209 × 0.993Age

Multiply by 1.018 for women

Multiply by 1.159 for African ancestry (currently under review)

where SCr is serum creatinine in mg/dL, κ is 0.7 for females and 0.9 for males, α is

–0.329 for females and –0.411 for males, min indicates the minimum of SCr/κ or 1,

and max indicates the maximum of SCr/κ or 1.

Abbreviation: CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration.

2312 PART 9 Disorders of the Kidney and Urinary Tract

A Kidney Failure Risk (KFR) equation has been devised to predict

the risk of progression to stage 5 dialysis-dependent kidney disease.

The equation is available on many sites online (for example, www

.kidneyfailurerisk.com) and uses age, sex, region (North American

or non–North American), GFR, and UACR. It has been validated in

several cohorts around the world, although the risk for progression

appears to be greater in North America, accounting for the regional

adjustment in the equation.

Stages 1 and 2 CKD are usually asymptomatic, such that the recognition of CKD occurs more often as a result of laboratory testing in

clinical settings other than suspicion of kidney disease. Moreover, in

the absence of the risk factors noted above, population-wide screening is not recommended. With progression to CKD stages 3 and 4,

clinical and laboratory complications become more prominent.

Virtually all organ systems are affected, but the most evident complications include anemia with easy fatigability; decreased appetite

with progressive malnutrition; abnormalities in calcium, phosphorus,

and mineral-regulating hormones, such as 1,25(OH)2

D3

 (calcitriol),

parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23); and abnormalities in sodium, potassium, water, and acid-base

homeostasis. Many patients, especially older individuals, will have

eGFR values compatible with stage 2 or 3 CKD. However, the majority of these patients will show no further deterioration of kidney

function. In this setting, it is advised to recheck kidney function,

and if it is stable and not associated with proteinuria, the patient

can usually be followed with interval repeat testing without referral

to a nephrologist. However, caution should be exercised in terms of

potential exposure to potential nephrotoxins or interventions that

risk AKI and also with respect to medication dose adjustment. If

repeat testing shows declining GFR, albuminuria, or uncontrolled

hypertension, referral to a nephrologist is appropriate. If the patient

progresses to stage 5 CKD (GFR <15 mL/min), toxins accumulate

such that patients usually experience a disturbance in their activities

of daily living, well-being, nutritional status, and water and electrolyte homeostasis, eventuating in the uremic syndrome.

■ ETIOLOGY AND EPIDEMIOLOGY

It has been estimated from population data that at least 6% of the

adult population in the United States has CKD at stages 1 and 2. An

additional 4.5% of the U.S. population is estimated to have stages 3

and 4 CKD. Table 311-4 lists the five most frequent categories of

causes of CKD, cumulatively accounting for >90% of the CKD disease burden worldwide. The relative contribution of each category

varies among different geographic regions. The most frequent cause

of CKD in North America and Europe is diabetic nephropathy, most

often secondary to type 2 diabetes mellitus. Patients with newly

diagnosed CKD often have hypertension. When no overt evidence

for a primary glomerular or tubulointerstitial kidney disease process

is present, CKD is frequently attributed to hypertension. However, it

is now appreciated that some of these patients may have a subclinical

primary glomerulopathy, such as focal segmental or global glomerulosclerosis. In other patients, progressive nephrosclerosis and hypertension are the renal correlates of a systemic vascular disease, often

also involving large and small vessels elsewhere, such as the heart and

brain. This latter combination is especially common in older patients,

among whom chronic kidney ischemia as a cause of CKD may be

underdiagnosed.

■ PATHOPHYSIOLOGY AND BIOCHEMISTRY

OF UREMIA

Although serum urea and creatinine concentrations are used to measure the excretory capacity of the kidneys, accumulation of these two

molecules themselves does not account for the symptoms and signs

that characterize the uremic syndrome in advanced CKD. Large numbers of toxins that accumulate when GFR declines have been implicated

in the uremic syndrome. These include water-soluble, hydrophobic,

protein-bound, charged, and uncharged nitrogen-containing nonvolatile products of metabolism. It is thus evident that the serum concentrations of urea and creatinine should be viewed as being readily

measured but very incomplete surrogate markers for retained toxins,

and monitoring the levels of urea and creatinine in the patient with

impaired kidney function represents a vast oversimplification of the

uremic state.

The uremic syndrome involves more than renal excretory failure.

A host of metabolic and endocrine functions normally performed by

the kidneys are also impaired and can result in anemia, malnutrition,

and abnormal metabolism of carbohydrates, fats, and proteins. Furthermore, plasma levels of many hormones, including PTH, FGF-23,

insulin, glucagon, steroid hormones including vitamin D and sex

hormones, and prolactin change with CKD as a result of reduced

excretion, decreased degradation, or abnormal regulation. Finally,

CKD is associated with increased systemic inflammation. Elevated

levels of C-reactive protein are detected along with other acute-phase

reactants, whereas levels of so-called negative acute-phase reactants, such

as albumin and fetuin, decline. Thus, the inflammation associated with

CKD is important in the malnutrition-inflammation-atherosclerosis/

calcification syndrome, which contributes in turn to the acceleration of

vascular disease and morbidity associated with advanced kidney disease.

In summary, the pathophysiology of the uremic syndrome can be

divided into manifestations in three spheres of dysfunction: (1) those

consequent to the accumulation of toxins that normally undergo renal

excretion; (2) those consequent to the loss of other kidney functions,

such as fluid and electrolyte homeostasis and hormone regulation; and

(3) progressive systemic inflammation and its vascular and nutritional

consequences.

CLINICAL AND LABORATORY

MANIFESTATIONS OF CKD AND UREMIA

Uremia leads to disturbances in the function of virtually every organ

system. Chronic dialysis can reduce the incidence and severity of many

of these disturbances, so that the florid manifestations of uremia have

largely disappeared in the modern health care setting. However, even

optimal dialysis therapy is not completely effective as renal replacement therapy because some disturbances resulting from impaired

kidney function fail to respond to dialysis.

■ FLUID, ELECTROLYTE, AND

ACID-BASE DISORDERS

Sodium and Water Homeostasis With normal kidney function,

tubular excretion of filtered sodium and water matches intake. Many

forms of kidney disease disrupt this balance such that dietary intake of

sodium exceeds its excretion, leading to sodium retention and attendant extracellular fluid volume (ECFV) expansion. This expansion

may contribute to hypertension, which itself can accelerate nephron

hyperfiltration and injury. As long as water intake does not exceed

the capacity for renal water clearance, the ECFV expansion will be

isonatric and the patient will have a normal plasma sodium concentration. Hyponatremia is not commonly seen in CKD patients but,

when present, often responds to water restriction. The patient with

ECFV expansion (peripheral edema, sometimes hypertension poorly

responsive to therapy) should be counseled regarding salt restriction.

Thiazide diuretics have limited utility in stages 3–5 CKD, such that

administration of loop diuretics, including furosemide, bumetanide,

or torsemide, may be needed. Resistance to loop diuretics in CKD

often mandates use of higher doses than those used in patients with

higher GFR. The combination of loop diuretics with metolazone may

TABLE 311-4 Leading Categories of Etiologies of Chronic Kidney

Disease (CKD)a

• Diabetic nephropathy

• Glomerulonephritis

• Hypertension-associated CKD (includes vascular and ischemic kidney disease

and primary glomerular disease with associated hypertension)

• Autosomal dominant polycystic kidney disease

• Other cystic and tubulointerstitial nephropathy

a

Relative contribution of each category varies with geographic region and race.

2313Chronic Kidney Disease CHAPTER 311

be helpful. Diuretic resistance with intractable edema and hypertension

in advanced CKD may serve as an indication to initiate dialysis.

Rarely, patients with CKD may have impaired renal conservation

of sodium and water. When an extrarenal cause for fluid loss, such as

gastrointestinal (GI) loss, is present, these patients may be prone to

ECFV depletion because of the inability of the failing kidney to reclaim

filtered sodium adequately. Any depletion of ECFV, whether due to GI

losses, renal sodium loss, or overzealous diuretic therapy, can further

compromise kidney function through underperfusion, or a “prerenal”

state, leading to acute-on-chronic kidney failure. In this setting, holding or adjusting the diuretic dose or even cautious volume repletion

with normal saline may return the ECFV to normal and restore renal

function to baseline.

Potassium Homeostasis In CKD, the decline in GFR is not

necessarily accompanied by a parallel decline in urinary potassium

excretion, which is predominantly mediated by aldosterone-dependent

secretion in the distal nephron. Another defense against potassium

retention in these patients is augmented potassium excretion in the

GI tract. Notwithstanding these two homeostatic responses, hyperkalemia may be precipitated in certain settings. These include increased

dietary potassium intake, hemolysis, transfusion of stored red blood

cells, and metabolic acidosis. Importantly, a host of medications can

inhibit renal potassium excretion and lead to hyperkalemia. The most

important medications in this respect include the RAS inhibitors and

spironolactone and other potassium-sparing diuretics such as amiloride, eplerenone, and triamterene. The benefits of the RAS inhibitors

in ameliorating hyperfiltration and progression of CKD often favor

their cautious and judicious use with very close monitoring of plasma

potassium concentration. Coadministration of potassium-lowering

agents such as patiromer may allow for the use of RAS inhibitors with

reduced risk of hyperkalemia.

Certain causes of CKD can be associated with earlier and more

severe disruption of potassium secretory mechanisms in the distal

nephron, out of proportion to the decline in GFR. These include conditions associated with hyporeninemic hypoaldosteronism, such as

diabetes, and renal diseases that preferentially affect the distal nephron,

such as obstructive uropathy and sickle cell nephropathy.

Hypokalemia is not common in CKD and usually reflects markedly

reduced dietary potassium intake, especially in association with excessive diuretic therapy or concurrent GI losses. The use of potassium

supplements and potassium-sparing diuretics may be risky in patients

with impaired renal function and needs to be monitored closely.

Metabolic Acidosis Metabolic acidosis is a common disturbance

in CKD. The majority of patients can still acidify the urine, but they

produce less ammonia and, therefore, cannot excrete the quantity

of protons required to maintain acid-base balance in most diets.

Hyperkalemia, if present, further depresses ammonia production. The

combination of hyperkalemia and hyperchloremic metabolic acidosis

is often present, even at earlier stages of CKD, in patients with diabetic

nephropathy or in those with predominant tubulointerstitial disease or

obstructive uropathy. With further declining GFR, the total urinary net

daily acid excretion may be severely limited to less than 30–40 mmol,

and the accumulation of anions of retained organic acids can then

lead to an anion-gap metabolic acidosis. Thus, the non-anion-gap

metabolic acidosis seen in earlier stages of CKD may be complicated

by the addition of an anion-gap metabolic acidosis as CKD progresses.

In most patients, the metabolic acidosis is mild; the pH is rarely <7.32

and can usually be corrected with oral sodium bicarbonate supplementation. Studies have suggested that even modest degrees of metabolic

acidosis may be associated with the development of protein catabolism

and progression of CKD.

TREATMENT

Fluid, Electrolyte, and Acid-Base Disorders

Dietary salt restriction and the use of loop diuretics, occasionally in combination with metolazone, may be needed to

maintain euvolemia. Water restriction is indicated only if there is

hyponatremia.

Hyperkalemia often responds to dietary restriction of potassium,

the use of kaliuretic diuretics, and both avoidance of potassium supplements (including occult sources, such as dietary salt substitutes)

and dose reduction or avoidance of potassium-retaining medications (especially RAS inhibitors). Kaliuretic diuretics promote

urinary potassium excretion, whereas potassium-binding resins,

such as calcium resonium, sodium polystyrene, or patiromer, can

promote potassium loss through the GI tract and may reduce the

incidence of hyperkalemia. Intractable hyperkalemia is an indication (although uncommon) to consider institution of dialysis in a

CKD patient. The renal tubular acidosis and subsequent anion-gap

metabolic acidosis in progressive CKD will respond to alkali supplementation, typically with sodium bicarbonate. Recent studies

suggest that this replacement should be considered when the serum

bicarbonate concentration falls below 20–23 mmol/L to avoid the

protein catabolic state seen with even mild degrees of metabolic

acidosis and to slow the progression of CKD. The sodium load

in sodium bicarbonate supplementation needs to be taken into

account, when ECFV expansion is present.

■ DISORDERS OF CALCIUM AND

PHOSPHATE METABOLISM

The principal complications of abnormalities of calcium and phosphate

metabolism in CKD occur in the skeleton and the vascular bed, with

occasional involvement of soft tissues. It is likely that disorders of bone

turnover and disorders of vascular and soft tissue calcification are

related to each other.

Bone Manifestations of CKD The major disorders of bone

disease can be classified into those associated with high bone turnover with increased PTH levels (including osteitis fibrosa cystica, the

classic lesion of secondary hyperparathyroidism), osteomalacia due to

reduced effect of the active forms of vitamin D, and low bone turnover

with low or normal PTH levels (adynamic bone disease) or most often

combinations of the foregoing.

The pathophysiology of secondary hyperparathyroidism and the

consequent high-turnover bone disease is related to abnormal mineral

metabolism through the following series of interrelated mechanisms:

(1) declining GFR leads to reduced excretion of phosphate and, thus,

phosphate retention; (2) the retained phosphate stimulates increased

synthesis of both FGF-23 by osteocytes and of PTH and also stimulates

growth of parathyroid gland mass; and (3) PTH production is stimulated by decreased levels of ionized calcium, which, in turn, result from

decreased levels of renal calcitriol production with reduced kidney

mass and suppression of calcitriol production due to phosphate retention and elevated levels of FGF-23, which also increases degradation

of calcitriol. Low calcitriol levels contribute to hyperparathyroidism,

both by leading to hypocalcemia and also by a direct effect on PTH

gene transcription. In addition, the normal inhibitory effect of FGF23 on PTH production is Klotho-dependent and is also attenuated in

CKD. These changes start to occur when the GFR falls below 60 mL/

min, though some studies point to retention of phosphate as an event

antedating measurable reduction in GFR, together with early elevation

of FGF-23 as well. FGF-23 is part of a family of phosphatonins that

promotes phosphate excretion, and high levels of FGF-23 are an independent risk factor for left ventricular hypertrophy and are associated

with increased mortality due to several classes of complications in

CKD, dialysis, and kidney transplant patients.

Hyperparathyroidism stimulates bone turnover and leads to osteitis

fibrosa cystica. Bone histology shows abnormal osteoid, bone and bone

marrow fibrosis, and, in advanced stages, the formation of bone cysts,

sometimes with hemorrhagic elements so that they appear brown in

color; hence, the term brown tumor. Clinical manifestations of severe

hyperparathyroidism include bone pain and fragility, brown tumors,

compression syndromes, and resistance to erythropoiesis-stimulating

agents (ESA) in part related to the bone marrow fibrosis. Furthermore,

PTH itself is considered a uremic toxin, and high levels are associated