Acute kidney injury is produced by a heterogeneous group of disorders
that have in common the rapid deterioration of renal function, resulting
in accumulation in the blood of nitrogenous wastes that would normally
be excreted in the urine. The patient presents with a rapidly rising
BUN and serum creatinine. Depending on the cause and when the patient
comes to medical attention, there may be other presenting features
as well (Table 16–3). Thus, diminished
urine volume (oliguria) is commonly but not
always seen. Urine volume may be normal early or indeed at any time
in milder forms of acute kidney injury. Patients presenting relatively
late may display any of the clinical manifestations described later.
Table 16–3 Initial Clinical and Laboratory Data Base for Defining Major Syndromes in Nephrology. |Favorite Table|Download (.pdf)
Table 16–3 Initial Clinical and Laboratory Data Base for Defining Major Syndromes in Nephrology.
|Syndrome||Important Clues to Diagnosis||Common Findings Not of Diagnostic Value|
|Acute or rapidly progressive renal failure||Anuria||Hypertension|
|Oliguria||Hematuria, proteinuria, pyuria, casts|
|Documented recent decline in GFR||Edema|
|Acute nephritis||Hematuria, red cell casts||Proteinuria, pyuria|
|Azotemia, oliguria||Circulatory congestion|
|Chronic renal failure||Azotemia for > 3 months||Hematuria, proteinuria, casts|
|Prolonged symptoms or signs of uremia||Oliguria, polyuria, nocturia|
|Symptoms or signs of renal osteodystrophy||Edema, hypertension|
|Kidneys reduced in size bilaterally||Electrolyte disorders|
|Broad casts in urinary sediment|
|Nephrotic syndrome||Proteinuria > 3.5 g/1.73 m2 per 24 hours||Casts|
|Asymptomatic urinary abnormalities||Hematuria|
|Proteinuria (below nephrotic range)|
|Sterile pyuria, casts|
|Urinary tract infection||Bacteriuria > 105 colonies/mL||Hematuria|
|Other infectious agent documented in urine||Mild azotemia|
|Pyuria, leukocyte casts||Mild proteinuria|
|Bladder tenderness, flank tenderness|
|Renal tubular defects||Electrolyte disorders||Hematuria|
|Polyuria, nocturia||Mild azotemia|
|Symptoms or signs of renal osteodystrophy||Mild proteinuria|
|Renal transport defects|
|Nephrolithiasis||History of stone passage or removal||Hematuria|
|Stone seen by x-ray||Pyuria|
|Renal colic||Frequency, urgency|
|Urinary tract obstruction||Azotemia, oliguria, anuria||Hematuria|
|Polyuria, nocturia, urinary retention||Pyuria|
|Slowing of urinary stream||Enuresis, dysuria|
|Large prostate, large kidneys |
|Flank tenderness, full bladder after voiding|
The major causes of acute kidney injury are presented in Table 16–4.
Table 16–4 Major Causes of Acute Kidney Injury. |Favorite Table|Download (.pdf)
Table 16–4 Major Causes of Acute Kidney Injury.
|Hypovolemia||Volume loss via the skin, gastrointestinal tract, or kidney.
Hemorrhage. Sequestration of extracellular fluid (burns, pancreatitis,
|Cardiovascular failure||Impaired cardiac output (infarction, tamponade). Vascular
pooling (anaphylaxis, sepsis, drugs).|
|Extrarenal obstruction||Urethral occlusion: vesical, pelvic, prostatic, or retroperitoneal
neoplasms. Surgical accident. Medication. Calculi. Pus, blood clots.|
|Intrarenal obstruction||Crystals (uric acid, oxalic acid, sulfonamides, methotrexate).|
|Vascular diseases||Vasculitis. Malignanthypertension. Thrombotic thrombocytopenia
purpura. Scleroderma. Arterial or venous occlusion.|
|Glomerulonephritis||Immune complex disease. Anti-GBM disease.|
|Interstitial nephritis||Drugs. Hypercalcemia. Infections. Idiopathic.|
|Postischemic||All conditions listed above under hypovolemia and cardiovascular
|Pigment-induced||Hemolysis (transfusion reaction, malaria). Rhabdomyolysis
(trauma, muscle disease, coma, heat stroke, severe exercise, potassium
or phosphate depletion).|
|Poison-induced||Antibiotics. Contrast material. Anesthetic agents. Heavy
metals. Organic solvents.|
|Pregnancy-related||Septic abortion. Uterine hemorrhage. Eclampsia.|
As demonstrated by the Starling equation, filtration across a glomerulus
is determined by the hydrostatic and oncotic pressures in both the
glomerular capillary and its surrounding tubular lumen as described
by the relationship: filtration = Kf [Pc –] Pt – σ[πc – πt].
Kf and σ are constants determined by the
permeability of a given glomerulus and the effective contribution
of osmotic pressure, respectively; Pc = intracapillary
hydrostatic pressure, πc = intracapillary
oncotic pressure, Pt = intratubular hydrostatic
pressure, and πt = intratubular
oncotic pressure. Perturbations in any of the above factors may
alter renal filtration. Of particular importance is the intracapillary
hydrostatic pressure which is determined by relative blood flow
into and out of the glomerular capillary. A normal kidney has the unique
ability to autoregulate blood flow both in and out of the glomerular
capillary through alterations in resistance of the afferent and
efferent arterioles across a wide range of systemic blood pressure.
Most capillary beds only possess the former. Lower relative flows
into the glomerulus with decreased renal blood flow or afferent
artery constriction may lower intracapillary hydrostatic pressure
and diminish filtration. Likewise, higher relative flows out of
glomerulus with efferent artery dilation may also lower intracapillary
hydrostatic pressure. Some patients who are dependent on prostaglandin-mediated
vasodilation to maintain renal perfusion can develop renal failure
simply from ingestion of nonsteroidal anti-inflammatory drugs (NSAIDs).
Similarly, patients with renal hypoperfusion (eg, from renal artery
stenosis, congestive heart failure, or intrarenal small vessel disease)
who are dependent on angiotensin II–mediated vasoconstriction
of the efferent renal arterioles to maintain renal perfusion pressure
may develop acute kidney injury on ingesting ACE inhibitors.
The intrarenal causes can be further divided into specific inflammatory
diseases (eg, vasculitis, glomerulonephritis, drug-induced
injury) and acute tubular necrosis resulting from many
causes (including ischemia, poisons, and hemolysis).
Notable among intrarenal causes are the toxic effects of aminoglycoside
antibiotics and rhabdomyolysis, in which myoglobin, released into
the bloodstream after crush injury to muscle, precipitates in the
renal tubules. The former may be mitigated by close monitoring of
renal function during antibiotic therapy, especially in elderly
patients and those with some degree of underlying renal compromise.
Rhabdomyolysis may be detected by obtaining a serum creatine kinase
level in patients admitted to the hospital with trauma or altered
mental status and may be mitigated by maintaining a vigorous alkaline
diuresis to prevent myoglobin precipitation in the tubules.
Sepsis is one of the most common causes of acute kidney injury.
As a complication of sepsis, acute kidney injury involves a combination
of prerenal and intrarenal factors. The prerenal factor is renal
hypoperfusion as a consequence of the hypotensive, low systemic
vascular resistance septic state. The intrarenal component may be
a consequence of the cytokine dysregulation that characterizes the
sepsis syndrome (Chapter 4), including elevated
blood levels of tumor necrosis factor, interleukin-1, and interleukin-6,
which contribute to intrarenal inflammation, sclerosis, and obstruction.
Patients with sepsis are often exposed also to nephrotoxic drugs
such as aminoglycoside antibiotics.
The postrenal causes are those that result in urinary tract obstruction,
such as renal stones.
Regardless of their origin, all forms of acute kidney injury,
if untreated, result in acute tubular necrosis, with sloughing of
cells that make up the renal tubule. Depending on the timing of
intervention between onset of initial injury and eventual acute
tubular necrosis, acute kidney injury may be irreversible or reversible, with
either prevention of or recovery from acute tubular necrosis.
The precise molecular mechanisms responsible for the development
of acute tubular necrosis remain unknown. Theories favoring either
a tubular or vascular basis have been proposed (Figure
16–5). According to
the tubular theory, occlusion of the tubular lumen with cellular
debris forms a cast that increases intratubular pressure sufficiently
to offset perfusion pressure and decrease or abolish net filtration
pressure. Vascular theories propose that decreased renal perfusion
pressure from the combination of afferent arteriolar vasoconstriction
and efferent arteriolar vasodilation reduces glomerular perfusion
pressure and, therefore, glomerular filtration. It may be that both
mechanisms act to produce acute kidney injury, varying in relative
importance in different individuals depending on the cause and time
of presentation. Studies suggest that one consequence of hypoxia
is disordered adhesion of renal tubular epithelial cells, resulting
both in their exfoliation and subsequent adhesion to other cells
of the tubule, thereby contributing to tubular obstruction (Figure 16–5). Another consequence
may be dysregulation of elements that secure tubular cells together
resulting in leak of filtrate out of the tubular lumen and abnormal
sorting of cellular transmembrane channels required for the normal
function of the nephron. Renal damage, whether caused by tubular
occlusion or vascular hypoperfusion, is potentiated by the hypoxic
state of the renal medulla, which increases the risk of ischemia
(Table 16–5). Research has implicated
cytokines and endogenous peptides such as endothelins and the regulation
of their production as possible explanations for why, subjected
to the same toxic insult, some patients develop acute kidney injury
and others do not and why some with acute kidney injury recover
and others do not. It appears that these products together with
activation of complement and neutrophils increase vasoconstriction
in the already ischemic renal medulla and in that way exacerbate the
degree of hypoxic injury that occurs in acute kidney injury.
Pathophysiology of ischemia-induced acute kidney injury.
Mild or uncomplicated medullary hypoxia results in tubuloglomerular
reflex adjustments that restore medullary oxygen sufficiency at
the price of diminished renal function. However, in the event of
extreme renal medullary hypoxia or when associated with complicating
factors such as those indicated in the figure, full-blown acute
kidney injury develops. Whether acute kidney injury is reversible
or irreversible depends on a balance of reparative and complicating factors.
Table 16–5 Agents and Events that Ameliorate or Exacerbate Hypoxia in the Renal Medulla. |Favorite Table|Download (.pdf)
Table 16–5 Agents and Events that Ameliorate or Exacerbate Hypoxia in the Renal Medulla.
|Decreased tubular transport|
|Decreased glomerular filtration rate|
|Polyene antibiotics (eg, amphotericin B)|
|Nonsteroidal anti-inflammatory drugs|
|Radiographic contrast agents|
The initial symptoms are typically fatigue and malaise, probably
early consequences of loss of the ability to excrete water, salt,
and wastes via the kidneys. Later, more profound symptoms and signs
of loss of renal water and salt excretory capacity develop: dyspnea,
orthopnea, rales, a prominent third heart sound (S3), and
peripheral edema. Altered mental status reflects the toxic effect
of uremia on the brain, with elevated blood levels of nitrogenous
wastes and fixed acids.
The clinical manifestations of acute kidney injury depend not only
on the cause but also on the stage in the natural history of the
disease at which the patient comes to medical attention. Patients
with renal hypoperfusion (prerenal causes of acute kidney injury)
first develop prerenal azotemia (elevated BUN without
tubular necrosis), a direct physiologic consequence of a decreased
GFR. With appropriate treatment, renal perfusion can typically be
improved, prerenal azotemia can be readily reversed, and the development
of acute tubular necrosis can be prevented. Without treatment, prerenal
azotemia may progress to acute tubular necrosis. Recovery from acute
tubular necrosis, if it occurs, will then follow a more protracted
course, often requiring supportive dialysis before adequate renal
function is regained.
A variety of clinical tests can help determine whether a patient with
signs of acute kidney injury is in the early phase of prerenal azotemia
or has progressed to full-blown acute tubular necrosis. However,
the overlap in clinical presentation along the continuum between
pre-renal azotemia and acute tubular necrosis is such that the results
of any one of these tests must be interpreted in the context of
other findings and the clinical history.
Perhaps the earliest manifestation of prerenal azotemia is an
elevated ratio of BUN to serum creatinine. Normally 10–15:1,
this ratio may rise to 20–30:1 in prerenal azotemia, with a
normal or near-normal serum creatinine. If the patient proceeds
to acute tubular necrosis, this ratio may return to normal but with
a progressively elevated serum creatinine. Likewise, a fluctuating
but not inexorably rising serum creatinine suggests prerenal azotemia.
Urinalysis may also be useful. There are no typical abnormal
findings in simple prerenal azotemia, whereas granular casts, tubular
epithelial cells, and epithelial cell casts are found in acute tubular
necrosis. Casts are formed when debris in the renal tubules (protein,
red cells, or epithelial cells) takes on the cylindric, smooth-bordered
shape of the tubule. Likewise, because hypovolemia is a stimulus
to vasopressin release (see Chapter 19), the
urine is maximally concentrated (up to 1500 mOsm/L) in
prerenal azotemia. However, with progression to acute tubular necrosis,
the ability to generate a concentrated urine is largely lost. Thus,
a urine osmolality of less than 350 mOsm/L is a typical
finding in acute tubular necrosis.
Finally, the fractional excretion of Na+
is an important indicator in oliguric acute kidney injury to
determine whether a patient has progressed from simple prerenal azotemia
to frank acute tubular necrosis. In simple prerenal azotemia, more
than 99% of filtered Na+ is reabsorbed.
This value allows accurate identification of Na+ retention
states (such as prerenal azotemia) even when there is water retention
as a result of vasopressin release. With progression of prerenal
azotemia to acute kidney injury with acute tubular necrosis, this
ability of the kidney to retain sodium avidly is generally lost.
However, there are some conditions in which the FE Na+ is
less than 1% in patients with acute tubular necrosis (Table 16–6).
Table 16–6 Causes of Acute Kidney Injury in Which FeNa+ May Be below 1%. |Favorite Table|Download (.pdf)
Table 16–6 Causes of Acute Kidney Injury in Which FeNa+ May Be below 1%.
|Acute tubular necrosis|
|10% of nonoliguric cases|
|Superimposed upon chronic prerenal state|
|Myoglobinuria or hemoglobinuria|
|Acute glomerulonephritis or vasculitis|
|Acute obstructive uropathy|
|Acute interstitial nephritis|
- 10. What are the current theories
for the development of acute tubular necrosis?
- 11. What clues are helpful in determining
whether newly diagnosed renal failure is acute or chronic?
- 12. What is the natural history of acute
Patients with chronic renal failure and uremia show a constellation
of symptoms, signs, and laboratory abnormalities in addition to
those observed in acute kidney injury. This reflects the long-standing
and progressive nature of their renal impairment and its effects
on many types of tissues (Table 16–7).
Thus, osteodystrophy, neuropathy, bilateral small kidneys shown
by abdominal ultrasonography, and anemia are typical initial findings that
suggest a chronic course for a patient newly diagnosed with renal
failure on the basis of elevated BUN and serum creatinine.
The most common cause of chronic renal failure is diabetes mellitus
(Chapter 18), followed closely by hypertension
and glomerulonephritis (Table 16–8).
Polycystic kidney disease, obstruction, and infection are among
the less common causes of chronic renal failure.
Table 16–8 Prevalence and Incidence by Etiology for United States Medicare–Treated End-Stage Renal Disease for 2005. |Favorite Table|Download (.pdf)
Table 16–8 Prevalence and Incidence by Etiology for United States Medicare–Treated End-Stage Renal Disease for 2005.
|Prevalence n = 485,012||Incidence
n = 106,912|
of Chronic Renal Failure
The pathogenesis of acute renal disease is very different from that
of chronic renal disease. Whereas acute injury to the kidney results
in death and sloughing of tubular epithelial cells, often followed
by their regeneration with reestablishment of normal architecture,
chronic injury results in irreversible loss of nephrons. As a result,
a greater functional burden is borne by fewer nephrons, manifested
as an increase in glomerular filtration pressure and hyperfiltration.
For reasons not well understood, this compensatory hyperfiltration,
which can be thought of as a form of “hypertension” at
the level of the individual nephron, predisposes to fibrosis and
scarring (glomerular sclerosis). As a result, the rate
of nephron destruction and loss increases, thus speeding the progression
to uremia, the complex of symptoms and signs that occurs
when residual renal function is inadequate.
Owing to the tremendous functional reserve of the kidneys, up
to 50% of nephrons can be lost without any short-term evidence
of functional impairment. This is why individuals with two healthy
kidneys are able to donate one for transplantation. When GFR is
further reduced, leaving only about 20% of initial renal
capacity, some degree of azotemia (elevation of blood levels of
products normally excreted by the kidneys) is observed. Nevertheless,
patients may be largely asymptomatic because a new steady state
is achieved in which blood levels of these products are not high
enough to cause overt toxicity. However, even at this apparently
stable level of renal function, hyperfiltration-accelerated evolution
to end-stage chronic renal failure is in progress. Furthermore,
because patients with this level of GFR have little functional reserve,
they can easily become uremic with any added stress (eg, infection, obstruction,
dehydration, or nephrotoxic drugs) or with any catabolic state associated
with increased turnover of nitrogen-containing products with reduction
The pathogenesis of chronic renal failure derives in part from a
combination of the toxic effects of (1) retained products normally
excreted by the kidneys (eg, nitrogen-containing products of protein
metabolism), (2) normal products such as hormones now present in
increased amounts, and (3) loss of normal products of the kidney
(eg, loss of erythropoietin).
Excretory failure results also in fluid shifts, with increased intracellular
Na+ and water and decreased intracellular K+. These
alterations may contribute to subtle alterations in function of
a host of enzymes, transport systems, and so on.
and Volume Status
Patients with chronic renal failure typically have some degree
of Na+ and water excess, reflecting loss of the
renal route of salt and water excretion. A moderate degree of Na+ and
water excess may occur without objective signs of extracellular
fluid excess. However, continued excessive Na+ ingestion
contributes to congestive heart failure, hypertension, ascites,
peripheral edema, and weight gain. On the other hand, excessive
water ingestion contributes to hyponatremia. A common recommendation
for the patient with chronic renal failure is to avoid excess salt
intake and to restrict fluid intake so that it equals urine output
plus 500 mL (insensible losses). Further adjustments in volume status
can be made either through the use of diuretics (in a patient who
still makes urine) or at dialysis.
Because these patients also have impaired renal salt and water
conservation mechanisms, they are more sensitive than normal to
sudden extrarenal Na+ and water losses (eg, vomiting,
diarrhea, and increased sweating with fever). Under these circumstances,
they more easily develop ECF depletion, further deterioration of
renal function (which may not be reversible), and even vascular
collapse and shock. The symptoms and signs of dry mucous membranes,
dizziness, syncope, tachycardia, and decreased jugular venous filling
suggest progression of volume depletion.
Hyperkalemia is a serious problem in chronic renal failure, especially
for patients whose GFR has fallen below 5 mL/min. Above
that level, as GFR falls, aldosterone-mediated K+ transport
in the distal tubule increases in a compensatory fashion. Thus,
a patient whose GFR is between 50 mL/min and 5 mL/min
is dependent on tubular transport to maintain K+ balance.
Treatment with K+-sparing diuretics, ACE inhibitors,
or β-blockers—drugs that may impair aldosterone-mediated
K+ transport—can, therefore, precipitate
dangerous hyperkalemia in a patient with chronic renal failure.
Patients with diabetes mellitus (the leading cause of chronic renal
failure) may have a syndrome of hyporeninemic hypoaldosteronism. This
syndrome is a condition in which lack of renin production by the
kidney diminishes the levels of angiotensin II and, therefore, impairs
aldosterone secretion. As a result, affected patients are unable
to compensate for falling GFR by enhancing their aldosterone-mediated
K+ transport and, therefore, have relative difficulty
handling K+. This difficulty is usually manifested
as hyperkalemia even before GFR has fallen below 5 mL/min.
Finally, not only are patients with chronic renal failure more susceptible
to the effects of Na+ or volume overload, but
they are also at greater risk of hyperkalemia in the face of sudden loads
of K+ from either endogenous sources (eg, hemolysis, infection,
trauma) or exogenous sources (eg, stored blood, K+-rich
foods, or K+-containing medications).
The diminished capacity to excrete acid and generate base in chronic
renal failure results in metabolic acidosis. In most cases when
the GFR is above 20 mL/min, only moderate acidosis develops
before reestablishment of a new steady state of buffer production
and consumption. The fall in blood pH in these individuals can usually
be corrected with 20–30 mmol (2–3 g) of sodium
bicarbonate by mouth daily. However, these patients are highly susceptible
to acidosis in the event of a sudden acid load or the onset of disorders
that increase the generated acid load.
Several disorders of phosphate, Ca2+, and bone
metabolism are observed in chronic renal failure as a result of
a complex series of events (Figure 16–6).
The key factors in the pathogenesis of these disorders include (1)
diminished absorption of Ca2+ from the gut, (2)
overproduction of PTH, (3) disordered vitamin D metabolism, and
(4) chronic metabolic acidosis. All of these factors contribute
to enhanced bone resorption. Hypophosphatemia and hypermagnesemia
can occur through overuse of phosphate binders and magnesium-containing antacids,
although hyperphosphatemia is more common. Hyperphosphatemia contributes
to the development of hypocalcemia and thus serves as an additional
trigger for secondary hyperparathyroidism, elevating blood PTH levels.
The elevated blood PTH further depletes bone Ca2+ and
contributes to osteomalacia of chronic renal failure (see later
Pathogenesis of bone diseases in chronic renal failure.
(Redrawn, with permission, from Brenner BM, Lazarus
JM. Chronic renal failure. In: Harrison’s Principles
of Internal Medicine, 13th ed. Isselbacher KJ et al [editors].
and Pulmonary Abnormalities
Congestive heart failure and pulmonary edema can develop in the
context of volume and salt overload. Hypertension is a common finding
in chronic renal failure, also usually on the basis of fluid and
Na+ overload. However, hyperreninemia is also
a recognized syndrome in which falling renal perfusion triggers
the failing kidney to overproduce renin and thereby elevate systemic
Pericarditis resulting from irritation and inflammation of the
pericardium by uremic toxins is a complication whose incidence in
chronic renal failure is decreasing owing to earlier institution
of renal dialysis.
Increased cardiovascular risk is a complication seen in patients
with chronic renal failure and remains the leading cause of mortality
in this population. It results in myocardial infarction, stroke,
and peripheral vascular disease. Cardiovascular risk factors in
these patients include hypertension, hyperlipidemia, glucose intolerance,
chronic elevated cardiac output, and valvular and myocardial calcification
as a consequence of elevated Ca2+ × PO43 product
as well as other, less well-characterized factors of the uremic
Patients with chronic renal failure have marked abnormalities in
red blood cell count, white blood cell function, and clotting parameters.
Normochromic, normocytic anemia, with symptoms of listlessness and
easy fatigability and hematocrit levels typically in the range of
20–25%, is a consistent feature. The anemia is
due chiefly to lack of production of erythropoietin and loss of
its stimulatory effect on erythropoiesis. Thus, patients with chronic
renal failure, regardless of dialysis status, show a dramatic improvement
in hematocrit when treated with erythropoietin (epoetin alpha).
Additional causes of anemia may include bone marrow suppressive
effects of uremic poisons, bone marrow fibrosis due to elevated
blood PTH, toxic effects of aluminum (from phosphate-binding antacids and
dialysis solutions), and hemolysis and blood loss related to dialysis
(while the patient is anticoagulated with heparin).
Patients with chronic renal failure display abnormal hemostasis
manifested as increased bruising, increased blood loss at surgery,
and an increased incidence of spontaneous GI and cerebrovascular
hemorrhage (including both hemorrhagic strokes and subdural hematomas).
Laboratory abnormalities include prolonged bleeding time, decreased
platelet factor III, abnormal platelet aggregation and adhesiveness,
and impaired prothrombin consumption, none of which are completely
reversible even in well-dialyzed patients.
Uremia is associated with increased susceptibility to infections,
believed to be due to leukocyte suppression by uremic toxins. The
suppression seems to be greater for lymphoid cells than neutrophils
and seems also to affect chemotaxis, the acute inflammatory response,
and delayed hypersensitivity more than other leukocyte functions.
Acidosis, hyperglycemia, malnutrition, and hyperosmolality also
are believed to contribute to immunosuppression in chronic renal
failure. The invasiveness of dialysis and the use of immunosuppressive
drugs in renal transplant patients also contribute to an increased
incidence of infections.
CNS symptoms and signs may range from mild sleep disorders and
impairment of mental concentration, loss of memory, errors in judgment,
and neuromuscular irritability (manifested as hiccups, cramps, fasciculations,
and twitching) to asterixis, myoclonus, stupor, seizures, and coma
in end-stage uremia. Asterixis is manifested as involuntary flapping
motions seen when the arms are extended and wrists held back to “stop
traffic.” It is due to altered nerve conduction in metabolic
encephalopathy from a wide variety of causes, including renal failure.
Peripheral neuropathy (sensory greater than motor, lower extremities
greater than upper), typified by the restless legs syndrome (poorly
localized sense of discomfort and involuntary movements of the lower
extremities), is a common finding in chronic renal failure and an
important indication for starting dialysis.
Patients receiving hemodialysis can develop aluminum toxicity,
characterized by speech dyspraxia (inability to repeat words), myoclonus,
dementia, and seizures. Likewise, aggressive acute dialysis can
result in a disequilibrium syndrome characterized by nausea, vomiting,
drowsiness, headache, and seizures in a patient with very high BUN
levels. Presumably, this is an effect of rapid pH or osmolality
change in ECF, resulting in cerebral edema.
Nonspecific GI findings in uremic patients include anorexia, hiccups,
nausea, vomiting, and diverticulosis. Although their precise pathogenesis
is unclear, many of these findings improve with dialysis.
and Metabolic Abnormalities
Women with uremia have low estrogen levels, which perhaps explains
the high incidence of amenorrhea and the observation that they rarely
are able to carry a pregnancy to term. Regular menses—but
not a higher rate of successful pregnancies—typically return
with frequent dialysis.
Similarly, low testosterone levels, impotence, oligospermia, and
germinal cell dysplasia are common findings in men with chronic
Finally, chronic renal failure eliminates the kidney as a site of
insulin degradation, thereby increasing the half-life of insulin.
This typically has a stabilizing effect on diabetic patients whose
blood glucose was previously difficult to control.
Skin changes arise from many of the effects of chronic renal
failure already discussed. Patients with chronic renal failure may display
pallor because of anemia, skin color changes related to accumulated
pigmented metabolites or a gray discoloration resulting from transfusion-mediated
hemochromatosis, ecchymoses and hematomas as a result of clotting
abnormalities, and pruritus and excoriations as a result of Ca2+ deposits
from secondary hyperparathyroidism. Finally, when urea concentrations
are extremely high, evaporation of sweat leaves a residue of urea
termed “uremic frost.”
- 13. What is uremia?
- 14. What are the most prominent symptoms
and signs of uremia?
- 15. What is the mechanism by which altered
sodium, potassium, and volume status develop in chronic renal failure?
- 16. What are the most common causes
of chronic renal failure?
& Nephrotic Syndrome
A number of disorders result in structural alterations of the glomerulus
and present with some combination of the following findings: hematuria,
proteinuria, reduced GFR, and hypertension. Some of these disorders
are specific to the kidney, whereas others are systemic diseases
in which the kidney is primarily or prominently involved.
Disorders resulting in glomerular disease, whether manifestations
of systemic injury or otherwise, fall into five categories:
Acute glomerulonephritis, in which there
is an abrupt onset of hematuria and proteinuria with reduced GFR
and renal salt and water retention, sometimes followed by recovery
of renal function. Patients with acute glomerulonephritis are a
subset of those with an intrarenal cause of acute kidney injury.
Rapidly progressive glomerulonephritis, in which
recovery from the acute disorder does not occur. Worsening renal
function results in irreversible and complete renal failure over
weeks to months. Early in the course of rapidly progressive glomerulonephritis,
these patients can be categorized as having a form of acute kidney
injury. Later, with progression of their renal failure over time,
they display all of the features described for chronic renal failure.
Chronic glomerulonephritis, in which renal impairment
after acute glomerulonephritis progresses slowly over a period of
years and eventually results in chronic renal failure.
Nephrotic syndrome, manifested as marked proteinuria, particularly
albuminuria (defined as 24-hour urine protein excretion > 3.5 g),
hypoalbuminemia, edema, hyperlipidemia, and fat bodies in the urine.
Nephrotic syndrome may be either isolated (eg, minimal change disease)
or part of some other glomerular syndrome (eg, with hematuria and
Asymptomatic urinary abnormalities, including hematuria
and proteinuria (usually in amounts below that seen in nephrotic
syndrome) but no functional abnormalities associated with reduced
GFR, edema, or hypertension. Many patients with these findings will
develop chronic renal failure slowly over decades.
Acute glomerulonephritis occurs most typically in the setting of
infectious diseases, classically pharyngeal or cutaneous infections
with certain “nephritogenic” strains of group
A beta-hemolytic streptococci but also other pathogens (Table 16–9).
Table 16–9 Causes of Acute Glomerulonephritis. |Favorite Table|Download (.pdf)
Table 16–9 Causes of Acute Glomerulonephritis.
|Nonstreptococcal postinfectious glomerulonephritis|
|Bacterial: infective endocarditis,* “shunt
nephritis,” sepsis,* pneumococcal pneumonia, typhoid
fever, secondary syphilis, meningococcemia|
|Viral: hepatitis B, infectious mononucleosis,
mumps, measles, varicella, echovirus, coxsackievirus|
|Parasitic: malaria, toxoplasmosis|
|Multisystem diseases: systemic lupus erythematosus,* vasculitis,* Henoch-Schönlein
purpura,* Goodpasture’s syndrome|
|Primary glomerular diseases: mesangiocapillary
glomerulonephritis, Berger’s disease (IgA nephropathy),* “pure” mesangial
|Miscellaneous: Guillain-Barré syndrome,
irradiation of Wilms’tumor, diphtheria-pertussis-tetanus
vaccine, serum sickness|
Rapidly progressive glomerulonephritis appears to be a heterogeneous
group of disorders, all of which display pathologic features common
to various categories of necrotizing vasculitis (Table
16–10; also see later discussion).
Table 16–10 Causes of Rapidly Progressive Glomerulonephritis. |Favorite Table|Download (.pdf)
Table 16–10 Causes of Rapidly Progressive Glomerulonephritis.
|Occult visceral sepsis|
|Hepatitis B infection (with vasculitis or cryoimmunoglobulinemia)|
|Human immunodeficiency virus infection|
|Systemic lupus erythematosus*|
|Systemic necrotizing vasculitis (including Wegener’s
|Essential mixed (IgG/IgM) cryoimmunoglobulinemia|
|Rheumatoid arthritis (with vasculitis)|
|Allopurinol (with vasculitis)|
|Idiopathic or primary glomerular disease|
|Idiopathic crescentic glomerulonephritis*|
|Type I—with linear deposits of immunoglobulin
|Type II—with granular deposits of immunoglobulin
|Type III—with few or no immune deposits
of immunoglobulin (“pauci-immune”)|
|Antineutrophil cytoplasmic antibody–induced? “forme
fruste” of vasculitis|
|Superimposed on another primary glomerular disease|
|Mesangiocapillary (membranoproliferative glomerulonephritis)* (especially
|Berger’s disease (IgA nephropathy)*|
Chronic glomerulonephritis and nephrotic syndrome are largely
of unclear origin. Progressive renal deterioration in patients with
chronic glomerulonephritis proceeds slowly but inexorably, resulting
in chronic renal failure as many as 20 years after initial discovery
of an abnormal urinary sediment.
Some cases of nephrotic syndrome are variants of acute glomerulonephritis,
rapidly progressive glomerulonephritis, or chronic glomerulonephritis
in which massive proteinuria is a presenting feature. Other cases
of nephrotic syndrome fall into the category of minimal change
disease, in which many of the pathologic consequences are
due to proteinuria.
The most common cause of asymptomatic urinary abnormalities is IgA
nephropathy, an immune complex disease characterized by diffuse
mesangial IgA deposition. Other causes are listed in Table
Table 16–11 Glomerular Causes of Asymptomatic Urinary Abnormalities. |Favorite Table|Download (.pdf)
Table 16–11 Glomerular Causes of Asymptomatic Urinary Abnormalities.
|Hematuria with or without proteinuria|
|Primary glomerular diseases|
|Berger’s disease (IgA nephropathy)*|
|Other primary glomerular hematurias accompanied
by “pure” mesangial proliferation, focal and segmental
proliferative glomerulonephritis, or other lesions|
|“Thin basement membrane” disease
(? “forme fruste” of Alport’s syndrome)|
|Associated with multisystem or heredofamilial diseases|
|Alport’s syndrome and other “benign” familial
|Sickle cell disease|
|Associated with infections|
|Resolving poststreptococcal glomerulonephritis*|
|Other postinfectious glomerulonephritides*|
|Isolated nonnephrotic proteinuria|
|Primary glomerular diseases|
|Focal and segmental glomerulosclerosis*|
|Associated with multisystem or heredofamilial diseases|
The different forms of glomerulonephritis and nephrotic syndrome
probably represent differences in the nature, extent, and specific
cause of immune-mediated renal damage. A number of cytokines—in
particular transforming growth factor-1 (TGF-1) and platelet-derived
growth factor (PDGF)—are synthesized by mesangial cells,
inciting an inflammatory reaction in some forms of glomerular disease. Classic associations between the natural
history and defining fluorescence and electron microscopic observations
have been made (Figure 16–4; Table 16–12). However, because it
is not known exactly how the various forms of immune-mediated renal
damage occur, each category is described separately with its associated
Table 16–12 Location of Electron-Dense Deposits in Glomerular Disease. |Favorite Table|Download (.pdf)
Table 16–12 Location of Electron-Dense Deposits in Glomerular Disease.
|Amorphous (epimembranous) deposits|
|Systemic lupus erythematosus|
|Acute postinfectious glomerulonephritis (eg,
post-streptococcal glomerulonephritis, bacterial endocarditis)|
|Membranoproliferative glomerulonephritis type II|
|Systemic lupus erythematosus|
|Membranoproliferative glomerulonephritis type I|
|Less commonly, bacterial endocarditis, IgA nephropathy, Henoch-Schönlein
purpura, mixed cryoglobulinemia|
|Systemic lupus erythematosus|
|Mild or resolving acute postinfectious glomerulonephritis|
|Subepithelial and subendothelial|
|Systemic lupus erythematosus|
|Membranoproliferative glomerulonephritis, type III|
Postinfectious acute glomerulonephritis is due to immune attack
on the infecting organism in which there is cross-reactivity between
an antigen of the infecting organism (eg, of group A beta-hemolytic
streptococci) and a host antigen. The result is deposition of immune
complexes and complement (Figure 16–4; Table 16–13) in glomerular capillaries
and the mesangium. Symptoms and signs typically occur 7–10
days after onset of the acute pharyngeal or cutaneous infection
and resolve over weeks after treatment of the infection.
Table 16–13 Factors Causing and Mediators of Glomerular Injury. |Favorite Table|Download (.pdf)
Table 16–13 Factors Causing and Mediators of Glomerular Injury.
|Factors affecting immune complex deposition|
|Host immune response|
|Rate of complex clearance|
|In situ complex formation|
|Antigenic or complex charge|
|Mediators of glomerular damage|
Immunofluorescence studies permit distribution into subgroups
correlating with other features of the disease. Linear immunoglobulin
deposits suggest antiglomerular basement membrane (GBM) antibody,
which may coincident with pulmonary hemorrhage, characteristic of
Goodpasture’s syndrome. Granular immunoglobulin deposits
are suggestive of immune complexes due to an underlying systemic
disease, such as IgA nephropathy, postinfectious glomerulonephritis, lupus
nephritis, or mixed cryoglobulinemia. Few or no immune deposits
(pauci-immune) are often coincident with an autoantibody pattern
(ANCA) typical of Wegener’s granulomatosis or microscopic
polyangiitis. ANCA-negative pauci-immune necrotizing glomerulonephritis
is seen less frequently but is also a recognized clinical entity.
Immunofluorescence studies permit distribution into subgroups
correlating with other features of the disease. From 5% to
20% of patients have linear anti-GBM antibody deposits
in glomeruli and a tendency to hemoptysis reminiscent of Goodpasture’s
syndrome. Further, 30–40% have granular immunoglobulin
deposits and an autoantibody pattern typical of Wegener’s
granulomatosis (antineutrophil cytoplasmic antibody). The latter
patients are typically older, with more systemic constitutional
Some patients with acute glomerulonephritis develop chronic renal
failure slowly over a period of 5–20 years. Cellular proliferation,
in either the mesangium or the capillary, is a pathologic structural
hallmark in some of these cases, whereas others are notable for
obliteration of glomeruli (sclerosing chronic glomerulonephritis, which
includes both focal and diffuse subsets), and yet others display
irregular subepithelial proteinaceous deposits with uniform involvement
of individual glomeruli (membranous glomerulonephritis).
In patients with nephrotic syndrome, the glomerulus may appear
intact or only subtly altered, without a cellular infiltrate as
a manifestation of inflammation. Immunofluorescence with antibodies
to immunoglobulin G (IgG) often demonstrates deposition of antigen-antibody
complexes in the glomerular basement membrane. In the subset of
patients with minimal change disease, in which proteinuria is the
sole urinary sediment abnormality and in which (often) no changes can
be seen by light microscopy, electron microscopy reveals obliteration
of epithelial foot processes (Table
Table 16–14 Clinical and Histologic Features of Idiopathic Nephrotic Syndrome. |Favorite Table|Download (.pdf)
Table 16–14 Clinical and Histologic Features of Idiopathic Nephrotic Syndrome.
|Glomerular Disease||Distinguishing Clinical and Laboratory Findings||Characteristic Morphologic Features|
|Minimal change disease||Commonest cause in children (75%);
steroid- or cyclophosphamide-sensitive (80% of cases);
nonprogressive; normal renal function; scant hematuria.||LM: normal|
|IF: negative to trace IgM|
|EM: podocyte effacement; no immune deposits|
|Focal and segmental glomerulosclerosis||Early-onset hypertension; microscopic hematuria;
progressive renal failure (75% of cases).||LM: early, segmental sclerosis in some glomeruli
with tubular atrophy; late, sclerosis of most glomeruli|
|IF: focal and segmental IgM, C3|
|EM: foot process fusion, sclerosis, hyalin|
|Membranous nephropathy||Commonest cause in adults (40–50%);
peak incidence fourth and sixth decades; male: female 2–3:1;
microscopic hematuria (55%); early hypertension (30%);
spontaneous remission (20%); progressive renal failure
(30–40%).||LM: early, normal; late, GBM thickening|
|IF: granular IgG and C3|
|EM: subepithelial deposits and GBM expansion|
|Membranoproliferative glomerulonephritis||Peak incidence second and third decades; mixed
nephrotic-nephritic features; slowly progressive in most, rapid
in some; hypocomplementemia.||LM: hypercellular glomeruli with duplicated
|IF: type I, diffuse C3, variable IgG and IgM;
type II, C3 capillary wall and mesangial nodules|
|EM: type I, subendothelial immune deposits;
type II, dense GBM|
In glomerulonephritic diseases, damage to the glomerular capillary
wall results in leakage of red blood cells and proteins, which are
normally too large to cross the glomerular capillary, into the renal
tubular lumen, giving rise to hematuria and proteinuria.
A fall in GFR results because either glomerular capillaries are
infiltrated with inflammatory cells or contractile cells (eg, mesangial
cells) respond to vasoactive substances by restricting blood flow
to many glomerular capillaries.
Edema and hypertension are a direct consequence of fluid and
salt retention secondary to the fall of GFR in the face of excess
consumption of salt and water.
A transient fall in serum complement is observed as a result
of immune complex and complement deposition in the glomerulus, as
can be seen with lupus nephritis, membranoproliferative glomerulonephritis,
and post-infectious glomerulonephritis.
An elevated titer of antibody to streptococcal antigens is observed
in cases associated with group A β-hemolytic streptococcal
infections. Another characteristic of the clinical course in poststreptococcal
acute glomerulonephritis is a lag between clinical signs of infection
and the development of clinical signs of nephritis.
Patients with the nephrotic syndrome have profoundly decreased
plasma oncotic pressures because of the loss of serum proteins in
the urine. This results in intravascular volume depletion and activation
of the renin-angiotensin-aldosterone system and the sympathetic
nervous system. The secretion of vasopressin is also increased.
Such patients also have altered renal responses to atrial natriuretic
peptide. Nevertheless, they may develop signs of intravascular volume depletion,
including syncope, shock, and acute kidney injury despite often
being edematous on clinical examination.
Hyperlipidemia associated with nephrotic syndrome appears to
be a result of decreased plasma oncotic pressure, which stimulates
hepatic very low-density lipoprotein synthesis and secretion.
Loss of other plasma proteins besides albumin in nephrotic syndrome
may present as any of the following: (1) A defect in bacterial opsonization
and thus increased susceptibility to infections (eg, as a result
of loss of IgG); (2) hypercoagulability (eg, resulting from antithrombin
deficiency, reduced levels of proteins C and S, hyperfibrinogenemia,
and hyperlipidemia); (3) vitamin D deficiency state and secondary
hyperparathyroidism (eg, resulting from loss of vitamin D–binding
proteins); (4) altered thyroid function tests without any true thyroid
abnormality (resulting from reduced levels of thyroxine-binding
- 17. What are the categories of glomerulonephritis,
and what are their common and distinctive features?
- 18. What are the pathophysiologic consequences
of nephrotic syndrome?
Patients with renal stones present with flank pain and hematuria
with or without fever. Depending on the level of the stone and the
patient’s underlying anatomy (eg, if there is only a single
functioning kidney or significant preexisting renal disease), the
presentation may be complicated by obstruction (Table
16–15) with decreased or absent urine production.
Table 16–15 Common Mechanical Causes of Urinary Tract Obstruction. |Favorite Table|Download (.pdf)
Table 16–15 Common Mechanical Causes of Urinary Tract Obstruction.
|Ureteropelvic junction arrowing or obstruction||Bladder neck obstruction|
|Ureterovesical junction arrowing or obstruction||Ureterocele|
|Ureterocele||Benign prostatic hypertrophy|
|Retrocaval ureter||Cancer of prostate|
|Calculi||Cancer of bladder|
|Sloughed papillae||Spinal cord disease|
|Tumor||Carcinomas of cervix, colon|
|Uric acid crystals||Urethra|
|Pregnant uterus||Posterior urethral valves|
|Retroperitoneal fibrosis||Anterior urethral valves|
|Uterine leiomyomas||Meatal stenosis|
|Carcinoma of uterus, prostate, bladder, colon,
|Accidental surgical ligation||Calculi|
Although a variety of disorders may result in the development of
renal stones (Table 16–16),
at least 75% of renal stones contain calcium. Most cases
of calcium stones are due to idiopathic hypercalciuria, with hyperuricosuria
and hyperparathyroidism as other major causes. Uric acid stones
are typically caused by hyperuricosuria, especially in patients
with a history of gout or excessive purine intake (eg, a diet high
in organ meat products). Defective amino acid transport, as occurs
in cystinuria, can result in stone formation. Finally, struvite
stones, made up of magnesium, ammonium, and phosphate salts, are
a result of chronic or recurrent urinary tract infection by urease-producing
organisms (typically Proteus).
Table 16–16 Major Causes of Renal Stones. |Favorite Table|Download (.pdf)
Table 16–16 Major Causes of Renal Stones.
|Stone Type and Causes||All Stones (%)||Occurrence of Specific Causes1||M:F Ratio||Etiology||Diagnosis||Treatment3|
|Calcium stones||75–85%||2:1 to 3:1|
|Idiopathic hypercalciuria||50–55%||2:1||Hereditary (?)||Normocalcemia, unexplained hypercalciuria2||Thiazide diuretic agents|
|Hyperuricosuria||20%||4:1||Diet||Urine uric acid > 750 mg/24h (women), > 800 mg/24 h
(men)||Allopurinol or diet|
|Primary hyperparathyroidism ||5%||3:10||Neoplasia||Unexplained hypercalcemia||Surgery|
|Distal renal tubular acidosis||Rare||1:1||Hereditary||Hyperchloremic acidosis, minimum urine pH > 5.5||Alkali replacement|
|Intestinal hyperoxaluria||≈1–2%||1:1||Bowel surgery||Urine oxalate > 50 mg/24 h||Cholestyramine or oral calcium loading|
|Hereditary hyperoxaluria||Rare||1:1||Hereditary||Urine oxalate and glycolic or l-glyceric acid
increased||Fluids and pyridoxine|
|Idiopathic stone disease||20%||2:1||Unknown||None of the above||Oral phosphate, fluids|
|Uric acid stones||5–8%|
|Gout||≈ 50%||3:1 to 4:1||Hereditary||Clinical diagnosis||Alkali to raise urine pH|
|Idiopathic||≈ 50%||1:1||Hereditary (?)||Uric acid stones, no gout||Allopurinol if daily urine uric acid above 1000 mg|
|Dehydration||?||1:1||Intestinal, habit||History, intestinal fluid loss||Alkali, fluids, reversal of cause|
|Lesch-Nyhan syndrome||Rare||Men||Hereditary||Reduced hypoxanthine-guanine phosphoribosyl transferase level||Allopurinol|
|Malignant tumors||Rare||1:1||Neoplasia||Clinical diagnosis||Allopurinol|
|Cystine stones||1%||1:1||Hereditary||Stone type; elevated cystine excretion||Massive fluids, alkali, penicillamine if needed|
|Struvite stones||10–15%||2:10||Infection||Stone type||Antimicrobial agents and judicious surgery|
Renal stones result from alterations in the solubility of various substances
in urine, such that there is nucleation and precipitation of salts.
A number of factors can tip the balance in favor of stone formation.
Dehydration favors stone formation, and a high fluid intake to
maintain a daily urine volume of 2 L or more appears to be protective.
The precise mechanism of this protection is unknown. Hypotheses
include dilution of unknown substances that predispose to stone
formation and decreased transit time of Ca2+ through
the nephron, minimizing the likelihood of precipitation.
A high-protein diet predisposes to stone formation in susceptible
individuals. A dietary protein load causes transient metabolic acidosis
and an increased GFR. Although serum Ca2+ is not
detectably elevated, there is probably a transient increase in calcium
resorption from bone, an increase in glomerular calcium filtration,
and inhibition of distal tubular calcium resorption. This effect
appears to be greater in known stone-formers than in healthy controls.
A high-Na+ diet predisposes to Ca2+ excretion
and calcium oxalate stone formation, whereas a low dietary Na+ intake
has the opposite effect. Furthermore, urinary Na+ excretion increases
the saturation of monosodium urate, which can act as a nidus for
Despite the fact that most stones are calcium oxalate stones, oxalate
concentration in the diet is generally too low to support a recommendation
to avoid oxalate to prevent stone formation. Similarly, calcium
restriction, formerly a major dietary recommendation to calcium
stone formers, is beneficial only to the subset of patients whose
hypercalciuria is diet dependent. In others, decreased dietary calcium
may actually increase oxalate absorption and predispose to stone
A number of factors are protective against stone formation. In
order of decreasing importance, fluids, citrate, magnesium, and
dietary fiber appear to have a protective effect. Citrate may prevent
stone formation by chelating calcium in solution and forming highly
soluble complexes compared with calcium oxalate and calcium phosphate.
Although pharmacologic supplementation of the diet with potassium
citrate has been shown to increase urinary citrate and pH and decrease the
incidence of recurrent stone formation, the benefits of a naturally
high-citrate diet have not been investigated. However, some studies
suggest that vegetarians have a lower incidence of stone formation.
Presumably, they avoid the stone-forming effect of high protein
and Na+ in the diet, combined with the protective
effects of fiber and other factors.
Stone formation per se within the renal pelvis is painless until
a fragment breaks off and travels down the ureter, precipitating
ureteral colic. Hematuria and renal damage can occur in the absence
The pain associated with renal stones is due to distention of
the ureter, renal pelvis, or renal capsule. The severity of pain
is related to the degree of distention that occurs and thus is extremely
severe in acute obstruction. Anuria and azotemia are suggestive
of bilateral obstruction or unilateral obstruction of a single functioning
kidney. The pain, hematuria, and even ureteral obstruction caused
by a renal stone are typically self-limited. For smaller stones,
passage usually requires only fluids, bed rest, and analgesia. The
major complications are (1) hydronephrosis and permanent renal damage
as a result of complete obstruction of a ureter, with resulting
backup of urine and buildup of pressure; (2) infection or abscess
formation behind a partially or completely obstructing stone, which
can rapidly destroy the involved kidney; (3) renal damage subsequent
to repeated kidney stones; and (4) hypertension resulting from increased
renin production by the obstructed kidney.
- 19. How do patients with renal stones
- 20. Why do renal stones form?
- 21. What are the common categories of
renal stones (by composition)?