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Harrisons
Trans 3.4-2 December 3, 2013
Azotemia and
Urinary Abnormalities Believe you can and youre halfway there.
AZOTEMIA: INTRODUCTION
Renal syndromes may arise as a:
o Consequence of a systemic illness or
o Can occur as a primary renal disease Nephrologic syndromes usually consist of several elements
that reflect the underlying pathologic processes
The duration and severity of the disease affect those findings and typically include one or more of the following: o Reduction in glomerular filtration rate (GFR)
(azotemia) o Abnormalities of urine sediment [red blood cells (RBC),
white blood cells, casts, and crystals] o Abnormal excretion of serum proteins (proteinuria) o Disturbances in urine volume (oliguria, anuria,
polyuria) o Presence of hypertension and/or expanded total body
fluid volume (edema) o Electrolyte abnormalities o In some syndromes, fever/pain
Initial Clinical And Laboratory Data Base For Defining Major Syndromes In Nephrology
SYNDROMES IMPORTANT CLUES
TO DIAGNOSIS
COMMON
FINDINGS
Acute or rapidly
progressive renal failure
Anuria
Oliguria Documented recent
decline in GFR
Hypertension,
hematuria Proteinuria,
pyuria
Casts, edema
Acute nephritis Hematuria, RBC casts
Azotemia, oliguria
Edema, hypertension
Proteinuria Pyuria
Circulatory
congestion
Chronic renal
failure
Azotemia for >3
months
Prolonged symptoms or signs
of uremia Symptoms or signs
of renal
osteodystrophy Kidneys reduced in
size bilaterally Broad casts in
urinary sediment
Proteinuria
Casts
Polyuria, nocturia
Edema, hypertension
Electrolyte
disorders
Nephrotic
syndrome
Proteinuria >3.5 g
per 1.73 m2 per 24h
Hypoalbuminemia
Edema Hyperlipidemia
Casts
Lipiduria
Asymptomatic
urinary
abnormalities
Hematuria
Proteinuria (below
nephrotic range) Sterile pyuria, casts
Urinary tract
infection/pyelon
ephritis
Bacteriuria >105
colonies/ml
Other infectious agent documented
in urine Pyuria, leukocyte
casts
Hematuria
Mild azotemia
Mild proteinuria Fever
Frequency, urgency Bladder tenderness,
flank tenderness
Renal tubule
defects
Electrolyte disorders
Polyuria, nocturia Renal calcification
Large kidneys
Renal transport defects
Hematuria
"Tubular" proteinuria (
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Azotemia and Urinary Abnormalities
A significantly reduced GFR (either acute or chronic)
usually is reflected in a rise in serum creatinine and
leads to retention of nitrogenous waste products (azotemia) such as urea.
Azotemia may result from: o Reduced renal perfusion
o Intrinsic renal disease
o Postrenal processes (ureteral obstruction)
Precise determination of GFR is problematic as both
commonly measured indices (urea and creatinine) have characteristics that affect their accuracy as markers of
clearance. o Urea clearance may underestimate GFR significantly
because of urea reabsorption by the tubule
Creatinine is derived from muscle metabolism of creatine,
and its generation varies little from day to day
Creatinine clearance, an approximation of GFR, is
measured from plasma and urinary creatinine excretion rates for a defined time period (usually 24 h) and is
expressed in milliliters per minute:
o Useful for estimating GFR because it is a small, freely filtered solute that is not reabsorbed by the
tubules
o Levels can increase acutely from dietary ingestion of cooked meat, however, and creatinine can be secreted
into the proximal tubule through an organic cation
pathway (especially in advanced progressive chronic kidney disease), leading to overestimation of GFR
o When a timed collection for creatinine clearance is not available, decisions about drug dosing must be based
on serum creatinine alone
o Two formulas are used widely to estimate kidney function from serum creatinine:
Cockcroft-Gault
MDRD (Modification of Diet in Renal Disease)
Several limitations of using serum creatininebased estimating equations must be acknowledged
o Gradual loss of muscle from chronic illness, chronic use of glucocorticoids, or malnutrition
Mask significant changes in GFR with small or imperceptible changes in serum creatinine concentration.
CYSTATIN C
Member of the cystatin superfamily of cysteineprotease inhibitors
Produced at a relatively constant rate from all nucleated
cells
More sensitive marker of early GFR decline than is
plasma creatinine
Influenced by age, race, and sex and additionally is associated with diabetes, smoking, and markers of
inflammation.
APPROACH TO PATIENT
Established that GFR is reduced
Determine whether it is acute or chronic renal injury
through the clinical situation, history, and laboratory data o However, the laboratory abnormalities characteristic of
chronic renal failure, including anemia, hypocalcemia, and hyperphosphatemia, often are
also present in patients presenting with acute renal
failure Radiographic evidence of renal osteodystrophy can be
seen only in chronic renal failure but is a very late finding, and these patients are usually on dialysis
The urinalysis and renal ultrasound occasionally can
facilitate distinguishing acute from chronic renal failure
Advanced chronic renal insufficiency often have: o Proteinuria
o Nonconcentrated urine (isosthenuria; isosmotic with
plasma) o Small kidneys on ultrasound, characterized by
increased echogenicity and cortical thinning
Treatment should be directed toward slowing the
progression of renal disease and providing symptomatic relief for edema, acidosis, anemia, and hyperphosphatemia
Acute renal failure can result from processes that affect: o Renal blood flow (prerenal azotemia) o Intrinsic renal diseases (affecting small vessels,
glomeruli, or tubules) o Postrenal processes (obstruction to urine flow in
ureters, bladder, or urethra)
PRERENAL FAILURE
Decreased renal perfusion accounts for 4080% of acute
renal failure and, if appropriately treated, is readily reversible
Etiologies of prerenal azotemia: o Decreased circulating blood volume
gastrointestinal haemorrhage burns diarrhea diuretics
o Volume sequestration
pancreatitis peritonitis rhabdomyolysis
o Decreased effective arterial volume cardiogenic shock sepsis
Renal perfusion also can be affected by reductions in
cardiac output from: o Peripheral vasodilation due to
Sepsis Drugs
o Profound renal vasoconstriction
Severe heart failure
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Azotemia and Urinary Abnormalities
Hepatorenal syndrome Drugs such as NSAIDs
True or "effective" arterial hypovolemia leads to a fall
in mean arterial pressure, which in turn triggers a series of neural and humoral responses that include:
o Activation of the sympathetic nervous
o Renin-angiotensinaldosterone system o Antidiuretic hormone (ADH) release
GFR is maintained by prostaglandin-mediated relaxation of afferent arterioles and angiotensin IImediated constriction of efferent arterioles.
Once the mean arterial pressure falls below 80 mmHg,
there is a steep decline in GFR.
Blockade of prostaglandin production by NSAIDs can
result in severe vasoconstriction and acute renal failure
Blocking angiotensin action with angiotensin-
converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) decreases efferent arteriolar
tone and in turn decreases glomerular capillary perfusion pressure
Patients on NSAIDs and/or ACE inhibitors/ARBs are most
susceptible to hemodynamically mediated acute renal failure when blood volume is reduced for any reason
Patients with bilateral renal artery stenosis (or stenosis
in a solitary kidney) are dependent on efferent arteriolar vasoconstriction for maintenance of glomerular filtration
pressure and are particularly susceptible to a precipitous decline in GFR when given ACE inhibitors or ARBs
Prolonged renal hypoperfusion may lead to acute tubular
necrosis (ATN). Prerenal analysis and urinary electrolytes can be useful in distinguishing prerenal azotemia from ATN
The urine of patients with prerenal azotemia can be predicted from the stimulatory actions of norepinephrine,
angiotensin II, ADH, and low tubule fluid flow rate on salt
and water reabsorption In prerenal conditions tubules are intact, leading to:
o Concentrated urine (>500 mosmol)
o Avid Na retention (urine Na concentration 20:1 10-15:1
Urine sodium (UNa),
meq/L
40
Urine osmolality, mosmol/L H2O
>500 40
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Azotemia and Urinary Abnormalities
o Infiltrative disorders (e.g., sarcoid, lymphoma, or
leukemia)
The urinalysis in 75% of cases usually shows: o Mild to moderate proteinuria o Hematuria o Pyuria o Occasionally white blood cell casts o Finding of RBC casts in interstitial nephritis has been
reported but should prompt a search for glomerular
diseases
Occasionally, renal biopsy will be needed to distinguish
among these possibilities. The finding of eosinophils in the urine is suggestive of allergic interstitial nephritis
or atheroembolic renal disease and is optimally
observed by using a Hansel stain. o The absence of eosinophiluria, however, does not
exclude these etiologies
Occlusion of large renal vessels including arteries and
veins is an uncommon cause of acute renal failure. A significant reduction in GFR by this mechanism suggests
bilateral processes or a unilateral process in a patient with a single functioning kidney
Renal arteries can be occluded with: o Atheroemboli o Thromboemboli o In situ thrombosis o Aortic dissection o Vasculitis
ATHEROEMBOLIC RENAL FAILURE
Can occur spontaneously but most often is associated with recent aortic instrumentation
Emboli are cholesterol-rich and lodge in medium and small renal arteries, leading to an eosinophil-rich inflammatory
reaction
Patients with atheroembolic acute renal failure often have a normal urinalysis, but the urine may contain
eosinophils and casts
Diagnosis: renal biopsy, but this is often unnecessary when other stigmata of atheroemboli are present (livedo
reticularis, distal peripheral infarcts, eosinophilia).
Renal artery thrombosis may lead to mild proteinuria
and hematuria, whereas renal vein thrombosis typically induces heavy proteinuria and hematuria.
Diseases of the glomeruli (glomerulonephritis and
vasculitis) and the renal microvasculature (hemolytic-
uremic syndromes, thrombotic thrombocytopenic purpura, and malignanthypertension) usually present with various
combinations of glomerular injury: o Proteinuria o Hematuria o Reduced GFR o Alterations of sodium excretion that lead to
hypertension, edema, and circulatory congestion (acute
nephritic syndrome)
These findings may occur as primary renal diseases or as renal manifestations of systemic diseases. The clinical
setting and other laboratory data help distinguish primary
renal diseases from systemic diseases.
OLIGRIA AND ANURIA
Oliguria UO:
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Azotemia and Urinary Abnormalities
FeNa, fractional excretion of sodium; GBM, glomerular basement membrane; RBC, red blood cell; WBC, white blood
cell
ABNORMALITIES OF THE URINE
PROTEINURIA
Diagnosis:
DIPSTICK detects mostly albumin
Disadvantage: False Positive: pH > 7.0 and concentrated or
contaminated urine which obscure significant
proteinuria in a much diluted urine
Designation Approximate amount
Concentration Daily
Trace 5-20 mg/dL
1+ 30 mg/dL Less than 0.5
g/day
2+ 100 mg/dL 0.5-1 g/day
3+ 300 mg/dL 1-2 g/day
4+ More than 2000 mg/dL
More than 2 g/day
Quantification of urinary albumin on a spot urine sample
(ideally from a first morning void) by measuring an albumin-to-creatinine ratio (ACR) helpful in approximating a 24-h albumin excretion rate (AER) where ACR (mg/g) AER (mg/24 h).
Proteinuria that is not predominantly albumin will be missed by dipstick screening. This is particularly important for the
detection of Bence Jones proteins in the urine of patients with multiple myeloma.
Tests to measure total urine protein concentration
accurately rely on precipitation with sulfosalicylic or trichloracetic acid.
The magnitude of proteinuria and the protein
composition of the urine depend on the mechanism of
renal injury that leads to protein losses
Both charge and size selectivity normally prevent virtually all plasma albumin, globulins, and other high-molecular-
weight proteins from crossing the glomerular wall
o If this barrier is disrupted, plasma proteins may leak into the urine (glomerular proteinuria)
o Smaller proteins (
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Azotemia and Urinary Abnormalities
The normal glomerular endothelial cell forms a barrier
composed of pores of 100 nm that retain blood cells but
offer little impediment to passage of most proteins. The glomerular basement membrane traps most large
proteins (>100 kDa), and the foot processes of epithelial cells (podocytes) cover the urinary side of the glomerular
basement membrane and produce a series of narrow
channels (slit diaphragms) to allow molecular passage of small solutes and water but not proteins.
When the total daily excretion of protein is >3.5 g, hypoalbuminemia, hyperlipidemia, and edema
(nephrotic syndrome) are often present as well.
Renal failure occurs through a variety of mechanisms,
including tubule obstruction (cast nephropathy) and light chain deposition.
Hypoalbuminemia in nephrotic syndrome occurs through excessive urinary losses and increased proximal tubule
catabolism of filtered albumin.
Edema forms from renal sodium retention and reduced plasma oncotic pressure, which favors fluid movement from
capillaries to interstitium.
To compensate for the perceived decrease in effective
intravascular volume, these occur (promote continued renal salt and water reabsorption and progressive edema.):
o activation of the renin-angiotensin system
o stimulation of ADH o activation of the sympathetic nervous system
A hypercoagulable state may arise from:
o urinary losses of antithrombin III
o reduced serum levels of proteins S and C o hyperfibrinogenemia
o enhanced platelet aggregation Hypercholesterolemia may be severe and results from
increased hepatic lipoprotein synthesis
HEMATURIA, PYURIA AND CASTS
Isolated hematuria without proteinuria, other cells, or casts
is often indicative of bleeding from the urinary tract.
HEMATURIA
Defined as two to five RBCs per high-power field (HPF)
and can be detected by dipstick.
A false positive dipstick for hematuria (where no RBCs are seen on urine microscopy) may occur when myoglobinuria
is present, often in the setting of rhabdomyolysis. Common causes of isolated hematuria: stones,
neoplasms, tuberculosis, trauma, and prostatitis.
Gross hematuria with blood clots is usually not an intrinsic renal process; rather, it suggests a postrenal
source in the urinary collecting system. A single urinalysis with hematuria is common and can
result from menstruation, viral illness, allergy, exercise, or
mild trauma. Persistent or significant hematuria (>3 RBCs/HPF on
three urinalyses, a single urinalysis with >100 RBCs, or
gross hematuria) is associated with significant renal or urologic lesions in 9.1% of cases.
Neoplasms are rare in the pediatric population, and isolated hematuria is more likely to be "idiopathic" or associated
with a congenital anomaly.
Hematuria with pyuria and bacteriuria is typical of infection and should be treated with antibiotics after appropriate
cultures.
Acute cystitis or urethritis in women can cause gross
hematuria.
Hypercalciuria and hyperuricosuria are also risk factors for unexplained isolated hematuria in both children and adults.
ISOLATED MICROSCOPIC HEMATURIA
Manifestation of glomerular diseases
RBCs of glomerular origin are often dysmorphic when examined by phase-contrast microscopy
Irregular shapes of RBCs may also result from pH and
osmolarity changes produced along the distal nephron. Common etiologies:
o IgA nephropathy (episodic gross hematuria) o hereditary nephritis (episodic gross hematuria)
o thin basement membrane disease (family history of
renal failure is often present in patients with hereditary nephritis, and patients with thin basement membrane
disease often have other family members with microscopic hematuria)
Definitive diagnosis: renal biopsy
RBC CASTS
Hematuria with dysmorphic RBCs, RBC casts, and protein excretion >500 mg/d is virtually diagnostic of
glomerulonephritis.
Form as RBCs that enter the tubule fluid become trapped in a cylindrical mold of gelled Tamm-Horsfall
protein
ISOLATED PYURIA
Unusual since inflammatory reactions in the kidney or collecting system also are associated with hematuria
Presence of bacteria suggests infection, and white blood cell
casts with bacteria are indicative of pyelonephritis White blood cells and/or white blood cell casts also may be
seen in acute glomerulonephritis as well as in tubulointerstitial processes such as interstitial nephritis
and transplant rejection
In chronic renal diseases, degenerated cellular casts called waxy casts can be seen in the urine.
Broad casts are thought to arise in the dilated tubules of
enlarged nephrons that have undergone compensatory hypertrophy in response to reduced renal mass (i.e.,
chronic renal failure). A mixture of broad casts typically seen with chronic renal
failure together with cellular casts and RBCs may be seen in
smoldering processes such as chronic glomerulonephritis.
ABNORMALITIES OF THE URINE VOLUME
The volume of urine produced varies with the fluid intake,
renal function, and physiologic demands of the individual.
POLYURIA
True polyuria - (>3 L/d) in quantification of volume by
24-h urine collection
Polyuria results from two potential mechanisms:
o Solute diuresis: excretion of nonabsorbable solutes
(such as glucose) urine volume is >3 L/d and urine osmolality is
>300 mosmol/L search for the responsible solute(s) is mandatory
(glucose, mannitol, or urea)
o Water diuresis: excretion of water (usually from a defect in ADH production or renal responsiveness).
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Azotemia and Urinary Abnormalities
urine output is >3 L/d and the urine is dilute
(
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