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U N I T 7
Kidney and Urinary Tract Function
ifosfamide, and radiocontrast agents.
3,5
Several factors
contribute to aminoglycoside nephrotoxicity, including
a decrease in the GFR, preexisting renal disease, hypo-
volemia, and concurrent administration of other drugs
that have a nephrotoxic effect. Cisplatin accumulates in
proximal tubule cells, inducing mitochondrial injury and
inhibition of adenosine triphosphatase (ATPase) activ-
ity and solute transport. Radiocontrast media–induced
nephrotoxicity is thought to result from direct tubular
toxicity and renal ischemia.
11
The risk for renal dam-
age caused by radiocontrast media is greatest in elderly
persons and those with preexisting kidney disease, vol-
ume depletion, diabetes mellitus, and recent exposure to
other nephrotoxic agents.
The presence of multiple myeloma light chains, excess
uric acid, hemoglobin, or myoglobin in the urine is the
most frequent cause of ATN due to intratubular obstruc-
tion. Both myeloma cast nephropathy (Chapter 11) and
acute urate nephropathy (Chapter 8) usually are seen in
the setting of widespread malignancy or massive tumor
destruction by therapeutic agents.
3
Hemoglobinuria
results from blood transfusion reactions and other
hemolytic crises. Skeletal and cardiac muscles contain
myoglobin, which corresponds to hemoglobin in func-
tion, serving as an oxygen reservoir in the muscle fibers.
Myoglobin normally is not found in the serum or urine.
It has a low molecular weight; if it escapes into the cir-
culation, it is rapidly filtered in the glomerulus. A life-
threatening condition known as
rhabdomyolysis
occurs
when increasing myoglobinuria levels cause myoglobin
to precipitate in the renal tubules, leading to obstruction
and damage to surrounding tubular cells. Myoglobinuria
most commonly results from muscle trauma, but may
result from extreme exertion, hyperthermia, sepsis, pro-
longed seizures, potassium or phosphate depletion, and
alcoholism or drug abuse. Both myoglobin and hemo-
globin discolor the urine, which may range from the
color of tea to red, brown, or black.
Clinical Manifestations of Acute Tubular Necrosis.
The clinical course of ATN, which is highly variable, is
often divided into an initiation, maintenance and recov-
ery phase. The onset or initiating phase, which lasts
hours or days, is the time from the onset of the precipi-
tating event (e.g., ischemic phase of prerenal failure or
toxin exposure) until tubular injury occurs.
The maintenance phase can involve either an oligu-
ric or nonoliguric phase. Nonoliguric ATN has a better
outcome. Conversion from a nonoliguric to an oligu-
ric state is characterized by a marked decrease in the
GFR, accompanied by retention of metabolic wastes
such creatinine, urea, and sulfate, which normally
are cleared by the kidneys. The urine output usually
is lowest at this point. Fluid retention gives rise to
edema, water intoxication, and pulmonary congestion.
If the period of oliguria is prolonged, hypertension
develops and with it signs of uremia (accumulation of
nitrogenous wastes in the blood). When untreated, the
neurologic manifestations of uremia progress from neu-
romuscular irritability to seizures, somnolence, coma,
and death.
The
recovery phase
is the period during which repair
of renal tissue takes place. Its onset usually is heralded
by a gradual increase in urine output and a fall in serum
creatinine, indicating that the nephrons have recovered
to the point at which urine excretion is possible. Diuresis
often occurs before renal function has fully returned
to normal. Consequently, BUN and serum creatinine,
potassium, and phosphate levels may remain elevated or
continue to rise even though urine output is increased.
In some cases, the diuresis may result from impaired
nephron function and may cause excessive loss of water
and electrolytes. Eventually, renal tubular function is
restored with improvement in concentrating ability. At
about the same time, the creatinine and BUN begin to
return to normal. In some cases, mild to moderate kid-
ney damage persists.
Diagnosis andTreatment
Given the high morbidity and mortality rates associated
with AKI, attention should be focused on prevention
and early diagnosis. This includes assessment measures
to identify persons at risk for development of AKI,
including those with preexisting renal insufficiency and
diabetes. These persons are particularly at risk for devel-
opment of AKI due to nephrotoxic drugs (e.g., amino-
glycosides and radiocontrast agents) or drugs such as
the NSAIDs that alter intrarenal hemodynamics. Elderly
persons are susceptible to all forms of AKI because of
the effects of aging on renal reserve.
Careful observation of urine output is essential for
persons at risk for development of AKI. Urine tests that
measure urine osmolality, urinary sodium concentra-
tion, and fractional excretion of sodium help differ-
entiate prerenal azotemia, in which the reabsorptive
capacity of the tubular cells is maintained, from tubular
necrosis, in which these functions are lost. One of the
earliest manifestations of tubular damage is the inability
to concentrate the urine. Further diagnostic information
that can be obtained from the urinalysis includes evi-
dence of proteinuria, hemoglobinuria, myoglobinuria,
and casts or crystals in the urine. Blood tests for BUN
and creatinine provide information regarding the ability
to remove nitrogenous wastes from the blood.
A major concern in the treatment of AKI is identifying
and correcting the cause (e.g., improving renal perfusion,
discontinuing nephrotoxic drugs). Fluids are carefully
regulated in an effort to maintain normal fluid volume
and electrolyte concentrations. Adequate caloric intake is
needed to prevent the breakdown of body proteins, which
increases nitrogenous wastes.
5,8,10
Parenteral hyperalimen-
tation may be used for this purpose. Because secondary
infections are a major cause of death in persons with
AKI, constant effort is needed to prevent and treat such
infections.
Either hemodialysis (to be discussed) or continuous
renal replacement therapy (CRRT) may be indicated
when nitrogenous wastes and the water and electrolyte
balance cannot be kept under control by other means.
5,10
Venovenous or arteriovenous CRRT has emerged as a
