Overview Of
Nephrotic Syndrome
The nephrotic syndrome encompasses a
constellation of clinical and laboratory findings related to the loss of large
quantities of protein in urine. The major symptom is edema, and the laboratory
findings include (1) “nephrotic-range” proteinuria, defined in adults as more
than 3.5 g of protein excretion per 24 hours, (2) hypoalbuminemia, and (3)
hyperlipidemia. The thresh old for nephrotic proteinuria in children is
lower and depends on body weight.
Pathophysiology
“Nephrotic syndrome” is a
nonspecific diagnosis that suggests underlying glomerular disease. The normal,
noninflamed glomerulus forms a tight barrier to proteins, such as albumin,
largely because of the slit diaphragms that connect podocyte (visceral
epithelial cell) foot processes on the outside surface of the glomerular
basement membrane.
In nephrotic syndrome, inflammation
disrupts the normal structure of the slit diaphragms, permitting the passage of
potentially large amounts of protein into the urine. In most cases, the foot
processes appear “fused” or “effaced,” meaning that a continuous layer of
podocyte cytoplasm is seen over the glomerular capillaries, rather than the
discrete, individual processes seen in the normal state. Such effacement
reflects widening, shortening, and retraction of the foot processes. Although
the glomerular inflammation is typically not severe enough to cause an acute
decline in overall filtration, scarring and loss of renal function may occur
over time.
The ongoing loss of albumin into
urine causes hypoalbuminemia. The decline in serum albumin concentration,
however, is often out of proportion to the degree of proteinuria. One possible
explanation is that the proximal tubular catabolism of albumin is accelerated
because of the increased filtered load.
In response to the low serum
albumin concentrations, the liver increases its production of numerous
proteins, including lipoproteins, leading to hyperlipidemia.
Edema occurs for at least two
possible reasons. The first, known as the “underfilling hypothesis,” argues that
low serum albumin concentrations lead to a reduction in intravascular oncotic
pressure. As a result, plasma moves from the capillary lumen to the
interstitium, which leads to edema. The resulting intravascular depletion
activates the renin-angiotensin-aldosterone system, which promotes retention of
sodium and water and thus further worsens the edema. The second hypothesis,
known as the “overfilling hypothesis,” argues that there is primary retention of
sodium at the level of the collecting duct, perhaps triggered by the filtered
proteins themselves, that leads to edema. It appears probable that both
hypotheses are correct, and that the primary mechanism for edema may vary
across patients and across time.
Patients with nephrotic syndrome
are at increased risk for lower extremity, pulmonary, and renal vein thromboses
(see Plate 4-35) because of urinary losses of anticoagulant proteins, such as
antithrombin and plasminogen, as well as increased hepatic production of
procoagulant proteins, such as fibrinogen and other clotting factors. Among the
nephrotic syndromes, thromboses are most often seen in patients with membranous
nephropathy, but any patient with proteinuria above 10 g/day and albumin levels
below 2 g/dL should be considered at risk.
Three primary glomerular diseases minimal
change disease (MCD, see Plate 4-8), focal segmental glomerulosclerosis (FSGS,
see Plate 4-10), and membranous nephropathy (MN, see Plate 4-12)—all cause
significant proteinuria, which is often sufficient to result in nephrotic
syndrome.
Other primary glomerular diseases,
such as the various glomerulonephritides (see Plate 4-14), typically cause
proteinuria, hematuria, and a variable degree of renal dysfunction. In a subset
of cases, the proteinuria is sufficient to result in nephrotic syndrome.
Finally, many systemic conditions
or environmental agents can cause nephrotic syndrome, either by causing a
distinct pattern of glomerular inflammation (i.e., amyloidosis see Plate 4-47],
diabetes mellitus [see Plate 4-45]) or by causing one of the renal diseases
listed previously. Examples of the latter include secondary MCD in the setting
of lymphoma, infection (e.g., tuberculosis), allergies, and lithium or NSAID
use; secondary FSGS in the setting of HIV infection, heroin abuse, and sickle
cell disease; and secondary MN in the setting of systemic lupus erythematosus,
rheumatoid arthritis, viral hepatitis infection, syphilis, penicillamine use,
gold poisoning, and solid tumors in general.
In both children and adults, the
annual incidence of nephrotic syndrome is approximately five cases per 100,000
individuals. This incidence, however, likely underestimates the true disease
burden because many cases, especially those secondary to diabetes, do not
undergo biopsy-proven diagnosis.
There are strong age and race
predilections for the various causes of nephrotic syndrome. In children, the
most common cause by far is MCD. In adults, the most common cause of secondary
nephrotic syndrome is diabetes mellitus, whereas the two most common causes of
idiopathic nephrotic syndrome are MN and FSGS. Until recently, MN was the most
common cause in white adults, whereas FSGS was the most common cause in black
adults. More recent data, however, shows a steadily rising incidence of FSGS,
in part because of the large number of cases occurring secondary to obesity. As
a result, FSGS may soon emerge as the most common cause of idiopathic nephrotic
syndrome in all adults.
Presentation And Diagnosis
Edema is the most common presenting
symptom. Gravity increases intracapillary hydrostatic pressure and is thus the
major determinant of the extravascular fluid distribution. Thus
edema is typically most severe in the lower extremities; however, after
sleeping in a prone position, the patient may experience
swelling of the face, especially in the periorbital region. Severe fluid
retention can also lead to pulmonary edema (with associated shortness of
breath), effusions, or frank anasarca. Hypertension may occur in a minority of
patients. Finally, patients may also describe weakness, malaise, and a “foamy”
or “bubbly” appearance to their urine.
Patients with edema do not
necessarily have nephrotic syndrome, since other diseases—notably congestive heart
failure and cirrhosis can present in this fashion. The diagnosis of
nephrotic syndrome is suggested, however, when urine dipstick reveals marked
proteinuria. Urine microscopy may reveal oval fat bodies, lipid droplets, and
fatty casts (which resemble “Maltese crosses” under polarized light), which
reflect the presence of lipoproteins in the urine. The presence of dysmorphic
red blood cells and red cell casts suggests the proteinuria is the result of an
underlying glomerulonephritis.
Once proteinuria is established, urine should
be sent for protein quantification using a 24-hour urine collection or, for the
sake of convenience, a spot urine protein: creatinine ratio. The latter offers
a reasonable approximation of 24-hour proteinuria, especially if it is based on
the first morning void.
Blood should be sent for
measurement of albumin, cholesterol, electrolyte, and creatinine
concentrations. Once laboratory tests reveal the triad of heavy proteinuria,
hypoalbuminemia, and hypercholesterolemia, the patient clearly has nephrotic
syndrome. The differential diagnosis at this point, therefore, is centered on
determining the cause.
In children, MCD accounts for such
an overwhelming majority of cases that treatment for this condition is offered
on an empiric basis. Further workup, including renal biopsy, is not performed
unless such treatment fails.
In adults, the differential
diagnosis of nephrotic syndrome is broad enough to warrant a renal biopsy in
cases where an apparent cause, such as long-standing diabetes mellitus, is not
present. The histologic findings associated with each particular disease are
described later in this section. In addition, adults should undergo screening
for the most common causes of secondary nephrotic syndrome. For example,
serologic testing should be performed for hepatitis B/C, HIV, lupus, and
syphilis, and serum and urine protein electrophoresis should be performed to
rule out amyloidosis and plasma cell disorders. Testing levels of serum
complements (C3 and C4) can also be helpful because some causes of nephrotic syndrome
are associated with depressed levels (e.g., membranoproliferative
glomerulonephritis).
Treatment
The optimal treatment strategies
depend on the underlying cause of nephrotic syndrome and are discussed later
in this book. Some treatments, however, are useful in almost all patients.
Renin-angiotensin system blockers
(e.g., ACE inhibitors), for example, should be provided to all patients to
lower blood pressure and reduce the degree of proteinuria. A
cholesterol-lowering medication, such as a statin, should also be provided to
minimize cardiovascular complications. Diuretics should be used as needed to
treat edema; combinations of loop diuretics (e.g., furosemide), thiazides (e.g.,
chlorthalidone), and potassium-sparing diuretics (e.g., spironolactone) may be
required. Anticoagulation may be necessary in patients who are at high risk for
thrombosis or have already experienced a clotting event.
Many patients receive at least a
short course of oral corticosteroids, although other
immune-suppressing agents (such as calcineurin inhibitors,
alkylating chemotherapy agents, and monoclonal antibodies) may also be used in
certain circumstances.
Lifestyle changes are also
important. Patients should adopt a low-salt diet to reduce edema and improve
blood pressure control. Exercise may help mobilize edema and allow natural
diuresis, as well as lower blood pressure and improve cholesterol levels.
Treatment success is defined as
reduction or resolution of proteinuria, ideally to less than 300 mg/day, with
preserved kidney function. Patients who achieve this endpoint generally have a
very favorable prognosis. In contrast, those patients with nephrotic-range
proteinuria that do not respond to treatment have a poor overall renal
prognosis because ongoing glomerular inflammation will eventually lead to
scarring and a permanent loss of renal function.
