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Nephrotic Syndrome: Background
Nephrotic Syndrome: Background
Author: Eric P Cohen, MD, Professor, Department of Medicine, Division of Nephrology, Medical College of
Wisconsin; Nephrology Section Chief, Zablocki Veterans Affairs Hospital
Contributor Information and Disclosures
Updated: Mar 17, 2010
Introduction
Background
Nephrotic syndrome is kidney disease with proteinuria, hypoalbuminemia, and edema. Nephrotic
range proteinuria is 3 grams per day or more. On a single, "spot" urine collection, it is 2 grams of
protein per gram of urine creatinine.
There are many specific causes of nephrotic syndrome. These include kidney diseases such as
minimal-change nephropathy, focal glomerulosclerosis, and membranous nephropathy. Nephrotic
syndrome can also result from systemic diseases that affect other organs in addition to the kidneys,
such as diabetes, amyloidosis, and lupus erythematosus. A schematic drawing of the glomerular
barrier is shown below.
Classification
Nephrotic syndrome can be primary, being a disease specific to the kidneys, or it can be secondary,
being a renal manifestation of a systemic general illness. In all cases, injury to glomeruli is an
essential feature.
Minimal-change nephropathy
Focal glomerulosclerosis
Membranous nephropathy
Hereditary nephropathies
Diabetes mellitus
Lupus erythematosus
Preeclampsia
Nephrotic-range proteinuria may occur in other kidney diseases, such as IgA nephropathy. In that
common glomerular disease, one third of subjects may have nephrotic-range proteinuria. 1 Nephrotic
syndrome may occur in persons with sickle cell disease and evolve to renal failure. Membranous
nephropathy may complicate bone marrow transplantation, in association with graft versus host
disease. Kidney diseases that affect tubules and interstitium, such as interstitial nephritis, will not
cause nephrotic syndrome.
The above causes of nephrotic syndrome are largely those for adults, and this article will concentrate
primarily on adult nephrotic syndrome.
However, nephrotic syndrome in infancy and childhood is an important entity. A study from New
Zealand found the incidence of nephrotic syndrome to be almost 20 cases per million children under
age 15 years.2 In specific populations, such as those of Finnish or Mennonite origin, congenital
nephrotic syndrome may occur in 1 in 10,000 or 1 in 500 births, respectively.3 According to the
International Study of Kidney Diseases in Childhood (ISKDC), 84.5% of all children with primary
nephrotic syndrome have minimal-change nephrotic syndrome (MCNS), 9.5% have focal segmental
glomerulosclerosis (FSGS), 2.5% have mesangial proliferation, and 3.5% have membranous
nephropathy or another cause of the disease.4,5 Increasing trends of FSGS incidence are being
reported, but MCNS remains the most important cause of chronic renal disease in children.
From a therapeutic perspective, nephrotic syndrome may be classified as steroid sensitive, steroid
resistant, steroid dependent, or frequently relapsing.
Recent studies
Pathophysiology
Glomerular permeability
In a healthy individual, less than 0.1% of plasma albumin may traverse the glomerular filtration
barrier.7 Controversy exists regarding the sieving of albumin across the glomerular permeability
barrier. Specifically, it is proposed that there is ongoing albumin passage into the urine, in many
grams per day, with equivalent substantial tubular uptake of albumin, the result being that the urine
has 80 mg per day or less of daily albumin.8 This controversy is based on studies in experimental
animals. However, studies of humans with tubular transport defects suggest that the glomerular
urinary space albumin concentration is 3.5 mg/L. 9 With this concentration, and a normal daily
glomerular filtration rate (GFR) of 150 liters, one would expect no more than 525 mg per day of
albumin in the final urine. Amounts above that level point to glomerular disease.
The glomerular capillaries are lined by a fenestrated endothelium that sits on the glomerular
basement membrane, which in turn is covered by glomerular epithelium, or podocytes, which
envelops the capillaries with cellular extensions called foot processes. In between the foot processes
are the filtration slits. These 3 structuresthe fenestrated endothelium, glomerular basement
membrane, and glomerular epitheliumare the glomerular filtration barrier. A schematic drawing of
the glomerular barrier is seen in the image below.
The glomerular structural changes that may cause proteinuria are (1) damage to the endothelial
surface, (2) damage to the glomerular basement membrane, and/or (3) damage of the podocytes.
One or more of these mechanisms may be seen in any one type of nephrotic syndrome. Albuminuria
alone may occur, or, with greater injury, leakage of all plasma proteins, (ie, proteinuria) may take
place.
Proteinuria that is more than 85% albumin is selective proteinuria. Albumin has a net negative
charge, and it is proposed that loss of glomerular membrane negative charges could be important in
causing albuminuria. Nonselective proteinuria, being a glomerular leakage of all plasma proteins,
would not involve changes in glomerular net charge but rather a generalized defect in permeability.
This construct does not permit clear-cut separation of causes of proteinuria, except in minimal-
change nephropathy, in which proteinuria is selective.
Pathogenesis of edema
In this formula, Qw is net flux of water, K is the capillary filtration coefficient, Pc is capillary hydrostatic
pressure, and Pi is the interstitial fluid hydrostatic pressure, while pp is the plasma oncotic pressure,
and pi is the interstitial fluid oncotic pressure. With a high enough capillary hydrostatic pressure or a
low enough intravascular oncotic pressure, the amount of fluid filtered exceeds the maximal
lymphatic flow, and edema occurs. In patients with nephrotic syndrome, this causes a reduction in
plasma volume, with a secondary increase of sodium and water retention by the kidneys.
An alternate hypothesis is that a condition of renal sodium retention occurs because of the
proteinuria, but this is not related to intravascular volume or to serum protein concentration. The
evidence supporting this hypothesis includes the fact that (1) sodium retention is observed even
before the serum albumin level starts falling and (2) intravascular volume is normal or even increased
in most patients with nephrotic syndrome. This could occur if intraluminal protein directly stimulated
renal epithelial sodium reabsorption.10
In the nephrotic syndrome, levels of serum lipids are usually elevated. This can occur via (1)
hypoproteinemia that stimulates protein, including lipoprotein, synthesis by the liver, and (2)
diminution of lipid catabolism caused by reduced plasma levels of lipoprotein lipase.
The loss of antithrombin III and plasminogen via urine, along with the simultaneous increase in
clotting factors, especially factors I, VII, VIII, and X, increases the risk for venous thrombosis and
pulmonary embolism. In the first 6 months that a patient has nephrotic syndrome, the occurrence rate
of venous thrombosis may reach 10%.12
Vitamin Dbinding protein may be lost in the urine, leading to hypovitaminosis D, with malabsorption
of calcium and development of bone disease.13
Urinary immunoglobulin losses may lower the patient's resistance to infections and increase the risk
of sepsis and peritonitis.
Frequency
United States
The figure below shows the incidence per million population of important causes of nephrotic
syndrome. Diabetic nephropathy with nephrotic syndrome is most common, at an estimated rate of at
least 50 cases per million population. That is an underestimation, however, since the rate of end-
stage renal disease from diabetes has reached 100 cases per million population in some Western
countries. In children, nephrotic syndrome may occur at a rate of 20 cases per million children. 2
International
Biopsy studies in children with nephrotic syndrome have shown similar types of histology in India and
Turkey, compared with what one would expect in Western countries. 14,15 In Pakistani adults with
nephrotic syndrome, the spectrum of histologies of kidney biopsies has been found to be similar to
that seen in western countries.16
Glomerular disease may be associated with schistosomal infection, as could occur in Egypt. 17
So-called "tropical nephrotic syndrome" may not be a true entity. Doe et al summarized the evidence
for causes of nephrotic syndrome in African children.18 All of the typical histologies may be found on
kidney biopsy. The connection of nephrotic syndrome to quartan malaria is not well-established.
Indeed, Pakasa and Sumaili call attention to the apparent decline of parasite-associated nephrotic
syndrome in the Congo.19,20 It is possible that the perceived association between nephrotic syndrome
and parasitic infections was coincidental, as supported by the ongoing and probably increasing
occurrence of chronic kidney disease in the Congo. 20
Mortality/Morbidity
In the preantibiotic era, infection was a major factor in the mortality rate among patients with
nephrotic syndrome.21 Treatments for nephrotic syndrome and its complications appear to
have reduced the morbidity and mortality once associated with the syndrome.
The prognosis may worsen because of (1) an increased incidence of renal failure and the
complications secondary to nephrotic syndrome, including thrombotic episodes and
infection, or (2) treatment-related conditions, such as infectious complications of
immunosuppressive treatments.
In secondary nephrotic syndromes, morbidity and mortality are related to the primary
disease process, such as diabetes or lupus, although in diabetic nephropathy, the magnitude
of proteinuria itself relates directly to mortality.24
Race
Because diabetes is major cause of nephrotic syndrome, American Indians, Hispanics, and
African Americans have a higher incidence of nephrotic syndrome than do white persons.
HIV nephropathy is a complication of HIV that is unusual in whites; it is seen with greater
frequency in African Americans.25
Sex
Age
The image below shows typical ages at which a given cause of nephrotic syndrome may occur. It
does not show every possible cause of nephrotic syndrome, such as lupus nephritis, which typically
affects young black women. The ages shown are averages.
A schema of the average patient ages associated with various common forms of
nephrotic syndrome.
Clinical
History
The first sign of nephrotic syndrome in children is usually swelling of the face; this is followed
by swelling of the entire body.
A thrombotic complication, such as deep vein thrombosis of the calf veins or even a
pulmonary embolus, may be the first clue indicating nephrotic syndrome.
Additional historical features that appear can be related to the cause of nephrotic
syndrome. Thus, the recent start of a nonsteroidal anti-inflammatory drug (NSAID) or a 10-
year history of diabetes may be very relevant.
Physical
Edema is the predominant feature of nephrotic syndrome and initially develops around the
eyes and legs. With time, the edema becomes generalized and may be associated with an
increase in weight, the development of ascites, or pleural effusions.
Additional features on exam will vary according to cause and as a result of whether or not
renal function impairment exists. Thus, in the case of longstanding diabetes, there may be
diabetic retinopathy, which correlates closely with diabetic nephropathy. If the kidney
function is reduced, there may be hypertension and/or anemia.
Causes
The usual causes of nephrotic syndrome are discussed above (see Background). They
include primary kidney diseases, such as minimal-change nephropathy, membranous
nephropathy, and focal glomerulosclerosis, as well as systemic diseases, such as diabetes
mellitus, lupus erythematosus, and amyloidosis.
Congenital and hereditary focal glomerulosclerosis may result from mutations of genes that
code for podocyte proteins, including nephrin, podocin, or the cation channel 6 protein.
Medication can cause nephrotic syndrome. This includes the very infrequent occurrence of
minimal-change nephropathy with NSAID use, and the occurrence of membranous
nephropathy with the administration of gold and penicillamine, which are older drugs used
for rheumatic diseases; there have also been reports of focal glomerulosclerosis in
association with bisphosphonates. Although recognized, these associations have not yet
been quantified.
Nephrotic-range proteinuria could occur with the use of anticancer agents, such as
bevacizumab, that inhibit vascular endothelial growth factor (VEGF). 28 However, the clinical
picture of this complication is of a thrombotic microangiopathy rather than of nephrotic
syndrome per se.
Differential Diagnoses
Diabetic Nephropathy Light Chain-Associated Renal Disorders
Focal Segmental Glomerulosclerosis Minimal-Change Disease
Glomerulonephritis, Acute Nephritis, Radiation
Glomerulonephritis, Chronic Sickle Cell Nephropathy
Glomerulonephritis, Membranous
HIV Nephropathy
IgA Nephropathy
Other Problems to Be Considered
Heart failure may cause a similar presentation to that of nephrotic syndrome. In typical cases of heart
failure, however, there will be a history of heart disease and/or features of poor heart function on
exam, such as a third heart sound and even low blood pressure. In heart failure without kidney
disease, there will be little or no proteinuria. Nephrotic syndrome with renal impairment, such as may
occur in IgA nephropathy, may cause secondary reduction in heart function, with cardiomegaly on
exam. Such cases would typically be hypertensive and there will be substantial proteinuria on
urinalysis.
Subjects with cirrhosis may have substantial fluid retention, both as ascites and as peripheral edema.
Unless there is associated kidney disease, however, there will be little or no proteinuria in cirrhosis.
Workup
Laboratory Studies
The presence of more than 2 red blood cells (RBCs) per high power field is
indicative of microhematuria. Microhematuria may occur in membranous
nephropathy but not in minimal-change nephropathy. Glomerular disease may allow
RBCs to traverse the damaged glomerular basement membrane, and the RBCs in
the sediment may then be deformed, or dysmorphic. This points to glomerular
disease with inflammation and destruction of the normal structures, ie, a nephritis
(and thus a nephritic picture). This could occur in, for example, nephrotic syndromes
associated with IgA nephropathy or proliferative glomerulonephritis.
More than 2 granular casts in the entire sediment is a biomarker for renal
parenchymal disease. Variable-caliber granular casts point to reduced renal
function.
The exact type of urine protein is of potential interest. This can be tested by urine protein
electrophoresis. Proteinuria that does not include albumin may point to overflow proteinuria
that occurs in paraproteinemias, such as multiple myeloma. There has been intermittent
interest in establishing whether proteinuria is "selective" for albumin, being more than 85%
composed of albumin, as opposed to nonselective. In the case of selective proteinuria, there
could be a charge-selective leak of albumin across the glomerular barrier, perhaps due to
reduced negative charges on that barrier, whereas nonselective proteinurias would point to
more substantial glomerular injury and perhaps also to lesser response to prednisone
treatment.
Serum tests for kidney function are essential. Serum creatinine will be in the normal range in
uncomplicated nephrotic syndrome, such as that occurring in minimal-change nephropathy.
In children, the serum creatinine level will be lower than it is in adults. The normal adult
serum creatinine level is approximately 1 mg/dL, whereas that of a child aged 5 years will
be about 0.5 mg/dL. Values higher than this indicate reduced kidney function.
The serum albumin is classically low in nephrotic syndrome, being below its normal range of
3.5-4.5 g/dL. A single-center study showed that when a patient's serum albumin level was
normal, rather than low, focal glomerulosclerosis, rather than other conditions, tended to be
the cause of nephrotic syndrome.30
Imaging Studies
Ultrasonographic scanning can be used to determine whether a patient possesses 2 kidneys
and to demonstrate their echogenicity. Individuals with a single kidney may be prone to
developing focal glomerulosclerosis. Having only 1 kidney is also a relative contraindication
to kidney biopsy. Increased renal echogenicity by ultrasonography is consistent with
intrarenal fibrosis, ie, chronic disease with reduced kidney function.
Other Tests
In infants with nephrotic syndrome, genetic testing for the NPHS1 and NPHS2 mutations
may be useful. These are mutations of nephrin and podocin, respectively. In children with
steroid-resistant nephrotic syndrome, testing for the NPHS2 mutation may be indicated.
In adults with nephrotic syndrome, tests for hepatitis B and C, HIV, and even syphilis may be
useful. Tests for lupus, including ANA, anti-dsDNA, and complement, may be useful. Testing
for antineutrophil cytoplasmic antibodies (ANCA) is not indicated in typical nephrotic
syndrome, because that test is associated with rapidly progressive glomerulonephritis, which
presents with a nephritic picture rather than one that is typically nephrotic. Tests for previous
streptococcal infection, such as antistreptolysin O, are not usually indicated for nephrotic
syndrome, since postinfectious glomerulonephritis usually causes a nephritic picture, not
nephrotic syndrome.
Future studies for urinary biomarkers by which the cause and severity of nephrotic syndrome
may be identified may become available.31
Procedures
For childhood nephrotic syndrome, a renal biopsy is indicated for the following:
o Steroid resistance
Adult nephrotic syndrome of unknown origin may require a renal biopsy for diagnosis.
A renal biopsy is not indicated in adults when nephrotic syndrome is due to an obvious
cause, such as diabetes mellitus. Thus, a subject with diabetes, diabetic retinopathy, and the
nephrotic syndrome may well have diabetic nephropathy and not need to undergo kidney
biopsy.
Staging
There are histopathologic stages for membranous nephropathy but not for other causes of nephrotic
syndrome.
Treatment
Medical Care
Acute management of childhood nephrotic syndrome
With good parental and patient education and close outpatient follow-up care, hospitalization is not
usually necessary. Hospitalization should be considered if a patient has generalized edema severe
enough to cause respiratory distress, if a patient has tense scrotal or labial edema, if he or she has
complications (eg, bacterial sepsis, peritonitis, pneumonia, thromboembolism, failure to thrive), or if
patient or family compliance with treatment is in doubt.
Diuretics will be needed; furosemide (1 mg/kg/d) and spironolactone (2 mg/kg/d) will help when fluid
retention is severe, provided no signs of renal failure or volume contraction are evident. Achieving a
satisfactory diuresis is difficult when the patient's serum albumin level is less than 1.5 g/dL. Albumin
at 1 g/kg may be given, followed by intravenous furosemide. Complications may occur, including
pulmonary edema. Some evidence suggests that albumin may delay the response to steroids and
may even induce more frequent relapses, probably by causing severe glomerular epithelial damage.
Fluid removal and weight loss remain transient unless proteinuria remits.
With regard to infection, oral penicillin can be prescribed as prophylaxis for children with gross
edema. Abdominal paracentesis should be performed if the patient develops signs of peritonitis, and
any bacterial infection should be treated promptly. A nonimmune patient with varicella should receive
zoster immunoglobulin therapy if exposed to chickenpox, and acyclovir should be given if the patient
develops chickenpox.
The principles for acute management of adults with nephrotic syndrome are similar to those for
children. Diuretics will be needed; furosemide, spironolactone, and even metolazone may be used.
Volume depletion may occur with diuretic use, which should be monitored by assessment of
symptoms, weight, pulse, and blood pressure.
Anticoagulation has been advocated by some for use in preventing thromboembolic complications,
but its use in primary prevention is of unproven value.
Hypolipidemic agents may be used, but if the nephrotic syndrome cannot be controlled, there will be
persistent hyperlipidemia.
In secondary nephrotic syndrome, such as that associated with diabetic nephropathy, angiotensin-
converting enzyme (ACE) inhibitors and/or angiotensin II receptor blockers are widely used. These
may reduce proteinuria by reducing the systemic blood pressure, by reducing intraglomerular
pressure, and also by direct action on podocytes.
Specific treatment
Surgical Care
Surgery is not applicable in itself for the treatment of nephrotic syndrome. It is possible that patients
with nephrotic syndrome may have poor wound healing, which places emphasis on optimal medical
treatments.
Consultations
Depending on the cause of nephrotic syndrome, a patient may need specialty consultation. For
example, an individual with lupus nephritis may benefit from rheumatologic consultation.
Diet
For patients with nephrotic syndrome, their diet should provide adequate energy (caloric)
intake and adequate protein (1-2 g/kg/d). Supplemental dietary protein is of no proven value.
Activity
There are no activity restrictions for patients with nephrotic syndrome. Ongoing activity, rather than
bedrest, will reduce the risk of blood clots.
Medication
Drugs used in the remittive treatment of nephrotic syndrome include corticosteroids (prednisone),
cyclophosphamide, and cyclosporine, while drugs used to reduce edema include diuretics and
those administered to reduce the proteinuria include ACE inhibitors and angiotensin II receptor
blockers.
Corticosteroids
Have anti-inflammatory properties and modify the body's immune response to diverse stimuli.
Prednisone (Sterapred)
Immunosuppressant for treatment of autoimmune disorders. May decrease inflammation by
reversing increased capillary permeability and suppressing PMN activity. May be administered as a
single dose in the morning or as divided doses. Studies show that a single dose is equally effective
and greatly improves compliance.
Dosing
Interactions
Contraindications
Precautions
Adult
60 mg/m2/d PO, titrate to a maximum 80 mg/m2/d until remission; then, 40 mg/m2/d, titrate to 60
mg/m2 qod for 4 wk
Pediatric
Dosing
Interactions
Contraindications
Precautions
Dosing
Interactions
Contraindications
Precautions
Dosing
Interactions
Contraindications
Precautions
Immunomodulators
These agents regulate key steps of the immune system.
Cyclophosphamide (Cytoxan)
Antineoplastic drug chemically related to nitrogen mustard. Potent immunomodulator that has been
used successfully in conditions that require immunosuppression. Highly effective for frequently
relapsing steroid-sensitive nephrotic syndrome; half of the children enter a prolonged remission.
Doses (below) are based on published studies. This drug is used for the time required to induce
remission and should be continued thereafter, but probably not for more than a year.
Dosing
Interactions
Contraindications
Precautions
Adult
Pediatric
2 mg/kg/d PO
Dosing
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Precautions
Dosing
Interactions
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Precautions
Dosing
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Precautions
Dosing
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Adult
Pediatric
Administer as in adults
Dosing
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Precautions
Dosing
Interactions
Contraindications
Precautions
Dosing
Interactions
Contraindications
Precautions
Immunosuppressants
Inhibit key steps that mediate immune reactions.32,33
Dosing
Interactions
Contraindications
Precautions
Adult
Pediatric
Dosing
Interactions
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Precautions
Dosing
Interactions
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Precautions
Dosing
Interactions
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Precautions
Diuretics
Used for symptomatic treatment of edema.
Furosemide (Lasix)
Increases urine output by inhibiting sodium transport in ascending loop of Henle and distal renal
tubule. Dose must be individualized to patient. Depending on response, administer at increments of
20-40 mg, no sooner than 6-8 h after the previous dose, until desired diuresis occurs.
Dosing
Interactions
Contraindications
Precautions
Adult
Pediatric
Dosing
Interactions
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Precautions
Dosing
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Precautions
Dosing
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Spironolactone (Aldactone)
For management of edema resulting from excessive aldosterone excretion. Competes with
aldosterone for receptor sites in distal renal tubules, thus enhancing sodium excretion.
Dosing
Interactions
Contraindications
Precautions
Adult
Pediatric
Dosing
Interactions
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Precautions
Dosing
Interactions
Contraindications
Precautions
Dosing
Interactions
Contraindications
Precautions
Angiotensin-converting Enzyme (ACE) Inhibitors
These agents improve hypertension by inhibiting renin or angiotensin II production.
Dosing
Interactions
Contraindications
Precautions
Adult
Pediatric
Not established
Dosing
Interactions
Contraindications
Precautions
Dosing
Interactions
Contraindications
Precautions
Dosing
Interactions
Contraindications
Precautions
Angiotensin II Receptor Antagonist
These agents inhibit angiotensin II activity by interfering with the binding of formed angiotensin II to
its endogenous receptor.
Losartan (Cozaar)
Angiotensin II receptor antagonist that blocks the vasoconstrictor and aldosterone-secreting effects
of angiotensin II. May induce a more complete inhibition of the renin-angiotensin system than ACE
inhibitors, does not affect the response to bradykinin, and is less likely to be associated with cough
and angioedema. For patients unable to tolerate ACE inhibitors.
Dosing
Interactions
Contraindications
Precautions
Adult
Pediatric
Not established
Follow-up
Long-term management
Ongoing use and adjustment of diuretics and angiotensin antagonists are necessary
according to the amount of edema and proteinuria that a patient has. This requires periodic
monitoring.
Other immunosuppressive medications - These medications are usually reserved for steroid-
resistant cases in patients who are persistently edematous or for steroid-dependent patients
with significant steroid-related adverse effects.
Deterrence/Prevention
Amniocentesis may show high levels of alpha-fetoprotein when the fetus has congenital nephrotic
syndrome of the Finnish type.34 This may assist in management and counseling.
Complications
Infection is a major concern in nephrotic syndrome; patients have an increased susceptibility to
infection with Streptococcus pneumoniae, Haemophilus influenzae, Escherichia coli, and other gram-
negative organisms. Varicella infection is also common. The most common infectious complications
are bacterial sepsis, cellulitis, pneumonia, and peritonitis. Proposed explanations for these
complications include decreased immunoglobulin levels, edema fluid acting as a culture medium,
protein deficiency, decreased bactericidal activity of the leukocytes, immunosuppressive therapy,
decreased perfusion of the spleen caused by hypovolemia, and urinary loss of a complement factor
(properdin factor B) that opsonizes certain bacteria.
The occurrence of hyperlipidemia may be considered a typical feature of the nephrotic syndrome,
rather than a mere complication. It is related to the hypoproteinemia and low serum oncotic pressure
of nephrotic syndrome, which then leads to reactive hepatic protein synthesis, including of
lipoproteins.35 Some of the elevated serum lipoproteins are filtered at the glomerulus, leading to
lipiduria and the classical findings of oval fat bodies and fatty casts in the urine sediment.
Atherosclerotic vascular disease appears to occur in greater frequency in subjects with nephrotic
syndrome than in healthy subjects of the same age. Curry and Roberts showed that the frequency
and extent of coronary artery disease stenoses were greater in patients with nephrotic syndrome
than in nonnephrotic control subjects.36 When their study was published (1977), lipid-lowering
treatments were less widely used than they are today. Accordingly, the average highest serum total
cholesterol in this series was over 400 mg/dL. That is in the range of serum cholesterol seen in
familial hypercholesterolemia, a disease that predisposes individuals to myocardial infarction.
Hypocalcemia is common in the nephrotic syndrome, but rather than being a true hypocalcemia, it is
usually caused by a low serum albumin level. Nonetheless, low bone density and abnormal bone
histology are reported in association with nephrotic syndrome. This could be caused by urinary
losses of vitamin D binding proteins, with consequent hypovitaminosis D and, as a result, reduced
intestinal calcium absorption. Tessitore et al reported that when the GFR was normal, subjects with
the nephrotic syndrome had no consistent calcium or bony abnormalities. 37 Yet in that same study,
when the GFR was reduced, there were bone mineralization defects found by biopsy.
A later study found osteomalacia on bone biopsy in over half of adults who had longstanding
nephrotic syndrome but whose GFR was preserved.13 A further complication derives from therapies,
especially prednisone use. Low bone mass may be found, in relation to cumulative steroid dose. 38
This subject remains controversial; as reported by Leonard et al, in 2004, intermittent corticosteroid
treatment of childhood steroid-sensitive nephrotic syndrome does not appear to be associated with
bone mineral deficits.39 It is possible that long duration of either the nephrotic syndrome or treatments
for it are the important risk factors for bone disease in these subjects.
Venous thrombosis and pulmonary embolism are well-known complications of the nephrotic
syndrome. Hypercoagulability in these subjects appears to derive from urinary loss of anticoagulant
proteins, such as anti-thrombin III, compounded by elevations in procoagulant proteins, such as
fibrinogen.
A study by Mahmoodi et al of almost 300 patients with nephrotic syndrome confirmed that venous
thromboembolism (VTE) was almost 10 times higher in these persons than in the normal
population.12 In the normal population, the average per year incidence of VTE is 0.1-0.2%, whereas
among the patients in Mahmoodi's study, the incidence rate reached 1%. Moreover, that risk
appeared especially elevated during the first 6 months of nephrotic syndrome, being at almost 10%.
This high incidence may justify the routine use of preventive anticoagulation treatment during the first
6 months of a persistent nephrotic syndrome.
Mahmoodi's study also showed an increased risk of arterial thrombotic events, including coronary
and cerebrovascular ones, in nephrotic syndrome. Unlike the risk of VTE, which was related to
proteinuria, this arterial risk was related to usual risk factors for arterial disease, such as
hypertension, diabetes, smoking, and reduced GFR.
Hypovolemia occurs when hypoalbuminemia decreases the plasma oncotic pressure, resulting in a
loss of plasma water into the interstitium and causing a decrease in circulating blood volume.
Hypovolemia is generally observed only when the patient's serum albumin level is less than 1.5 g/dL.
Symptoms include vomiting, abdominal pain, and diarrhea. The signs include cold hands and feet,
delayed capillary filling, oliguria, and tachycardia. Hypotension is a late feature.
Acute renal failure may indicate an underlying glomerulonephritis but is more often precipitated by
hypovolemia or sepsis. Edema of the kidneys that causes a pressure-mediated reduction in the GFR
has also been hypothesized.
Hypertension related to fluid retention and reduced kidney function may occur.
Failure to thrive may develop in patients with chronic edema, including ascites and pleural effusion.
Failure to thrive may be caused by anorexia, hypoproteinemia, increased protein catabolism, or
frequent infectious complications. Edema of the gut may cause defective absorption, leading to
chronic malnutrition.
Adverse treatment effects may occur. Corticosteroids and other immunosuppressive drugs have
significant adverse effects.
Prognosis
The prognosis for patients with primary nephrotic syndrome depends on its cause.
The prognosis with congenital nephrotic syndrome is bad. Survival beyond several months is
possible only with dialysis and kidney transplantation.
o Most children respond to steroid therapy; still, about 50% of children have 1 or 2
relapses within 5 years and approximately 20% of them continue to relapse 10
years after diagnosis. Only 30% of children never have a relapse after the initial
episode. Approximately 3% of patients who initially respond to steroids become
steroid-resistant.
o Poor patient response to steroid therapy may predict a poor outcome, and children
who present with hematuria and hypertension are more likely to be steroid-resistant
and have a poorer prognosis than are those who do not present with these
conditions.
Patient Education
o Progression to renal failure will require preparation for dialysis and/or kidney
transplantation.
o Forms of nephrotic syndrome that cannot be cured may evolve into renal failure and
the need for dialysis or kidney transplantation.
Miscellaneous
Medicolegal Pitfalls
A study using the Cochrane database has put into question whether prednisone treatment is
beneficial in adult minimal-change nephropathy.40 Nonetheless, when the nephrotic
syndrome causes illness, by uncomfortable edema or associated coagulopathy, treatment
would appear needed.
The role of preventive anticoagulation in nephrotic syndrome has been reported, but there is
no proof that it is beneficial.