5 Overview of Heavy Proteinuria and The Nephrotic Syndrome

17/12/2010
Overview of heavy proteinuria and th
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2010 UpToDate
Overview of heavy proteinuria and the nephrotic syndrome

Authors
Ellie Kelepouris, MD, FAHA
Zalman S Agus, MD
Section Editor
Richard J Glassock, MD, MACP
Last literature review version 18.3: Setembro 2010 |

2010
Deputy Editor
Alic e M Sheridan, MD
This topic last updated: Outubro 7,
CLASSIFICATION OF GLOMERULAR DISEASES Diseases of the glomerulus can result in three

different urinary and c linical patterns: focal nephritic; diffuse nephritic ; and nephrotic. (See
"Differential diagnosis of glomerular disease".)
Focal nephritic Disorders resulting in a focal nephritic sediment are generally assoc iated
with inflammatory lesions in less than one-half of glomeruli on light mic roscopy. The
urinalysis reveals red cells (which often have a dysmorphic appearance), oc casionally red
cell casts, and mild proteinuria (usually less than 1.5 g/day). The findings of more
advanced disease are usually absent, such as heavy proteinuria, edema, hypertension, and
renal insuffic ienc y. These patients often present with asymptomatic hematuria and
proteinuria discovered on routine examination or, occ asionally, with episodes of gross
hematuria.
Diffuse nephritic The urinalysis in diffuse glomerulonephritis is similar to foc al disease,
but heavy proteinuria (which may be in the nephrotic range), edema, hypertension, and/or
renal insuffic ienc y may be observed. Diffuse glomerulonephritis affec ts most or all of the
glomeruli.
Nephrotic The nephrotic sediment is assoc iated with heavy proteinuria and lipiduria, but
few c ells or casts. The term nephrotic syndrome refers to a distinc t constellation of clinical
and laboratory features of renal disease. It is specific ally defined by the presenc e of heavy
proteinuria (protein exc retion greater than 3 g/24 hours), hypoalbuminemia (less than 3.0
g/dL), and peripheral edema. Hyperlipidemia and thrombotic disease are also frequently
observed.
Isolated heavy proteinuria without edema or other features of the nephrotic syndrome is
suggestive of a glomerulopathy (with the same etiologies as the nephrotic syndrome), but is not
nec essarily associated with the multiple clinical and management problems charac teristic of the
nephrotic syndrome. This is an important c linical distinction because heavy proteinuria in
patients without edema or hypoalbuminemia is more likely to be due to secondary focal
segmental glomerulosclerosis (see below) [1].
This topic review will provide an overview of heavy proteinuria and the nephrotic syndrome, with
emphasis on those disorders with a nephrotic presentation (ie, bland rather active urine
sediment). More specific issues relating to the nephrotic syndrome, particularly the treatment of
the individual disorders, are disc ussed separately on the appropriate topic reviews.
ETIOLOGY Heavy proteinuria and the nephrotic syndrome may occ ur in association with a
wide variety of primary and systemic diseases. Minimal change disease is the predominant cause
in c hildren. In adults, approximately 30 percent have a systemic disease such as diabetes
mellitus, amyloidosis, or systemic lupus erythematosus; the remaining cases are usually due to
primary renal disorders suc h as minimal change disease, focal segmental glomerulosclerosis, and
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membranous nephropathy [2-9]. (See "Differential diagnosis of glomerular disease".)

Between the years 1994 and 2001, the frequency of the different forms of nephropathy
underlying the nephrotic syndrome was evaluated in a study based upon the glomerulonephritis
registry of Spain [2]. Among the 2000 patients between 15 and 65 years of age, the most
common causes were membranous nephropathy (24 perc ent), minimal c hange disease (16
percent), lupus (14 percent), focal segmental glomerulosclerosis (12 perc ent),
membranoproliferative glomerulonephritis (7 percent), amyloidosis (6 percent), and IgA
nephropathy (6 perc ent). A similar distribution was observed among the 725 elderly individuals
(age greater than 65 years) except for an increased incidence of amyloidosis (17 percent) and a
dec reased inc idenc e of lupus (1 perc ent).
The relative frequenc y of the different disorders has varied over time in some series as
illustrated by the following observations:
A study of 233 renal biopsies performed between 1995 and 1997 at the University of
Chic ago in adults with full-blown nephrotic syndrome (in the absenc e of an obvious
underlying disease suc h as diabetes mellitus or lupus) found the major causes to be
membranous nephropathy and focal segmental glomerulosclerosis (33 perc ent each),
minimal change disease (15 percent), and amyloidosis (4 perc ent overall, but 10 perc ent in
patients over age 44) [3].
The main change over time (c ompared to 1976-1979) was a marked increase in frequency
of focal segmental glomerulosclerosis (35 versus 15 percent), partic ularly in black patients
in whom it accounted for more than 50 percent of cases.
Similar findings were noted in a report from Springfield, Massachusetts which compared
renal biopsies at a single c enter that were performed in two time periods: 1975-1979 and
1990-1994 [4]. Over time, the relative frequency of membranous nephropathy fell from 38
to 15 perc ent, while the frequency of foc al segmental glomerulosclerosis increased from 14
to 25 perc ent overall; this increase was primarily seen in black and Hispanic patients. The
relative incidenc e of focal segmental glomerulosclerosis also appears to have increased in
Brazil [7].
The nephrotic syndrome can also develop in patients with postinfectious glomerulonephritis,
membranoproliferative glomerulonephritis, and IgA nephropathy. However, these individuals
typically have a "nephritic" type of urinalysis with hematuria and cellular (including red c ell) c asts
as a prominent feature. (See 'Classification of glomerular diseases' above.)
Minimal change disease Minimal change disease (also called nil disease or lipoid nephrosis)
acc ounts for 90 perc ent of c ases of the nephrotic syndrome in children under the age of 10, and
more than 50 percent of cases in older children. It also may occur in adults as an idiopathic
condition, in assoc iation with the use of nonsteroidal antiinflammatory drugs (NSAIDS), or as a
paraneoplastic effect of malignancy, most often Hodgkin lymphoma. (See "Diagnosis and causes
of minimal change disease in adults".)
The terms minimal change and nil disease reflec t the observation that light microscopy in this
disorder is either normal or reveals only mild mesangial cell proliferation (picture 1A-B).
Immunofluorescenc e and light microscopy typically show no evidenc e of immune complex
deposition. The c haracteristic histologic finding in minimal change disease is diffuse fusion of the
epithelial c ell foot proc esses on electron microscopy.
Focal segmental glomerulosclerosis Focal segmental glomerulosc lerosis (FSGS) is among
the most common cause of the idiopathic nephrotic syndrome in adults, ac counting for 35
percent of all cases in the United States and over 50 percent of cases among blacks [3]. FSGS
is characterized on light mic roscopy by the presence in some but not all glomeruli (hence the
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name focal) of segmental areas of mesangial collapse and sclerosis (picture 2A-B) [10]. FSGS
can present as an idiopathic syndrome (primary FSGS) or may be associated with HIV infec tion,
reflux nephropathy, healed previous glomerular injury, an idiosyncratic reaction to NSAIDs, or
massive obesity. (See "Pathogenesis and diagnosis of foc al segmental glomerulosclerosis".)
Diagnostic issues There are three important diagnostic concerns in FSGS:
Sampling error
Distinguishing primary and sec ondary FSGS
Identifying FSGS associated with c ollapsing glomerulopathy.
Sampling error can easily lead to misclassification of a patient with FSGS as having minimal
change disease. Clinical features that are more common in FSGS are hematuria, hypertension,
and dec reased renal function. There is, however, substantial overlap in these features. In
addition to careful review of the renal biopsy, steroid-resistanc e in a patient considered to have
minimal change disease should raise suspicion about FSGS. (See "Diagnosis and causes of minimal
change disease in adults".)
Primary FSGS is an epithelial cell disorder that may be related etiologically to minimal change
disease. In addition, as noted above, FSGS can oc cur as a secondary response to nephron loss
(as is reflux nephropathy) or previous glomerular injury. Differentiating primary and secondary
FSGS has important therapeutic implications. The former may respond to immunosuppressive
agents such as corticosteroids, while sec ondary disease is best treated with modalities aimed at
lowering the intraglomerular pressure, such as angiotensin converting enzyme inhibitors. (See
"Treatment of primary focal segmental glomerulosclerosis".)
The distinction between primary and secondary FSGS can usually be made from the history
(such as one of the disorders associated with secondary disease) and the rate of onset and
degree of proteinuria. Patients with primary FSGS typically present with the acute onset of the
nephrotic syndrome, whereas slowly increasing proteinuria and renal insufficiency over time are
characteristic of the secondary disorders. The proteinuria in secondary FSGS is often
nonnephrotic ; even when protein exc retion exceeds 3 to 4 g/day, both hypoalbuminemia and
edema are unusual [1].
Collapsing FSGS is a histologic variant that is usually but not always associated with HIV
infection. Two major features distinguish it from primary FSGS: a tendency to c ollapse and
sc lerosis of the entire glomerular tuft, rather than segmental injury; and often severe tubular
injury with proliferative microcyst formation and tubular degeneration (picture 3A-B). These
patients often have rapidly progressive renal failure and optimal therapy is uncertain. (See
"Collapsing focal segmental glomerulosclerosis and other renal diseases associated with HIV
infection" and "Collapsing foc al segmental glomerulosclerosis not associated with HIV infection".)
Membranous nephropathy Membranous nephropathy is among the most common cause of
primary nephrotic syndrome in adults. It is c haracterized by basement membrane thickening with
little or no cellular proliferation or infiltration, and the presence of elec tron dense deposits across
the glomerular basement membrane (picture 4A-F) [11,12].
Membranous nephropathy is most often idiopathic, although it can be associated with hepatitis B
antigenemia, autoimmune diseases, thyroiditis, c arcinoma, and the use of certain drugs such as
gold, penicillamine, captopril, and NSAIDs. The malignanc y in presumed tumor-induced
membranous nephropathy has usually been diagnosed or is c linically apparent at the time the
proteinuria is discovered. (See "Causes and diagnosis of membranous nephropathy".)
Amyloidosis As previously noted above, amyloidosis acc ounts for 4 to 17 percent of cases of
seemingly idiopathic nephrotic syndrome, with the increased infrequency observed among older
individuals [2,3]. There are two major types of renal amyloidosis: AL or primary amyloid, whic h is
a light chain dyscrasia in which fragments of monoclonal light c hains form the amyloid fibrils; and
AA or secondary amyloidosis, in which the acute phase reactant serum amyloid A forms the
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amyloid fibrils. AA amyloid is assoc iated with a chronic inflammatory disease such as rheumatoid
arthritis or osteomyelitis. (See "Renal amyloidosis".)
The diagnosis is suspected by a history of a chronic inflammatory disease or, with primary
disease, detection of a monoc lonal paraprotein in the serum or urine.
PATHOPHYSIOLOGY
Proteinuria There are three basic types of proteinuria; glomerular; tubular; and overflow.
(See "Evaluation of isolated proteinuria in adults".)
It is glomerular proteinuria that is responsible for protein loss in the nephrotic syndrome. The
proteinuria in glomerular disease is due to inc reased filtration of macromolecules across the
glomerular c apillary wall. This is commonly due to abnormalities in glomerular podoc ytes, including
podocyte foot process retrac tion and/or reorganization of the slit diaphragm [13]. Albumin is the
principal urinary protein, but other plasma proteins including clotting inhibitors, transferrin, and
hormone carrying proteins such as vitamin D-binding protein may be lost as well.
Hypoalbuminemia Serum albumin falls as a consequence of the proteinuria; hepatic albumin
synthesis inc reases in response to the albumin loss. The normal liver has a synthetic capacity to
increase the total albumin pool by approximately 25 grams per day. However, it remains unclear
why the liver of most patients exc reting 4 or 6 grams of protein per day is unable to increase
albumin synthesis suffic iently to normalize the plasma albumin conc entration. It is possible that
increased renal catabolism of filtered protein in these individuals leads to underestimation of
protein lost from the body as estimated from urinary protein exc retion. (See "Mechanism and
treatment of edema in nephrotic syndrome", section on 'Mec hanism of hypoalbuminemia'.)
Edema Two mec hanisms have been proposed to explain the occ urrenc e of edema in the
nephrotic syndrome. In some patients, marked hypoalbuminemia leads to egress of fluid into the
interstitial space by producing a dec rease in plasma oncotic pressure. In many others, there is a
parallel fall in the interstitial protein c onc entration and little c hange in the transc apillary oncotic
pressure gradient (figure 1) [14,15]. In the latter patients, edema appears to be the
consequence of primary renal sodium retention in the collec ting tubules (figure 2) [16,17]. The
lack of major arterial underfilling has important implications for diuretic therapy since the exc ess
fluid can usually be removed without inducing volume depletion [18]. (See "Mec hanism and
treatment of edema in nephrotic syndrome".)
Hyperlipidemia and lipiduria The two most c ommon lipid abnormalities in the nephrotic
syndrome are hyperc holesterolemia and hypertriglyceridemia. Decreased plasma oncotic pressure
appears to stimulate hepatic lipoprotein synthesis resulting in hypercholesterolemia. Diminished
clearanc e may also play a role in the development of hypercholesterolemia. Impaired metabolism
is primarily responsible for nephrotic hypertriglyceridemia. (See "Hyperlipidemia in nephrotic
syndrome".)
Lipiduria is usually present in the nephrotic syndrome. Urinary lipid may be present in the
sediment, entrapped in casts, enclosed by the plasma membrane of degenerative epithelial cells
(oval fat bodies), or free in the urine. Lipid c ontaining epithelial c ells are thought to be
degenerated renal tubular epithelial cells c ontaining cholesterol esters. Under polarized light
these oval fat bodies have the appearanc e of a Maltese cross (pic ture 5A-B). (See "Significance
of lipiduria".)
COMPLICATIONS Proteinuria and edema are the principal clinic al manifestations of the
nephrotic syndrome. Interstitial fluid tends to ac cumulate in dependent areas where tissue
turgor is low. Thus periorbital edema upon awakening in the morning and pedal edema are
common. Edema is often ac companied by serous effusions when it becomes generalized and
massive (anasarc a).
Less well apprec iated manifestations of the nephrotic syndrome include protein malnutrition,
hypovolemia, acute renal failure, urinary loss of hormones, hyperlipidemia and the potential for
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acc elerated atherosclerosis, a tendency to venous or arterial thrombosis, and inc reased
susc eptibility to infec tion [19].
Protein malnutrition A loss in lean body mass with negative nitrogen balanc e often occ urs in
patients with marked proteinuria, although it may be masked by concurrently inc reasing edema.
This may be compounded by gastrointestinal symptoms of anorexia and vomiting which are
secondary to edema of the gastrointestinal trac t.
Hypovolemia Symptomatic hypovolemia c an occ ur in nephrotic patients, often as a result of
over diuresis in those with a serum albumin less than 1.5 g/dL. Occ asional untreated children
show signs of volume depletion thought to be due to severe hypoalbuminemia c ausing fluid
movement into the interstitium.
Acute renal failure Acute renal failure c an develop in some patients with the nephrotic
syndrome, particularly minimal change disease. The mechanism is not understood; several
fac tors inc luding hypovolemia, interstitial edema, ischemic tubular injury, and the use of NSAIDs
have been suggested. (See "Ac ute kidney injury (acute renal failure) in minimal c hange disease
and other forms of nephrotic syndrome".) Two other major settings are c ollapsing FSGS, in which
the tubular injury is thought to play an important role, and c rescentic glomerulonephritis
superimposed upon membranous nephropathy, in which the urine sediment becomes active. (See
"Causes and diagnosis of membranous nephropathy".)
Thromboembolism Patients with the nephrotic syndrome have an increased incidence (10 to
40 perc ent of patients) of arterial and venous thrombosis (particularly deep vein and renal vein
thrombosis) and pulmonary emboli [20,21]. Cerebral vein thrombosis has also been rarely
reported [22]. The mechanism of the hypercoagulability is not completely understood. (See
"Renal vein thrombosis and hypercoagulable state in nephrotic syndrome".)
Renal vein thrombosis is found disproportionately in patients with membranous nephropathy,
particularly those excreting more than 10 g of protein per day. It can present acutely or, much
more commonly, in an indolent manner. The ac ute presentation includes flank pain, gross
hematuria, and a decline in renal function. Most patients are asymptomatic, and the diagnosis of
renal vein thrombosis is suspected only when pulmonary thromboembolism develops.
Infection Patients with the nephrotic syndrome are susceptible to infection, which was the
leading c ause of death in c hildren with the nephrotic syndrome before antibiotics became
available. Pneumococ cal infec tions, especially peritonitis, were particularly common. The
mec hanism of the impairment of normal defense mechanisms is not well understood; low levels of
immunoglobulin G may play a role.
Miscellaneous Proximal tubular dysfunction has been noted in some patients with the
nephrotic syndrome, often in association with advanced disease. This c an result in gluc osuria,
aminoaciduria, phosphaturia, renal tubular acidosis, and vitamin D deficiency. A decrease in
thyroxine-binding globulins can cause marked c hanges in various thyroid function tests, although
patients are clinic ally euthyroid. (See "Endocrine dysfunction in the nephrotic syndrome".)
Anemia, perhaps due to the urinary loss or impaired synthesis of erythropoietin, has also been
described in a few patients [23-25].
DIAGNOSIS Protein excretion can be measured on a 24-hour urine collec tion, with the normal
value being less than 150 mg/day. Patients excreting more than 3 g/day are c onsidered to have
nephrotic -range proteinuria.
There is an alternative to the cumbersome 24-hour urine c ollec tion: c alculating the total
protein-to-creatinine ratio (mg/mg) on a random urine specimen (figure 3) [26]. This ratio
correlates closely with daily protein exc retion in g/1.73 m2 of body surface area. Thus, a ratio of
4.9 (as with respective urinary protein and creatinine c oncentrations of 210 and 43 mg/dL)
represents daily protein excretion of approximately 4.9 g/1.73 m2 (calculator 1). There are some
limitations to estimating proteinuria from a random urine specimen. (See "Measurement of urinary
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protein exc retion" and "Patient information: Collec tion of a 24-hour urine spec imen".)
Once it has been determined that the patient has heavy proteinuria, the etiology may be
suggested from the history and physical examination. This is particularly true for patients who
have a systemic disease such as diabetes mellitus, systemic lupus erythematosus, HIV infection,
and intake of a commonly offending drug such as NSAIDs, gold, or penic illamine. In most cases,
however, renal biopsy is required to establish the diagnosis. A review of the findings suggesting
that a diabetic patient might have a different form of renal disease is available in a separate
topic review. (See "Overview of diabetic nephropathy".)
Serologic studies A number of serologic studies often are obtained in the evaluation of
patients with the nephrotic syndrome, inc luding antinuclear antibodies (ANA), complement
(C3/C4 and total hemolytic c omplement), serum free light chains and urine protein
elec trophoresis and immunofixation, syphilis serology, hepatitis B and hepatitis C serologies, and
the measurement of cryoglobulins. The value of all of these tests on a routine basis is uncertain
[27], but there are c ertain serologic tests that are highly suggestive of a particular disorder and
may preclude the need for renal biopsy: (see "Serologic tests in the evaluation of nephrotic
syndrome").
Serum free light chains and urine elec trophoresis and immunofixation, for the diagnosis of
amyloidosis; the presenc e of a paraprotein should be followed by fat pad or rectal biopsy
Antistreptococcal antibodies for the diagnosis of poststreptoc occ al glomerulonephritis
Cryoglobulins for the diagnosis of mixed cryoglobulinemia, which is most often due hepatitis
C virus infection
Although serologic tests and hypocomplementemia can establish the diagnosis of systemic lupus
erythematosus, renal biopsy is still indicated to determine the type of disease that is present.
(See "Types of renal disease in systemic lupus erythematosus".)
Renal biopsy Renal biopsy is the standard procedure for determining the c ause of proteinuria.
Pediatric nephrologists often use a trial of steroids bec ause of the high incidence of minimal
change disease. Most adult nephrologists, however, feel that biopsy is indicated when the
etiology of persistent nephrotic range proteinuria is in doubt in order to determine management
dec isions and occ asionally make an unexpected diagnosis. In one study of 28 adults with
nephrotic range proteinuria, for example, knowledge of the histology altered management in 24
(86 perc ent) [28]. (See "Indications for and complic ations of renal biopsy".)
Percutaneous renal biopsy is generally c ontraindic ated in the following settings:
Unc orrectable bleeding diathesis
Small kidneys which are generally indicative of chronic irreversible disease
Severe hypertension, whic h cannot be controlled with antihypertensive medications
Multiple, bilateral cysts or a renal tumor
Hydronephrosis
Active renal or perirenal infection
An unc ooperative patient
TREATMENT This section will review the general management issues in patients with
nephrotic syndrome. The treatment of the underlying disorder is discussed separately.
Proteinuria In the absenc e of spec ific therapy directed against the underlying disease,
efforts to lower intraglomerular pressure, which may be manifested as a reduction in protein
excretion, may slow the rate of disease progression. This is usually achieved by the
administration of an angiotensin converting enzyme inhibitor or angiotensin II receptor blocker.
Potentially adverse effects of these agents include acute renal failure and hyperkalemia; serum
creatinine and potassium levels should be measured during the initiation of therapy. (See
"Antihypertensive therapy and progression of nondiabetic c hronic kidney disease".)
Although protein restriction also may slow disease progression, the evidenc e is unclear and this
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modality is not usually used in nephrotic patients because of the heavy protein losses. (See
"Protein restric tion and progression of c hronic kidney disease".)
Edema Peripheral edema and asc ites is due to primary renal sodium retention in most patients
and should be treated with dietary sodium restriction (to approximately 2 g of sodium per day)
and diuretics. Edema should be reversed slowly to prevent acute hypovolemia. (See "Mechanism
and treatment of edema in nephrotic syndrome" and "Patient information: Low sodium diet".)
Loop diuretics are usually required. There generally is a lesser natriuresis than seen in normal
patients bec ause of hypoalbuminemia (causing decreased delivery of protein bound drug to the
kidney) and albuminuria (binding the drug within the tubular lumen). For these reasons, the
diuretic dose often has to be increased. An important guide for the evaluation of diuretic therapy
is serial measurement of body weight.
Hyperlipidemia The lipid abnormalities induc ed by the nephrotic syndrome reverse with
resolution of the disease, as with corticosteroid therapy in minimal change disease. The optimal
treatment of patients with persistent nephrosis is unc ertain. Dietary modification is generally of
little benefit. Most patients are initially treated with an HMG CoA reductase inhibitor (statin)
[29]. (See "Hyperlipidemia in nephrotic syndrome".)
Hypercoagulability There is a relatively high incidence of arterial and venous thromboemboli
among patients with the nephrotic syndrome, particularly with membranous nephropathy [30]. At
present, however, we do not rec ommend routine prophylac tic anticoagulation. If thrombosis
occ urs, it is typically treated with heparin followed by warfarin for as long as the patient remains
nephrotic . (See "Renal vein thrombosis and hypercoagulable state in nephrotic syndrome".)
INFORMATION FOR PATIENTS Educ ational materials on this topic are available for patients.
(See "Patient information: Protein in the urine (proteinuria)" and "Patient information: The
nephrotic syndrome" and "Patient information: Low sodium diet".) We encourage you to print or
e-mail these topic reviews, or to refer patients to our public web site,
www.uptodate.com/patients, which includes these and other topics.
SUMMARY AND RECOMMENDATIONS
The nephrotic syndrome is defined by the presence of heavy proteinuria (protein excretion
greater than 3 g/24 hours), hypoalbuminemia (less than 3.0 g/dL), and peripheral edema.
Hyperlipidemia and thrombotic disease may be present. (See 'Classification of glomerular
diseases' above.)
The predominant cause of the nephrotic syndrome in children is minimal change disease.
Approximately 30 percent of adults with the nephrotic syndrome have a systemic disease
such as diabetes mellitus, amyloidosis, or systemic lupus erythematosus; the remaining
cases are usually due to primary disorders inc luding minimal c hange disease, focal
segmental glomerulosc lerosis, and membranous nephropathy. Heavy proteinuria in patients
without edema or hypoalbuminemia is more likely to be due to secondary focal segmental
glomerulosclerosis. (See 'Etiology' above.)
Proteinuria and edema are the principal clinic al manifestations of the nephrotic syndrome.
Other manifestations include protein malnutrition, hypovolemia, ac ute renal failure, urinary
loss of hormones, hyperlipidemia and the potential for accelerated atherosc lerosis, a
tendency to venous and/or arterial thromboses and pulmonary embolism, and inc reased
susceptibility to infection. (See 'Complications' above.)
Proteinuria is due to increased filtration of macromolec ules ac ross the glomerular c apillary
wall. Albumin is the princ ipal urinary protein, but other plasma proteins including c lotting
inhibitors, transferrin, and hormone carrying proteins such as vitamin D-binding protein may
be lost as well. (See 'Proteinuria' above.)
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The etiology of heavy proteinuria may be suggested from the history and physic al. In most
cases a renal biopsy is required to establish the diagnosis. Serologic tests that are highly
suggestive of a particular disorder, and may preclude the need for renal biopsy, include
serum free light chains and urinary electrophoresis or immunofixation, for the diagnosis of
amyloidosis; antistreptococ cal antibodies for the diagnosis of poststreptococcal
glomerulonephritis; and cryoglobulins for the diagnosis of mixed cryoglobulinemia, which is
most often due hepatitis C virus infec tion. Although serologic tests and
hypoc omplementemia can establish the diagnosis of systemic lupus erythematosus, renal
biopsy is still indicated to determine the type of disease that is present. (See
'Diagnosis' above.)
Treatment inc ludes the administration of an angiotensin c onverting enzyme inhibitor or
angiotensin II receptor blocker to lower intraglomerular pressure, and dietary sodium
restriction and loop diuretic s to slowly reduce edema. The lipid abnormalities induced by
the nephrotic syndrome usually reverse with resolution of the disease, but most patients
are initially treated with an HMG CoA reductase inhibitor (statin). Arterial and venous
thromboemboli are typically treated with heparin followed by warfarin for as long as the
patient remains nephrotic. (See 'Treatment' above.)
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20. Llach, F. Hypercoagulability, renal vein thrombosis, and other thrombotic complications of
nephrotic syndrome. Kidney Int 1985; 28:429.
21. Rabelink, TJ, Zwaginga, JJ, Koomans, HA, Sixma, JJ. Thrombosis and hemostasis in renal
disease. Kidney Int 1994; 46:287.
22. Nishi, H, Abe, A, Kita, A, et al. Cerebral venous thrombosis in adult nephrotic syndrome due
to systemic amyloidosis. Clin Nephrol 2006; 65:61.
23. Vaziri, ND, Kaupke, CJ, Barton, CH, Gonzales, E. Plasma concentration and urinary exc retion
of erythropoietin in adult nephrotic syndrome. Am J Med 1992; 92:35.
24. Vaziri, ND. Endoc rinological consequences of the nephrotic syndrome. Am J Nephrol 1993;
13:360.
25. Mhr, N, Neyer, U, Prischl, F, et al. Proteinuria and hemoglobin levels in patients with
primary glomerular disease. Am J Kidney Dis 2005; 46:424.
26. Ginsberg, JM, Chang, BS, Matarese, RA, Garella, S. Use of single voided urine samples to
estimate quantitative proteinuria. N Engl J Med 1983; 309:1543.
27. Howard, AD, Moore J, Jr, Gouge, SF, et al. Routine serologic tests in the differential
diagnosis of the adult nephrotic syndrome. Am J Kidney Dis 1990; 15:24.
28. Richards, NT, Darby, S, Howie, AJ, et al. Knowledge of renal histology alters patient
management in over 40% of cases. Nephrol Dial Transplant 1994; 9:1255.
29. Wheeler, DC, Bernard, DB. Lipid abnormalities in the nephrotic syndrome: causes,
consequences, and treatment. Am J Kidney Dis 1994; 23:331.
30. Orth, SR, Ritz, E. The nephrotic syndrome. N Engl J Med 1998; 338:1202.
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GRAPHICS
Minimal change disease
Light micrograph of an essentially normal glomerulus in minimal

change disease. There are only 1 or 2 cells per capillary tuft,
the capillary lumens are open, the thickness of the glomerular
capillary walls is normal, and there is neither expansion nor
hypercellularity in the mesangial areas in the central or stalk
regions of the tuft (arrows). Courtesy of Helmut G Rennke.
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Normal glomerulus
Light micrograph of a normal glomerulus. There are only 1 or 2

cells per capillary tuft, the capillary lumens are open, the
thickness of the glomerular capillary wall (long arrow) is similar
to that of the tubular basement membranes (short arrow),
and the mesangial cells and mesangial matrix are located in the
central or stalk regions of the tuft (arrows). Courtesy of Helmut G
Rennke.
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Minimal change disease
Electron micrograph in minimal change disease showing a

normal glomerular basement membrane (GBM), no immune
deposits, and the characteristic widespread fusion of the
epithelial cell foot processes (arrows). Courtesy of Helmut Rennke,
MD.
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Normal glomerulus
Electron micrograph of a normal glomerular capillary loop

showing the fenestrated endothelial cell (Endo), the glomerular
basement membrane (GBM), and the epithelial cells with its
interdigitating foot processes (arrow). The GBM is thin and no
electron dense deposits are present. Two normal platelets are
seen in the capillary lumen. Courtesy of Helmut Rennke, MD.
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Mild FGS
Light micrograph shows early changes in focal

glomerulosclerosis with segmental capillary collapse (arrows) in
areas of epithelial cell injury (small arrowhead). Courtesy of
Helmut Rennke, MD.
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Normal glomerulus

Rennke.
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Moderate FGS
Light micrograph in focal segmental glomerulosclerosis shows

a moderately large segmental area of sclerosis with capillary
collapse on the upper left side of the glomerular tuft; the lower
right segment is relatively normal. Focal deposition of hyaline
material (arrow) is also seen. Courtesy of Helmut Rennke, MD.
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Normal glomerulus

Rennke.
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Collapsing FGS
Light micrograph showing collapsing glomerulosclerosis with

few open loops in the sclerotic areas (long arrows); these
findings are characteristic of HIV nephropathy but can also be
seen in idiopathic disease. The degree of collapse can be
appreciated by the openness of Bowman's space.
Vacuolization and crowding of the glomerular epithelial cells
(short arrows) is also frequently seen and reflects the primary
epithelial cell injury in this disorder. Courtesy of Helmut Rennke,
MD.
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Normal glomerulus

Rennke.
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Tubuloreticular structures in HIV nephropathy
Electron micrograph in HIV-induced focal collapsing

glomerulosclerosis shows numerous intraendothelial (End)
tubuloreticular structures (arrow). These structures are not
seen in the idiopathic form of the disease. The epithelial cell
(Ep) has no discrete foot processes, a reflection of primary
epithelial cell injury. Courtesy of Helmut Rennke, MD.
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Normal glomerulus

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Membranous nephropathy
Light micrograph of membranous nephropathy, showing

diffuse thickening of the glomerular basement membrane (long
arrows) with essentially normal cellularity. Note how the
thickness of the glomerular capillary walls is much greater than
that of the adjacent tubular basement membranes (short
arrow). There are also areas of mesangial expansion
(asterisks). Immunofluorescence microscopy (showing granular
IgG deposition) and electron microscopy (showing subepithelial
deposits) are generally required to confirm the diagnosis.
Courtesy of Helmut Rennke, MD.
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Normal glomerulus

Rennke.
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Immunofluorescence microscopy in membranous nephropathy

showing diffuse, granular IgG deposition along the capillary
walls. Courtesy of Helmut Rennke, MD.
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Electron micrograps shows stage II membranous nephropathy.

Electron dense deposits (D) are present in the subepithelial
space across the glomerular basement membrane (GBM) and
under the epithelial cells (Ep). New basement membrane is
growing between the deposits, leading to a spike appearance
on silver stain. Courtesy of Helmut Rennke, MD.
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Normal glomerulus

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Silver stain in membranous nephropathy
Light micrograph silver stain of membranous nephropathy

shows a spike appearance (arrows). The spikes represent new
basement membrane growing between the subepithelial
immune deposits which are visible on electron microscopy, but
not with this stain. Courtesy of Helmut Rennke, MD.
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Stage III membranous nephropathy
Electron micrograph in stage III membranous nephropathy.

The subepithelial immune deposits (D) have a lucent, motheaten appearance and have been incorporated into the
glomerular basement membrane (GBM) as new basement
membrane has grown around the deposits (arrows). Courtesy of
Helmut Rennke, MD.
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Normal glomerulus

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Membranous lupus nephritis
Electron micrograph of membranous lupus nephritis. The

subepithelial immune deposits (D) are characteristic of any
form of membranous nephropathy, but the intraendothelial
tubuloreticular structures (arrow) strongly suggest underlying
lupus. GBM: glomerular basement membrane; Ep: epithelial cell.
Courtesy of Helmut Rennke, MD.
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Normal glomerulus

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Little change in oncotic pressure gradient in nephrotic

syndrome
Relation between plasma and interstitial oncotic pressures in

patients with the nephrotic syndrome due to minimal change
disease before (open circles) and after (closed circles) steroidinduced remission of the proteinuria. Both parameters are reduced
in the nephrotic state, resulting in little change in the transcapillary
oncotic pressure gradient and therefore little tendency to
promoting edema formation. Data from Koomans, HA, Kortlandt, W,
Geers, AB, Dorhout Mees, EJ, Nephron 1985; 40:391.
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Increased collecting tubule sodium reabsorption in nephrotic

syndrome
Micropuncture studies (in which samples are taken via micropipettes

from different nephron segments) of sodium handling in unilateral
nephrotic syndrome in the rat. Although less sodium is filtered in the
nephrotic kidney, less is reabsorbed so that the quantity of sodium
remaining in the tubular lumen at the end of the distal tubule is the
same in the two kidneys. Thus, sodium reabsorption must be
increased in the collecting tubules to account for the two-thirds
reduction in total sodium excretion in the nephrotic kidney when
compared to the normal kidney. Data from Ichikawa, I, Rennke, HG, Hoyer,
JR, et al, J Clin Invest 1983; 71:91.
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Fatty cast
Urine sediment showing a fatty cast. The fat droplets (or

globules) can be distinguished from red cells (which also have
a round appearance) by their variable size (from much smaller
to much larger than a red cell), dark outline, and "Maltese
cross" appearance under polzarized light. Courtesy of Frances
Andrus, BA, Victoria Hospital, London, Ontario.
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Fatty cast
Urine sediment showing fatty cast under polarized light. The

fat droplets have a characteristic "Maltese cross" appearance
(arrow). Courtesy of Harvard Medical School.
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Protein-creatinine ratio to estimate protein excretion
This graph illustrates the relation between total 24-hour

urinary protein excretion and the total protein-to-creatinine
ratio (mg/mg) determined on a random urine specimen.
Athough there appears to be a close correlation, there can be
wide variability in 24-hour protein excretion at a given total
protein-to-creatinine ratio. At a ratio of 2, for example, 24hour protein excretion varied from 2 to almost 8 g/day. Data
from Ginsberg, JM, Chang, BS, Matarese, RA, Garella, S. N Engl J Med
1983; 309:1543.
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Overview of heavy proteinuria and th

Offic ial reprint from UpToDate

Overview of heavy proteinuria and the nephrotic syndrome

Last literature review version 18.3: Setembro 2010 |

This topic last updated: Outubro 7,

CLASSIFICATION OF GLOMERULAR DISEASES Diseases of the glomerulus can result in three

Overview of heavy proteinuria and th

membranous nephropathy [2-9]. (See "Differential diagnosis of glomerular disease".)

Overview of heavy proteinuria and th

Overview of heavy proteinuria and th

Overview of heavy proteinuria and th

Overview of heavy proteinuria and th

Overview of heavy proteinuria and th

Overview of heavy proteinuria and th

Use of UpToDate is subjec t to the Subscription and License Agreement.

Overview of heavy proteinuria and th

Overview of heavy proteinuria and th

Light micrograph of an essentially normal glomerulus in minimal

Overview of heavy proteinuria and th

Light micrograph of a normal glomerulus. There are only 1 or 2

Overview of heavy proteinuria and th

Minimal change disease

Electron micrograph in minimal change disease showing a

Overview of heavy proteinuria and th

Electron micrograph of a normal glomerular capillary loop

Overview of heavy proteinuria and th

Light micrograph shows early changes in focal

Overview of heavy proteinuria and th

Light micrograph of a normal glomerulus. There are only 1 or 2

Overview of heavy proteinuria and th

Light micrograph in focal segmental glomerulosclerosis shows

Overview of heavy proteinuria and th

Light micrograph of a normal glomerulus. There are only 1 or 2

Overview of heavy proteinuria and th

Light micrograph showing collapsing glomerulosclerosis with

Overview of heavy proteinuria and th

Light micrograph of a normal glomerulus. There are only 1 or 2

Overview of heavy proteinuria and th

Tubuloreticular structures in HIV nephropathy

Electron micrograph in HIV-induced focal collapsing

Overview of heavy proteinuria and th

Electron micrograph of a normal glomerular capillary loop

Overview of heavy proteinuria and th

Light micrograph of membranous nephropathy, showing

Overview of heavy proteinuria and th

Light micrograph of a normal glomerulus. There are only 1 or 2

Overview of heavy proteinuria and th

Immunofluorescence microscopy in membranous nephropathy

Overview of heavy proteinuria and th

Electron micrograps shows stage II membranous nephropathy.

Overview of heavy proteinuria and th

Electron micrograph of a normal glomerular capillary loop

Overview of heavy proteinuria and th

Silver stain in membranous nephropathy

Light micrograph silver stain of membranous nephropathy

Overview of heavy proteinuria and th

Stage III membranous nephropathy

Electron micrograph in stage III membranous nephropathy.

Overview of heavy proteinuria and th

Electron micrograph of a normal glomerular capillary loop

Overview of heavy proteinuria and th

Membranous lupus nephritis