5 overview of heavy proteinuria and the nephrotic syndrome

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Official reprint from UpToDate

www.uptodate.com

2010 UpToDate

AuthorsEllie Kelepouris, MD, FAHAZalman S Agus, MD

Section EditorRichard J Glassock, MD, MACP

Deputy EditorAlice M Sheridan, MD

Overview of heavy proteinuria and the nephrotic syndrome

Last literature review version 18.3:Setembro 2010 | This topic last updated:Outubro 7,2010

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

different urinary and clinical patterns: focal nephritic; diffuse nephritic; and nephrotic. (See

"Differential diagnosis of glomerular disease".)

Focal nephritic Disorders resulting in a focal nephritic sediment are generally associatedwith inflammatory lesions in less than one-half of glomeruli on light microscopy. The

urinalysis reveals red cells (which often have a dysmorphic appearance), occasionally 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 insufficiency. These patients often present with asymptomatic hematuria and

proteinuria discovered on routine examination or, occasionally, with episodes of gross

hematuria.

Diffuse nephritic The urinalysis in diffuse glomerulonephritis is similar to focal disease,

but heavy proteinuria (which may be in the nephrotic range), edema, hypertension, and/or

renal insufficiency may be observed. Diffuse glomerulonephritis affects most or all of theglomeruli.

Nephrotic The nephrotic sediment is associated with heavy proteinuria and lipiduria, but

few cells or casts. The term nephrotic syndrome refers to a distinct constellation of c linical

and laboratory features of renal disease. It is specifically 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 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

necessarily associated with the multiple clinical and management problems characteristic of the

nephrotic syndrome. This is an important clinical 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 discussed separately on the appropriate topic reviews.

ETIOLOGY Heavy proteinuria and the nephrotic syndrome may occur in association with awide variety of primary and systemic diseases. Minimal change disease is the predominant cause

in children. 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 such 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 percent), minimal change disease (16

percent), lupus (14 percent), focal segmental glomerulosclerosis (12 percent),

membranoproliferative glomerulonephritis (7 percent), amyloidosis (6 percent), and IgA

nephropathy (6 percent). 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

decreased incidence of lupus (1 percent).

The relative frequency 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

Chicago in adults with full-blown nephrotic syndrome (in the absence of an obvious

underlying disease such as diabetes mellitus or lupus) found the major causes to be

membranous nephropathy and focal segmental glomerulosclerosis (33 percent each),

minimal change disease (15 percent), and amyloidosis (4 percent overall, but 10 percent inpatients over age 44) [3].

The main change over time (compared to 1976-1979) was a marked increase in frequency

of focal segmental glomerulosclerosis (35 versus 15 percent), particularly 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 center 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 percent, while the frequency of focal segmental glomerulosclerosis increased from 14to 25 percent overall; this increase was primarily seen in black and Hispanic patients. The

relative incidence 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 cell) casts

as a prominent feature. (See 'Classification of glomerular diseases'above.)

Minimal change disease Minimal change disease (also called nil disease or lipoid nephrosis)

accounts for 90 percent of cases of the nephrotic syndrome in children under the age of 10, andmore than 50 percent of cases in older children. It also may occur in adults as an idiopathic

condition, in association 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 reflect the observation that light microscopy in this

disorder is either normal or reveals only mild mesangial cell proliferation (picture 1A-B).

Immunofluorescence and light microscopy typically show no evidence of immune complex

deposition. The characteristic histologic finding in minimal change disease is diffuse fusion of the

epithelial cell foot processes on electron microscopy.

Focal segmental glomerulosclerosis Focal segmental glomerulosclerosis (FSGS) is among

the most common cause of the idiopathic nephrotic syndrome in adults, accounting for 35

percent of all cases in the United States and over 50 percent of cases among blacks [3]. FSGS

is characterized on light microscopy 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 infection,

reflux nephropathy, healed previous glomerular injury, an idiosyncratic reaction to NSAIDs, or

massive obesity. (See "Pathogenesis and diagnosis of focal segmental glomerulosclerosis".)

Diagnostic issues There are three important diagnostic concerns in FSGS:

Sampling error

Distinguishing primary and secondary FSGS

Identifying FSGS associated with collapsing 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 decreased renal function. There is, however, substantial overlap in these features. In

addition to careful review of the renal biopsy, steroid-resistance 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 secondaryFSGS has important therapeutic implications. The former may respond to immunosuppressive

agents such as corticosteroids, while secondary 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 excretion 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 collapse and

sclerosis 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 focal segmental glomerulosclerosis not associated with HIV infection".)

Membranous nephropathy Membranous nephropathy is among the most common cause ofprimary nephrotic syndrome in adults. It is characterized by basement membrane thickening with

little or no cellular proliferation or infiltration, and the presence of electron 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, carcinoma, and the use of certain drugs such as

gold, penicillamine, captopril, and NSAIDs. The malignancy in presumed tumor-induced

membranous nephropathy has usually been diagnosed or is clinically apparent at the time the

proteinuria is discovered. (See "Causes and diagnosis of membranous nephropathy".)

Amyloidosis As previously noted above, amyloidosis accounts for 4 to 17 percent of cases ofseemingly 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, which is

a light chain dyscrasia in which fragments of monoclonal light chains 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 monoclonal 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 increased filtration of macromolecules across the

glomerular capillary wall. This is commonly due to abnormalities in glomerular podocytes, including

podocyte foot process retraction 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 increases 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 unclearwhy the liver of most patients excreting 4 or 6 grams of protein per day is unable to increase

albumin synthesis sufficiently to normalize the plasma albumin concentration. 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 excretion. (See "Mechanism and

treatment of edema in nephrotic syndrome", section on 'Mechanism of hypoalbuminemia'.)

Edema Two mechanisms have been proposed to explain the occurrence of edema in the

nephrotic syndrome. In some patients, marked hypoalbuminemia leads to egress of fluid into the

interstitial space by producing a decrease in plasma oncotic pressure. In many others, there is a

parallel fall in the interstitial protein concentration and little change in the transcapillary oncotic

pressure gradient (figure 1) [14,15]. In the latter patients, edema appears to be theconsequence of primary renal sodium retention in the collecting tubules (figure 2) [16,17]. The

lack of major arterial underfilling has important implications for diuretic therapy since the excess

fluid can usually be removed without inducing volume depletion [18]. (See "Mechanism and

treatment of edema in nephrotic syndrome".)

Hyperlipidemia and lipiduria The two most common lipid abnormalities in the nephrotic

syndrome are hypercholesterolemia and hypertriglyceridemia. Decreased plasma oncotic pressure

appears to stimulate hepatic lipoprotein synthesis resulting in hypercholesterolemia. Diminished

clearance 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 containing epithelial cells are thought to be

degenerated renal tubular epithelial cells containing cholesterol esters. Under polarized light

these oval fat bodies have the appearance of a Maltese cross (picture 5A-B). (See "Significance

of lipiduria".)

COMPLICATIONS Proteinuria and edema are the principal clinical manifestations of the

nephrotic syndrome. Interstitial fluid tends to accumulate in dependent areas where tissue

turgor is low. Thus periorbital edema upon awakening in the morning and pedal edema arecommon. Edema is often accompanied by serous effusions when it becomes generalized and

massive (anasarca).

Less well appreciated 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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accelerated atherosclerosis, a tendency to venous or arterial thrombosis, and increased

susceptibility to infection [19].

Protein malnutrition A loss in lean body mass with negative nitrogen balance often occurs in

patients with marked proteinuria, although it may be masked by concurrently increasing edema.

This may be compounded by gastrointestinal symptoms of anorexia and vomiting which are

secondary to edema of the gastrointestinal tract.

Hypovolemia Symptomatic hypovolemia can occur in nephrotic patients, often as a result of

over diuresis in those with a serum albumin less than 1.5 g/dL. Occasional untreated children

show signs of volume depletion thought to be due to severe hypoalbuminemia causing fluid

movement into the interstitium.

Acute renal failure Acute renal failure can develop in some patients with the nephrotic

syndrome, particularly minimal change disease. The mechanism is not understood; several

fac tors including hypovolemia, interstitial edema, ischemic tubular injury, and the use of NSAIDs

have been suggested. (See "Acute kidney injury (acute renal failure) in minimal change disease

and other forms of nephrotic syndrome".) Two other major settings are collapsing FSGS, in which

the tubular injury is thought to play an important role, and crescentic 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 percent 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 acute presentat ion 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 infect ion, which was the

leading cause of death in children with the nephrotic syndrome before antibiotics became

available. Pneumococcal infections, especially peritonitis, were particularly common. The

mechanism 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 can result in glucosuria,

aminoaciduria, phosphaturia, renal tubular acidosis, and vitamin D deficiency. A decrease inthyroxine-binding globulins can cause marked changes in various thyroid function tests, although

patients are clinically 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 collection, with the normal

value being less than 150 mg/day. Patients excreting more than 3 g/day are considered to have

nephrotic-range proteinuria.

There is an alternative to the cumbersome 24-hour urine collection: calculating the total

protein-to-creatinine ratio (mg/mg) on a random urine specimen (figure 3) [26]. This ratiocorrelates closely with daily protein excretion in g/1.73 m2 of body surface area. Thus, a ratio of

4.9 (as with respective urinary protein and creatinine concentrations 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 excretion"and "Patient information: Collection 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 penicillamine. 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, including antinuclear antibodies (ANA), complement

(C3/C4 and total hemolytic complement), serum free light chains and urine protein

electrophoresis 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 certain 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 electrophoresis and immunofixation, for the diagnosis of

amyloidosis; the presence of a paraprotein should be followed by fat pad or rectal biopsy

Antistreptococcal antibodies for the diagnosis of poststreptococc 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 cause of proteinuria.

Pediatric nephrologists often use a trial of steroids because 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

decisions and occasionally 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 percent) [28]. (See "Indications for and complications of renal biopsy".)

Percutaneous renal biopsy is generally contraindicated in the following settings:

Uncorrectable bleeding diathesis

Small kidneys which are generally indicative of chronic irreversible disease

Severe hypertension, which cannot be controlled with antihypertensive medications

Multiple, bilateral cysts or a renal tumorHydronephrosis

Active renal or perirenal infection

An uncooperative 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 absence of specific 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 chronic kidney disease".)

Although protein restriction also may slow disease progression, the evidence is unclear and this




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modality is not usually used in nephrotic patients because of the heavy protein losses. (See

"Protein restriction and progression of chronic kidney disease".)

Edema Peripheral edema and ascites 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 because 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 induced 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 uncertain. 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 thromboemboliamong patients with the nephrotic syndrome, particularly with membranous nephropathy [30]. At

present, however, we do not recommend routine prophylactic anticoagulation. If thrombosis

occurs, it is typically treated with heparin followed by warfarinfor as long as the patient remains

nephrotic. (See "Renal vein thrombosis and hypercoagulable state in nephrotic syndrome".)

INFORMATION FOR PATIENTS Educational 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 including minimal change disease, focalsegmental glomerulosclerosis, 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 clinical manifestations of the nephrotic syndrome.

Other manifestations include protein malnutrition, hypovolemia, acute renal failure, urinary

loss of hormones, hyperlipidemia and the potential for accelerated atherosclerosis, a

tendency to venous and/or arterial thromboses and pulmonary embolism, and increased

suscept ibility to infection. (See 'Complications'above.)

Proteinuria is due to increased filtration of macromolecules across the glomerular capillarywall. 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. (See 'Proteinuria'above.)




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The etiology of heavy proteinuria may be suggested from the history and physical. 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; antistreptococcal antibodies for the diagnosis of poststreptococcal

glomerulonephritis; and 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'Diagnosis'above.)

Treatment includes the administration of an angiotensin converting enzyme inhibitor or

angiotensin II receptor blocker to lower intraglomerular pressure, and dietary sodium

restriction and loop diuretics 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 t reated with heparin followed by warfarinfor as long as the

patient remains nephrotic. (See 'Treatment'above.)

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3. Haas, M, Meehan, SM, Karrison, TG, Spargo, BH. Changing etiologies of unexplained adultnephrotic syndrome: a comparison of renal biopsy findings from 1976-1979 and 1995-1997.Am J Kidney Dis 1997; 30:621.

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(1979-1999): is the frequency of focal and segmental glomerulosclerosis increasing? ClinNephrol 2004; 61:90.

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11. Austin, HA 3d, Antonovych, TT, MacKay, K, et al. NIH Conference. Membranousnephropathy. Ann Intern Med 1992; 116:672.

12. Wasserstein, AG. Membranous glomerulonephritis. J Am Soc Nephrol 1997; 8:664.

13. Reiser, J, von Gersdorff, G, Loos, M, et al. Induction of B7-1 in podocytes is associatedwith nephrotic syndrome. J Clin Invest 2004; 113:1390.

14. Noddeland, H, Riisnes, SM, Fadnes, HO. Interstitial fluid colloid osmotic and hydrostaticpressures in subcutaneous tissue of patients with nephrotic syndrome. Scand J Clin LabInvest 1982; 42:139.




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15. Koomans, HA, Kortlandt, W, Geers, AB, Dorhout Mees, EJ. Lowered protein content oftissue fluid in patients with the nephrotic syndrome: observations during disease andrecovery. Nephron 1985; 40:391.

16. Ichikawa, I, Rennke, HG, Hoyer, JR, et al. Role for intrarenal mechanisms in the impaired saltexcretion of experimental nephrotic syndrome. J Clin Invest 1983; 71:91.

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18. Geers, AB, Koomans, HA, Roos, JC, Dorhout Mees, EJ. Preservation of blood volume duringedema removal in nephrotic subjects. Kidney Int 1985; 28:652.

19. Crew, RJ, Radhakrishnan, J, Appel, G. Complications of the nephrotic syndrome and theirtreatment. Clin Nephrol 2004; 62:245.

20. Llach, F. Hypercoagulability, renal vein thrombosis, and other thrombotic complications ofnephrotic syndrome. Kidney Int 1985; 28:429.

21. Rabelink, TJ, Zwaginga, JJ, Koomans, HA, Sixma, JJ. Thrombosis and hemostasis in renaldisease. Kidney Int 1994; 46:287.

22. Nishi, H, Abe, A, Kita, A, et al. Cerebral venous thrombosis in adult nephrotic syndrome dueto systemic amyloidosis. Clin Nephrol 2006; 65:61.

23. Vaziri, ND, Kaupke, CJ, Barton, CH, Gonzales, E. Plasma concentration and urinary excretionof erythropoietin in adult nephrotic syndrome. Am J Med 1992; 92:35.

24. Vaziri, ND. Endocrinological 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 withprimary glomerular disease. Am J Kidney Dis 2005; 46:424.

26. Ginsberg, JM, Chang, BS, Matarese, RA, Garella, S. Use of single voided urine samples toestimate quantitative proteinuria. N Engl J Med 1983; 309:1543.

27. Howard, AD, Moore J, Jr, Gouge, SF, et al. Routine serologic tests in the differentialdiagnosis 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 patientmanagement 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 minimalchange disease. There are only 1 or 2 cells per capillary tuft,the capillary lumens are open, the thickness of the glomerularcapillary walls is normal, and there is neither expansion norhypercellularity in the mesangial areas in the central or stalkregions 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 2cells per capillary tuft, the capillary lumens are open, the

thickness of the glomerular capillary wall (long arrow) is similarto that of the tubular basement membranes (short arrow),and the mesangial cells and mesangial matrix are located in thecentral or stalk regions of the tuft (arrows). Courtesy of Helmut GRennke.




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Minimal change disease

Electron micrograph in minimal change disease showing anormal glomerular basement membrane (GBM), no immune

deposits, and the characteristic widespread fusion of theepithelial 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 glomerularbasement membrane (GBM), and the epithelial cells with itsinterdigitating foot processes (arrow). The GBM is thin and noelectron dense deposits are present. Two normal platelets areseen in the capillary lumen. Courtesy of Helmut Rennke, MD.




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Mild FGS

Light micrograph shows early changes in focalglomerulosclerosis with segmental capillary collapse (arrows) inareas of epithelial cell injury (small arrowhead). Courtesy ofHelmut Rennke, MD.




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Normal glomerulus






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Moderate FGS

Light micrograph in focal segmental glomerulosclerosis showsa moderately large segmental area of sclerosis with capillarycollapse on the upper left side of the glomerular tuft; the lowerright segment is relatively normal. Focal deposition of hyalinematerial (arrow) is also seen. Courtesy of Helmut Rennke, MD.




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Normal glomerulus






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Collapsing FGS

Light micrograph showing collapsing glomerulosclerosis withfew open loops in the sclerotic areas (long arrows); thesefindings are characteristic of HIV nephropathy but can also be

seen in idiopathic disease. The degree of collapse can beappreciated by the openness of Bowman's space.Vacuolization and crowding of the glomerular epithelial cells(short arrows) is also frequently seen and reflects the primaryepithelial cell injury in this disorder. Courtesy of Helmut Rennke,MD.




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Normal glomerulus






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Tubuloreticular structures in HIV nephropathy

Electron micrograph in HIV-induced focal collapsingglomerulosclerosis 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 primaryepithelial cell injury. Courtesy of Helmut Rennke, MD.




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Normal glomerulus






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Membranous nephropathy

Light micrograph of membranous nephropathy, showingdiffuse thickening of the glomerular basement membrane (long

arrows) with essentially normal cellularity. Note how thethickness of the glomerular capillary walls is much greater thanthat of the adjacent tubular basement membranes (shortarrow). There are also areas of mesangial expansion(asterisks). Immunofluorescence microscopy (showing granularIgG deposition) and electron microscopy (showing subepithelialdeposits) are generally required to confirm the diagnosis.Courtesy of Helmut Rennke, MD.




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Normal glomerulus






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Immunofluorescence microscopy in membranous nephropathyshowing diffuse, granular IgG deposition along the capillarywalls. 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) andunder the epithelial cells (Ep). New basement membrane isgrowing between the deposits, leading to a spike appearanceon 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 newbasement membrane growing between the subepithelialimmune deposits which are visible on electron microscopy, butnot 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, moth-

eaten appearance and have been incorporated into theglomerular basement membrane (GBM) as new basementmembrane has grown around the deposits (arrows). Courtesy ofHelmut Rennke, MD.




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Normal glomerulus






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Membranous lupus nephritis

Electron micrograph of membranous lupus nephritis. Thesubepithelial immune deposits (D) are characteristic of anyform of membranous nephropathy, but the intraendothelial

tubuloreticular structures (arrow) strongly suggest underlyinglupus. 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 nephroticsyndrome

Relation between plasma and interstitial oncotic pressures in

patients with the nephrotic syndrome due to minimal changedisease before (open circles) and after (closed circles) steroid-induced remission of the proteinuria. Both parameters are reducedin the nephrotic state, resulting in little change in the transcapillaryoncotic pressure gradient and therefore little tendency topromoting 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 nephroticsyndrome

Micropuncture studies (in which samples are taken via micropipettesfrom different nephron segments) of sodium handling in unilateralnephrotic syndrome in the rat. Although less sodium is filtered in the

nephrotic kidney, less is reabsorbed so that the quantity of sodiumremaining in the tubular lumen at the end of the distal tubule is thesame in the two kidneys. Thus, sodium reabsorption must beincreased in the collecting tubules to account for the two-thirdsreduction in total sodium excretion in the nephrotic kidney whencompared 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 (orglobules) can be distinguished from red cells (which also havea round appearance) by their variable size (from much smallerto much larger than a red cell), dark outline, and "Maltesecross" 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. Thefat 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-creatinineratio (mg/mg) determined on a random urine specimen.Athough there appears to be a close correlation, there can bewide variability in 24-hour protein excretion at a given totalprotein-to-creatinine ratio. At a ratio of 2, for example, 24-hour protein excretion varied from 2 to almost 8 g/day. Datafrom Ginsberg, JM, Chang, BS, Matarese, RA, Garella, S. N Engl J Med

1983; 309:1543.



5 overview of heavy proteinuria and the nephrotic syndrome

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