Overview of heavy proteinuria and the nephrotic syndrome.pdf

2/2/2015 Overview of heavy proteinuria and the nephrotic syndrome

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Official reprint from UpToDate www.uptodate.com 2015 UpToDate

AuthorsEllie Kelepouris, MD, FAHABrad H Rovin, MD

Section EditorRichard J Glassock, MD,MACP

Deputy EditorJohn P Forman, MD, MSc

Overview of heavy proteinuria and the nephrotic syndrome

All topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Nov 2014. | This topic last updated: Jul 02, 2014.

INTRODUCTION AND TERMINOLOGY Diseases of the glomerulus can result in three different urinary and

clinical patterns: focal nephritic; diffuse nephritic; and nephrotic. (See "Differential diagnosis and evaluation of

glomerular disease".)

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 (FSGS) (due, for example, to diabetes) [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 than active urine sediment). More specific issues relating to

complications of the nephrotic syndrome are presented elsewhere. (See "Pathophysiology and treatment of edema

in patients with the nephrotic syndrome" and "Renal vein thrombosis and hypercoagulable state in nephrotic

syndrome" and "Endocrine dysfunction in the nephrotic syndrome" and "Lipid abnormalities in nephrotic syndrome"

and "Acute kidney injury (AKI) in minimal change disease and other forms of nephrotic syndrome".)

The individual disorders that cause the nephrotic syndrome are discussed in detail in separate topic reviews.

Readers will be referred to these individual topics where appropriate.

ETIOLOGY Heavy proteinuria with or without the nephrotic syndrome may occur in association with a wide

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

Focal nephritic Disorders resulting in a focal nephritic sediment are generally associated with 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 the glomeruli.

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 clinical and laboratory features of renal

disease. It is specifically defined by the presence of heavy proteinuria (protein excretion greater than 3.5 g/24

hours), hypoalbuminemia (less than 3 g/dL), and peripheral edema. Hyperlipidemia and thrombotic disease

are also frequently observed.



erythematosus; the remaining cases are usually due to primary renal disorders such as minimal change disease,

focal segmental glomerulosclerosis (FSGS), and membranous nephropathy [2-9]. (See "Differential diagnosis and

evaluation of glomerular disease".)

The frequency of the different forms of nephropathy underlying the nephrotic syndrome in adults was evaluated in a

Spanish glomerulonephritis registry of 2000 patients biopsied between the years 1994 and 2001 [2]. Among

patients between 15 and 65 years of age, the most common causes of nephrotic syndrome were membranous

nephropathy (24 percent), minimal change disease (16 percent), lupus (14 percent), FSGS (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 prevalence of amyloidosis (17 percent) and a decreased prevalence of lupus (1 percent).

The relative frequency of the different disorders has varied over time in some series as illustrated by the following

observations:

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 'Introduction and terminology'

above and "Differential diagnosis and evaluation of glomerular disease".)

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 years, and more 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 anti-inflammatory drugs (NSAIDS), or as a paraneoplastic effect of malignancy, most often Hodgkin

lymphoma. (See "Etiology, clinical features, and diagnosis 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 effacement of the epithelial cell foot processes on electron microscopy.

Focal segmental glomerulosclerosis Focal segmental glomerulosclerosis (FSGS) is among the most

common lesion found to underlie the idiopathic nephrotic syndrome in adults, accounting for 35 percent of all cases

A study of 233 renal biopsies performed between 1995 and 1997 at the University of Chicago in adults with

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 FSGS (33 and 35 percent, respectively), minimal

change disease (15 percent), and amyloidosis (4 percent overall, but 10 percent in patients over age 44 years)

[3]. FSGS accounted for more than 50 percent of cases of nephrotic syndrome in black individuals.

The frequency of FSGS was much lower (15 percent) among biopsies for nephrotic syndrome performed at the

same institution between 1976 and 1979. The increased prevalence of FSGS in the 1995 to 1997 series was

observed in both black and white individuals.

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 FSGS increased from

14 to 25 percent overall; this increase was primarily seen in black and Hispanic patients. The relative

incidence of FSGS also appears to have increased in Brazil [7].

The increase in FSGS is not restricted to black populations. A retrospective analysis of the patterns of

glomerular disease a in predominantly white cohort from Minnesota showed a 13-fold increase in FSGS and

no change in membranous nephropathy frequency between 1994 and 2003 compared with the interval

between 1974 and 1983 [10]. Nephrotic proteinuria was present in 80 percent of the patients with FSGS.



in the United States and over 50 percent of cases among blacks. FSGS is characterized on light microscopy by

the presence in some but not all glomeruli (hence the name focal) of segmental areas of mesangial collapse and

sclerosis (picture 2A-B) [11]. FSGS can present as an idiopathic syndrome (primary FSGS) or may be associated

with HIV infection, reflux nephropathy, healed previous glomerular injury, or massive obesity. (See "Epidemiology,

classification, and pathogenesis of focal segmental glomerulosclerosis".)

Diagnostic issues There are three important diagnostic concerns in FSGS:

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 "Etiology,

clinical features, and diagnosis of minimal change disease in adults".)

Primary FSGS is an epithelial cell disorder that may be related etiologically to minimal change disease; congenital

forms also exist. (See "Epidemiology, classification, and pathogenesis of focal segmental glomerulosclerosis".) In

addition, as noted above, FSGS can occur 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 sometimes responds 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

(ACE) 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 non-nephrotic; even when protein excretion exceeds 3 to 4 g/day, both hypoalbuminemia and edema are

unusual.

Collapsing FSGS is a histologic variant that is usually but not always associated with HIV infection,

bisphosphonate therapy, or systemic lupus erythematosus. Two major features distinguish it from primary FSGS: a

tendency toward 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 "HIV-associated nephropathy (HIVAN)"

and "Collapsing focal 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 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).

(See "Causes and diagnosis of membranous nephropathy", section on 'Pathology'.)

Membranous nephropathy is most often a primary (idiopathic) disorder in adults and a secondary disorder in

children. Many cases of idiopathic membranous nephropathy may be due to autoantibodies directed against the

phospholipase A2 receptor found on podocytes. Secondary causes include hepatitis B antigenemia, autoimmune

diseases, thyroiditis, carcinoma, and the use of certain drugs such as gold, penicillamine, captopril, and

nonsteroidal anti-inflammatory drugs. 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", section on 'Phospholipase A2 receptor' and "Causes and diagnosis of

membranous nephropathy" and "Causes and diagnosis of membranous nephropathy", section on 'Malignancy'.)

Sampling error

Distinguishing primary and secondary FSGS

Identifying FSGS associated with collapsing glomerulopathy



Amyloidosis As previously noted above, amyloidosis accounts for 4 to 17 percent of cases of seemingly

idiopathic nephrotic syndrome, with an increased frequency 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 amyloid fibrils. AA amyloid is associated 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. (See "Clinical presentation, laboratory manifestations, and diagnosis

of immunoglobulin light chain (AL) amyloidosis (primary amyloidosis)" and "Causes and diagnosis of secondary

(AA) amyloidosis and relation to rheumatic diseases".)

PATHOPHYSIOLOGY

Proteinuria There are three basic types of proteinuria; glomerular; tubular; and overflow. (See "Assessment of

urinary protein excretion and evaluation of isolated non-nephrotic proteinuria in adults".)

In the nephrotic syndrome, protein loss is due to glomerular proteinuria, characterized by increased filtration of

macromolecules across the glomerular capillary wall. Electrical potential differences generated by transglomerular

flow may modulate the flux of macromolecules across the glomerular capillary wall [12], although other theories

exist for the mechanism of glomerular proteinuria.

The podocyte appears to be the major target of injury in diseases that cause idiopathic nephrotic syndrome in

adults and children (membranous nephropathy, minimal change disease, and focal segmental glomerulosclerosis

[FSGS]), as illustrated by the following observations:

In patients with nephrotic syndrome, albumin is the principal urinary protein, but other plasma proteins including

clotting inhibitors, transferrin, immunoglobulins, and hormone carrying proteins such as vitamin D-binding protein

may be lost as well. (See "Renal vein thrombosis and hypercoagulable state in nephrotic syndrome" and

"Endocrine dysfunction in the nephrotic syndrome" and "Lipid abnormalities in nephrotic syndrome".)

Hypoalbuminemia The mechanism of hypoalbuminemia in nephrotic patients is not completely understood.

Most of albumin loss is due to urinary excretion [16,17]. However, at the same level of albumin loss, patients with

the nephrotic syndrome have a plasma albumin concentration that is approximately 1 g/dL (10 g/L) lower than

patients treated with continuous ambulatory peritoneal dialysis, in which there is significant albumin loss in the

dialysate (figure 1). One proposed explanation is that, in patients with nephrotic syndrome, a substantial fraction of

the filtered albumin is taken up by and catabolized in the proximal tubular cells, resulting in a much greater degree

of albumin loss than estimated from the rate of albumin excretion, although this hypothesis is controversial [16,17].

The common ultrastructural phenotype seen in these diseases is podocyte foot process effacement, slit

diaphragm disruption, and a relative or absolute depletion of podocytes [13-15].

Hereditary podocyte injury (eg, in patients with congenital nephrotic syndrome) is due to mutations of

podocyte proteins that are important in the maintenance of the slit diaphragm such as nephrin and podocin, or

mutations in proteins that affect the integrity of the podocyte cytoskeleton such as alpha-actinin-4 [15]. (See

"Congenital and infantile nephrotic syndrome".)

Adult onset idiopathic membranous nephropathy and FSGS may be due to autoantibodies to podocyte

antigens, circulating factors like soluble urokinase-type plasminogen activator receptor that active podocyte

integrins, or circulating factors like cytokines or microbial products that may induce podocyte CD80. The

engagement or activation of these podocyte proteins alters the arrangement of the slit diaphragm or podocyte

cytoskeleton. (See "Causes and diagnosis of membranous nephropathy", section on 'Pathogenesis' and

"Epidemiology, classification, and pathogenesis of focal segmental glomerulosclerosis", section on

'Pathogenesis'.)



Hepatic albumin synthesis does increase in response to the albumin loss. This effect is mediated by an increase in

hepatic albumin gene expression [18] stimulated in part by the low oncotic pressure [19]. Hypoalbuminemia may

also lead to the release of an as yet unidentified circulating factor that contributes to the elevation in hepatic

albumin synthesis [20]. The low oncotic pressure has a second clinically important effect: it increases hepatic

lipoprotein synthesis, which plays an important role in the development of hyperlipidemia. (See 'Hyperlipidemia and

lipiduria' below and "Lipid abnormalities in nephrotic syndrome".)

It remains unclear why, in a patient excreting 4 to 6 g of protein per day, the liver is usually unable to sufficiently

increase albumin synthesis to normalize the plasma albumin concentration. There are patients with nephrotic-range

proteinuria who have little or no hypoalbuminemia; these patients are more likely to have one of the secondary

forms of FSGS (such as reflux nephropathy) rather than one of the primary nephrotic disorders such as

membranous nephropathy or minimal change disease [1]. One contributory factor may be the release of cytokines

in the latter conditions; tumor necrosis factor and interleukin-1, for example, directly suppress hepatic albumin

synthesis [21]. (See "Epidemiology, classification, and pathogenesis of focal segmental glomerulosclerosis",

section on 'Distinguishing between primary and secondary FSGS'.)

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 most patients however, there is a parallel fall in the interstitial protein concentration

and little change in the transcapillary oncotic pressure gradient (figure 2). In the latter patients, edema appears to

be the consequence of primary renal sodium retention in the collecting tubules (figure 3) mediated through the

epithelial sodium channel and the basolateral Na-K-ATPase (figure 4) [22]. The lack of major arterial underfilling has

important implications for diuretic therapy since the excess fluid can usually be removed without inducing volume

depletion. (See "Pathophysiology and treatment of edema in patients with the 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 "Lipid abnormalities in nephrotic syndrome".)

Lipiduria is usually present in the nephrotic syndrome. Urinary lipid may be present in the sediment, entrapped in

casts (fatty casts), enclosed by the plasma membrane of degenerative epithelial cells (oval fat bodies), or free in the

urine. Under polarized light, the fat droplets have the appearance of a Maltese cross (picture 5A-B). (See

"Urinalysis in the diagnosis of kidney disease", section on 'The assessment 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 are common. 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

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

tendency to venous or arterial thrombosis, and increased susceptibility to infection [23].

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 weight gain due to concurrently increasing edema. Protein

malnutrition 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 kidney injury Acute kidney injury can develop in some patients with the nephrotic syndrome, particularly

in older adults with minimal change disease and profound hypoalbuminemia [24]. The mechanism is not

understood; several factors including hypovolemia, interstitial edema, ischemic tubular injury, and the use of

nonsteroidal anti-inflammatory drugs have been suggested. (See "Acute kidney injury (AKI) in minimal change

disease and other forms of nephrotic syndrome".)

Two other major settings are collapsing focal glomerulosclerosis, 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.

Cerebral vein thrombosis has also been rarely reported. 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 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. (See "Renal vein thrombosis and hypercoagulable state in nephrotic syndrome", section on 'Renal vein

thrombosis'.)

Infection Patients with the nephrotic syndrome are susceptible to infection, which was the leading cause of

death in children with the nephrotic syndrome before antibiotics became available. Pneumococcal infections, are

particularly common, and all patients should receive pneumococcal vaccinations. (See "Pneumococcal vaccination

in adults".)

The mechanism of the impairment of normal defense mechanisms is not well understood; low levels of

immunoglobulin G due to urinary loss may play a role. (See "Complications of idiopathic nephrotic syndrome in

children", section on 'Infection'.)

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,

bicarbonaturia, and vitamin D deficiency (all features of a proximal renal tubular acidosis). A decrease in thyroxine-

binding globulins can cause marked changes in various thyroid function tests, although patients are clinically

euthyroid. Anemia, perhaps due to the urinary loss or impaired synthesis of erythropoietin, has also been described

in a few patients [25-27]. (See "Endocrine dysfunction in the nephrotic syndrome".)

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 3.5 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 [28]. This ratio correlates closely with daily protein excretion in g/1.73 m 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 m (calculator 1). There are limitations to

estimating proteinuria from a random urine specimen, particularly in patients whose daily creatinine generation

varies substantially from 1000 mg. We prefer to obtain a 24-hour urine collection in most patients during the initial

evaluation of proteinuria. (See "Patient information: Collection of a 24-hour urine specimen (Beyond the Basics)"

and "Assessment of urinary protein excretion and evaluation of isolated non-nephrotic proteinuria in adults".)

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, or have been taking drugs such as nonsteroidal anti-

inflammatory drugs, interferons, bisphosphonates, lithium, gold, or penicillamine. In most cases, however, renal

2

2



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",

section on 'Nondiabetic renal disease'.)

Serologic studies A number of serologic studies often are obtained in the evaluation of patients with the

nephrotic syndrome depending upon clinical setting, 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 [29]. (See "Differential diagnosis and evaluation of glomerular disease",

section on 'Laboratory testing in patients with suspected glomerular disease'.)

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 and classification 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 an initial empiric 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. In one study of 28 adults with nephrotic-range

proteinuria, for example, knowledge of the histology altered management in 24 (86 percent). (See "Indications for

and complications of renal biopsy".)

Percutaneous renal biopsy is generally contraindicated in the following settings:

There are also several relative contraindications (eg, solitary kidney). (See "Indications for and complications of

renal biopsy", section on 'Relative contraindications'.)

TREATMENT This section will review the general management issues in patients with nephrotic syndrome (ie,

proteinuria, edema, hyperlipidemia, and hypercoagulability).

Immunosuppressive therapy in patients with one of the major causes of idiopathic nephrotic syndrome is discussed

separately. (See "Treatment of idiopathic membranous nephropathy" and "Treatment of primary focal segmental

glomerulosclerosis" and "Treatment of minimal change disease in adults" and "Treatment of idiopathic nephrotic

syndrome in children" and "Renal amyloidosis" and "Treatment and prognosis of IgA nephropathy".)

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 (ACE)

inhibitor or angiotensin receptor blockers (ARBs). Potentially adverse effects of these agents include an acute

decline in glomerular filtration rate and hyperkalemia; serum creatinine and potassium levels should be measured

during the initiation and titration of these drugs. (See "Antihypertensive therapy and progression of nondiabetic

chronic kidney disease in adults" and "Major side effects of angiotensin-converting enzyme inhibitors and

angiotensin II receptor blockers".)

Although protein restriction also may slow disease progression, the evidence is unclear and this modality is not

usually used in nephrotic patients because of the heavy protein losses. (See "Protein restriction and progression of

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 tumor

Hydronephrosis

Active renal or perirenal infection

An uncooperative patient



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 "Pathophysiology and treatment of edema in patients with the

nephrotic syndrome" and "Patient information: Low-sodium diet (Beyond the Basics)".)

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. Addition of diuretics

that act on different nephron segments may also be useful. An important guide for the evaluation of diuretic therapy

is serial measurement of body weight. (See "General principles of the treatment of edema in adults" and "Treatment

of refractory edema in adults".)

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). (See "Lipid abnormalities in nephrotic syndrome".)

Hypercoagulability There is a relatively high incidence of arterial and venous thromboemboli among patients

with the nephrotic syndrome; however, this seems to be particularly prevalent in those with membranous

nephropathy. If thrombosis occurs, it is typically treated with heparin followed by warfarin for as long as the patient

remains nephrotic. The issue of routine prophylactic anticoagulation in patients with nephrotic syndrome is

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

INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and

"Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5 to 6 grade

reading level, and they answer the four or five key questions a patient might have about a given condition. These

articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the

Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the

10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with

some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these

topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on

"patient info" and the keyword(s) of interest.)

SUMMARY

th th

th th

Beyond the Basics topics (see "Patient information: Protein in the urine (proteinuria) (Beyond the Basics)"

and "Patient information: The nephrotic syndrome (Beyond the Basics)" and "Patient information: Low-sodium

diet (Beyond the Basics)")

The nephrotic syndrome is defined by the presence of heavy proteinuria (protein excretion greater than 3.5

g/24 hours in an adult), hypoalbuminemia (less than 3 g/dL), and peripheral edema. Hyperlipidemia and

thrombotic disease may be present. (See 'Introduction and terminology' 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, focal segmental glomerulosclerosis (FSGS), and membranous

nephropathy. Heavy proteinuria in patients without edema or hypoalbuminemia is more likely to be due to

secondary FSGS. (See 'Etiology' above.)

Proteinuria and edema are the principal clinical manifestations of the nephrotic syndrome. Other



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REFERENCES

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

4. Braden GL, Mulhern JG, O'Shea MH, et al. Changing incidence of glomerular diseases in adults. Am JKidney Dis 2000; 35:878.

5. Simon P, Ramee MP, Boulahrouz R, et al. Epidemiologic data of primary glomerular diseases in westernFrance. Kidney Int 2004; 66:905.

6. Malafronte P, Mastroianni-Kirsztajn G, Betnico GN, et al. Paulista Registry of glomerulonephritis: 5-yeardata report. Nephrol Dial Transplant 2006; 21:3098.

7. Bahiense-Oliveira M, Saldanha LB, Mota EL, et al. Primary glomerular diseases in Brazil (1979-1999): is thefrequency of focal and segmental glomerulosclerosis increasing? Clin Nephrol 2004; 61:90.

8. Gesualdo L, Di Palma AM, Morrone LF, et al. The Italian experience of the national registry of renal biopsies.Kidney Int 2004; 66:890.

9. Heaf J. The Danish Renal Biopsy Register. Kidney Int 2004; 66:895.

10. Swaminathan S, Leung N, Lager DJ, et al. Changing incidence of glomerular disease in Olmsted County,Minnesota: a 30-year renal biopsy study. Clin J Am Soc Nephrol 2006; 1:483.

11. D'Agati V. The many masks of focal segmental glomerulosclerosis. Kidney Int 1994; 46:1223.

12. Hausmann R, Kuppe C, Egger H, et al. Electrical forces determine glomerular permeability. J Am SocNephrol 2010; 21:2053.

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

14. Schnenberger E, Ehrich JH, Haller H, Schiffer M. The podocyte as a direct target of immunosuppressiveagents. Nephrol Dial Transplant 2011; 26:18.

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 susceptibility to infection. (See 'Complications' above.)

Proteinuria is due to increased filtration of macromolecules across the glomerular capillary wall. 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.)

The etiology of heavy proteinuria may be suggested from the history and physical. In most adults, however, a

renal biopsy is required to establish the diagnosis. (See 'Diagnosis' above.)

Treatment includes the administration of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin

receptor blockers (ARBs) 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 treated with heparin followed by warfarin for as long as the

patient remains nephrotic. Patients with primary (idiopathic) nephrotic syndrome often receive

immunosuppressive therapy. (See 'Treatment' above.)


http://www.uptodate.com/contents/overview-of-heavy-proteinuria-and-the-nephrotic-syndrome?topicKey=NEPH%2F3084&elapsedTimeMs=1&source=search_ 10/38

15. Gbadegesin R, Lavin P, Foreman J, Winn M. Pathogenesis and therapy of focal segmentalglomerulosclerosis: an update. Pediatr Nephrol 2011; 26:1001.

16. Kaysen GA, Gambertoglio J, Jimenez I, et al. Effect of dietary protein intake on albumin homeostasis innephrotic patients. Kidney Int 1986; 29:572.

17. Kaysen GA, Kirkpatrick WG, Couser WG. Albumin homeostasis in the nephrotic rat: nutritionalconsiderations. Am J Physiol 1984; 247:F192.

18. Sun X, Martin V, Weiss RH, Kaysen GA. Selective transcriptional augmentation of hepatic gene expressionin the rat with Heymann nephritis. Am J Physiol 1993; 264:F441.

19. Pietrangelo A, Panduro A, Chowdhury JR, Shafritz DA. Albumin gene expression is down-regulated byalbumin or macromolecule infusion in the rat. J Clin Invest 1992; 89:1755.

20. Sun X, Kaysen GA. Albumin and transferrin synthesis are increased in H4 cells by serum fromanalbuminemic or nephrotic rats. Kidney Int 1994; 45:1381.

21. Moshage HJ, Janssen JA, Franssen JH, et al. Study of the molecular mechanism of decreased liversynthesis of albumin in inflammation. J Clin Invest 1987; 79:1635.

22. Zacchia M, Trepiccione F, Morelli F, et al. Nephrotic syndrome: new concepts in the pathophysiology ofsodium retention. J Nephrol 2008; 21:836.

23. Crew RJ, Radhakrishnan J, Appel G. Complications of the nephrotic syndrome and their treatment. ClinNephrol 2004; 62:245.

24. Chen T, Lv Y, Lin F, Zhu J. Acute kidney injury in adult idiopathic nephrotic syndrome. Ren Fail 2011; 33:144.

25. Vaziri ND, Kaupke CJ, Barton CH, Gonzales E. Plasma concentration and urinary excretion of erythropoietinin adult nephrotic syndrome. Am J Med 1992; 92:35.

26. Vaziri ND. Endocrinological consequences of the nephrotic syndrome. Am J Nephrol 1993; 13:360.

27. Mhr N, Neyer U, Prischl F, et al. Proteinuria and hemoglobin levels in patients with primary glomerulardisease. Am J Kidney Dis 2005; 46:424.

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

29. Howard AD, Moore J Jr, Gouge SF, et al. Routine serologic tests in the differential diagnosis of the adultnephrotic syndrome. Am J Kidney Dis 1990; 15:24.

Topic 3084 Version 18.0



GRAPHICS

Light microscopy in 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.

Graphic 71232 Version 2.0

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, MD.




Electron microscopy in 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.


Electron micrograph of a 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.




Mild FGS

Light micrograph shows early changes in focal glomerulosclerosis with

segmental capillary collapse (arrows) in areas of epithelial cell injury

(small arrowhead).



Normal glomerulus











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.



Normal glomerulus








Light micrograph showing 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.



Normal glomerulus









Electron micrograph showing 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.









lumen.



Light micrograph showing 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.



Normal glomerulus






Immunofluorescence microscopy showing

membranous nephropathy

Immunofluorescence microscopy in membranous nephropathy showing

diffuse, granular IgG deposition along the capillary walls.





Electron micrograph showing membranous

nephropathy

Electron micrograph 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.











lumen.





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.





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 the glomerular basement

membrane (GBM) as new basement membrane has grown around the

deposits (arrows).









lumen.



Electron micrograph showing 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 inclusions (arrow)

strongly suggest underlying lupus.

GBM: glomerular basement membrane; Ep: epithelial cell.









lumen.



Plasma albumin in nephrotic syndrome and CAPD

Relationship between total albumin loss and the plasma albumin

concentration in patients undergoing continuous ambulatory peritoneal

dialysis (CAPD), in which albumin is primarily lost in the dialysate fluid,

and those with the nephrotic syndrome. At any level of albumin loss,

the plasma albumin concentration is approximately 1 g/dL (10 g/L)

lower in patients with the nephrotic syndrome, suggesting that some

factor in addition to urinary albumin excretion must be involved.

Data from Kaysen, GA, Schoenfeld, PY, Kidney Int 1984; 25:107.




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) steroid-induced 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.




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.




Ion transport in collecting tubule principal cells

Schematic representation of sodium and potassium transport in the

sodium reabsorbing principal cells in the collecting tubules. The entry

of filtered Na into these cells is mediated by selective sodium channels

in the apical (luminal) membrane (ENaC); the energy for this process

is provided by the favorable electrochemical gradient for Na (cell

interior electronegative and low cell Na concentration). Reabsorbed Na

is pumped out of the cell by the Na-K-ATPase pump in the basolateral

(peritubular) membrane. The reabsorption of cationic Na makes the

lumen electronegative, thereby creating a favorable gradient for the

secretion of K into the lumen via K channels (ROMK and BK) in the

apical membrane. Aldosterone, after combining with the cytosolic

mineralocorticoid receptor (Aldo-R), leads to enhanced Na

reabsorption and potassium secretion by increasing both the number

of open Na channels and the number of Na-K-ATPase pumps. The

potassium-sparing diuretics (amiloride and triamterene) act by directly

inhibiting the epithelial sodium channel; spironolactone acts by

competing with aldosterone for binding to the mineralocorticoid

receptor.




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.




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.




Disclosures: Ellie Kelepouris, MD, FAHA Grant/Research/Clinical Trial Support: Sanofi [vitamin D/CHF(Doxercalciferol)]. Consultant/Advisory Boards: Questcor [glomerular disease (acthar)]. Brad H Rovin,MD Grant/Research/Clinical Trial Support: Teva Pharmaceutical Industries [LN (Laquinamod)]; Biogen-IDEC[LN (Anti-TWEAK MAB)]; Questcor [LN (ACTHar gel)]; GSK [LN, FSGS (Belimumab, p38 MAPK inhibitor)];Centocor [LN (Anti-IL6 MAB)]; Onyx Pharmaceuticals [LN (Proteosome inhibitor)]; Genentech, Inc [IMN(Rituximab)]. Consultant/Advisory Boards: Astellas [LN (General consulting)]; Bristol-Myers Squibb [LN(Abatacept)]; Biogen-IDEC [LN (Anti-TWEAK BIIB023)]; GSK [LN (Belimumab)]; Eli Lilly and Company [LN(Tabalumab)]; Teva Pharmaceutical Industries [LN (Laquinamod)]; Onyx Pharmaceuticals [LN(Carfilzomib)]; Questcor [LN (ACTHar)]; Ambit Biosciences [LN (AC708)]; Alexion [LN (Eculizumab)];Centocor [LN (Sirukumab)]; Genentech, Inc [LN (Rituximab)]; Sanofi [Diabetic nephropathy (Generalconsulting)]; Ardea Biosciences [Hyperuricemia (Lesinurad)]; Aurinia Pharmaceuticals [LN (Voclosporin)];Auven Therapeutics [Amyloid (Eprodisate sodium)]. Richard J Glassock, MD, MACP Speaker's Bureau:Genentech, Inc/Roche; American Society of Nephrology (Board Review Course & Update [BRCU];Associate Editor, NephSAP). Consultant/Advisory Boards: AbbVie [lupus nephritis]; Novartis (Chairman,Renal and Hypocalcemia Event Adjudication Committee [zoledronic acid]); Genentech, Inc/Roche;Genzyme/Sanofi; Bristol-Myers Squibb; Questcor Pharmaceuticals, Inc; Eli Lilly and Company (Chair, DataSafety and Monitoring Board); ChemoCentryx; Astellas Pharma; Mitsubishi-Tanabe Pharma America;University Kidney Research Organization AKA UKRO (Board of Directors); Los Angeles BiomedicalResearch Institute (Board of Directors); American Renal Associates, Inc (Medical Advisory Board);American Association of Kidney Patients (Medical Advisory Board). Employment: American Society ofNephrology (NephSAP Editorial Board [Associate Editor and Editor Emeritus]); American Journal ofNephrology (Associate Editor); Karger Publications (Consultant, journal article blogs); Various legal f irms(paid testimony regarding product liability/medical negligence). Equity Ow nership/Stock Options: La JollaPharmaceutical Company (stock); Reata Pharmaceuticals, Inc (stock, limited partnership). Other FinancialInterest: Oxford University Press (royalties for "Treatment of Primary Glomerular Disease," 2nd ed). JohnP Forman, MD, MSc Employee of UpToDate, Inc.

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