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Visão geral da proteinúria pesada e da síndrome nefrótica

Autores: Ellie Kelepouris, MD, FAHA, Brad H Rovin, MD


Editor de seção: Richard J Glassock, MD, MACP
Editor adjunto: Albert Q Lam, MD

Todos os tópicos são atualizados à medida que novas evidências ficam disponíveis e nosso processo de
revisão pelos pares está completo.
Revisão da literatura atual até: julho de 2017. | Este tópico foi atualizado pela última vez: 05 de julho
de 2016.

INTRODUÇÃO E TERMINOLOGIA - Doenças do glomérulo podem resultar em três padrões urinários e


clínicos diferentes: nefritic focal; Nefritico difuso; E nefrótico. (Ver "Diagnóstico diferencial e avaliação da
doença glomerular" .)

● Nefítico leve - Os distúrbios resultantes de um sedimento nefritico leve são geralmente associados a
lesões inflamatórias em menos de metade dos glomérulos em microscopia óptica (glomerulonefrite
focal). O exame de urina revela os glóbulos vermelhos (que muitas vezes apresentam uma aparência
dismórfica), ocasionalmente moldes de glóbulos vermelhos e proteinúria leve (geralmente inferior a 1,5
g / dia) . Os achados de doenças mais avançadas geralmente estão ausentes, como proteinúria pesada,
edema, hipertensão e insuficiência renal. Esses pacientes geralmente apresentam hematúria
assintomática e proteinúria descobertas no exame de rotina ou ocasionalmente com episódios de
hematúria bruta.

● Nefritico grave - O exame de urina na glomerulonefrite difusa é semelhante à doença focal, mas pode
ser observada uma proteinúria pesada (que pode estar no intervalo nefrótico), edema, hipertensão e /
ou insuficiência renal. A glomerulonefrite difusa afeta a maioria ou todos os glomérulos.

● Nephrotic - O sedimento nephrotic é associado com proteinúria pesada e lipidúria, mas poucas células
ou moldes. O termo "síndrome nefrótica" refere-se a uma constelação distinta de características clínicas
e laboratoriais da doença renal. É especificamente definido pela presença de proteinúria pesada
(excreção protéica superior a 3,5 g / 24 horas), hipoalbuminemia (menos de 3 g / dL) e edema
periférico. A hiperlipidemia e a doença trombótica também são freqüentemente observadas.

A proteinúria pesada isolada sem edema ou outras características da síndrome nefrótica é sugestiva de uma
glomerulopatia (com as mesmas etiologias que a síndrome nefrótica), mas não está necessariamente
associada aos múltiplos problemas clínicos e gerenciais característicos da síndrome nefrótica. Esta é uma
distinção clínica importante porque a proteinúria pesada em pacientes sem edema ou hipoalbuminemia é
mais provável devido à glomerulosclerose segmentar focal secundária (FSGS) (devido, por exemplo, à
diabetes) [ 1 ].

Esta revisão do tópico fornecerá uma visão geral da proteinúria pesada e da síndrome nefrotica, com ênfase
em distúrbios com apresentação nefrotica (ou seja, em vez de sedimento de urina ativo). Problemas mais
específicos relacionados às complicações da síndrome nefrótica são apresentados em outros lugares. (Ver
"Fisiopatologia e tratamento de edema em pacientes com síndrome nefrótica" e "Trombose da veia renal e
estado hipercoagulável na síndrome nefrótica" e "Disfunção endócrina na síndrome nefrótica" e
"Anormalidades lipídicas na síndrome nefrótica" e "Lesão renal aguda ( AKI) em doença de mudança mínima
e outras formas de síndrome nefrótica " .)

Os distúrbios individuais que causam a síndrome nefrótica são discutidos em detalhes em análises de
tópicos separadas. Os leitores serão encaminhados para esses tópicos individuais quando apropriado.
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ETIOLOGIA - A proteinúria pesada com ou sem a síndrome nefrótica pode ocorrer em associação com
uma grande variedade de doenças primárias e sistêmicas. A doença de mudança mínima é a causa
predominante em crianças. Em adultos, aproximadamente 30 por cento têm uma doença sistêmica, como
diabetes mellitus, amiloidose ou lúpus eritematoso sistêmico; Os casos restantes geralmente são devidos a
distúrbios renais primários, como doença de alteração mínima, glomerulosclerose segmentar focal (FSGS) e
nefropatia membranosa [ 2-9 ]. (Ver "Diagnóstico diferencial e avaliação da doença glomerular" .)

A freqüência das diferentes formas de nefropatia subjacente à síndrome nefrotica em adultos foi avaliada em
um registro espanhol de glomerulonefritos de 2000 pacientes biopsiados entre os anos de 1994 e 2001 [ 2 ].
Entre os pacientes com idade entre 15 e 65 anos, as causas mais comuns de síndrome nefrótica foram a
nefropatia membranosa (24 por cento), a alteração mínima da doença (16 por cento), lúpus (14 por cento),
FSGS (12 por cento), glomerulonefrite membranoproliferativa (7 por cento ), Amiloidose (6 por cento) e
nefropatia de IgA (6 por cento). Uma distribuição semelhante foi observada entre os 725 indivíduos adultos
mais velhos (idade superior a 65 anos), exceto por uma prevalência aumentada de amiloidose (17 por cento)
e uma diminuição da prevalência de lúpus (1 por cento).

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 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.

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".)

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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 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
● 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 "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 sometimes 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

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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'.)

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:

● 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 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'.)

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
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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].

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].

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
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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 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.

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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 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 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 education: 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 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:

● 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

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).

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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 "Dietary recommendations
for patients with nondialysis CKD".)

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 education: 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".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected
countries and regions around the world are provided separately. (See "Society guideline links: Glomerular
disease in adults".)

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 5th to 6th
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 10th to 12th grade reading level and are best for patients who want
in-depth information and are comfortable with some medical jargon.

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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.)

● Beyond the Basics topics (see "Patient education: Protein in the urine (proteinuria) (Beyond the Basics)"
and "Patient education: The nephrotic syndrome (Beyond the Basics)" and "Patient education: Low-
sodium diet (Beyond the Basics)")

SUMMARY

● 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
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.)

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

1. Praga M, Borstein B, Andres A, et al. Nephrotic proteinuria without hypoalbuminemia: clinical


characteristics and response to angiotensin-converting enzyme inhibition. Am J Kidney Dis 1991;
17:330.
2. Rivera F, López-Gómez JM, Pérez-García R, Spanish Registry of Glomerulonephritis. Clinicopathologic
correlations of renal pathology in Spain. Kidney Int 2004; 66:898.

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3. Haas M, Meehan SM, Karrison TG, Spargo BH. Changing etiologies of unexplained adult nephrotic
syndrome: 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 J
Kidney Dis 2000; 35:878.
5. Simon P, Ramee MP, Boulahrouz R, et al. Epidemiologic data of primary glomerular diseases in western
France. Kidney Int 2004; 66:905.
6. Malafronte P, Mastroianni-Kirsztajn G, Betônico GN, et al. Paulista Registry of glomerulonephritis: 5-
year data 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 the frequency 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 Soc
Nephrol 2010; 21:2053.
13. Reiser J, von Gersdorff G, Loos M, et al. Induction of B7-1 in podocytes is associated with nephrotic
syndrome. J Clin Invest 2004; 113:1390.
14. Schönenberger E, Ehrich JH, Haller H, Schiffer M. The podocyte as a direct target of
immunosuppressive agents. Nephrol Dial Transplant 2011; 26:18.
15. Gbadegesin R, Lavin P, Foreman J, Winn M. Pathogenesis and therapy of focal segmental
glomerulosclerosis: an update. Pediatr Nephrol 2011; 26:1001.
16. Kaysen GA, Gambertoglio J, Jimenez I, et al. Effect of dietary protein intake on albumin homeostasis in
nephrotic patients. Kidney Int 1986; 29:572.
17. Kaysen GA, Kirkpatrick WG, Couser WG. Albumin homeostasis in the nephrotic rat: nutritional
considerations. Am J Physiol 1984; 247:F192.
18. Sun X, Martin V, Weiss RH, Kaysen GA. Selective transcriptional augmentation of hepatic gene
expression in 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 by
albumin 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 from
analbuminemic or nephrotic rats. Kidney Int 1994; 45:1381.
21. Moshage HJ, Janssen JA, Franssen JH, et al. Study of the molecular mechanism of decreased liver
synthesis 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 of
sodium retention. J Nephrol 2008; 21:836.
23. Crew RJ, Radhakrishnan J, Appel G. Complications of the nephrotic syndrome and their treatment. Clin
Nephrol 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
erythropoietin in adult nephrotic syndrome. Am J Med 1992; 92:35.

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26. Vaziri ND. Endocrinological consequences of the nephrotic syndrome. Am J Nephrol 1993; 13:360.
27. Mähr N, Neyer U, Prischl F, et al. Proteinuria and hemoglobin levels in patients with primary glomerular
disease. Am J Kidney Dis 2005; 46:424.
28. Ginsberg JM, Chang BS, Matarese RA, Garella S. Use of single voided urine samples to estimate
quantitative proteinuria. N Engl J Med 1983; 309:1543.
29. Howard AD, Moore J Jr, Gouge SF, et al. Routine serologic tests in the differential diagnosis of the adult
nephrotic syndrome. Am J Kidney Dis 1990; 15:24.

Topic 3084 Version 21.0

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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.

Graphic 75094 Version 4.0

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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.

Graphic 58414 Version 2.0

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.

Courtesy of Helmut G Rennke, MD.

Graphic 50018 Version 7.0

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Mild FSGS

Light micrograph shows early changes in focal glomerulosclerosis with


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

Courtesy of Helmut Rennke, MD.

Graphic 67677 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.

Graphic 75094 Version 4.0

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Moderate FSGS

Light micrograph in focal segmental glomerulosclerosis shows a moderately


large segmental area of sclerosis with capillary collapse on the upper left side of
the glomerular tuft; the lower right segment is relatively normal. Focal
deposition of hyaline material (arrow) is also seen.

Courtesy of Helmut Rennke, MD.

Graphic 63456 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.

Graphic 75094 Version 4.0

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Light micrograph showing collapsing FSGS

Light micrograph showing collapsing glomerulosclerosis with few open loops in


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

Courtesy of Helmut Rennke, MD.

Graphic 81601 Version 4.0

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.

Graphic 75094 Version 4.0

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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.

Courtesy of Helmut Rennke, MD.

Graphic 59839 Version 2.0

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.

Courtesy of Helmut G Rennke, MD.

Graphic 50018 Version 7.0

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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.

Courtesy of Helmut Rennke, MD.

Graphic 57841 Version 3.0

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.

Graphic 75094 Version 4.0

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Immunofluorescence microscopy showing membranous


nephropathy

Immunofluorescence microscopy in membranous nephropathy showing diffuse,


granular IgG deposition along the capillary walls.

Courtesy of Helmut Rennke, MD.

Graphic 74698 Version 3.0

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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.

Courtesy of Helmut Rennke, MD.

Graphic 55226 Version 5.0

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.

Courtesy of Helmut G Rennke, MD.

Graphic 50018 Version 7.0

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Silver stain in membranous nephropathy

Light micrograph silver stain of membranous nephropathy shows a spike


appearance (arrows). The spikes represent new basement membrane growing
between the subepithelial immune deposits, which are visible on electron
microscopy, but not with this stain.

Courtesy of Helmut Rennke, MD.

Graphic 69629 Version 2.0

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Electron micrograph in stage III membranous


nephropathy

Electron micrograph in stage III membranous nephropathy. The subepithelial


immune deposits (asterisk) have a lucent, moth-eaten appearance and have
been incorporated into the glomerular basement membrane (Δ) as new
basement membrane has grown around the deposits (arrows).

Courtesy of Helmut Rennke, MD.

Graphic 62937 Version 2.0

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.

Courtesy of Helmut G Rennke, MD.

Graphic 50018 Version 7.0

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Electron micrograph showing lupus membranous


nephropathy

Electron micrograph of lupus membranous nephropathy. 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.

Courtesy of Helmut G Rennke, MD.

Graphic 69348 Version 7.0

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.

Courtesy of Helmut G Rennke, MD.

Graphic 50018 Version 7.0

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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.

Graphic 59892 Version 1.0

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Little change in oncotic pressure gradient in nephrotic


syndrome

Relation between plasma and interstitial oncotic pressures in patients with the
nephrotic syndrome due to minimal change disease before (open circles) and after
(closed circles) 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.

Graphic 74352 Version 1.0

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Increased collecting tubule sodium reabsorption in nephrotic


syndrome

Micropuncture studies (in which samples are taken via micropipettes from different
nephron segments) of sodium handling in unilateral nephrotic syndrome in the rat.
Although less sodium is filtered in the nephrotic kidney, less is reabsorbed so that the
quantity of sodium remaining in the tubular lumen at the end of the distal tubule is the
same in the two kidneys. Thus, sodium reabsorption must be increased in the collecting
tubules to account for the two-thirds reduction in total sodium excretion in the nephrotic
kidney when compared to the normal kidney.

Data from Ichikawa, I, Rennke, HG, Hoyer, JR, et al, J Clin Invest 1983; 71:91.

Graphic 82649 Version 1.0

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Ion transport in collecting tubule principal cells

Schematic representation of sodium (Na) and potassium (K) transport in the sodium-
reabsorbing principal cells in the collecting tubules. The entry of filtered sodium 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 sodium (cell interior
electronegative and low cell sodium concentration). Reabsorbed sodium is pumped out of the
cell by the Na-K-ATPase pump in the basolateral (peritubular) membrane. The reabsorption of
cationic sodium makes the lumen electronegative, thereby creating a favorable gradient for the
secretion of potassium into the lumen via potassium channels (ROMK and BK) in the apical
membrane. Aldosterone (Aldo), after combining with the cytosolic mineralocorticoid receptor
(Aldo-R), leads to enhanced sodium reabsorption and potassium secretion by increasing both
the number of open sodium 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.

Graphic 60693 Version 13.0

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Fatty cast

Urine sediment showing a fatty cast. The fat droplets (or globules) can be
distinguished from red cells (which also have a round appearance) by their
variable size (from much smaller to much larger than a red cell), dark outline,
and "Maltese cross" appearance under polzarized light.

Courtesy of Frances Andrus, BA, Victoria Hospital, London, Ontario.

Graphic 69603 Version 1.0

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Fatty cast

Urine sediment showing fatty cast under polarized light. The fat droplets have a
characteristic "Maltese cross" appearance (arrow).

Courtesy of Harvard Medical School.

Graphic 79604 Version 1.0

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Contributor Disclosures
Ellie Kelepouris, MD, FAHA Grant/Research/Clinical Trial Support: Mallinkrodt [Nephrotic syndrome
(ACTHar gel)]; Relypsa [Hyperkalemia (Veltassa)]; Mallinkdrodt [Proteinuria (ACTHar gel)]; Mallinkrodt
[Proteinuria ACTHar gel)]. Consultant/Advisory Boards: Relypsa [Hyperkalemia (Veltassa)]. Brad H Rovin,
MD Grant/Research/Clinical Trial Support: Mallinkrodt [lupus nephritis (acth gel)]. Consultant/Advisory
Boards: Alexion; Aurinia; Biogen Idec; Chemocentryx; Eli Lilly; Genentech; Genzyme; GlaxoSmithKline;
Mallinkrodt; Medimmune; Novartis; Pfizer; Roche [lupus nephritis (complement system antagonists,
voclosporin, anti-TWEAK, c5a receptor antagonist, acth gel, anti-interferon alpha receptor)]. Richard J
Glassock, MD, MACP Gabinete do Presidente: Genentech [Vasculitis (Rituximab)]. Consultor / Conselho
Consultivo: Bristol-Myers-Squibb [Nefrite Lúpica, FSGS (Abatacept)]; ChemoCentryx [Vasculite, diabetes
(Acocapan)]; Retrophin [FSGS (Sparsentan)]. Equity Ownership / Stock Options: Reata (Bardoxolone).
Albert Q Lam, MD Nada a divulgar

As divulgações dos contribuintes são revistas para conflitos de interesse pelo grupo editorial. Quando
encontrados, estes são abordados através de um processo de revisão de vários níveis e através de
requisitos para as referências a serem fornecidas para suportar o conteúdo. É necessário um conteúdo
referenciado de forma apropriada de todos os autores e deve obedecer aos padrões de evidência do
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