Review en inglés bastante bueno y resumido

1. Nephrotic Syndrome in Adults:
Diagnosis and Management
CHARLES KODNER, MD, University of Louisville School of Medicine, Louisville, Kentucky
Nephrotic syndrome may be caused by primary (idiopathic) renal disease or by a variety of
secondary causes. Patients present with marked edema, proteinuria, hypoalbuminemia, and
often hyperlipidemia. In adults, diabetes mellitus is the most common secondary cause, and
focal segmental glomerulosclerosis and membranous nephropathy are the most common pri-
mary causes. Venous thromboembolism is a possible complication; acute renal failure and
serious bacterial infection are also possible, but much less common. There are no established
guidelines on the diagnostic workup or management of nephrotic syndrome. Imaging stud-
ies are generally not needed, and blood tests should be used selectively to diagnose specific
disorders rather than for a broad or unguided workup. Renal biopsy may be useful in some
cases to confirm an underlying disease or to identify idiopathic disease that is more likely to
respond to corticosteroids. Treatment of most patients should include fluid and sodium restric-
tion, oral or intravenous diuretics, and angiotensin-converting enzyme inhibitors. Some adults
with nephrotic syndrome may benefit from corticosteroid treatment, although research data
are limited. Intravenous albumin, prophylactic antibiotics, and prophylactic anticoagulation
are not currently recommended. (Am Fam Physician. 2009;80(10):1129-1134, 1136. Copyright
© 2009 American Academy of Family Physicians.)
I
Patient information: n nephrotic syndrome, a variety of dis- idiopathic nephrotic syndrome.2 Other
▲
A handout on nephrotic orders cause proteinuria, often resulting conditions, such as membranoprolifera-
syndrome, written by the in marked edema and hypoalbumin- tive glomerulonephritis, are less common.
author of this article, is
provided on page 1136. emia. Hyperlipidemia is a common FSGS accounts for approximately 3.3 per-
associated finding. Family physicians may cent of new cases of end-stage renal dis-
encounter persons with nephrotic syndrome ease.2 A large number of secondary causes
This clinical content con- from primary (idiopathic) renal disease or of nephrotic syndrome have been identified
forms to AAFP criteria for a number of secondary causes, and should (Table 2),3 with diabetes mellitus being the
evidence-based continu-
ing medical education initiate appropriate diagnostic workup and most common.
(EB CME). medical management pending specialist
consultation. Pathophysiology
The underlying pathophysiology of nephrotic
Causes syndrome is not completely clear.4 Although
Most cases of nephrotic syndrome appear to the more intuitive “underfill” mechanism of
be caused by primary kidney disease. Table 1 edema from reduced oncotic pressure caused
summarizes the recognized histologic pat- by marked proteinuria may be the primary
terns and features of primary nephrotic mechanism in children with acute nephrotic
syndrome.1 Membranous nephropathy and syndrome, edema in adults may be caused by
focal segmental glomerulosclerosis (FSGS) a more complex mechanism. Massive protein-
each account for about one third of cases uria causes renal tubulointerstitial inflam-
of primary nephrotic syndrome; however, mation, with resulting increased sodium
FSGS is the most common cause of idio- retention that overwhelms the physiologic
pathic nephrotic syndrome in adults.2 Mini- mechanisms for removing edema.5 Patients
mal change disease and (less commonly) may have an “overfilled” or expanded plasma
immunoglobulin A (IgA) nephropathy volume in addition to expanded intersti-
cause approximately 25 percent of cases of
tial fluid volume. This may be clinically
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2. SORT: KEY RECOMMENDATIONS FOR PRACTICE
Evidence
Clinical recommendation rating References
Random urine protein/creatinine ratio should be used to assess the C 6
degree of proteinuria in persons with nephrotic syndrome.
Renal biopsy may be helpful to guide diagnosis and treatment, but is not C 13
indicated in all persons with nephrotic syndrome.
Sodium and fluid restriction and high-dose diuretic treatment are C 3, 14
indicated for most persons with nephrotic syndrome.
Angiotensin-converting enzyme inhibitor treatment is indicated for most C 16
persons with nephrotic syndrome.
Corticosteroid treatment has no proven benefit, but is recommended C 19, 20
by some physicians for persons with nephrotic syndrome who are not
responsive to conservative treatment.
A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evi-
dence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information
about the SORT evidence rating system, go to http://www.aafp.org/afpsort.xml.
important if over-rapid diuresis leads to acute have nephrotic syndrome. Although a
renal failure from reduced glomerular blood urine dipstick proteinuria value of 3+ is a
flow, despite persistent edema. useful semiquantitative means of identify-
ing nephrotic-range proteinuria, given the
Clinical Features logistic difficulties of collecting a 24-hour
Progressive lower extremity edema, weight urine sample, the random urine protein/
gain, and fatigue are typical presenting symp- creatinine ratio is a more convenient quan-
toms of nephrotic syndrome. In advanced titative measure. The numeric spot urine
disease, patients may develop periorbital or protein/creatinine ratio, in mg/mg, accu-
genital edema, ascites, or pleural or pericardial rately estimates protein excretion in g per
effusion. Persons who present with new edema day per 1.73 m2 of body surface area, so a
or ascites, without typical dyspnea of conges- ratio of 3 to 3.5 represents nephrotic-range
tive heart failure or stigmata of cirrhosis, proteinuria.6 Low serum albumin levels
should be assessed for nephrotic syndrome. (less than 2.5 g per dL [25 g per L]) and
Nephrotic-range proteinuria is typically severe hyperlipidemia are also typical fea-
defined as greater than 3 to 3.5 g of protein tures of nephrotic syndrome. In one study
in a 24-hour urine collection; however, not of persons with nephrotic syndrome, 53 per-
all persons with this range of proteinuria cent had a total cholesterol level greater than
Table 1. Histologic Patterns and Features of Primary Nephrotic Syndrome
Histologic pattern Key pathologic features Key clinical features
Focal segmental Sclerosis and hyalinosis of segments of May be associated with hypertension, renal insufficiency,
glomerulosclerosis less than 50 percent of all glomeruli on and hematuria
electron microscopy
Membranous Thickening of the glomerular basement Peak incidence at 30 to 50 years of age; may have
nephropathy membrane on electron microscopy; microscopic hematuria; approximately 25 percent of
immunoglobulin G and C3 deposits patients have underlying systemic disease, such as systemic
with immunofluorescent staining lupus erythematosus, hepatitis B, or malignancy, or drug-
induced nephrotic syndrome
Minimal change Normal-appearing glomeruli on renal Relatively mild or benign cases of nephrotic syndrome; may
disease biopsy microscopy; effacement of foot occur following upper respiratory infection or immunization
processes on electron microscopy
Information from reference 1.
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3. Nephrotic Syndrome
300 mg per dL (7.77 mmol per L) and 25 per- therapeutic drug complications, sepsis, renal
cent had a total cholesterol level greater than venous thrombosis, renal interstitial edema,
400 mg per dL (10.36 mmol per L).7 and marked hypotension may cause or con-
Possible complications of nephrotic syn- tribute to acute renal failure.12
drome include venous thromboembolism
caused by loss of clotting factors in the urine, Diagnostic Evaluation
infection caused by urinary loss of immuno- Typical clinical and laboratory features of
globulins, and acute renal failure. Throm- nephrotic syndrome are sufficient to estab-
boembolism has long been recognized as a lish the diagnosis of nephrotic syndrome.
complication of nephrotic syndrome.8 In a The diagnostic evaluation focuses on iden-
large retrospective review, the relative risk of tification of an underlying cause and on the
deep venous thrombosis (DVT) in patients role of renal biopsy. However, there are no
with nephrotic syndrome was 1.7 compared published practice guidelines available about
with those without nephrotic syndrome, the diagnostic evaluation of persons with
with an annual incidence of DVT of 1.5 per- nephrotic syndrome.3
cent9 ; the risk seems highest in the first six Initial investigation should include history,
months after diagnosis.10 The relative risk of physical examination, and a serum chemistry
pulmonary embolism was 1.4 and was espe- panel. Given the large number of potential
cially high in persons 18 to 39 years of age causes of nephrotic syndrome and the rela-
(relative risk = 6.8). Renal venous throm- tively nonspecific aspect of therapy, the diag-
bosis is a possible complication of nephrotic nostic evaluation should be guided by clinical
syndrome, but was uncommon in this case suspicion for specific disorders, rather than
series. Membranous nephropathy and serum a broad or unguided approach to ruling out
albumin levels less than 2.0 to 2.5 g per dL multiple illnesses. Table 3 lists selected diag-
(20 to 25 g per L) seem to confer an increased nostic studies for some common secondary
risk of DVT. Arterial thrombotic complica-
tions can occur, but are rare.9
Infection is also a possible complication Table 2. Common Secondary Causes of Nephrotic Syndrome
of nephrotic syndrome; however, this risk
appears primarily in children and in persons Cause Key features
who have relapses of nephrotic syndrome or
Diabetes mellitus Glucosuria, hyperglycemia, polyuria
who require longer-term corticosteroid ther-
Systemic lupus Anemia, arthralgias, autoantibodies, photosensitivity,
apy.11 Invasive bacterial infections, especially erythematosus pericardial or pleural effusion, rash
cellulitis, peritonitis, and sepsis, are the most Hepatitis B or C Elevated transaminases; high-risk sexual activity,
common infections attributable to nephrotic history of transfusion, intravenous drug use, or
syndrome. The mechanisms of infection other risk factors for disease transmission
are unclear, but may relate to the degree of Nonsteroidal anti- Causes minimal change disease
edema, loss of serum IgG with overall pro- inflammatory drugs
teinuria,1 effects of corticosteroid therapy, Amyloidosis Cardiomyopathy, hepatomegaly, peripheral
reduced complement or T cell function, or neuropathy
impaired phagocytic function.3 The risk of Multiple myeloma Abnormal urine protein electrophoresis, back pain,
renal insufficiency
serious bacterial infection attributable to
HIV Pathologically similar to focal segmental
nephrotic syndrome in adults in the United glomerulosclerosis; risk factors for HIV
States is unclear, but seems low. transmission, possible reduced CD4 cell count
Acute renal failure is a rare, spontane- Preeclampsia Edema and proteinuria during pregnancy; elevated
ous complication of nephrotic syndrome. blood pressure
Although older persons, children, and those
with more profound edema and proteinuria NOTE: Causes are in approximate order of most to least common.
are at highest risk, there are many possible HIV = human immunodeficiency virus.
causes or contributing factors to acute renal Information from reference 3.
failure in this setting. Excessive diuresis,
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4. Nephrotic Syndrome
Table 3. Diagnostic Evaluation in Persons
with Nephrotic Syndrome
Diagnostic studies Disorder suggested
likelihood that nephrotic syndrome will
Baseline
respond to corticosteroid treatment, there
Patient history Identify medication or toxin exposure;
risk factors for HIV or viral hepatitis; and
are no biopsy findings that accurately pre-
symptoms suggesting other causes of edema dict corticosteroid responsiveness. No
Obtain history of diabetes, systemic lupus recent studies have elucidated the true
erythematosus, or other systemic illness benefit of renal biopsy in guiding manage-
Urine dipstick Confirm proteinuria ment; the best available evidence is from
Random urine protein/ Quantify degree of proteinuria (ratio greater a prospective study in which the results of
creatinine ratio than 3 to 3.5) renal biopsy changed management in 24 of
Serum creatinine Rule out acute renal failure, assess glomerular 28 persons with nephrotic syndrome, pri-
filtration rate marily through the addition of corticoste-
Serum albumin Assess degree of hypoalbuminemia roid treatment, although the actual patient
Lipid panel Assess degree of hyperlipidemia benefit is unknown.13 In most cases, fam-
Additional studies suggested by patient factors ily physicians should consult specialists in
HIV screening test Identify HIV renal medicine about the need for renal
Hepatitis serology panel Identify hepatitis B or C biopsy in individual patients.
Serum or urine protein Suggests amyloidosis or multiple myeloma
electrophoresis Management
Rapid plasma reagin Identify syphilis There are no clinical guidelines and few
Antinuclear antibodies Identify systemic lupus erythematosus; high-quality studies on the management
or complement (C3 complement levels may also be reduced in
of nephrotic syndrome in adults. Recom-
and C4) levels membranoproliferative disease
mendations are based primarily on early
HIV = human immunodeficiency virus. case series, other observational studies, and
expert opinion.3
FLUID AND NUTRITION
causes of nephrotic syndrome, as well as base-
line evaluations that should be obtained in all Creating a negative sodium balance will help
persons with nephrotic syndrome. reduce edema, presumably as the underlying
Imaging studies are generally not helpful illness is treated or as renal inflammation
in assessing persons with nephrotic syn- slowly resolves. Patients should limit their
drome. Renal ultrasonography may identify sodium intake to 3 g per day, and may need
renal venous thrombosis if suggestive fea- to restrict fluid intake (to less than approxi-
tures, such as flank pain, hematuria, or acute mately 1.5 L per day).
renal failure, are present.
DIURETICS
Renal biopsy is often recommended in per-
sons with nephrotic syndrome to establish the Diuretics are the mainstay of medical man-
pathologic subtype of the disease, to assess agement; however, there is no evidence to
disease activity, or to confirm the diagnosis guide drug selection or dosage. Based on
of diseases, such as amyloidosis or systemic expert opinion, diuresis should aim for a
lupus erythematosus. There are, however, no target weight loss of 1 to 2 lb (0.5 to 1 kg) per
clear guidelines on when renal biopsy is indi- day 3 to avoid acute renal failure or electrolyte
cated or whether it is needed in all persons with disorders. Loop diuretics, such as furose-
nephrotic syndrome. For example, in diabetic mide (Lasix) or bumetanide, are most com-
nephropathy, the leading cause of secondary monly used. Large doses (e.g., 80 to 120 mg
nephrotic syndrome, renal biopsy may not be of furosemide) are often required,14 and these
necessary if the patient has enlarged kidneys, drugs typically must be given intravenously
a bland urinary sediment without cellular because of the poor absorption of oral drugs
casts, or other evidence of microvascular caused by intestinal edema.3 Low serum
disease, such as proliferative retinopathy or
albumin levels also limit diuretic effective-
peripheral neuropathy. Although renal ness and necessitate higher doses. Thiazide
biopsy is often recommended to assess the diuretics, potassium-sparing diuretics, or
1132 American Family Physician www.aafp.org/afp Volume 80, Number 10 ◆ November 15, 2009

5. Nephrotic Syndrome
metolazone (Zaroxolyn) may be useful as on the treatment of nephrotic syndrome
adjunctive or synergistic diuretics.14 in adults found no benefit for mortality or
need for dialysis with corticosteroid therapy
ACE INHIBITORS for membranous nephropathy or minimal
Angiotensin-converting enzyme (ACE) change disease, but found a weak benefit for
inhibitors have been shown to reduce pro- disease remission and proteinuria in persons
teinuria and reduce the risk of progression to with membranous nephropathy.20,24 How-
renal disease in persons with nephrotic syn- ever, the findings for minimal change disease
drome.15,16 One study found no improvement were based on only one randomized trial, and
in response when corticosteroid treatment the role of corticosteroid treatment remains
was added to treatment with ACE inhibi- unclear. Many experts recommend the use of
tors.17 The recommended dosage is unclear, corticosteroids, particularly for persons with
and enalapril (Vasotec) dosages from 2.5 to minimal change disease1; however, adverse
20 mg per day were used. Most persons with effects from corticosteroids often lead to
nephrotic syndrome should be started on discontinuation.
ACE inhibitor treatment to reduce protein- Family physicians should discuss with
uria, regardless of blood pressure. patients and consulting nephrologists whether
treatment with corticosteroids is advisable,
ALBUMIN weighing the uncertain benefits and pos-
Intravenous albumin has been proposed to sibility of adverse effects. Alkylating agents
aid diuresis, because edema may be caused (e.g., cyclophosphamide [Cytoxan]) also have
by hypoalbuminemia and resulting oncotic weak evidence for improving disease remission
pressures. However, there is no evidence to and reducing proteinuria, but may be consid-
indicate benefit from treatment with albu- ered for persons with severe or resistant dis-
min,18 and adverse effects, such as hyperten- ease who do not respond to corticosteroids.
sion or pulmonary edema, as well as high
LIPID-LOWERING TREATMENT
cost, limit its use.
A Cochrane review is underway to investi-
CORTICOSTEROIDS gate the benefits and harms of lipid-lowering
Treatment with corticosteroids remains con- agents in nephrotic syndrome.25 Some evi-
troversial in the management of nephrotic syn- dence suggests an increased risk of athero-
drome in adults. It has no proven benefit, but genesis or myocardial infarction in persons
is recommended in some persons who do not with nephrotic syndrome, possibly related
respond to conservative treatment.19,20 Treat- to increased lipid levels.25 However, the role
ment of children with nephrotic syndrome of treatment for increased lipids is unknown
is different, and it is more clearly established and, at present, the decision to start lipid-
that children respond well to corticosteroid lowering therapy in persons with nephrotic
treatment.21 Classically, minimal change dis- syndrome should be made on the same basis
ease responds better to corticosteroids than as in other patients.
FSGS; however, this difference is found pri-
marily in children with nephrotic syndrome. ANTIBIOTICS
One older study found that corticosteroid There are no data from prospective clini-
treatment improved proteinuria and renal cal trials about treatment and prevention of
function in persons with minimal change infection in adults with nephrotic syndrome.
disease, but not membranous nephropathy or Given the uncertain risks of infection in
proliferative glomerulonephritis.22 Another adults with nephrotic syndrome in the
small older study found that persons with less United States, there are currently no indica-
severe glomerular changes responded well to tions for antibiotics or other interventions
corticosteroids.23 One case series in black per- to prevent infection in this population. Per-
sons with FSGS found no benefit from corti- sons who are appropriate candidates should
costeroid treatment.19 Two Cochrane reviews receive pneumococcal vaccination.
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6. Nephrotic Syndrome
ANTICOAGULATION THERAPY 10. Mahmoodi BK, ten Kate MK, Waandes F, et al. High
absolute risks and predictors of venous and arterial
There are currently no recommendations thromboembolic events in patients with nephrotic syn-
for prophylactic anticoagulation to prevent drome: results from a large retrospective cohort study.
thromboembolic events in persons with Circulation. 2008;117(2):224-230.
11. Wu HM, Tang JL, Sha ZH, Cao L, Li YP. Interventions for
nephrotic syndrome who have not had pre-
preventing infection in nephrotic syndrome. Cochrane
vious thrombotic events, and clinical prac- Database Syst Rev. 2004;(2):CD003964.
tice varies. A Cochrane review is in process.26 12. Koomans HA. Pathophysiology of acute renal failure in
Physicians should remain alert for signs or idiopatic nephrotic syndrome. Nephrol Dial Transplant.
2001;16(2):221-224.
symptoms suggesting thromboembolism
13. Richards NT, Darby S, Howie AJ, Adu D, Michael J.
and, if it is diagnosed, these events should be Knowledge of renal histology alters patient management
treated as in other patients. Persons who are in over 40% of cases. Nephrol Dial Transplant. 1994;
otherwise at high risk of thromboembolism 9(9):1255-1259.
14. Brater DC. Diuretic therapy. N Engl J Med. 1998;339(6):
(e.g., based on previous events, known coag-
387-395.
ulopathy) should be considered for prophy- 15. Ruggenenti P, Mosconi L, Vendramin G, et al. ACE inhi-
lactic anticoagulation while they have active bition improves glomerular size selectivity in patients
nephrotic syndrome. with idiopathic membranous nephropathy and per-
sistent nephrotic syndrome. Am J Kidney Dis. 2000;
35(3):381-391.
The Author 16. Korbet SM. Angiotensin antagonists and steroids in
the treatment of focal segmental glomerulosclerosis.
CHARLES KODNER, MD, is an associate professor in the Semin Nephrol. 2003;23(2):219-228.
Department of Family and Geriatric Medicine at the Uni-
17. Stiles KP, Abbott KC, Welch PG, Yuan CM. Effects of
versity of Louisville (Ky.) School of Medicine. angiotensin-converting enzyme inhibitor and steroid
Address correspondence to Charles Kodner, MD, Univer- therapy on proteinuria in FSGS: a retrospective study in
sity of Louisville School of Medicine, Med Center One a single clinic. Clin Nephrol. 2001;56(2):89-95.
Building, Louisville, KY 40292. Reprints are not available 18. Dorhout Mees EJ. Does it make sense to administer
from the author. albumin to the patient with nephrotic oedema? Nephrol
Dial Transplant. 1996;11(7):1224-1226.
Author disclosure: Nothing to disclose. 19. Crook ED, Habeeb D, Gowdy O, Nimmagadda S, Salem
M. Effects of steroids in focal segmental glomeruloscle-
rosis in a predominantly African-American population.
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