N ephrotic Syn d ro me

Bhavna Chopra,

MD

, Leslie Thomas,

MD

b,

KEYWORDS
 Nephrotic syndrome  Proteinuria  Edema  Minimal change disease
 Focal segmental glomerulosclerosis  Membranous nephropathy

HOSPITAL MEDICINE CLINICS CHECKLIST

1. Diagnose nephrotic syndrome by demonstrating edema, proteinuria >3.5

g/24 hours, hypoalbuminemia, and hyperlipidemia.
2. Individuals with nephrotic-range proteinuria who do not develop the nephrotic
syndrome likely suffer from chronic glomerular injury or scarring (eg, from diabetic nephropathy).
3. Minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS),
and membranous nephropathy (MN) are the most common causes of the
nephrotic syndrome.
4. MCD, FSGS, and MN vary by renal prognosis and known secondary causes
(drugs, infections, malignancies, associated immune diseases).
5. Consider secondary causes of the nephrotic syndrome before the initiation of
traditional immunologic (ie, corticosteroid) therapy.
6. Although other tests may help identify secondary causes of the nephrotic syndrome, renal biopsy is the gold standard for the proper diagnosis of MCD,
FSGS, and MN.
7. Management of the nephrotic syndrome is 2-fold: treatment of symptoms and
complications (ie, edema, hyperlipidemia) and treatment of the underlying disease process (eg, corticosteroid therapy for primary diseases).

DEFINITION

1. What defines the nephrotic syndrome?

The nephrotic syndrome is defined classically as a tetrad of findings:
 Edema
 Proteinuria (>3.5 g/24 hours)
a
Division of Nephrology, Allegheny General Hospital, 320 E North Avenue, Pittsburgh, PA
15212, USA; b Division of Nephrology & Hypertension, Mayo Clinic, 13400 E. Shea Blvd,
Scottsdale, AZ 85259, USA
* Corresponding author.
E-mail address: thomas.leslie@mayo.edu

Hosp Med Clin 3 (2014) e245e254

http://dx.doi.org/10.1016/j.ehmc.2013.11.008
2211-5943/14/$ see front matter 2014 Elsevier Inc. All rights reserved.

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Chopra & Thomas

 Hypoalbuminemia
 Hyperlipidemia
2. Does nephrotic-range proteinuria invariably lead to the nephrotic syndrome?
Individuals with nephrotic-range proteinuria (ie, >3.5 g/24 hours) stemming from
chronic glomerular injury or scarring (eg, from diabetic nephropathy) do not necessarily develop the nephrotic syndrome. The mechanisms by which these individuals
do not develop nephrotic syndrome remain incompletely understood.
EPIDEMIOLOGY

1. What are the most common diseases leading to the nephrotic syndrome?
The most common diseases leading to the nephrotic syndrome are:
1. Minimal change disease (MCD)
2. Focal segmental glomerulosclerosis (FSGS)
3. Membranous nephropathy (MN)
DIAGNOSIS

1. How do the clinical features of MCD, FSGS, and MN vary?

MCD may lead to a mild or benign case of nephrotic syndrome. MCD is the most common cause of nephrotic syndrome in children. Onset may be rapid, and spontaneous
remissions may occur. The progression to end-stage renal disease (ESRD) in patients
with MCD is relatively unlikely in comparison with patients with FSGS or MN. However,
ongoing nephrotic syndrome from MCD may lead to the same complications that may
occur in individuals experiencing the nephrotic syndrome from other causes, including
dyslipidemia, infection, thromboembolism, and atherosclerosis. Seventy-five percent
of adult patients will respond to corticosteroid therapy, but many will relapse and may
be steroid dependent. Most cases are idiopathic or primary in nature. Box 1 outlines
causes of secondary disease.1
FSGS more commonly leads to a significant reduction in glomerular filtration rate
(GFR) and ESRD. Poor prognostic factors include resistance to corticosteroid or
immunotherapy, baseline level of kidney function, degree of proteinuria, and degree
of renal interstitial damage. In individuals without significant response to therapy,
5-year kidney survival may only be 65% and 10-year kidney survival may be as low
as 30%. FSGS may also be divided into primary and secondary forms. Primary
FSGS is usually characterized by the sudden onset of edema. A causal association between primary FSGS and soluble urokinase plasminogen activator receptor (suPAR)
may exist. Increased levels of suPAR in mice appear to result in nephrotic-range proteinuria and progressive glomerulopathy. Additional data in humans show that an increase in suPAR may be present most (eg, 70%) individuals diagnosed with primary
FSGS.2 However, more study is currently needed to draw firm conclusions about this
preliminary evidence. Other recent data have shown a strong association between
FSGS and 2 independent sequence variants (G1 and G2) in the last exon of the gene
encoding apolipoprotein L1 (APOL1). One current hypothesis that may explain the
observed higher propensity of FSGS in blacks than in whites proposes that the G1
and G2 haplotypes were under strong selection in Africa but not Europe. Selection
for the G1 or G2 haplotype confirms protection against Trypanosoma brucei

Nephrotic Syndrome

Box 1
Secondary causes of minimal change disease
1. Neoplasms:
a. Hodgkin lymphoma
b. Non-Hodgkin lymphoma
c. Leukemia
d. Thymoma
e. Various solid tumors
2. Drugs:
a. Nonsteroidal anti-inflammatory drugs
b. Antibiotics: ampicillin, rifampin, cephalosporins
c. Lithium
d.

D-Penicillamine

e. Pamidronate
f. Sulfasalazine
g. Immunizations
h. g-Interferon
3. Infections:
a. Viral: human immunodeficiency virus, hepatitis C virus
b. Tuberculosis
c. Parasites: ehrlichiosis, schistosomiasis
4. Allergies:
a. Pollen
b. Food allergy
c. House dust
d. Contact dermatitis
e. Bee or wasp stings
5. Stimulation associated with immune activation:
a. Guillain-Barre syndrome
b. Still disease
c. Dermatitis herpetiformis
d. Autoimmune thyroiditis
e. Sclerosing cholangitis
Adapted from Schrier RW, Coffman TM, Falk RJ, et al. Schriers diseases of the kidney.
9th edition. Philadelphia: Lippincott Williams & Wilkins; 2012.

rhodesiense, a subspecies of the parasite that causes sleeping sickness, Trypanosoma

brucei brucei.3 Secondary FSGS is typically slowly progressive and may not lead to
the nephrotic syndrome. Common causes of secondary FSGS are listed in Box 2.4
MN may present in similar fashion to MCD or primary FSGS. Previous study of the
natural history of patients with MN treated with conservative (nonimmunologic)

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Box 2
Secondary causes of focal segmental glomerulosclerosis
1. Adaptive changes:
a. Reduced renal mass:
i. Oligomeganephronia
ii. Unilateral renal agenesis
iii. Kidney dysplasia
iv. Cortical necrosis
v. Reflux nephropathy
vi. Surgical nephrectomy
vii. Chronic allograft nephropathy
viii. Advanced renal disease
b. Initially normal kidney mass:
i. Diabetes mellitus
ii. Hypertension
iii. Obesity
iv. Cyanotic congenital heart disease
v. Sickle-cell anemia
2. Neoplasms:
a. Lymphoma
b. Various solid tumors (rare)
3. Viral infections:
a. Human immunodeficiency virus
b. Parvovirus B19
c. Simian virus 40
d. Cytomegalovirus
e. Epstein-Barr virus
4. Drugs:
a. Heroin
b. Interferon-a
c. Lithium
d. Pamidronate
e. Alendronate
f. Sirolimus
g. Anabolic steroids
5. Other glomerular disease
a. Proliferative glomerulonephritis
b. Alport syndrome
c. Membranous nephropathy
d. Thrombotic angiopathy
6. Familial (multiple mutations)

Nephrotic Syndrome

therapy shows that 65% of patients will achieve partial or complete remission,
whereas only 14% will progress to ESRD within 5 years of initial diagnosis.5 Poor prognostic factors include male gender, age greater than 50 years, and severe nephrotic
syndrome. Primary MN may result in many cases from the development of autoantibodies against phospholipase A2 receptor (PLA2R).6,7
Secondary causes of MN are listed in Box 3.8
2. What diagnostic process should one pursue to identify common secondary causes of
the nephrotic syndrome?

The diagnosis of secondary causes is of utmost importance before the initiation of

immunosuppressive medications. A list of commonly considered diagnostic tests is
given in Box 4.
3. How do MCD, FSGS, and MN differ by renal biopsy findings?
Table 1 outlines the various findings for the most common causes of the nephrotic
syndrome.
MANAGEMENT

The approach to management of the nephrotic syndrome is 2-fold:

 Management of proteinuria, edema, dyslipidemia, and other complications of the
syndrome
 Therapy targeting the individual patients underlying disease process
1. What are the nonimmunologic therapies given for the nephrotic syndrome?
Angiotensin-converting enzyme (ACE) inhibitors and angiotensin-II receptor blockers
(ARBs) are the mainstays of current practice for reducing proteinuria and controlling
blood pressure. These agents are usually well tolerated, but are only variably effective
at substantially reducing proteinuria in individuals with the nephrotic syndrome.
Increased dosing and combinations should be used with care because complications
may occur, including hyperkalemia and significantly reduced GFR. For this reason,
electrolytes and creatinine concentrations should be measured frequently in patients
receiving these drugs.
A low-sodium (<2 g/24 hours) diet and diuretic therapy are essential for control of
edema in most individuals with the nephrotic syndrome. The use of a loop diuretic
(eg, furosemide, torsemide, bumetanide) is preferred for inducing a net negative
sodium and water balance. The shorter-acting loop diuretics, furosemide and bumetanide, are generally given twice daily to achieve a clinical effect. Metolazone may be
added for further effect, as it is generally effective even in states of decreased GFR
(ie, <30 mL/min/1.73 m2). Aldosterone antagonists (eg, eplerenone, spironolactone)
may also be used for additional natriuresis, if necessary. As with ACE inhibitors and
ARBs, frequent monitoring of electrolytes and renal clearance (ie, GFR) is warranted
for the monitoring of potential side effects.
The use of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors (ie, statins)
may be effective in treating the dyslipidemia associated with the nephrotic syndrome,
and should be considered.
The hypercoagulability associated with the nephrotic syndrome has been well
described and is not insubstantial. Some data show an annual incidence of 9% and

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Box 3
Secondary causes of membranous nephropathy
1. Rheumatologic disorders:
a. Systemic lupus erythematosus
b. Sjogren syndrome
c. Rheumatoid arthritis
d. Mixed connective tissue disease
e. Various other autoimmune disorders
2. Drugs:
a. Nonsteroidal anti-inflammatory drugs
b. Cyclooxygenase-2 inhibitors
c. Clopidogrel
d. Lithium
e. Penicillamine
f. Bucillamine
g. Mercury
h. Gold
i. Captopril
j. Probenecid
p. Trimethadione
q. Antitumor necrosis factor therapy
r. Hydrochlorothiazide
s. Formaldehyde
t. Hydrocarbons
3. Graft versus host disease
4. Infections:
a. Hepatitis B
b. Hepatitis C
c. Human immunodeficiency virus
d. Syphilis
e. Various other infections
5. Neoplasms:
a. Carcinomas:
i. Gastric
ii. Renal cell
iii. Lung
iv. Prostatic
v. Small cell
vi. Colorectal
vii. Breast
viii. Various others

Nephrotic Syndrome

b. Noncarcinomas:
i. Hodgkin lymphoma
ii. Non-Hodgkin lymphoma
iii. Leukemia
iv. Mesothelioma
v. Melanoma
vi. Wilms tumor
vii. Various others

5% for venous and arterial thrombosis, respectively.911 Individuals with MN appear to

have the highest risk, and the degree of hypoalbuminemia may correlate with the relative risk. To date, no randomized controlled trials have been performed that might
guide therapy aimed at lowering the risk of thrombosis in patients with the nephrotic
syndrome. Patients who are diagnosed with symptomatic renal vein thrombosis or any
other deep vein thrombosis (DVT), or a pulmonary embolism (PE), are treated similarly
to any other patient with a DVT or PE. Anticoagulation is usually initiated with heparin,
followed by warfarin for at least 6 months. Some experts suggest that anticoagulation
should be continued as long as the nephrotic syndrome is present.
Box 4
Diagnosing common secondary causes of nephrotic syndrome
 Patient history:
 Medication or toxin exposures
 Pregnancy
 Risk factors for viral infections
 History of diabetes mellitus, systemic lupus erythematosus, or other systemic illness
 Signs and symptoms suggestive of malignancy
 Laboratory:
 Blood:
-

Complete blood count, electrolytes, glucose, lipid profile, liver tests, albumin

Cryoglobulins

Viral serologies: hepatitis B, hepatitis C, human immunodeficiency virus

Syphilis antibody

Antinuclear antibody, rheumatoid factor, complement levels (C3, C4, CH50)

Thyroid-stimulating hormone

Protein electrophoresis with immunofixation, free light chains (l, k)

 Urine:
-

Urinalysis

Spot protein/creatinine (confirm with total protein from 24-hour collection)

Protein electrophoresis with immunofixation (from 24-hour collection)

 Renal biopsy (confirmatory test)

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Table 1
Major renal biopsy findings of the primary forms of the most common nephrotic diseases
Light Microscopy

Immunofluorescence
Microscopy

Electron Microscopy

Minimal change
disease (MCD)

Absence of
glomerular
abnormalities
(or mild mesangial
expansion)

No staining

Diffuse podocyte
foot process
effacement

Focal segmental
glomerulosclerosis
(FSGS)

Mesangial
expansion
associated with
segmental
sclerosis with or
without scarring

No staining

Diffuse podocyte
foot process
effacement

Membranous
nephropathy (MN)

Capillary wall
thickening

Capillary wall
immunoglobulin
G and C3

Subepithelial
(subpodocyte)
deposits

Table 2
Summary of commonly used immunologic agents for the treatment of nephrotic syndrome
First-line immunologic therapy
MCD

 Prednisone 1 mg/kg (maximum to 80 mg/d) for a duration of 1216 wk

 Once complete remission is achieved, prednisone is tapered over 46 mo

FSGS

 Prednisone 1 mg/kg (maximum to 80 mg/d) for a duration of 416 wk

 Once complete remission achieved, prednisone is tapered over 46 mo
 Note: in patients with steroid-resistant FSGS, prednisone may be tapered over
68 wk

MN

 As a large number of patients with MN may develop spontaneous remission, only

a subset of these patients might be initially provided immunologic treatment
 Monotherapy with corticosteroids is not recommended for MN
 Prednisone 1 mg/kg (maximum to 80 mg/d) and cyclophosphamide (2 mg/kg/d)
comprise some of traditional immunologic therapies provided to patients with
MN who demonstrate:
 Persistent proteinuria exceeding 4 g/24 hours OR
 A 30% increase in serum creatinine OR
 Life-threatening complications from the nephrotic syndrome

Alternative therapy for relapsing disease, steroid dependence, or steroid resistance

MCD

 Relapsing disease: cyclophosphamide (2 mg/kg/d) for a duration of 812 wk after

complete remission is achieved with prednisone
 Steroid-dependent disease: cyclophosphamide (2 mg/kg/d) for a duration of
812 wk after complete remission is achieved with prednisone
 Steroid-resistant disease: CNI therapy (eg, cyclosporine) therapy for a duration of
6 mo continuing on for 12 mo if a remission is achieved
 Note: cyclophosphamide is not recommended for steroid-resistant disease
 Note: for adults with steroid resistance, consider a reevaluation for other causes
of nephrotic syndrome (eg, FSGS)

FSGS

 Cyclosporine 35 mg/kg/d in 2 divided doses (initial target blood trough levels

125175 ng/mL) for 12 mo

MN

 Relapsing disease: initial therapy may be repeated. Cyclophosphamide-based

regimens are generally not repeated more than once. Rituximab may be used
 Resistant disease: CNI therapy (eg, cyclosporine) may be used. For CNI-resistant
disease, rituximab may be used

Abbreviation: CNI, calcineurin inhibitors.

Nephrotic Syndrome

2. What are the immunologic therapies given for the nephrotic syndrome?
Immunologically targeted therapy for primary MCD, FSGS, and MN generally consists
of corticosteroid therapy with or without another immunosuppressive agent. Most investigators recommend an initial daily dose of prednisone of 1 mg/kg (no greater than
80 mg). As most forms of primary disease may not show a clinical response for 3 to
4 months, a 12- to 16-week course as tolerated is recommended before tapering.
The use of additional medication depends on a variety of other factors including the
side-effect risk profiles of such agents and the known response to previous therapy
in individuals being treated for relapsed disease. Alkylating agents (eg, cyclophosphamide), purine synthesis inhibitors (eg, azathioprine, mycophenolate mofetil), and calcineurin inhibitors (eg, cyclosporine, tacrolimus) have all been studied for the treatment
of MCD, FSGS, and MN. More recently, the chimeric (human/murine) CD20 antibody
rituximab has been shown to successfully treat antineutrophil cytoplasmic antibody
associated glomerulonephritis (for which it is approved by the Food and Drug
Administration), and also appears to be an effective therapy for MN. Strong evidence
of rituximabs efficacy for MCD or FSGS is presently absent. Purified porcine adrenocorticotropin hormone gel has recently been reported to be effective therapy for cases
of resistant nephrotic syndrome stemming from MCD, FSGS, and MN. Table 2 outlines some of the commonly used medications for immunologic therapy for the
nephrotic syndrome.8
CLINICAL GUIDELINES

Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work

Group. KDIGO clinical practice guideline for glomerulonephritis. Kidney Int Suppl
2012;2:139274.
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1. Schrier RW, Coffman TM, Falk RJ, et al. Schriers diseases of the kidney.
9th edition. Philadelphia: Lippincott Williams & Wilkins; 2012.
2. Wei C, El Hindi S, Li J, et al. Circulating urokinase receptor as a cause of focal
segmental glomerulosclerosis. Nat Med 2011;17:952.
3. Genovese G, Friedman DJ, Ross MD, et al. Association of trypanolytic ApoL1
variants with kidney disease in African Americans. Science 2010;329:8415.
4. Deegens JK, Seteenbergen EJ, Wetzels JF. Review on diagnosis and treatment of
focal segmental glomerulosclerosis. Neth J Med 2008;66:312.
5. Schieppati A, Mosconi L, Perna A, et al. Prognosis of untreated patients with idiopathic membranous nephropathy. N Engl J Med 1993;329:859.
6. Beck LH Jr, Bonegio RG, Lambeau G, et al. M-type phospholipase A2 receptor
as target antigen in idiopathic membranous nephropathy. N Engl J Med 2009;
361:11.
7. Hofstra JM, Beck LH Jr, Beck DM, et al. Anti-phospholipase A2 receptor antibodies correlate with clinical status in idiopathic membranous nephropathy.
Clin J Am Soc Nephrol 2011;6:1286.
8. Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work
Group. KDIGO clinical practice guideline for glomerulonephritis. Kidney Int Suppl
2012;2:139274.
9. Mahmoodi BK, ten Kate MK, Waanders F, et al. High absolute risks and predictors of venous and arterial thromboembolic events in patients with nephrotic

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117(2):224.
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thromboembolic events is increased in idiopathic glomerulonephritis. Kidney Int
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membranous nephropathy. Clin J Am Soc Nephrol 2012;7:43.