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Nephrotic Syndrome

Bhavna Chopra, MDa, Leslie Thomas, MDb,*

HOSPITAL MEDICINE CLINICS CHECKLIST

1. Diagnose nephrotic syndrome by demonstrating edema, proteinuria >3.5g/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 dia-

betic 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 syn-

drome, 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 dis-

ease 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, PA15212, USA; b Division of Nephrology & Hypertension, Mayo Clinic, 13400 E. Shea Blvd,Scottsdale, AZ 85259, USA* Corresponding author.E-mail address: [email protected]

KEYWORDS

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

Hosp Med Clin 3 (2014) e245e254http://dx.doi.org/10.1016/j.ehmc.2013.11.0082211-5943/14/$ see front matter 2014 Elsevier Inc. All rights reserved.
mailto:[email protected]://dx.doi.org/10.1016/j.ehmc.2013.11.008http://dx.doi.org/10.1016/j.ehmc.2013.11.008mailto:[email protected]


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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 fromchronic glomerular injury or scarring (eg, from diabetic nephropathy) do not neces-

sarily 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 com-

mon cause of nephrotic syndrome in children. Onset may be rapid, and spontaneousremissions 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 1outlines

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 orimmunotherapy, 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 be-

tween primary FSGS and soluble urokinase plasminogen activator receptor (suPAR)

may exist. Increased levels of suPAR in mice appear to result in nephrotic-range pro-

teinuria and progressive glomerulopathy. Additional data in humans show that an in-

crease 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 thispreliminary 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

Chopra & Thomase246


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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)

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. Lithiumd. 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.

Nephrotic Syndrome e247


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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-ac. 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)

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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 prog-

nostic factors include male gender, age greater than 50 years, and severe nephrotic

syndrome. Primary MN may result in many cases fromthe development of autoanti-

bodies against phospholipase A2receptor (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 patientsreceiving these drugs.

A low-sodium (


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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. Clopidogreld. 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

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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 rela-

tive risk. To date, no randomized controlled trials have been performed that mightguide 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.

b. Noncarcinomas:

i. Hodgkin lymphoma

ii. Non-Hodgkin lymphoma

iii. Leukemia

iv. Mesothelioma

v. Melanoma

vi. Wilms tumor

vii. Various others

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 changedisease (MCD)

Absence ofglomerular

abnormalities(or mild mesangialexpansion)

No staining Diffuse podocytefoot process

effacement

Focal segmentalglomerulosclerosis(FSGS)

Mesangialexpansionassociated withsegmentalsclerosis with orwithout scarring

No staining Diffuse podocytefoot processeffacement

Membranousnephropathy (MN)

Capillary wallthickening

Capillary wallimmunoglobulinG 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, onlya 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 withMN who demonstrate: Persistent proteinuria exceeding 4 g/24 hours OR A 30% increase in serum creatinine OR

Life-threatening complications from the nephrotic syndromeAlternative therapy for relapsing disease, steroid dependence, or steroid resistance

MCD Relapsing disease: cyclophosphamide (2 mg/kg/d) for a duration of 812 wk aftercomplete remission is achieved with prednisone

Steroid-dependent disease: cyclophosphamide (2 mg/kg/d) for a duration of812 wk after complete remission is achieved with prednisone

Steroid-resistant disease: CNI therapy (eg, cyclosporine) therapy for a duration of6 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 levels125175 ng/mL) for 12 mo

MN Relapsing disease: initial therapy may be repeated. Cyclophosphamide-basedregimens are generally not repeated more than once. Rituximab may be used

Resistant disease: CNI therapy (eg, cyclosporine) may be used. For CNI-resistantdisease, rituximab may be used

Abbreviation:CNI, calcineurin inhibitors.

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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 in-

vestigators 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, cyclophospha-

mide), purine synthesis inhibitors (eg, azathioprine, mycophenolate mofetil), and calci-

neurin 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 DrugAdministration), and also appears to be an effective therapy for MN. Strong evidence

of rituximabs efficacy for MCD or FSGS is presently absent. Purified porcine adreno-

corticotropin hormone gel has recently been reported to be effective therapy for cases

of resistant nephrotic syndrome stemming from MCD, FSGS, and MN. Table 2 out-

lines some of the commonly used medications for immunologic therapy for the

nephrotic syndrome.8

CLINICAL GUIDELINES

Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis WorkGroup. KDIGO clinical practice guideline for glomerulonephritis. Kidney Int Suppl

2012;2:139274.

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