Updated: 7/14/2018

Nephrotic Syndrome

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Snapshot
  • A 6-year-old boy is brought to the emergency department by his mother due to swelling around his eyes and legs. The mother reports that the patient recently recovered from an upper respiratory tract infection. Physical exam is significant for periorbital and lower extremity edema. Laboratory testing is significant for hypoalbuminemia and normal complement levels. Urinalysis demonstrates 4+ protein. A presumptive diagnosis of minimal change disease is made and the patient is started on steroid therapy.
Introduction
  • Clinical definition
    • a type of kidney disease that results in proteinuria, peripheral edema, hyperlipidemia, and hypoalbuminemia
  • Epidemiology
    • incidence
      • annually there are 3 cases per 100,000 adults
  • Etiology
    • primary glomerular disease
      • focal segmental glomerulosclerosis
      • membranous nephropathy
      • minimal change disease
    • secondary causes
      • diabetic nephropathy
      • systemic lupus erythematosus
      • amyloidosis
  • Pathogenesis
    • the glomerulus becomes permeable to large molecules (e.g., albumin)
      • this loss of albumin (proteinuria) results in hypoalbuminemia and edema
      • associated with a hypercoagulable state
        • pathophysiology unclear but may be due to loss of antithrombin and plasminogen proteins
      • increased lipid synthesis secondary to proteinuria
        • this in turn results in hypercholesterolemia and hyperlipidemia
  • Associated conditions
    • chronic kidney disease
  • Prognosis
    • depends on the underlying cause
      • e.g., patients with minimal change disease typically respond well to steroid therapy
Presentation
  • Symptoms
    • edema
      • periorbital, lower extremity, and genital edema
    • frothy urine
    • ascites
    • weight gain
    • fatigue
    • shortness of breath
  • Physical exam
    • hypertension
    • edema
    • leukonychia
      • suggestive of a low albumin state and presents as white streaking on the fingernails
Studies
  • Labs
    • hypoalbuminemia (serum albumin of < 2.5 g/dL)
    • hyperlipidemia
  • Urine studies
    • proteinuria > 3-3.5 g/day 
      • or > 300-350 mg/mmol on spot urine protein to creatinine ratio
    • fatty casts with "maltese cross" sign

Nephrotic Syndrome
Type
Pathophysiology
Renal Biopsy
Treatment and Notes
Focal segmental glomerulosclerosis
  • Podocyte injury or decreased glomerular filtration barrier integrity
  • Light microscopy
    • segmental scarring
  • Treat underlying etiology in secondary causes
  • Steroid therapy
  • Can be secondary to
    • HIV
    • sickle cell disease
    • heroin abuse
    • interferon treatment
Minimal change disease
  • Unclear but may be due to an immune-related mechanism 
  • Light microscopy
    • normal appearing
  • Electron microscopy
    • effacement of the foot processes  
  • Steroid therapy
  • Most common in children
  • May follow recent infection, immunizations, or may be idiopathic
Membranous nephropathy 
  • Antibody-immune complex deposition
    • IgG antibodies target podocyte antigens or antigens in close proximity to the podocytes
  • Complement-mediated podocyte injury
  • Light microscopy
    • glomerular basement membrane thickening
  • Immunofluoresence
    • immune complex deposition leading to granular appearance
  • Electron microscopy
    • "spike and dome"
    • subepithelial deposits
  • Immunosuppressive therapy in primary cases
    • steroids and cyclophosphamide
  • Most common cause of primary nephrotic syndrome in Caucasian adults
  • Primary causes
    • antibodies targeting phospholipase A2 receptors 
  • Secondary causes
    • medications
    • systemic lupus erythematosus
    • nonsteroidal anti-inflammatory drugs
    • gold
    • penicillamine
    • hepatitis B and C infection
Amyloidosis
  • Amyloid deposits in the mesangium
  • Electron microscopy
    • apple-green birefringence on Congo red stain under polarized light
  • Treatment involves addressing the plasma cell dyscrasia
Diabetic glomerulonephropathy
  • Glomerular hyperperfusion and hyperfiltration result in albumin leaking
    • under these conditions the glomerulus responds via
      • glomerular basement membrane thickening
        • due to non-enzymetic glycosylation
      • hypertrophy
      • sclerosing
      • podocyte injury
  • Light microscopy
    • expansion of the mesangium
    • Kimmelstiel-Wilson lesions
  • Angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs)
  • Adequately controlling diabetes
 
 

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Questions (15)
Lab Values
Blood, Plasma, Serum Reference Range
ALT 8-20 U/L
Amylase, serum 25-125 U/L
AST 8-20 U/L
Bilirubin, serum (adult) Total // Direct 0.1-1.0 mg/dL // 0.0-0.3 mg/dL
Calcium, serum (Ca2+) 8.4-10.2 mg/dL
Cholesterol, serum Rec: < 200 mg/dL
Cortisol, serum 0800 h: 5-23 μg/dL //1600 h:
3-15 μg/dL
2000 h: ≤ 50% of 0800 h
Creatine kinase, serum Male: 25-90 U/L
Female: 10-70 U/L
Creatinine, serum 0.6-1.2 mg/dL
Electrolytes, serum  
Sodium (Na+) 136-145 mEq/L
Chloride (Cl-) 95-105 mEq/L
Potassium (K+) 3.5-5.0 mEq/L
Bicarbonate (HCO3-) 22-28 mEq/L
Magnesium (Mg2+) 1.5-2.0 mEq/L
Estriol, total, serum (in pregnancy)  
24-28 wks // 32-36 wks 30-170 ng/mL // 60-280 ng/mL
28-32 wk // 36-40 wks 40-220 ng/mL // 80-350 ng/mL
Ferritin, serum Male: 15-200 ng/mL
Female: 12-150 ng/mL
Follicle-stimulating hormone, serum/plasma Male: 4-25 mIU/mL
Female: premenopause: 4-30 mIU/mL
midcycle peak: 10-90 mIU/mL
postmenopause: 40-250
pH 7.35-7.45
PCO2 33-45 mmHg
PO2 75-105 mmHg
Glucose, serum Fasting: 70-110 mg/dL
2-h postprandial:<120 mg/dL
Growth hormone - arginine stimulation Fasting: <5 ng/mL
Provocative stimuli: > 7ng/mL
Immunoglobulins, serum  
IgA 76-390 mg/dL
IgE 0-380 IU/mL
IgG 650-1500 mg/dL
IgM 40-345 mg/dL
Iron 50-170 μg/dL
Lactate dehydrogenase, serum 45-90 U/L
Luteinizing hormone, serum/plasma Male: 6-23 mIU/mL
Female: follicular phase: 5-30 mIU/mL
midcycle: 75-150 mIU/mL
postmenopause 30-200 mIU/mL
Osmolality, serum 275-295 mOsmol/kd H2O
Parathyroid hormone, serume, N-terminal 230-630 pg/mL
Phosphatase (alkaline), serum (p-NPP at 30° C) 20-70 U/L
Phosphorus (inorganic), serum 3.0-4.5 mg/dL
Prolactin, serum (hPRL) < 20 ng/mL
Proteins, serum  
Total (recumbent) 6.0-7.8 g/dL
Albumin 3.5-5.5 g/dL
Globulin 2.3-3.5 g/dL
Thyroid-stimulating hormone, serum or plasma .5-5.0 μU/mL
Thyroidal iodine (123I) uptake 8%-30% of administered dose/24h
Thyroxine (T4), serum 5-12 μg/dL
Triglycerides, serum 35-160 mg/dL
Triiodothyronine (T3), serum (RIA) 115-190 ng/dL
Triiodothyronine (T3) resin uptake 25%-35%
Urea nitrogen, serum 7-18 mg/dL
Uric acid, serum 3.0-8.2 mg/dL
Hematologic Reference Range
Bleeding time 2-7 minutes
Erythrocyte count Male: 4.3-5.9 million/mm3
Female: 3.5-5.5 million mm3
Erythrocyte sedimentation rate (Westergren) Male: 0-15 mm/h
Female: 0-20 mm/h
Hematocrit Male: 41%-53%
Female: 36%-46%
Hemoglobin A1c ≤ 6 %
Hemoglobin, blood Male: 13.5-17.5 g/dL
Female: 12.0-16.0 g/dL
Hemoglobin, plasma 1-4 mg/dL
Leukocyte count and differential  
Leukocyte count 4,500-11,000/mm3
Segmented neutrophils 54%-62%
Bands 3%-5%
Eosinophils 1%-3%
Basophils 0%-0.75%
Lymphocytes 25%-33%
Monocytes 3%-7%
Mean corpuscular hemoglobin 25.4-34.6 pg/cell
Mean corpuscular hemoglobin concentration 31%-36% Hb/cell
Mean corpuscular volume 80-100 μm3
Partial thromboplastin time (activated) 25-40 seconds
Platelet count 150,000-400,000/mm3
Prothrombin time 11-15 seconds
Reticulocyte count 0.5%-1.5% of red cells
Thrombin time < 2 seconds deviation from control
Volume  
Plasma Male: 25-43 mL/kg
Female: 28-45 mL/kg
Red cell Male: 20-36 mL/kg
Female: 19-31 mL/kg
Cerebrospinal Fluid Reference Range
Cell count 0-5/mm3
Chloride 118-132 mEq/L
Gamma globulin 3%-12% total proteins
Glucose 40-70 mg/dL
Pressure 70-180 mm H2O
Proteins, total < 40 mg/dL
Sweat Reference Range
Chloride 0-35 mmol/L
Urine  
Calcium 100-300 mg/24 h
Chloride Varies with intake
Creatinine clearance Male: 97-137 mL/min
Female: 88-128 mL/min
Estriol, total (in pregnancy)  
30 wks 6-18 mg/24 h
35 wks 9-28 mg/24 h
40 wks 13-42 mg/24 h
17-Hydroxycorticosteroids Male: 3.0-10.0 mg/24 h
Female: 2.0-8.0 mg/24 h
17-Ketosteroids, total Male: 8-20 mg/24 h
Female: 6-15 mg/24 h
Osmolality 50-1400 mOsmol/kg H2O
Oxalate 8-40 μg/mL
Potassium Varies with diet
Proteins, total < 150 mg/24 h
Sodium Varies with diet
Uric acid Varies with diet
Body Mass Index (BMI) Adult: 19-25 kg/m2
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(M1.RL.70) A 7-year-old boy suffers from generalized edema. Urine protein excretion is 5.2 g over 24 hours, and serum analysis reveals hyperlipidemia. The patient responds to treatment with prednisone, and, 8 weeks later, his urine does not contain measurable protein. If a kidney biopsy had been performed while the patient’s condition was pathologic, which of the following would you expect to find upon glomerular electron microscopy? Review Topic

QID: 101024
1

Effacement of podocyte foot processes

83%

(92/111)

2

Subepithelial ‘spike and dome’ deposits

6%

(7/111)

3

Subepithelial humps

2%

(2/111)

4

Thin glomerular basement membrane

6%

(7/111)

5

Subendothelial thickening

1%

(1/111)

M1

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(M1.RL.59) A 52-year-old African American male with a history of HIV and obesity presents to his primary care physician because of recent changes to his health. He states that while he has been compliant on his HIV medication, he has noticed recent fatigue and increased swelling in his face and legs. A routine urinalysis demonstrates proteinuria and fatty casts. Based on these findings, the physician decided to proceed with a kidney biopsy. Which of the following figures most likely represents the findings of this patient's kidney biopsy? Review Topic

QID: 104506
FIGURES:
1

Figure A

9%

(6/68)

2

Figure B

60%

(41/68)

3

Figure C

12%

(8/68)

4

Figure D

10%

(7/68)

5

Figure E

6%

(4/68)

M1

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(M1.RL.88) A 57-year-old male with diabetes mellitus type II presents for a routine check-up. His blood glucose levels have been inconsistently controlled with medications and diet since his diagnosis 3 years ago. At this current visit, urinalysis demonstrates albumin levels of 250 mg/day. All prior urinalyses have shown albumin levels below 20 mg/day. At this point in the progression of the patient’s disease, which of the following is the most likely finding seen on kidney biopsy? Review Topic

QID: 101042
1

Normal kidney biopsy, no pathological finding is evident at this time

0%

(0/18)

2

Glomerular hypertrophy with slight glomerular basement membrane thickening

28%

(5/18)

3

Glomerular basement membrane thickening and mesangial expansion

39%

(7/18)

4

Kimmelstiel-Wilson nodules and tubulointerstitial fibrosis

22%

(4/18)

5

Significant global glomerulosclerosis

11%

(2/18)

M1

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(M1.RL.74) A 57-year-old female visits her primary care physician with 2+ pitting edema in her legs. She takes no medications and does not use alcohol, tobacco, or illicit drugs. 4.5 grams of protein are collected during 24-hour urine excretion. A kidney biopsy is obtained. Examination with light microscopy shows diffuse thickening of the glomerular basement membrane. Electron microscopy shows subepithelial spike and dome deposits. Which of the following is the most likely diagnosis: Review Topic

QID: 101028
1

Minimal change disease

0%

(0/21)

2

Postinfectious glomerulonephritis

0%

(0/21)

3

Focal segmental glomerulosclerosis

5%

(1/21)

4

Rapidly progressive glomerulonephritis

5%

(1/21)

5

Membranous glomerulopathy

90%

(19/21)

M1

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(M1.RL.24) An 11-year-old boy presents to your office with pitting edema and proteinuria exceeding 3.5g in 24 hours. You suspect that this patient has experienced a loss of polyanions in his glomerular basement membranes. Which of the following findings would confirm your diagnosis? Review Topic

QID: 100978
1

WBC casts in the urine

6%

(4/67)

2

RBC casts in the urine

6%

(4/67)

3

Selective albuminuria

79%

(53/67)

4

Negatively birefringent crystals in the urine

0%

(0/67)

5

Bence-Jones proteinuria

7%

(5/67)

M1

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(M1.RL.19) A 55-year-old African American male presents to his primary care physician with complaints of persistent back pain and fatigue over 12 months. Physical examination reveals a blood pressure of 190/150 mm Hg, and laboratory tests reveal hyperlipidemia and a serum creatinine level of 3.0 mg/dL. 4.5 g of protein are excreted in the urine over 24 hours. Renal biopsy shows eosinophilic, acellular material in the glomerular tuft and capillary walls that display apple green-colored birefringence in polarized light upon Congo red tissue staining. The patient most likely suffers from which of the following: Review Topic

QID: 100973
1

Membranous nephropathy

0%

(0/12)

2

Focal segmental glomerular sclerosis

8%

(1/12)

3

Drug-induced acute tubular necrosis

0%

(0/12)

4

Multiple myeloma

92%

(11/12)

5

Malignant hypertension

0%

(0/12)

M1

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(M1.RL.8) A 5-year-old female presents to your office with periorbital edema and proteinuria. Her mother reports that she "just got over a cold" last week. On examination, you note a pulse rate of 70/minute and a blood pressure of 95/53. Which protein(s) would likely be found in large amounts in this patient's urine? Review Topic

QID: 100962
1

IgG

7%

(11/153)

2

IgA

10%

(16/153)

3

Albumin

52%

(80/153)

4

Albumin and IgG

15%

(23/153)

5

Albumin, IgG, and IgA

13%

(20/153)

M1

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(M1.RL.81) A 67-year-old man presents to your office with a chief complaint of constipation and many other perturbing minor medical concerns. He reports tiring easily, which he attributes to old age and years of persistent pain in his back and ribs. A complete blood count shows low hemoglobin and elevated serum creatinine. A peripheral blood smear shows stacks of red blood cells among other findings, and serum electropheresis reveals an abnormal concentration of protein resulting in a spike. Which of the following additional findings would you expect to see in this patient? Review Topic

QID: 101035
1

Early satiety and splenomegaly

20%

(4/20)

2

Smudge cells on peripheral smear

10%

(2/20)

3

An elevated PSA and a nodular prostate

0%

(0/20)

4

Bence-Jones proteins in the urine

70%

(14/20)

5

No additional findings - normal aging explains symptoms

0%

(0/20)

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(M1.RL.84) A 6-year-old girl presents to your clinic two weeks after receiving a routine immunization in preparation for a trip overseas. Periorbital edema is present on exam and 24 hour urine collection shows excretion of 4.3 grams of protein/day. Which pathological change would likely be seen on microscopy?
Review Topic

QID: 101038
1

Linear IgG deposition on light microscopy

6%

(2/36)

2

IgA-immune complexes in the mesangium on electron microscopy

14%

(5/36)

3

“Tram-track” appearance on light microscopy

6%

(2/36)

4

Subepithelial deposits with “spike and dome” appearance on electron microscopy

11%

(4/36)

5

Podocyte effacement on electron microscopy

58%

(21/36)

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