Nephrotic Syndrome, Emergency Medicine

Basics

Description

Diseases causing defect in glomerular filtration barrier, producing proteinuria:
- Proteinuria >3 g in 24 hr
- Hypoalbuminemia (serum albumin <3 g/dL)
- Peripheral edema due to hypoalbuminemia
- Hypogammaglobulinemia
- Hyperlipidemia (fasting cholesterol >200 mg/dL)
Urine fat (oval fat bodies, fatty/waxy casts)
Glomerular basement membrane altered by:
- Immune complexes
- Nephrotoxic antibodies
- Nonimmune mechanisms
- Result: More permeable glomerular membranes and excretion of albumin and large proteins

Pathophysiology

Proteinuria due to increased filtration within renal glomeruli
Edema due to sodium retention and hypoalbuminemia
Postural hypotension, syncope, and shock due to severe hypoalbuminemia
Hyperlipidemia due to hepatic lipoprotein synthesis stimulated by decreased plasma oncotic pressure
Cumulative thromboembolism risk increased if:
- Hypovolemia
- Low serum albumin
- High protein excretion
- High fibrinogen levels
- Low antithrombin III levels

Etiology

Due to primary renal or systemic diseases
Membranous nephropathy:
- Primary cause of nephrotic syndrome in adults
- Other causes include chronic infection (hepatitis B virus, hepatitis C virus, autoimmune disorders).
- Renal biopsy shows involvement of all glomeruli.
- Women have better prognosis.
- 30% may slowly progress to renal failure.
- Renal vein thrombosis causes sudden loss of renal function.
- Treat with steroids and cytotoxic agents in severe cases.
Minimal change disease:
- Most common cause (90%) of nephrotic syndrome in children
- Other causes: Idiopathic, NSAIDs, paraneoplastic syndrome associated with malignancy (often Hodgkin lymphoma)
- Best prognosis among all nephrotic syndromes
- Good response to steroids
Focal segmental glomerulosclerosis (FSGS):
- Young patients (15 " 30 yr) with nephrotic syndrome
- Presents with high BP, renal insufficiency, proteinuria, microscopic or gross hematuria.
- Causes include HIV, heroin abuse, obesity, hematologic malignancies.
- Primary FSGS responds to steroids.
- Secondary FSGS treated with ACE inhibitors (ACEI)
- Collapsing FSGS usually seen in HIV patients
Membranoproliferative glomerulonephritis:
- May present with nephrotic, non-nephrotic, or nephritic sediment
- Complement levels are persistently low
- Supportive care: Steroids may be helpful in children.
- Aspirin and dipyridamole may slow progression.
Diabetes mellitus/diabetic nephropathy:
- Most common secondary cause of nephrotic range proteinuria in adults
- Microalbuminuria (30 " 300 mg/24hr) is primary indicator of renal disease.
- Worsening of renal function in 5 " 7 yr
- Does not cause rapid decline in renal function
- Strict control of blood sugar and ACEI therapy slow progression.
Monoclonal gammopathies:
- Include amyloidosis, multiple myeloma, and light-chain nephropathy
- Renal manifestations include proteinuria, nephrotic syndrome, nephritic syndrome, and acute renal failure.
- Lab findings include pseudohyponatremia, low anion gap, hypercalcemia, and Bence Jones proteinuria.
- Congo red stain of amyloid shows apple green birefringence in polarized light.
- Supportive care: Steroids and melphalan have some benefit.
Systemic lupus erythematosus (SLE):
- Can present initially as a nephritic process, with progression to nephrotic syndrome
HIV-associated nephropathy:
- FSGS is most common nephropathy.
- Collapsing glomerulopathy in seropositive HIV carriers with supernephrotic syndrome results in end-stage renal failure that is rapidly progressive (months).
Other causes include pre-eclampsia, hepatitis, and drug reactions (culprits include NSAIDs, gold, penicillamine).

Diagnosis

Signs and Symptoms

Many patients are asymptomatic.
Proteinuria
Peripheral edema:
- Mild pitting edema to generalized anasarca with ascites
Hyperlipidemia
Lipiduria (urine fatty casts and oval fat bodies)
Postural hypotension, syncope, shock
Hypertension
Hematuria:
- Microscopic or gross hematuria (secondary to renal vein thrombosis)
Renal insufficiency to acute renal failure in some cases
Tachypnea, tachycardia, with or without hypotension:
- Acute onset: Suggests pulmonary embolus (PE), secondary to renal or deep venous thrombosis and hypercoagulable state
- Up to 30% occurrence of PE in membranous glomerulonephritis
- Chronic or exertional tachypnea due to:
  - Pulmonary edema
  - Pleural effusions
  - Infection risk due to immunosuppressive treatment and frequent exposure to infections such as Pneumococcus
  - Ascites
Protein malnutrition

History

Systemic disease such as diabetes, SLE, HIV
Use of NSAIDS, gold, or penicillamine
History of unintentional weight gain (due to fluid retention)
History of "foamy " appearance of urine

Physical Exam
Varies depending on degree of hypoalbuminemia, hemodynamic status, and etiology of nephrotic syndrome:

Edema
Hypotension/hypertension
Shock

Essential Workup

Urinalysis:

Dipstick protein largely positive:
- Urine specific gravity >1.025 lowers the diagnostic significance of proteinuria.
Microscopic analysis for urinary casts and the presence of cellular elements:
- Oval fat bodies
- Free lipid droplets

Diagnosis Tests & Interpretation

Lab

CBC + differential:
- Anemia common
- Leukocytosis: Infection
- Leukopenia: Neoplastic disease or sepsis
- Thrombocytopenia: Liver disease
PT/PTT, international normalized ratio:
- Coagulation profiles abnormal with concurrent liver disease
d-dimer, fibrinogen, antithrombin III
- Suspected thromboembolic event:
  - Often patients are asymptomatic with PE or renal vein thrombosis; therefore need high clinical suspicion.
24-hr urine protein, total protein to creatinine ratio
Serum albumin: <3 g/dL
Serum total protein
Basic metabolic panel with Ca, Mg, P
Lipid profile: Elevated total cholesterol, LDL, and VLDL
Additional lab tests may be necessary for systemic diseases:
- Examples include antinuclear antibody, serum and urine protein electrophoresis, hepatitis profile, syphilis, cryoglobulins, complement levels

Imaging
Renal US:

Used in suspected secondary causes of nephrotic syndrome

Diagnostic Procedures/Surgery

Renal biopsy:
- Definitive test for patients who do not respond to a short course of corticosteroids
- Helps discern primary vs. secondary pathology
Renal angiography, CT scan, or MRI for suspected renal vein thrombosis

Differential Diagnosis

Proteinuria resulting from other causes:

Renal parenchymal disease:
- Chronic renal disease
- Mechanical nephropathy (outlet obstruction/reflux)
- Acute pyelonephritis
- Sickle cell disease
Other causes:
- CHF
- Essential hypertension
- Acute febrile illness
- Pregnancy (pre-eclampsia)
- Severe obesity

Treatment

Pre-Hospital

Support ABCs

Initial Stabilization/Therapy

ABCs:

Supplemental oxygen if respiratory distress
IV fluids:
- For decreased BP or orthostatic hypotension due to decreased intravascular volume
- Active rehydration in the presence of severe hypotension, shock

Ed Treatment/Procedures

Control edema:
- Restrict sodium intake: 2 g NaCl/d
- Loop diuretic (furosemide): Titrate dose until response seen
- Thiazides and potassium-sparing diuretics
- Goal: Slow diuresis:
  - Aggressive diuresis can precipitate acute renal failure due to hypovolemia and increase the risk of thromboembolic complications.
Thromboembolic prevention/treatment:
- Heparin: 80 IU/kg bolus followed by 18 IU/kg drip IV for thromboembolic event
- Prophylactic anticoagulation now considered acceptable when level of hypoalbuminemia is extremely low (<2.5 g/dL): Goal INR 1.8 " 2
- Consider low-dose aspirin 81 mg
- Support stockings
Plasmapheresis, for severe cases
Glucocorticosteroid: Mainstay of treatment for primary nephrotic syndrome
ACEIs/ARBs: Decreases proteinuria, prevents worsening of renal function:
- Adverse effects of ACEI include renal failure and hyperkalemia.
Cholesterol-lowering agents/dietary manipulation (e.g., bile acid resin, statins)
Other agents to be considered, under supervision of a specialist:
- Cytotoxic agents/cyclosporine
- Recombinant erythropoietin for anemia

Medication

Enoxaparin (Lovenox): 30 " 40 mg (peds: 0.5 " 0.75 mg/kg) SC q12h
Furosemide: 20 " 80 mg (peds: 1 " 6 mg/kg) PO daily/BID
Heparin: 80 IU/kg bolus followed by 18 IU/kg/h drip IV
Lisinopril (ACEI): 10 " 40 mg (peds: >6 yr: 0.07 mg/kg) PO daily
Losartan (ARB): 25 " 100 mg (peds: >6 yr: 0.7 mg/kg) PO daily
Metolazone: 5 " 20 mg (peds: 0.2 " 0.4 mg/kg) PO daily
Prednisone: 5 " 60 mg (peds: 0.5 " 2 mg/kg) PO daily

Follow-Up

Disposition

Admission Criteria

Moderate to severe heart failure, ascites, respiratory compromise
Signs of comorbid illness, such as undiagnosed malignancy, poorly controlled diabetes, immunocompromised patients
Acute renal failure
Evidence of thromboembolic event

Discharge Criteria

Patients with no comorbid disease, normal vital signs, and normal blood work
Close follow-up with a nephrologist for further evaluation and treatment is mandatory.

Issues for Referral
Nephrology:

Routine follow-up for BP and disease management
Renal biopsy for appropriate patients

Follow-Up Recommendations

In addition to nephrology, patients should follow up with rheumatology, infectious disease, hematology/oncology, or endocrine specialist (dependent on underlying disorder contributing to nephritic syndrome).
Strict BP control and attention to low-cholesterol diet allow for best prognosis in long-term disease management.

Pearls and Pitfalls

Characterized by proteinuria, hypoalbuminemia, and peripheral edema
Most common causes are minimal change disease in pediatric patients and diabetic nephropathy in adults.
May present along spectrum from hypertensive to severe hypotension and shock; maintain high index of suspicion in the appropriate setting.
Consider associated risks of thromboembolic disease.

Additional Reading

Crew RJ, Radhakrishnan J, Appel G. Complications of the nephrotic syndrome and their treatment. Clin Nephrol. 2004;62(4):245 " 259.
Glassock RJ. Prophylactic anticoagulation in nephrotic syndrome: A clinical conundrum. J Am Soc Nephrol. 2007;18(8):2221 " 2225.
Huerta C, Castellsague J, Varas-Lorenzo C, et al. Nonsteroidal anti-inflammatory drugs and risk of ARF in the general population. Am J Kidney Dis. 2005;45(3):531 " 539.

Codes

ICD9

581.1 Nephrotic syndrome with lesion of membranous glomerulonephritis
581.3 Nephrotic syndrome with lesion of minimal change glomerulonephritis
581.9 Nephrotic syndrome with unspecified pathological lesion in kidney
581.0 Nephrotic syndrome with lesion of proliferative glomerulonephritis
581.2 Nephrotic syndrome with lesion of membranoproliferative glomerulonephritis
581.81 Nephrotic syndrome in diseases classified elsewhere
581.89 Nephrotic syndrome with other specified pathological lesion in kidney
581.8 Nephrotic syndrome with other specified pathological lesion in kidney
581 Nephrotic syndrome

ICD10

N04.0 Nephrotic syndrome with minor glomerular abnormality
N04.2 Nephrotic syndrome w diffuse membranous glomerulonephritis
N04.9 Nephrotic syndrome with unspecified morphologic changes
N04.1 Nephrotic syndrome w focal and segmental glomerular lesions
N04.3 Nephrotic syndrome w diffuse mesangial prolif glomrlneph
N04.4 Nephrotic syndrome w diffuse endocaplry prolif glomrlneph
N04.5 Nephrotic syndrome w diffuse mesangiocapillary glomrlneph
N04.6 Nephrotic syndrome with dense deposit disease
N04.7 Nephrotic syndrome w diffuse crescentic glomerulonephritis
N04.8 Nephrotic syndrome with other morphologic changes
N04 Nephrotic syndrome

SNOMED

52254009 Nephrotic syndrome (disorder)
197590001 Nephrotic syndrome with membranous glomerulonephritis (disorder)
44785005 Minimal change disease (disorder)
236403004 Focal segmental glomerulosclerosis (disorder)
363234001 Nephrotic syndrome secondary to systemic disease (disorder)

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