EM@3AM: Nephrotic Syndrome

Author: Andrea Nillas, MD (EM Resident Physician, UTSW/Parkland Hospital) // Reviewed by: Alex Koyfman, MD (@EMHighAK); Brit Long, MD (@long_brit)

Welcome to EM@3AM, an emDOCs series designed to foster your working knowledge by providing an expedited review of clinical basics. We’ll keep it short, while you keep that EM brain sharp.


A 25-year-old female with no significant past medical history presents to the emergency department with progressive periorbital and lower extremity edema for one week. She denies recent fever, chest pain, shortness of breath, allergies, or recent travel. Vital signs include BP 120/90, HR 90, RR 18, Temp 98.7F. Exam shows a developmentally normal female in no acute distress. On auscultation there are no murmurs and lungs are clear. Abdomen is soft, non-distended, and non-tender. She has bilateral pitting edema up to knees without skin changes. Her pregnancy test is negative.

What is the likely diagnosis?


Answer: Nephrotic syndrome

 

Background:

-Epidemiology

  • Annual incidence in adults is 3 per 100,000 individuals [1]
  • Majority of causes (90%) are primary (idiopathic) while secondary causes are rarer [2]
  • Primary causes:
    • Minimal change disease (MCD) – most common in children [3]
    • Membranous nephropathy – most common cause in Caucasian populations
      • Generally favorable prognosis where 1/3 are benign with high remission rate, 1/3 have chronic proteinuria/edema without renal dysfunction, and 1/3 progress to ESRD within 10yrs [1]
    • Focal segmental glomerulosclerosis (FSGS) – most common cause in African Americans
      • Tend to have poorer prognosis with degree of proteinuria being a significant prognostic factor [1]
  • Secondary causes:

-Nephrotic syndrome is classically characterized by:

  • Heavy proteinuria (urine protein >3-3.5g in 24hrs)
  • Hypoalbuminemia (serum Albumin <2.5g/dL)
  • Hyperlipidemia (serum cholesterol >200mg/dL)
  • Edema [2]
  • *Hyperlipidemia may not always be present and is not required for diagnosis [1,3]

 

Pathophysiology:

  • Permeability of the renal glomerulus is increased when podocytes in the glomerular membrane are damaged by immune dysfunction or systemic disease
    • Proteinuria and hypoproteinemia – diagnostic hallmarks of nephrotic syndrome
      • Low intravascular oncotic pressure + Sodium and water retention leads to systemic edema
      • Reactive hepatic lipoprotein synthesis and decreased lipid catabolism leads to hyperlipidemia
  • Renin-angiotensin-aldosterone system (RAAS) is stimulated by fluid shifts to extracellular space and intravascular volume depletion
    • Increased distal sodium absorption, worsening cycle and hypertension
  • Thrombogenesis- multifactorial; venous and arterial
    • Increased platelet aggregation
    • Impaired fibrinolysis – fibrinogen levels are increased and plasminogen is decreased
    • Loss of coagulation factors (antithrombin III, protein C) in urine [4]

 

Clinical Presentation:

  • Edema is the most common complaint [1]
    • Anasarca = significant peripheral edema, ascites, genitourinary and periorbital edema
  • Respiratory- shortness of breath, orthopnea or cough could suggest pleural effusion or pulmonary edema
  • Gastrointestinal- abdominal fullness, nausea/vomiting may result from ascites or bowel edema
    • Fever raises suspicion for spontaneous bacterial peritonitis (SBP)
  • Foamy/frothy urine
  • Hypertension – presence varies with underlying etiology (e.g. not common in minimal change disease)

 

Complications:

  • Infections- loss of complement and antibodies in urine, in addition to steroid therapy leads to relative immunocompromised state [2,3]
  • Thromboembolic risk is increased by up to 44%
    • Risk is greatest in the first 3 months, but remains for over 5 years
    • Serum albumin <2.5g/dL increases risk by 3-fold [5]
  • Acute kidney injury
  • Malnutrition

 

Evaluation:

  • Careful history including medication review and family history may suggest underlying systemic diseases [2]
  • Laboratory analysis
    • CBC- elevated Hgb may suggest hemoconcentration while anemia may indicate chronic kidney disease or secondary cause
    • CMP- assess albumin, electrolytes, renal and liver function
      • Hyponatremia may be secondary to hypertriglyceridemia
    • Coagulation studies
    • Lipid panel
    • Urinalysis
      • Nephrotic syndrome criteria = proteinuria >3.5g in 24hrs OR
      • Spot urine protein to creatinine ratio > 3-3.5
    • Serum complement (C3, C4)
    • ANA, anti-dsDNA Ab
    • Hepatitis panel
  • Imaging- usually not indicated unless there is concern for thrombotic event or pleural effusion
    • CXR for pulmonary edema vs pleural effusion
    • Duplex ultrasound for deep vein thrombosis (DVT)
    • Renal US evaluating for renal vein thrombosis if hematuria and/or flank pain present
    • CT chest angiogram if clinically concerned about PE
    • MRI brain or venogram for stroke or cerebral venous thrombosis, respectively, if headache and/or neurologic deficit present

 

Differential diagnoses: 

  • Congestive heart failure
  • Hepatic failure
  • Hypothyroidism
  • Anaphylaxis
  • DVT
  • Cellulitis
  • Venous insufficiency
  • Lymphedema

 

Management:

Steroids are the mainstay of treatment

  • Prednisone 2mg/kg/d, max 60mg/d [2]
    • Duration varies, but may continue for weeks to months
    • If patient with steroid responsive disease presents in relapse, steroids may be restarted in the ED in consultation with nephrology
    • Steroid-dependent or resistant disease necessitates nephrology consult for initiation of treatment plan, as this may entail second-line therapy [3]
  • Second-line options for refractory disease include cyclosporine, cyclophosphamide, mycophenolate, tacrolimus, and rituximab
  • Minimal change disease and mesangial proliferative nephritis are usually steroid responsive
  • Membranous nephropathy may be steroid responsive or resistant
  • Focal segmental sclerosis is usually resistant

Diuresis – treatment for edema if euvolemic or hypervolemic

  • Oral furosemide 1-2 mg/kg/d, adding spironolactone 2-4 mg/kg/d will prevent hypokalemia if prolonged use of furosemide > 7 days
    • Maximize furosemide to 4mg/kg/d if refractory to above combination
    • Can then add Hydrochlorothiazide PO 1-2mg/kg/d or Metolazone 0.1-0.3mg/kg/d
  • If failed PO treatment, initiate IV furosemide 1-3 mg/kg bolus or infusion at 0.1-1 mg/kg/h
    • Can add 20% albumin 0.5-1g/kg over 2-4hr IV followed by IV furosemide if severe hypoalbuminemia (albumin <1.5g/dL)
      • Ensure adequate urine output prior to albumin administration to avoid worsened hypertension resulting in pulmonary edema [2]

Fluids– initiate resuscitation with isotonic fluid for hypovolemic or hypotensive patients regardless of edema severity as these patients are intra-vascularly depleted [5]

Anticoagulation– despite risk of thrombosis, the benefit of routine prophylactic anticoagulation is unclear due to limited data available and lack of randomized control trials

  • No guidelines exist on indications or duration of treatment [1]
  • Decision should be on a case-by-case basis

Antihypertensives– RAS inhibitors (ACEIs and ARBs) are indicated for persistent hypertension despite control of edema or decline in steroid use, and has been shown to reduce proteinuria [6]

 

Disposition:

-Admit if evidence of the following [3]:

  • Severe edema and anasarca
  • Pulmonary effusions or respiratory distress
  • Infection or thrombotic complications

-Discharge with nephrology follow up for mild to moderate edema

  • Recommend low salt diet to prevent worsening edema

 

Key points:

  • Proteinuria and hypoalbuminemia are the hallmarks for nephrotic syndrome
  • Nephrotic syndrome patients are at increased risk of infection and thrombotic events
  • Mild disease will need nephrology follow up while severe disease warrants IV diuresis and admission

 

From Dr. Katy Hanson at Hanson’s Anatomy:


Further FOAMed Reading:

https://pedemmorsels.com/nephrotic-syndrome/

https://coreem.net/core/nephrotic-syndrome/

 

Resources

  1. Kodner C. Diagnosis and management of nephrotic syndrome in adults. Am Fam Physician.3(6):479-485.
  2. Sinha A and Bagga A. Nephrotic syndrome. Indian J Pediatr.79(8):1045-1055
  3. Dixon A and Stauffer B. Renal emergencies in children. In:Tintinalli JE, Ma O, Yealy DM, Meckler GD, Stapczynski J, Cline DM, Thomas SH. eds. Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 9e. McGraw Hill.
  4. Liebeskind DS. Nephrotic syndrome. In: Biller J, Ferro FM eds. Handbook of Clinical Neurology Vol 119. 2014.
  5. Kelddal S, Nykjaer KM, Gregersen JW, et al. Prophylactic anticoagulation in nephrotic syndrome prevents thromboembolic complications. BMC Nephrology.20:139
  6. Nishi S, et al. Evidence-based clinical practice guidelines for nephrotic syndrome 2014. Clin Exp Nephrol.20:342-370.

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