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Nephrotic Syndrome, Emergency Medicine

Basics

Description

- 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

- 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

- 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.

- 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

- CBC + differential: - Anemia common - Leukocytosis: Infection - Leukopenia: Neoplastic disease or sepsis - Thrombocytopenia: Liver disease

- Renal biopsy: - Definitive test for patients who do not respond to a short course of corticosteroids - Helps discern primary vs. secondary pathology

- Renal parenchymal disease: - Chronic renal disease - Mechanical nephropathy (outlet obstruction/reflux) - Acute pyelonephritis - Sickle cell disease

- 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

- 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.

- 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

  • Diseases causing defect in glomerular filtration barrier, producing proteinuria:Proteinuria >3 g in 24 hrHypoalbuminemia (serum albumin <3 g/dL)Peripheral edema due to hypoalbuminemiaHypogammaglobulinemiaHyperlipidemia (fasting cholesterol >200 mg/dL)
  • Urine fat (oval fat bodies, fatty/waxy casts)
  • Glomerular basement membrane altered by:Immune complexesNephrotoxic antibodiesNonimmune mechanismsResult: 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:HypovolemiaLow serum albuminHigh protein excretionHigh fibrinogen levelsLow antithrombin III levels

Etiology

  • Due to primary renal or systemic diseases
  • Membranous nephropathy:Primary cause of nephrotic syndrome in adultsOther 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 childrenOther causes: Idiopathic, NSAIDs, paraneoplastic syndrome associated with malignancy (often Hodgkin lymphoma)Best prognosis among all nephrotic syndromesGood response to steroids
  • Focal segmental glomerulosclerosis (FSGS):Young patients (15 " 30 yr) with nephrotic syndromePresents 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 sedimentComplement levels are persistently lowSupportive 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 adultsMicroalbuminuria (30 " 300 mg/24hr) is primary indicator of renal disease.Worsening of renal function in 5 " 7 yrDoes not cause rapid decline in renal functionStrict control of blood sugar and ACEI therapy slow progression.
  • Monoclonal gammopathies:Include amyloidosis, multiple myeloma, and light-chain nephropathyRenal 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 stateUp to 30% occurrence of PE in membranous glomerulonephritisChronic or exertional tachypnea due to:Pulmonary edemaPleural effusionsInfection risk due to immunosuppressive treatment and frequent exposure to infections such as PneumococcusAscites
  • 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 bodiesFree lipid droplets

Diagnosis Tests & Interpretation

Lab

  • CBC + differential:Anemia commonLeukocytosis: InfectionLeukopenia: Neoplastic disease or sepsisThrombocytopenia: Liver disease
  • PT/PTT, international normalized ratio:Coagulation profiles abnormal with concurrent liver disease
  • d-dimer, fibrinogen, antithrombin IIISuspected 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 corticosteroidsHelps 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 diseaseMechanical nephropathy (outlet obstruction/reflux)Acute pyelonephritisSickle cell disease
  • Other causes:CHFEssential hypertensionAcute febrile illnessPregnancy (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 volumeActive rehydration in the presence of severe hypotension, shock

Ed Treatment/Procedures

  • Control edema:Restrict sodium intake: 2 g NaCl/dLoop diuretic (furosemide): Titrate dose until response seenThiazides and potassium-sparing diureticsGoal: 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 eventProphylactic anticoagulation now considered acceptable when level of hypoalbuminemia is extremely low (<2.5 g/dL): Goal INR 1.8 " 2Consider low-dose aspirin 81 mgSupport 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/cyclosporineRecombinant 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.

See Also (Topic, Algorithm, Electronic Media Element)

  • Acute Renal Failure
  • Glomerulonephritis
  • Nephritic Syndrome

The author gratefully acknowledges the contribution of Anwer Hussain.

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)