Nephrotic syndrome (NS)

Important definitions

Nephrotic syndrome

• Heavy (nephrotic range) proteinuria
• Hypoalbuminemia (serum albumin <3.0 g/dL or <30 g/L)
• Edema
  • Often present, especially at disease onset, but not required for diagnosis unless albumin level is not known
• Hyperlipidemia (total cholesterol ≥200 mg/dL)
  • Almost always present and often severe (>350 mg/dL or >9.06 mmol/L), but not required for diagnosis

Nephrotic range proteinuria

• First morning urine protein/creatinine ratio (UPCR, PCR, UPC) ≥2.0 g/g (or ≥200 mg/mmol)
• First morning urine protein ≥300 mg/dL
• First morning urine dipstick with ≥3+ protein
  • UPCR is preferred over dipstick for establishing diagnosis
• 24-hour urine ≥40 mg/m²/hour
• There is no universally accepted definition of nephrotic range proteinuria when using urine albumin creatinine ratio (UACR)

Remission

• Complete remission: negative/trace first morning dipstick for ≥3 consecutive days
  • Alternatively, first morning UPCR ≤0.2 g/g (or ≤20 mg/mmol) Cr for ≥3 consecutive days
    • Sequential UPCR is rarely performed in the outpatient setting
• Partial remission: sub-nephrotic range proteinuria (UPCR ≥0.2 but <2.0 g/g) and serum albumin ≥3.0 g/dL (30 g/L)
• Sustained remission: no relapses for >12 months, with or without therapy

Relapse

• Recurrence of nephrotic range proteinuria for ≥3 consecutive days
  • Typically detected by home urine dipstick

Steroid sensitive nephrotic syndrome (SSNS)

• Complete remission within 4 weeks of prednisone or prednisolone at a standard dose
• Recommend avoiding use of “steroid responsive NS” as this can be confused with steroid resistant NS when abbreviated to SRNS
• SSNS can be subclassified in terms of frequency of relapse:

  • Frequently relapsing nephrotic syndrome (FRNS)

    • ≥2 relapses within 6 months of disease onset or ≥4* relapses in any subsequent 12 month period
      • *IPNA guidelines recommends ≥3 relapses in any subsequent 12 month period [PMID 36269406]

  • Infrequently relapsing nephrotic syndrome (IRNS, IFRNS, iFRNS)

    • Encompasses patients who do not meet criteria for frequently relapsing nephrotic syndrome:
      • No more than 1 relapse within 6 months of disease onset
      • No more than 3 relapses in any subsequent 12 month period

  • Steroid dependent nephrotic syndrome (SDNS)

    • Two consecutive relapses during appropriate therapy with prednisone/prednisolone (either at full daily dose or during tapering) or within 14 days of stopping steroids
      • In other words, patients with SDNS are unable to come off steroids for >2 weeks without relapsing

Steroid resistant nephrotic syndrome (SRNS)

• Lack of complete remission after 4 weeks of therapy with daily prednisone or prednisolone at standard dose

  • Late responder

    • Achieved complete remission after 4 weeks but before 6 weeks of daily steroid therapy

  • Calcineurin inhibitor (CNI) responsive SRNS

    • Partial remission is achieved within 6 months of treatment and/or complete remission is achieved within 12 months of treatment with a CNI at adequate doses and/or levels

  • Calcineurin inhibitor (CNI) resistant SRNS

    • Partial remission is not achieved after 6 months of treatment with a CNI at adequate doses and/or levels

  • Multidrug resistant SRNS

    • Absence of complete remission after 12 months of treatment with two steroid sparing agents
    • The two steroid sparing agents must have distinct mechanisms and be administered at standard doses

  • Secondary SRNS

    • When a patient with SSNS at disease onset has a subsequent relapse in which they are a late responder

New diagnosis

Laboratory workup

• CMP
  • Evaluate for severe hypoalbuminemia, electrolyte derangements
• CBC
  • More data to evaluate degree of hemoconcentration
• Other potential causes of glomerular disease (if risk factors):
  • Syphilis, HIV, hepatitis B (HBV), and hepatitis C (HCV)

Indications for kidney biopsy

• Steroid resistance
• Impaired kidney function (AKI) not due to hypovolemia
• Macroscopic hematuria
• Sustained hypertension
• Persistent microscopic hematuria in setting of hypertension
• Low C3
• Elevated ANA screen
• Arthritis and/or rash suggestive of glomerulonephritis (GN)
• Onset <12 months of age
  • Genetic testing or empiric treatment with steroids are also reasonable strategies in patients aged 3-12 months

Management

• If patient is at high risk for latent tuberculosis, send QuantiFERON-TB Gold or place PPD before starting steroids
  • PPD testing preferred if <2 years old
  • IGRA (e.g., QuantiFERON-TB Gold Plus or T-Spot) preferred if patient has received BCG vaccine or if unable to return for PPD check

Steroids

• Oral prednisone/prednisolone (PDN) per KDIGO and IPNA guidelines:
  • 2 mg/kg/day (or 60 mg/m²/day, max of 60 mg/day) daily for 6 weeks, then
  • 1.5 mg/kg/dose (or 40 mg/m²/dose, max of 50 mg/dose) every other day for 6 weeks
• Alternatively, reducing these courses to 4 weeks each is also acceptable:
  • 2 mg/kg/day (or 60 mg/m²/day, max of 60 mg/day) daily for 4 weeks, then
    • 1.5 mg/kg/dose (or 40 mg/m²/dose, max of 50 mg/dose) every other day for 4 weeks

• KDIGO also recommends steroid gastritis prophylaxis (typically an H2 blocker such as famotidine is used), though this is not universally practiced
• Teaching by nephrology RNs if applicable
• Ensure vaccinations are up to date

Dietary/fluid restrictions

• Fluid restriction is not routinely necessary
  • Recommended if there is moderate hyponatremia (<130 mEq/L)
    • Ensure there is true hypotonic hyponatremia; the hyperlipidemia seen in NS can result in pseudohyponatremia
  • May be indicated (along with loop diuretics) in hospitalized patients with severe edema
  • Inappropriate fluid restriction may contribute to AKI, hypovolemia, and thromboses: avoid fluid restricting patients with intravascular volume depletion
  • When indicated, a fluid restriction of ~1 L/m²/day is a reasonable starting point
    • See: kidney.wiki BSA calculator
• Low sodium diet (2-3 mEq/kg/day, usually simplified to 2 grams Na/day)
  • Fluid restriction is infeasible without concurrent sodium restriction
• Continue restrictions until in remission and edema improved

Inpatient management

Indications for hospitalization

• Significant hemoconcentration (↑ risk of AKI, hypovolemia, thromboses)
• Significant AKI
• Poor enteral intake
• Concern for sepsis
• Social factors (e.g., need for patient/family education)
• If diagnosis other than minimal change disease is suspected, admission is often necessary for timely evaluation and management

Inpatient medications

• Consider using IV methylprednisolone in lieu of PO steroids if unable to tolerate PO, concern for poor adherence, or concern for poor absorption of oral medications in setting of gut edema
• Diuretics +/- albumin
  • If albumin ≥2, generally try furosemide (Lasix) without albumin to see if responsive before using combination
  • If albumin <2, consider Albumin + furosemide in combination:
    • 0.5-1 g/kg IV 25% albumin (rounded to increment of 12.5 g) over 8 hours
    • 0.5-1 mg/kg IV furosemide at 4 hours and again at 8 hours
    • Prefer to do during daytime - at least initially - in case of complication (i.e., flash pulmonary edema)
    • Repeat PRN based on exam and weight