Nephrotic syndrome (NS)

Epidemiology

• Minimal change disease (MCD) is the most common cause of nephrotic syndrome in children, affecting 2-7 in 100,000 children

Minimal change disease

• Presents with nephrotic range proteinuria, hypoalbuminemia, gravity-dependent edema, and hyperlipidemia without evidence of systemic disease
  • Can have microscopic hematuria in ~25% of patients
  • Gross hematuria is rare

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
  • Often periorbital edema
  • Periorbital and peripheral edema may be more prominent in the morning and improve during the day as the interstitial fluid is mobilized and excreted
• 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
  • Mostly due to impaired clearance (↓ hepatic LDL uptake, ↓ hepatic lipase activity, ↓ lipoprotein lipase activity), with a small contribution from increased synthesis
  • HDL levels unaffected

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

Differential diagnosis of edema

• Hypoproteinemia → ↓ capillary oncotic pressure
  • Proteinuria (nephrotic syndrome)
  • Malnutrition
  • Liver failure
  • Protein losing enteropathy (PLE)
    • Usually in patients with cardiovascular abnormalities with elevated central venous pressure (e.g., Fontan physiology)
      • Can also be caused by intestinal lymphangiectasia, Ménétrier disease, inflammatory bowel disease (IBD)
    • May have edema (ascites, pleural edema, peripheral edema), diarrhea, failure to thrive, abdominal bloating
    • Elevated α1-antitrypsin in stool (resists intestinal proteases, excreted intact)
• ↑ capillary hydrostatic pressure
  • Heart failure
    • Impaired left ventricular function leads to pulmonary edema, respiratory distress
    • Impaired right ventricular function leads to peripheral edema
    • Edema is usually worse as the day progresses (more exertion/activity)
  • Acute kidney disease (e.g., acute glomerulonephritis)
  • Chronic kidney disease
  • Vasodilators
  • Venous obstruction (e.g., thrombosis, localized edema)
• ↑ capillary permeability
  • Sepsis
  • Allergic reaction
• Lymphatic obstruction
  • Edema may be nonpitting

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)
• Ultrasonography unlikely to add value if presumed minimal change disease (MCD)

Biopsy

• In most patients, the diagnosis can be made clinically and a kidney biopsy is not necessary

Indications for kidney biopsy

• Steroid resistance
• Impaired kidney function (AKI) not due to hypovolemia
• Macroscopic (gross) 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
• Consider biopsy if onset >12 years of age
  • If there are no other indications for biopsy, it is still reasonable to presume minimal change disease (MCD) and trial steroids first and biopsy if resistant to steroids or other manifestations emerge

Biopsy findings

• Light microscopy (LM): classically normal appearing (thus the name, “minimal change”), but can have nonspecific global glomerulosclerosis
• Immunofluorescence (IF): classically normal appearing, but can have nonspecific IgM staining
  • A granular pattern of albumin staining highlighting the Bowman space and proximal renal tubular lumen can be seen
    • Reflects a glomerular basement membrane (GBM) with an impaired negative charge barrier, allowing albumin to filter more freely from the glomerular capillary into the Bowman space
• Electronic microscopy (EM): extensive (typically >80%) podocyte foot process effacement (retraction, widening, and shortening)
  • If foot process effacement is <50%, it is unlikely to be minimal change disease unless it was partially treated already
  • Degree of effacement isn’t necessarily proportional to amount of proteinuria, but foot processes can return to normal as the patient enters remission
  • No other findings: no immune deposits, normal mesangial cellularity and matrix, normal thickness of glomerular basement membrane

Management

• If low risk for latent tuberculosis, can start steroids once the clinical diagnosis is made
• 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 40 mg/dose [IPNA] or 50 mg/dose [KDIGO]) 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 40 mg/dose [IPNA] or 50 mg/dose [KDIGO]) 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 (MCD) 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

Dyslipidemia

• Should normalize when remission is achieved
  • The temporary dyslipidemia that results from relapsing childhood nephrotic syndrome has not been shown to increase cardiovascular disease risk when they become adults
• If in relapse/nephrotic state for several months, it is reasonable to consider lipid lowering therapy
• If there is persistent dyslipidemia when in remission, treatment may be indicated per routine childhood dyslipidemia management

Prognosis

• Most patients who respond to treatment will maintain normal kidney function into adulthood
• Over 2/3 of patients have at least one relapse
• Relapses become less likely with time, but can still occur many years after entering remission

Infectious complications

Pneumocystis pneumonia (PCP)

• Opportunistic fungal infection caused by Pneumocystis jirovecii
• Manifests with hypoxemia in immunocompromised host

Diagnosis

• Ground glass opacities on chest CT
• Diagnose with bronchoalveolar lavage (BAL) and one of:
  • Specific tinctorial (dye-based) screening
  • Fluorescent antibody staining
  • Polymerase chain reaction (PCR)

Prevention

• Some centers use PJP prophylaxis in patients who have received rituximab
  • Typically trimethoprim-sulfamethoxazole (TMP-SMX)

Prognosis

• Can be life threatening
  • Outcomes worse in immunocompromised patients without HIV compared to those with HIV