CKD Staging (Cr vs. Cystatin C, Albuminuria & more): Mind The Gap Segment

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Welcome to the “Stage”: GFR and Albuminuria

Reviewing CKD Classification!

• Kidney Disease: Improving Global Outcomes (KDIGO) introduced a dual-staging criteria for chronic kidney disease (CKD)
  • eGFR Staging (G-Stage)
    • eGFR between 60 - 120 ml/min/1.73 m2
      • NOT clinically significant CKD
    • Stage G3
      • Stage G3a
        • 45 < eGFR < 59
      • Stage G3b
        • 30 < eGFR < 44
    • Stage G4
      • 15 < eGFR < 29
    • Stage G5
      • eGFR < 15
  • Albuminuria (A-Stage)
    • Measured by albumin-to-creatinine ratio (ACR) in mg/g
      • Stage A1
        • 0 < ACR < 30 mg/g
      • Stage A2
        • 30 < ACR < 300 mg/g
        • Moderately elevated (previously “microalbuminuria”)
      • Stage A3
        • > 300 mg/g  ACR
        • Severely elevated (previously “macroalbuminuria”)
• Both the G-stage and A-stage are independent risk factors for cardiovascular and renal events! 

What’s WRONG with how we estimate GFR?

• The ideal molecule to estimate GFR does NOT exist!
  • Ideal Qualities:
    • Exact serum quantity is known
    • Freely filtered at glomerulus
    • Neither secreted NOR reabsorbed in the tubules 
    • Ex: Insulin used historically
      • but cumbersome since requires injection
• Why is creatinine flawed as an estimator of GFR? 
  • Creatinine is used as an endogenous estimator
  • Varies with muscle mass
    • Differs between patients based on:
      • Sex
      • Age 
    • Low muscle mass → lower levels of creatinine
      • Result: Cr will overestimate eGFR measurements & give false reassurance!
        • Example: Cr of 1 mg/dl in a 90-year-old frail female
    • Higher muscle mass → higher levels of creatinine
      • Result: Cr will underestimate eGFR measurements
        • Ex. Serum Cr of 1.8 mg/dL in Arnold Schwarzenegger or Shaq

• • Actively secreted in the renal tubules
    • Secretion rate is influenced by medications!
      • Bactrim

• • Race-adjusted eGFR formula
    • African Americans were systematically under-staged (i.e., for a given creatinine, higher eGFR would be reported → undiagnosed CKD)
• Enter a NEW Contender: Cystatin C! 
  • Advantages  
    • Does not vary based on muscle mass
      • • Since it is made in every nucleated cell!
    • Freely filtered in the glomerulus
    • Neither secreted or reabsorbed in the renal tubules 
  • Disadvantages
    •  Affected by sex and age
      • • But, you can correct for these!
    • Affected by inflammation and chronic diseases
      • • Diabetes
        • Cigarette smoking
        • Thyroid disease
        • Cancer
        • HIV
        • Steroid use
  • Which patient should I order Cystatin C for?!
    • Patients with low muscle mass
      • • Who may be under staged by creatinine measurements alone
          1. Erroneously reporting higher eGFR 
    • Patients with high muscle mass
      • • Who may be falsely labeled with CKD
          1. From a creatinine derived eGFR
• Which marker of eGFR is the best?
  • On a populational level, assessing eGFR using BOTH Cystatin C and creatinine is more accurate than using either markers alone!

Assessing Qualitative Renal Function using A-Stage! (Albuminuria)

• A Dive into the Endothelium!
  • Endothelial dysfunction → Albuminuria
    • Urine = Direct pathway to observe endothelial dysfunction
    • Can start to occur well BEFORE  any significant changes to GFR! 
• A-Stage
  • Helps identify patients who (1) are in early stages of renal dysfunction and (2) who can respond well to more aggressive interventions!
    • Potential treatments:
      • ACE-i/ARBs
        • ONLY have renal-protective function in patients with albuminuria!
          • Otherwise are just like other BP meds
      • SGLT2i
        • Shown to decrease decline in GFR, ESRD, and death
          • DAPA-CKD trial
            • Pro tip! If proteinuria is still > 500 mg/g with RAASi and SGLT2i, can consider adding finerenone!
    • You can trend A-Stage to assess the effectiveness of treatment interventions!
    • Make sure to measure albuminuria ESPECIALLY in patients with:
      • Diabetes AND known CKD
• Confounding Factors for albuminuria
  • The following activities can lead to spillage of albumin into urine! (not actual renal dysfunction) → transient albuminuria
    • Exercise
    • Standing upright
    • Inflammation
• How do we measure A-Stage? 
  • Urine albumin-to-creatinine ratio (ACR)
    • Most commonly used!
      • Influenced by denominator (creatinine)
        • Note: Urine albumin WITHOUT reporting urine creatinine is NOT meaningful!
      • But this is affected by all the aforementioned flaws of creatinine measurement
  • 24-hour urine albumin
    • Gold standard!
      • Can be quite cumbersome to collect/perform, especially in outpatient settings

Contributors

Shreya Trivedi, MD, ACP Member – Editor
Gregory Katz, MD – Host, Editor
Cary Blum, MD – Host, Editor
Yichi Zhang, MD, MBA – Editor, MOC Questions

Reviewers

Tomas Guerrero, MD
Tejas Patel, MD

Those named above, unless otherwise indicated, have no relevant financial relationships to disclose with ineligible companies whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.  All relevant relationships have been mitigated.

Release Date:  November 8, 2023

Expiration Date: November 7, 2026

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