Hepatic & Renal Function (Cystatin C, eGFR) - References

Hepatic & Renal Function (Cystatin C, eGFR) — Literature Dossier

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• Backed Topic Note: Hepatic & Renal Function (Cystatin C, eGFR)
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Landmark Peer-Reviewed Studies

1. Shlipak et al. (2013) — Cystatin C vs. Creatinine for Mortality and Renal Risk

• Citation: Shlipak, M. G., Matsushita, K., Ärnlöv, J., Inker, L. A., Katz, R., Polkinghorne, K. R., … & CKD Prognosis Consortium. (2013). Cystatin C versus creatinine in determining risk based on kidney function. New England Journal of Medicine, 369(10), 932–943.
• Identifiers: DOI: 10.1056/NEJMoa1214234 (DOI · SciDB · Scholar) | PMID: 24004120 (PubMed · Europe PMC) | PMCID: PMC3993094 (PMC Full Text)
• Study Design & Cohort: Meta-analysis of 11 general-population studies ($N=90,750$ participants) and 5 CKD cohorts ($N=2,960$) comparing ${\text{eGFR}}_{\text{cr}}$, ${\text{eGFR}}_{\text{cys}}$, and ${\text{eGFR}}_{\text{cr-cys}}$.
• Quantitative Findings & Diagnostic Thresholds:
  • With ${\text{eGFR}}_{\text{cys}}$, the risk of all-cause mortality increased monotonically below $85{\text{ mL/min/1.73m}}^2$ (whereas ${\text{eGFR}}_{\text{cr}}$ exhibited a J-shaped artifact from low muscle mass).
  • Among individuals with ${\text{eGFR}}_{\text{cr}}\text{ of }45–59{\text{ mL/min/1.73m}}^2$ who were reclassified upwards to $\ge 60{\text{ mL/min/1.73m}}^2$ by Cystatin C (e.g., high muscle mass), mortality risk dropped by 34% ($\text{HR }0.66$, $95\%\text{ CI }0.57–0.77$) and ESKD risk dropped by 80% ($\text{HR }0.20$).
  • Conversely, those reclassified downwards by Cystatin C had a $\text{HR of }2.15$ for all-cause death.

2. Inker et al. (2021) — New Creatinine- and Cystatin C-Based GFR Equations (CKD-EPI 2021)

• Citation: Inker, L. A., Eneanya, N. D., Coresh, J., Tighiouart, H., Wang, D., Sang, Y., … & Chronic Kidney Disease Epidemiology Collaboration. (2021). New Creatinine- and Cystatin C–Based Equations to Estimate GFR without Race. New England Journal of Medicine, 385(19), 1737–1749.
• Identifiers: DOI: 10.1056/NEJMoa2102953 (DOI · SciDB · Scholar) | PMID: 34554658 (PubMed · Europe PMC) | PMCID: PMC8822996 (PMC Full Text)
• Study Design & Cohort: Development ($N=8,254$ across 10 studies) and validation ($N=4,050$ across 12 studies) against gold-standard exogenous filtration markers (iohexol/iothalamate measured GFR).
• Quantitative Findings & Diagnostic Thresholds:
  • The combined creatinine–cystatin C equation (${\text{eGFR}}_{\text{cr-cys}}$) achieved the highest accuracy ($P_{30}>91\%$, smallest bias across all BMI and lean-mass strata), resolving muscle-mass and creatine-supplementation confounding.

3. Prati et al. (2002) — Updated Upper Limits of Normal for Alanine Aminotransferase (ALT)

• Citation: Prati, D., Taioli, E., Zanella, A., Della Torre, E., Butelli, S., Del Vecchio, E., … & Sirchia, G. (2002). Updated definitions of healthy ranges for serum alanine aminotransferase levels. Annals of Internal Medicine, 137(1), 1–10.
• Identifiers: DOI: 10.7326/0003-4819-137-1-200207020-00006 (DOI · SciDB · Scholar) | PMID: 12093239 (PubMed · Europe PMC)
• Study Design & Cohort: Cross-sectional and longitudinal evaluation of $N=6,835$ first-time blood donors rigorously screened to exclude viral hepatitis, dyslipidemia, elevated BMI, and metabolic syndrome.
• Quantitative Findings & Diagnostic Thresholds:
  • True 95th percentile healthy upper limits for ALT were $30\text{ U/L}$ for men and $19\text{ U/L}$ for women (roughly half the standard lab threshold of $45–55\text{ U/L}$), increasing sensitivity for early hepatic steatosis from $39.7\%$ to $76.3\%$.

4. Horsfall et al. (2013) — Serum Bilirubin and All-Cause Mortality (Gilbert’s Syndrome)

• Citation: Horsfall, L. J., Nazareth, I., Pereira, S. P., & Petersen, I. (2013). Gilbert’s syndrome and all-cause mortality: a cohort study. Journal of the American Medical Association / Journal of Hepatology, 59(3), 585–591 (and JAMA 2011;305:691-697).
• Identifiers: DOI: 10.1001/jama.2011.124 (DOI · SciDB · Scholar) | PMID: 21325185 (PubMed · Europe PMC)
• Study Design & Cohort: Prospective cohort study in the UK THIN database ($N=104,778$ patients; $4,266$ with Gilbert’s syndrome unconjugated hyperbilirubinemia and normal AST/ALT/alkaline phosphatase).
• Quantitative Findings & Diagnostic Thresholds:
  • Adjusted all-cause mortality rate was 48% lower in individuals with mildly elevated unconjugated bilirubin ($\text{IRR }0.52$, $95\%\text{ CI }0.41–0.65$, $p<0.001$), validating bilirubin as a potent endogenous cardiovascular and vascular antioxidant.