Renal Function Markers - Kidney Disease

Diagnosis

Indications for Testing

• Any risk factors for chronic kidney disease
• Assess diabetics for early renal function abnormalities

Laboratory Testing

• Serum creatinine, blood urea nitrogen (BUN), and estimated glomerular filtration rate (EGFR) – use for initial diagnosis of acute or chronic disease
• Urine albumin – initial test in diabetes to assess renal function
• Other biomarkers – usefulness in assessing renal function has not been determined; studies are ongoing

Differential Diagnosis

See Risk Factors in Background.

Screening

Estimated glomerular filtration rate (using creatinine) and albumin testing in individuals with hypertension, diabetes mellitus, cardiovascular disease, and family history of cardiovascular disease (CVD)

Monitoring

Urinary albumin – use to monitor renal function in diabetes

Background

Epidemiology

• Prevalence
  • Acute kidney injury – 5-20% of patients in ICU
  • Chronic kidney disease – >10 million in U.S.

Risk Factors

• Acute kidney injury
  • Trauma
  • Sepsis
  • Blood loss
  • Hypotension
  • Contrast induced
• Chronic kidney disease
  • Hypertension
  • Diabetes mellitus
  • Atherosclerotic vascular disease
  • Nephrotoxic drugs
    • Nonsteroidal anti-inflammatory drugs
    • Radiocontrast
  • Familial disease
  • Polycystic kidney disease

Pathophysiology

• Tubular proteinuria results when glomerular function is normal but the proximal tubules have diminished absorbing capacity
• Established biomarkers of chronic tubular dysfunction – acute and chronic
  • Glomerular filtration rate (GFR)/BUN/creatinine (serum) – provide estimates of renal function
    • BUN/creatinine – biomarkers of protein metabolism
    • EGFR is best measure – accounts for age, BMI, and sex
    • Useful in both acute and chronic renal failure
  • Albumin (urine)
    • Normally very little excreted by the kidney
    • Albuminuria – 30-300 mg albumin/24 hours or 30 mg/g creatinine
    • Sensitive marker of glomerular disease in patients with diabetes, chronic kidney disease
    • Limited ability to predict disease progression
  • Cystatin-C (serum and urine)
    • Cysteine protease inhibitor is a marker of GFR
    • Not influenced by changes in muscle mass – may make it a better marker than creatinine
    • Urine test measures proximal tubular injury
    • Affected by steroid use and thyroid dysfunction
  • Beta-2-microglobulins (urine)
    • Filtered freely in the glomerulus and nearly completely reabsorbed – normally <1% appears in urine 
    • Occur during the course of advanced diabetic nephropathy
    • May be useful as a marker of progressing idiopathic membranous nephropathy
  • Alpha-1-microglobulins (α₁-MG) (urine)
    • Evaluates primarily proximal tubular region (may also be assessed by urinary retinol binding protein)
    • Occur during the course of nephritis or advanced diabetic nephropathy
    • Occur after heavy metal exposure or treatment with nephrotoxic medications
    • Occur in urinary tract infections, where elevated α₁-MG concentrations signal renal involvement
    • May be a promising candidate as a biomarker of acute renal failure
  • Alpha-2-macroglobulin (α₂-MG) (serum)
    • One of a family of protease inhibitors that includes alpha-1-antitrypsin
    • α₂-MG is a protease inhibitor capable of irreversibly binding, and therefore inhibiting, a wide variety of proteases, including plasmin, pepsin, trypsin, chymotrypsin and cathepsin-D
    • α₂-MG molecule tends to remain intravascular due to its large size; levels increase during renal disease where smaller proteins are leaked into the urine
    • α₂-MG is synthesized in the liver
    • May also be increased in the following
      • Estrogen stimulation due to pregnancy, contraceptives
      • Nephrotic syndrome – retained by damaged glomerular membranes because of its large size
      • Diabetes mellitus with renal disease
      • Hepatorenal syndrome
      • Interruption of blood/brain barrier; presence of α₂-MG in cerebrospinal fluid (CSF)
• Novel biomarkers
  • Neutrophil gelatinase-associated lipocalin (NGAL) (urine/plasma) – for research purposes only; testing currently not available in the U.S.
    • Protein that is covalently bound to gelatinase from human neutrophils
    • Expressed in kidney after ischemia and drug-induced toxicity
    • Also increased in systemic and urinary tract infections
    • May be useful as a marker for acute renal injury in certain situations
    • Levels appear to correlate with severity
  • IL18 (urine)
    • Proinflammatory cytokine/upregulated protein
    • May have a role in ischemic acute tubular necrosis
  • Kidney injury molecule 1 (KIM-1)
    • Transmembrane protein expressed in low levels by normal kidney
    • Evaluates proximal tubular damage – upregulated in injury to proximal tubule
    • Overexpressed in response to ischemic or nephrotoxic injury