Renal Function Markers - Kidney Disease

Renal dysfunction occurs in a variety of diseases and scenarios. Acute kidney injury results from trauma to the kidney during an accident or a medical procedure, including ICU acute renal failure. Chronic kidney disease results from another disease, such as diabetes mellitus, or from an inherited syndrome. Early detection of dysfunction may be important in prevention of further dysfunction.

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Clinical Overview

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 microalbumin – 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 microalbumin testing in individuals with hypertension, diabetes mellitus, cardiovascular disease, and family history of cardiovascular disease (CVD)

Monitoring

Urinary microalbumin – 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
- Microalbumin (urine)
  - Normally very little excreted by the kidney
  - Microalbuminuria – 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
  - 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

ARUP Lab Tests

Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

Urea Nitrogen, Serum or Plasma 0020023
Method: Quantitative Spectrophotometry

Recommended Use

Screening test to evaluate kidney function

Creatinine, Serum or Plasma 0020025
Method: Quantitative Enzymatic

Recommended Use

Screening test to evaluate kidney function

Limitations

Assay interference (negative) may be observed when high concentrations of N-acetylcysteine (NAC) are present

Negative interference has also been reported with NAPQI (an acetaminophen metabolite) but only when concentrations are at or above those expected during acetaminophen overdose

Microalbumin, Urine 0050203
Method: Quantitative Immunoturbidimetry

Recommended Use

Detect early kidney disease in those with diabetes or other risk factors (eg, hypertension)

Glomerular Filtration Rate, Estimated 0020725
Method: Quantitative Enzymatic

Recommended Use

Estimate renal function and use as monitoring tool

(Test reports serum creatinine reference intervals)

Cystatin C, Serum with Reflex to Estimated Glomerular Filtration Rate (eGFR) 0095229
Method: Quantitative Nephelometry

Recommended Use

Calculate glomerular filtration rate in patients for whom serum creatinine may be misleading, such as the very obese, elderly, or malnourished patients

Reflex pattern – if patient age is either unknown or is ≥18 years, then cystatin C reflex will be added

Limitations

Lacks specificity

Beta-2-Microglobulin, Urine 0080432
Method: Quantitative Chemiluminescent Immunoassay

Recommended Use

May indicate renal involvement in patients with diabetic nephropathy, cadmium toxicity, or progressing idiopathic membranous nephropathy

Alpha-1-Microglobulin, Urine 0050043
Method: Quantitative Nephelometry

Recommended Use

Aid in diagnosis of proximal tubule injury and/or impaired proximal tubular function

Alpha-2-Macroglobulin 0050005
Method: Quantitative Nephelometry

Recommended Use

May be used as a marker of membrane permeability in urine

Limitations

Limited clinical use

Medical Reviewers

Delgado, Julio, MD, MS, Chief Medical Officer; Director of Laboratories; Chief, Division of Clinical Pathology at ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

Genzen, Jonathan R., MD, PhD, Laboratory Section Chief, Clinical Chemistry, and Medical Director, Automated Core Laboratory, at ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

Straseski, Joely A., PhD, MS, MT(ASCP), DABCC, Medical Director, Endocrinology and Automated Core Laboratory at ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

References

Guidelines

McCullough PA, Bouchard J, Waikar SS, Siew ED, Endre ZH, Goldstein SL, Koyner JL, Macedo E, Doi K, Di Somma S, Lewington A, Thadhani R, Chakravarthi R, Ice C, Okusa MD, Duranteau J, Doran P, Yang L, Jaber BL, Meehan S, Kellum JA, Haase M, Murray PT, Cruz D, Maisel A, Bagshaw SM, Chawla LS, Mehta RL, Shaw AD, Ronco C. Implementation of novel biomarkers in the diagnosis, prognosis, and management of acute kidney injury: executive summary from the tenth consensus conference of the Acute Dialysis Quality Initiative (ADQI). Contrib Nephrol. 2013; 182: 5-12. PubMed

General References

Al-Ismaili Z, Palijan A, Zappitelli M. Biomarkers of acute kidney injury in children: discovery, evaluation, and clinical application. Pediatr Nephrol. 2011; 26(1): 29-40. PubMed

Cruz DN, Bagshaw SM, Maisel A, Lewington A, Thadhani R, Chakravarthi R, Murray PT, Mehta RL, Chawla LS. Use of biomarkers to assess prognosis and guide management of patients with acute kidney injury. Contrib Nephrol. 2013; 182: 45-64. PubMed

Edelstein CL. Biomarkers of acute kidney injury. Adv Chronic Kidney Dis. 2008; 15(3): 222-34. PubMed

Fliser D. Assessment of renal function in elderly patients. Curr Opin Nephrol Hypertens. 2008; 17(6): 604-8. PubMed

Hallan SI, Stevens P. Screening for chronic kidney disease: which strategy? J Nephrol. 2010; 23(2): 147-55. PubMed

Jerums G, Premaratne E, Panagiotopoulos S, Clarke S, Power DA, MacIsaac RJ. New and old markers of progression of diabetic nephropathy. Diabetes Res Clin Pract. 2008; 82 Suppl 1: S30-7. PubMed

McMahon GM, Waikar SS. Biomarkers in nephrology: Core Curriculum 2013. Am J Kidney Dis. 2013; 62(1): 165-78. PubMed

Odutayo A, Cherney D. Cystatin C and acute changes in glomerular filtration rate. Clin Nephrol. 2012; 78(1): 64-75. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology^®

Chindarkar NS, Chawla LS, Straseski JA, Jortani SA, Uettwiller-Geiger D, Orr RR, Kellum JA, Fitzgerald RL. Demographic data for urinary Acute Kidney Injury (AKI) marker [IGFBP7]·[TIMP2] reference range determinations Data Brief. 2015; 5: 888-92. PubMed

Jovanovich A, Chonchol M, Cheung AK, Kaufman JS, Greene T, Roberts WL, Smits G, Kendrick J, HOST Investigators. Racial differences in markers of mineral metabolism in advanced chronic kidney disease. Clin J Am Soc Nephrol. 2012; 7(4): 640-7. PubMed

Koopmann M, Shea J, Kholmovski E, de Bever J, Minalga E, Holbrook M, Merrill R, Hadley R, Owan T, Salama ME, Marrouche NF, Payne A. Renal sympathetic denervation using MR-guided high-intensity focused ultrasound in a porcine model. J Ther Ultrasound. 2016; 4: 3. PubMed

Schmidt RL, Straseski JA, Raphael KL, Adams AH, Lehman CM. A Risk Assessment of the Jaffe vs Enzymatic Method for Creatinine Measurement in an Outpatient Population PLoS One. 2015; 10(11): e0143205. PubMed

Sviridov D, Owen WE, Roberts WL, Edelman LS, Drake SK, Hortin GL. Proteinuria without albuminuria: urinary protein excretion by a subset of patients with burn injuries. Clin Chim Acta. 2009; 403(1-2): 42-6. PubMed

Educational Videos

(48 min)

Last Update: March 2018


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	Renal Function Markers - Kidney Disease. ARUP Consult^©. Retrieved April 18, 2018, from: https://arupconsult.com/content/renal-function-markers

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Renal Function Markers - Kidney Disease

Tabs Content

Diagnosis

Indications for Testing

Laboratory Testing

Differential Diagnosis

Screening

Monitoring

Background

Epidemiology

Risk Factors

Pathophysiology

ARUP Lab Tests

Medical Reviewers

References

Guidelines

General References

References from the ARUP Institute for Clinical and Experimental Pathology®

References from the ARUP Institute for Clinical and Experimental Pathology^®