Kidney Function Tests

The kidneys, solid organs located in the lower back, are extremely important in regulating homeostasis through their role in maintaining blood volume, electrolyte balance, acid–base equilibrium, blood-pressure regulation, and removal of metabolic waste from the blood. Evaluation of renal function and early detection of kidney dysfunction is of primary importance. Tests of renal function are useful in identifying the presence of renal disease, monitoring the response of kidneys to treatment, and determining the progression of renal disease.

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Overview

Anatomy of the nephron

Nephron:

  • The basic structural and functional unit of the kidney
  • Filters and cleanses the blood and produces urine
  • Each kidney contains > 1 million nephrons.

Parts of nephron:

  • Afferent arteriole: renal artery arteriole that enters the glomerulus 
  • Efferent arteriole: renal artery arteriole that exits the glomerulus
  • Glomerulus: capillary tuft that receives its blood supply from an afferent arteriole of the renal circulation
  • Bowman capsule: surrounds the glomerulus
  • Renal tubule: coiled tube that converts blood filtrate into urine. 
    • Proximal convoluted tubule (PCT): portion close to the glomerulus in the renal cortex
    • Loop of Henle: forms a loop (with descending and ascending limbs) that goes through the renal medulla
    • Distal convoluted tubule (DCT): portion of the tubule restricted to the renal cortex

Physiology of urine production

Urine is a waste by-product composed of excess water and metabolic waste filtered out of the bloodstream by nephrons. Urine formation is a stepwise process.  

  • Glomerular filtration:
    • The kidneys filter about 180 L of plasma per day (125 mL/min).
    • Takes place inside glomerulus
    • Water and nitrogenous waste are filtered out of the blood and form glomerular filtrate.
    • Nonfilterable components exit the glomerulus via the efferent arteriole.
  • Tubular reabsorption:
    • Reabsorption of nutrients shed by glomerulus
    • Occurs in the PCT 
    • Can be passive (along gradients) or active (using ATP-generated energy)
    • Water and electrolyte reabsorption hormonally regulated
  • Tubular secretion:
    • Undesirable products like metabolic wastes, urea, uric acid, and certain drugs
    • Most of the tubular secretion happens in the DCT.

Serologic Parameters of Renal Function

Creatinine and estimated glomerular filtration rate (eGFR)

The most commonly used marker to assess kidney function is the measurement of excreted creatinine, based on which the eGFR can be calculated.

  • Creatinine: by-product of creatine phosphate metabolism in muscle:
    • Produced at a constant rate by the body
    • Amount produced per day depends on muscle bulk and meat consumption
    • Cleared from the blood entirely by the kidney
    • Commonly used endogenous marker for assessment of glomerular function: calculated clearance of creatinine → eGFR
  • Mean serum values:
    • Dependent on sex and ethnicity 
    • 1.13 mg/dL for men (higher muscle mass and creatinine excretion)
    • 0.93 mg/dL for women (lower muscle mass and creatinine excretion)
    • Mean values have been shown to be higher in non-Hispanic Black Americans → considered when calculating the eGFR  
  • Creatinine clearance should be corrected for body surface area.
  • Creatinine clearance overestimates GFR by around 10%–20% because of tubular secretion.

Glomerular filtration rate (GFR)

  • The most exact overall indicator of glomerular function 
  • Rate (in milliliters per minute) at which a substance in plasma is filtered through the glomeruli
  • Commonly measured by administering inulin:
    • Polysaccharide that cannot be broken down and is completely filtered
    • Used as a marker by measuring rate at which it appears in the urine
  • Time-consuming and expensive to measure → performed only in specialized centers

Blood urea nitrogen (BUN)

  • Nitrogen-containing compound formed in the liver 
  • End product of protein metabolism and the urea cycle 
  • 85% of urea is eliminated via the kidneys.
  • Less accurate than creatinine but increases earlier in renal disease
  • Levels increase in acute and chronic renal impairment
  • May increase in other conditions:
    • Upper GI bleeding
    • Dehydration
    • Catabolic states
    • High-protein diets

Ratio of BUN:creatinine

  • Useful to differentiate prerenal from renal causes when the BUN is increased
  • In prerenal disease, ratio is close to 20:1.
  • In intrinsic renal disease, it is closer to 10:1.

Cystatin C

  • Cystatin C is a low-molecular-weight protein that functions as a protease inhibitor. 
  • Formed at a constant rate, filtered by the kidneys, reabsorbed, and metabolized by proximal renal tubules
  • Serum levels of cystatin C are inversely correlated with the GFR.
  • Cystatin C is measured in serum and urine: normally not found in urine
  • Less dependent on age, sex, ethnicity, diet, and muscle mass than creatinine
  • May be more specific than creatinine for estimation of GFR

Urinalysis

There are 3 basic components to urinalysis: 

  • Gross examination
  • Chemical evaluation (usually done using urine dipstick)
  • Microscopic examination

Gross examination

  • Turbidity: a visual evaluation of how cloudy the urine appears
  • Color:
    • Yellow-amber: normal
    • Yellow-cloudy: infectious causes (pyuria)
    • Orange: dehydration
    • Red: hemolysis
    • Dark brown: myoglobinuria (due to rhabdomyolysis)
    • Brownish black to black: alkaptonuria
    • Green, or dark with a greenish hue: jaundice (bilirubinuria)

Chemical evaluation

  • Nitrite: indicates the presence of coliform bacteria
  • Leukocyte esterase: indicates the presence of WBCs
  • Proteins: 
    • Albuminuria: increased permeability of glomerulus, usually secondary to chronic diseases such as diabetes mellitus 
    • hCG: appears during pregnancy in females and testicular cancer in males
  • pH: Normal range is 4.5–8; elevated or decreased urine pH levels are associated with kidney stones or infections.
  • Specific gravity: 
    • Detects the ion concentration of urine
    • Value < 1.010 indicates diluted urine.
    • Value > 1.020 indicates concentrated urine.
  • Glucose (glucosuria), seen in diabetes mellitus 
  • Ketone bodies, seen in diabetic ketoacidosis
  • Bilirubin: increased due to RBC hemolysis and liver damage
  • Urobilinogen: Increased levels are seen in liver damage.

Microscopic examination

  • Cells:
    • RBCs (hematuria): various renal, bladder, or urethral etiologies
    • Acanthocytes: dysmorphic RBCs seen in glomerular disease
    • RBC casts: seen in glomerulonephritis or hypertensive emergency 
    • WBCs: infectious causes (pyuria)
  • Urinary casts: 
    • Microscopic cylindrical structures formed in the DCT and collecting ducts of the kidneys
    • Present in the urine in certain disease states
Table: Urinary casts and their clinical significance
CastClinical significance/diseases
RBC casts
  • Glomerulonephritis
  • Hypertensive emergency
WBC casts
  • Tubulointerstitial inflammation
  • Acute pyelonephritis
  • Transplant rejection
Epithelial cell casts
  • Glomerulonephritis
  • Interstitial nephritis
Fatty castsNephrotic syndrome
Granular, muddy brown castsAcute tubular necrosis (ATN)
Waxy casts
  • End-stage renal disease (ESRD)
  • Chronic renal failure
Hyaline casts
  • Precipitation of Tamm–Horsfall mucoprotein (secreted by renal tubule cells)
  • Nonspecific, can be a normal finding

Clinical Relevance

The following conditions are associated with abnormal kidney function tests:

  • Acute renal failure: classified into prerenal, intrinsic, and postrenal categories, depending on the etiology. Acute renal failure is marked by decreased urine output, metabolic acidosis, fatigue, confusion, and nausea. Laboratory test shows elevated creatinine levels. 
  • Chronic kidney disease: characterized by progressive deterioration of renal function. Associated symptoms and findings of CKD include fatigue, water retention, pruritus, muscle weakness, confusion, and peripheral neuropathy. Treatment includes hemodialysis or peritoneal dialysis and renal transplantation in combination with supportive measures.
  • Tumor lysis syndrome: complication of cancer treatment when large amounts of cells are suddenly lysed as a result of chemotherapy. Tumor lysis syndrome usually occurs with acute leukemias and non-Hodgkin’s lymphomas but can also occur with other hematologic malignancies or solid tumors. The syndrome can lead to AKI in association with a number of metabolic abnormalities (hypocalcemia, hyperphosphatemia, hypokalemia, elevated uric acid). Uric acid–lowering medications can prevent the syndrome and should be initiated prior to chemotherapy.

The following conditions are associated with abnormal urinalysis:

  • Glomerulonephritis: Acute glomerulonephritis is defined as glomerular injury that is accompanied by inflammation of the glomeruli. Acute glomerulonephritis is a clinical constellation of sudden onset of hematuria and proteinuria, edema, and hypertension with or without RBC casts and can be due to a number of underlying pathologies, such as infection, connective tissue disorders, drug toxicity, hematologic dyscrasias, glomerular basement membrane diseases, and hereditary disorders.
  • Rhabdomyolysis: clinical syndrome characterized by the breakdown of skeletal muscle. The acute  release of muscle protein (myoglobin) into the circulation is followed by myoglobinuria, which can lead to AKI. Rhabdomyolysis can follow trauma, sepsis, or exposure to drugs. The diagnosis is established by history and the finding of elevated CK in the serum. 
  • Diabetic ketoacidosis: acute metabolic complication of diabetes characterized by hyperglycemia (> 11 mmol/L), ketonemia (> 31 mg/mL)/ ketonuria (3+), and metabolic acidosis (pH < 7.3). Diabetic ketoacidosis occurs mostly with type 1 diabetes mellitus. Treatment involves insulin, IV fluids, and prevention of hypokalemia.

References

  1. Teo SH, Endre ZH. (2017). Biomarkers in acute kidney injury (AKI). Best Pract Res Clin Anaesthesiol 31:331–344. https://pubmed.ncbi.nlm.nih.gov/29248140/
  2. Gounden V, Bhatt H, Jialal I. (2020). Renal function tests. StatPearls. https://pubmed.ncbi.nlm.nih.gov/29939598/
  3. Ferguson TW, Komenda P, Tangri N. (2015). Cystatin C as a biomarker for estimating glomerular filtration rate. Curr Opin Nephrol Hypertens. https://pubmed.ncbi.nlm.nih.gov/26066476/
  4. Le T, Bhusan V, Sochat M, et al. (Eds.) (2020). First Aid for the USMLE Step 1, 30th ed., pp. 582, 590. McGraw-Hill Education.
  5. Soveri I, Berg UB, Björk J, Elinder CG, Grubb A, Mejare I, Sterner G, Bäck SE. (2014). SBU GFR Review Group. Measuring GFR: a systematic review. Am J Kidney Dis. https://pubmed.ncbi.nlm.nih.gov/24840668/

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