37. Laboratory diagnosis of acute renal diseases.

Kidney function tests

Several laboratory tests can be used to estimate the kidney function. These are important in the evaluation of chronic kidney disease (CKD) and acute kidney injury (AKI). The most common one is using the serum creatinine level to calculate the estimated glomerular filtration rate (eGFR). The normal GFR is approximately 120 mL/min for a person with 1,73 m2 of body surface.

Serum creatinine

Creatinine is a breakdown product of creatine phosphate following the creatine kinase reaction. It is eliminated by the kidneys by glomerular filtration (and to a smaller degree tubular secretion). It is normally not reabsorbed in the tubuli, except when there is oliguria. The rate at which blood plasma is cleared of creatine is called the creatinine clearance. Because creatinine is freely filtered in the glomeruli and is only secreted in the tubuli to a small degree, the creatinine clearance is approximately equal to the glomerular filtration rate. 1-2% of free creatine phosphate in skeletal muscle is broken down to creatinine daily. The rate of production depends on the muscle mass of the individual; the higher the mass, the higher the production. Serum creatinine levels are approx 30% higher in the evening than in the morning, likely due to muscle movement during the day. The normal range of creatinine is approximately 60 - 100 µmol/L.

Because creatinine is produced more or less constantly and because it's eliminated by the kidney almost exclusively by glomerular filtration, serum creatinine level is approximately inversely correlated to the GFR. The serum creatinine is used to evaluate the kidney function in acute kidney injury. It is not used in chronic kidney injury; eGFR is used instead.

Shortcomings of serum creatinine

Consumption of large amounts of red meat ahead of measurement may falsely elevate the creatinine level and therefore give the impression of falsely decreased kidney function. Cimetidin and trimethoprim inhibit tubular secretion of creatinine, also falsely elevating the creatinine level.

Serum creatinine levels are approx 30% higher in the evening than in the morning, likely due to muscle use during the day.

Estimated glomerular filtration rate

Because creatinine clearance is approximately equal to the GFR, and because production and elimination of creatinine is relatively constant, the serum creatinine level is relatively constant as well and can be used to estimate the GFR, giving the so-called estimated GFR (eGFR). The most commonly used formula for this is the CKD-EPI formula. The formula itself is complicated and not necessary to know, and the laboratory will calculate it for us, but it estimates the GFR based on the serum creatinine level and the age and sex of the patient.

Correcting for body surface area

The eGFR is given in units of ml/min/1,73 m², while GFR itself is measured in units of ml/min. This is because the result of the GFR formula is normalised to a "normal" body surface area of 1,73 m². A body surface area of 1.73 m² corresponds to a person who is 60 kg at 175 cm or 57 kg at 180 cm; in other words, it assumes a slim person. As such, this formula will underestimate the true GFR in persons with higher body surface areas.

To account for the patient's body surface area and calculate the specific patient's absolute eGFR (in min/ml), one must first calculate the body surface area of the patient based on formulas found elsewhere, then divide the eGFR (in units of ml/min/1,73 m²) by 1,73 and then multiply the result by the body surface area of the patient. This is usually only necessary in very large or very small patients.

Because the grading of CKD assumes the eGFR in units of ml/min/1,73 m², it's not necessary to calculate the absolute eGFR when grading (but it may be useful if the patient changes their body surface area by losing or gaining weight, for example). However, certain medications are dosed according to the GFR, and in these cases, calculating the absolute eGFR is important.

Shortcomings of the formula

The eGFR formula requires that the creatinine clearance and creatinine production has been stable for some time. If glomerular filtration rate (and thereby creatinine clearance) is suddenly decreased, the eGFR formula is not accurate. As such, the eGFR is not equal to the true GFR in case of acute kidney injury. In case of AKI, serum creatinine level must be used to estimate kidney function instead.

The non-GFR determinants mentioned earlier which influence serum creatinine (meat content in diet, medications, and time of day) will also influence the eGFR formula accuracy.

Cystatin C

Cystatin C is a protein which is produced in all cells. It's freely filtered in the glomeruli and not secreted or reabsorbed; as such, the cystatin C clearance is even more closely equal to the true GFR than the creatinine clearance.

Cystatin C should be measured to estimate the GFR instead of creatinine alone in those patients who have significant non-GFR determinants of creatinine, such as extremes of BMI and in elderly. Formulas which estimate the GFR based on both the serum creatinine and serum cystatin C levels are recommended, but formulas which use cystatin C alone exist.

Measurement of glomerular filtration rate

In some cases, there may be situations where a precise measurement of GFR is necessary but factors are present which increase the inaccuracy of the estimation of GFR. In these cases it's possible to measure the true GFR. This can for example be in the extremes of BMI, when there is advanced liver disease, or if there is a high meat or vegetarian diet. Potential kidney donors require measurement of true GFR as well.

Methods

To measure the GFR, one may measure the urinary clearance or plasma clearance of an exogenous compound which is 100% freely filtered in the glomeruli and which experiences no tubular secretion or reabsorption. Many compounds exist for this, but the most commonly used are iohexol and EDTA. Inulin is the gold standard but is complicated to use in clinical practice.

Urea

Urea, also called carbamide, is a nitrogen-containing amino acid and protein breakdown product. It is freely filtered in the glomeruli and is neither secreted or reabsorbed in the tubules, but is does passively diffuse back to the plasma after filtration.

In chronic kidney disease, several toxic compounds accumulate as the kidney cannot eliminate them. The level of urea in the serum correlates to the level of these toxic compounds, in addition to being a toxic compound itself, although it is uncertain how toxic urea actually is in vivo.

Urea also accumulates in acute kidney injury. In prerenal and postrenal AKI, urea increases more than creatinine. In intrarenal AKI, the creatinine increases more than the urea. The "rule" that (for American units) a blood urea nitrogen (BUN) to creatinine ratio of > 20:1 indicates a prerenal AKI, while a ratio of < 10:1 indicates intrarenal cause of AKI, but studies have not shown this to be reliable on its own to determine the type of AKI.

Urea can also be elevated from other causes, including gastrointestinal bleeding and increased protein catabolism.

Tubular function

There is no serum marker for tubular function. To evaluate function of the kidney tubules, one must examine the urine. Low urine osmolality, high urinary sodium concentration, and proteinuria are typical features of kidney tubule dysfunction or injury. This may reflect tubulointerstitial AKI or CKD.

Acute kidney injury

Acute kidney injury (AKI) is a clinical syndrome which is characterised by an acute decrease kidney function (GFR) (over hours or days), as evidenced by elevated creatinine. There may also be accumulation of urinary waste products and oliguria/anuria, but not always. The cause may be prerenal, renal, or postrenal, but the most common causes are prerenal and acute tubular necrosis. AKI is a common problem in critically ill patients in the intensive care unit.

Etiology

AKI is classified according to the underlying cause, whether it’s a prerenal cause, a renal cause, or a postrenal cause. However, there are usually multiple factors involved.

• Prerenal AKI
  • Hypovolaemia/hypotension
  • Decreased RBF (heart failure, renal artery stenosis)
  • Abnormal kidney haemodynamics (sepsis, hepatorenal syndrome)
• Renal AKI
  • Tubulointerstitial disorders
    • Acute ischaemic/toxic tubular necrosis
    • Acute tubulointerstitial nephritis
  • Glomerulonephritis
  • Thrombotic microangiopathies (TTP/HUS)
  • Obstruction of tubules
    • Myeloma proteins
    • Crystals
• Postrenal AKI
  • Benign prostate hyperplasia
  • Stone
  • Prostate cancer
  • Gynaecological cancer

Diagnosis and evaluation

In the evaluation of AKI, we use serum creatinine as a marker of kidney function (normal range 60 – 100 µmol/L); the estimated GFR (eGFR) can not be used, as it's estimated according to formulas which are made for chronic kidney disease. The definition of AKI requires either (1) an increase in serum creatinine by 27 µmol/L, or (2) an increase to more than 150% of baseline serum creatinine over 48 hours, or (3) a decrease in urine volume to < 3 mL/kg over 6 hours.Previously it was suggested that the urea:creatinine ratio was useful in distinguishing between prerenal and intrinsic AKI, but a study designed to investigate this found that the ratio can not distinguish them.