A13. Kidney function investigations
Creatinine and eGFR
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[1] 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[2], 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.
Proteinuria
Proteinuria refers to pathological amounts of protein in the urine, defined as urinary protein content of > 150 mg per day. Physiologically, 50 - 150 mg protein is excreted in urine per day, most of which secreted by the tubuli with only small amounts filtered through the glomeruli. 99% of filtered proteins are reabsorbed in the tubuli.
Most normal plasma proteins are not filtered in the glomeruli because they are too large for the glomerular pores and they are negative, just like the filter surface. The small amount of protein that is filtered are small in size (below 65 kD) and are reabsorbed by proximal tubular cells where they are metabolized.
Proteinuria is often a sign of kidney damage, except orthostatic proteinuria, which is physiological. The amount of albumin in the urine, albuminuria, is used to stage chronic kidney disease.
Etiology
Different types of proteinuria can be distinguished based on the underlying pathology and resulting distinguishing clinical features.
Glomerular proteinuria (300 - 20000 mg/day) occurs because of damage to the glomeruli. It can occur because of diabetes mellitus (diabetic nephropathy), nephrotic syndrome, preeclampsia, or chronic hypertension. The damage usually allows for large proteins (like albumin) to be filtered.
Tubular proteinuria (150 - 2000 mg/day) occurs due to tubular injury, for example due to acute tubular necrosis or interstitial nephritis. Only small (< 65 kD) proteins will be lost, like alpha-1 microglobulin and beta-2 microglobulin. The tubular injury prevents the physiological reabsorption of small proteins which are (physiologically) filtered through the glomeruli.
Overflow proteinuria (150 - 2000 mg/day), sometimes called prerenal proteinuria, occurs when a small protein (which is physiologically filtered but usually completely reabsorbed in the tubuli) is produced to such an extent that the tubuli cannot reabsorb all of it. This occurs in multiple myeloma (which produces immunoglobulin light chains, called Bence Jones proteins) and rhabdomyolysis (myoglobin). It may also be physiological if it only occurs when standing, called orthostatic proteinuria, which may occur because of compression of the renal vein while standing, as well as after exercise.
Postrenal proteinuria (300 - 1000 mg/day) can occur due to urinary tract infection.
Consequences
Proteinuria is a sign of pathology, usually kidney damage. Glomerular filtration of protein damages the glomeruli further and so eventually causes progressive kidney damage. Proteinuria, even small amounts, is associated with cardiovascular disease. Massive proteinuria (especially nephrotic proteinuria) can cause hypoproteinaemia, which may affect muscle growth, immune system function, and may cause oedema.