1. What is the glomerular filtration rate (GFR)?
The production of urine and the removal of waste products by the kidneys begin by filtering blood across the glomerular membrane. Blood enters the glomerulus and then can exit either through the efferent arteriole or by becoming filtrate by passing through the glomerular membrane into Bowman space and the tubules of the nephron. The GFR quantifies how fast fluid is crossing the glomerular membrane.
2. What is the difference between single nephron GFR and total GFR?
Single nephron glomerular filtration rate (SNGFR), an experimentally derived value typically performed in animal models, refers to the filtration of a single nephron. SNGFR can be affected by hemodynamic alterations or structural damage. As part of the adaptation of the kidney to injury, uninjured nephrons undergo hypertrophy and hyperfiltration to compensate for the loss of functioning nephrons (compensatory hyperfiltration). Thus the total GFR that is measured or estimated) might remain relatively normal despite a decrease in functioning nephrons (see questions 5 and 8 for how to measure or estimate GFR). As such, the GFR is dependent on the number of nephrons (N) and the SNGFR, as described as follows:
A change in measured or estimated GFR could reflect either a change in nephron number or SNGFR.
3. What is the clinical significance of the GFR?
The GFR is the generally accepted, best index of kidney function. Chronic kidney disease (CKD) is defined as GFR less than 60 mL/min per 1.73 m 2 as well as markers of kidney damage. In the United States the most common marker of kidney damage is urine albumin. Other markers are kidney cysts or pathologic changes in the kidney, for example. The severity of CKD is also determined by the level of GFR ( Table 3.1 ).
|1||GFR ≥ 90 mL/min per 1.73 m 2 with other signs of kidney disease (usually an abnormal ultrasound or urinalysis)||Normal or high GFR|
|2||Slightly decreased GFR (60–89 mL/min per 1.73 m 2 with other signs of kidney disease||Mildly decreased GFR|
|3a||GFR of 45–59 mL/min per 1.73 m 2||Mildly to moderately decreased GFR|
|3b||GFR of 30–44 mL/min per 1.73 m 2||Moderately to severely decreased GFR|
|4||GFR 15–29 mL/min per 1.73 m 2||Severely decreased GFR|
|5||GFR < 15 mL/min per 1.73 m 2||Kidney failure|
a Once the GFR falls below 60 mL/min the GFR alone is enough to define CKD. in the most recent KDIGO guidelines, CKD stages have been replaced with GFR categories, albuminuria categories, and assessment of the etiology of CKD.
Decreases in GFR are associated with increasing symptoms and metabolic abnormalities. These abnormalities include anemia, acidosis, malnutrition, and bone and mineral disorders. In addition, medications that are metabolized or excreted by the kidney need to be dose adjusted (or avoided completely) in patients with decreased GFR. Even drugs that are not excreted by the kidneys can have altered pharmacodynamics and pharmacokinetics in the presence of decreased GFR. Most importantly, a GFR less than 60 mL/min per 1.73 m 2 is associated with complications of CKD, including risk for kidney failure and increased total and cardiovascular disease mortality. For these reasons the GFR is the single number that best expresses kidney function.
5. How is GFR measured?
GFR is measured as the clearance of an ideal filtration marker. Clearance refers to the amount of plasma that is completely cleared of a substance over a set amount of time. For example, if a person has substance X in his blood at a concentration of 2 g X per liter and he excretes 1 g of X in the urine, he will have theoretically removed all the X from half a liter of blood. If the person took 1 day to produce enough urine to get rid of 1 g of X, then his clearance will be 0.5 L (of plasma cleared of X) per day. The equation for calculating clearance is as follows:
where Cl x is the clearance of substance x, Ur x is the urine concentration of X, and V is the urine flow rate.
Plasma clearance is an alternative to urinary clearance for measurement of GFR. Plasma clearance is performed by measurement timed plasma levels following a bolus intravenous injection of an exogenous filtration marker computed from the following:
where A x is the amount of the marker administered and Px is the plasma concentration computed from the entire area under the disappearance curve.
An ideal filtration marker is one that is freely filtered at the glomerulus but not reabsorbed, secreted, or metabolized by the kidney. Clearance of an ideal filtration marker can therefore be used to measure GFR. Inulin is the ideal filtration marker. Inulin is freely filtered by the glomerulus but is neither secreted nor reabsorbed by the tubules. However, inulin is rarely used, and alterative markers include iohexol and iothalamate and are more commonly used. In addition to exogenous substances, endogenous molecules that are filtered by the glomerulus can be measured to assess GFR. In particular, creatinine clearance assessed using timed urine collections is often used to estimate GFR.
6. Why are units of GFR in milliliters/minute per 1.73 m 2 ?
The clearance of substances is computed in units of milliliters/minutes. However, because kidney size (and therefore amount that can be cleared) varies by a person’s body size, to determine whether a person has normal GFR, the clearance in units of mL/min is then adjusted for normal body surface area (BSA) by multiplying by 1.73 and dividing by the individual’s BSA.
7. How is measured creatinine clearance calculated?
Creatinine clearance is calculated using timed urine collection. The time is often 24 hours but can be as short as 4 or 6 hours. The clearance formula and an example is as follows.
where A is the generic clearance formula. B substitutes some typical values. C. Shows that the units all cancel out except mL/min.
Note: to convert the 24-hour measurement to the conventional units of mL/min, one needs to convert 24 hours to minutes, by dividing by the number of minutes in a day, 1440. All the units cancel each other out except mL/min.
8. What are limitations to use of measured creatinine clearance?
Several problems can compromise the utility of creatinine clearance. Firstly, accurate measurements of creatinine clearance require complete and carefully timed urine collections; inadequate urine collections yield spurious results. Secondly, because creatinine is secreted by the kidney tubules, the creatinine clearance systematically overestimates GFR. Between 10% and 20% of urinary creatinine is secreted rather than filtered, so the creatinine clearance will overestimate the GFR by a similar percentage. Cimetidine, the over-the-counter H2-blocker, competitively inhibits creatinine secretion. Thus a 24-hour urine creatinine clearance while a patient is on cimetidine is theoretically closer to the actual GFR. However, there the extent to which cimetidine blocks secretion occurs variable among individuals. Drugs that block creatinine secretion will also cause a slight elevation in serum creatinine that does not reflect a change in GFR, just a loss of tubular creatinine secretion.
Drugs that block creatinine secretion in the proximal tubule
9. How is GFR estimated in routine clinical practice?
GFR is usually estimated using the serum creatinine and an estimating equation. Serum creatinine is the most common endogenous filtration marker. Endogenous filtration markers are markers produced by the body but are filtered by the glomerulus. All endogenous filtration markers are not perfect filtration markers in that there are non-GFR determinants of their levels in the blood, in particular, variation in generation (i.e., production) among people, secretion, or reabsorption by the tubule or extrarenal elimination.
Estimating equations combine endogenous filtration marker(s), such as creatinine and cystatin C, with other variables, such as age, sex, race, and body size, as surrogates for non-GFR determinants of the filtration markers, and therefore can overcome some of the limitations of the filtration marker alone. An estimating equation is derived using regression techniques to model the observed relationship between the serum level of the marker and measured GFR in a study population.
10. What is the most accurate creatinine-based estimating equations?
Kidney Disease International Global Outcomes (KDIGO) Guideline on Chronic Kidney Disease currently recommends using the Chronic Kidney Disease Epidemiology (CKD-EPI) 2009 creatinine equation:
where x is 0.7 for females and 0.9 for males
where α is 0.329 for females and 0.411 for males
where min indicates the minimum of SCr/x or 1
where max indicates the maximum of SCr/x or 1
Several online calculators are also available that can easily compute estimated GFR (eGFR) values from creatinine ( http://ckdepi.org/equations/gfr-calculator/ ). The CKD-EPI equation estimates GFR from serum creatinine, age, sex, and race. It was developed in a cohort of 8254 subjects pooled together from 10 research studies and clinical populations with diverse characteristics, including people with and without kidney diseases, and across a range of GFRs (2 to 198 mL/min per 1.73 m 2 ) and ages (18 to 97 years). The equation was validated in a separate cohort of 3896 people from 16 separate studies, GFR range (2 to 200 mL/min per 1.73 m 2 ) and age range (18 to 93 years).