11.1 KDIGO stages of chronic kidney disease
The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines provide significant updates from the original 2002 Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines in order to add the recognized risk of albuminuria to estimated glomerular filtration rate (eGFR) in staging the severity of chronic kidney disease (CKD).
11.1.1 Current CKD nomenclature used by KDIGO
“CKD is defined as abnormalities of kidney structure or function, present for >3 months, with implications for health, and CKD is classified based on cause, GFR category, and albuminuria category” as shown below.
KDIGO “recommends referral to specialist kidney care services for people with CKD” in the following circumstances:
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Acute kidney injury (AKI) or abrupt sustained fall in glomerular filtration rate (GFR)
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GFR <30 mL/min/1.73 m 2 or GFR categories G4 to G5
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A consistent finding of significant albuminuria (albumin to creatinine ratio [ACR] > 300 mg/g [>30 mg/mmol] or albumin excretion rate [AER] > 300 mg/24 hours, approximately equivalent to protein to creatinine ratio [PCR] >500 mg/g [>50 mg/mmol] or protein excretion rate [PER] >500 mg/24 hr)
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Progression of CKD, defined based on one or both of the following:
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A drop in GFR category (e.g., from G1 to G2) accompanied by a 25% or greater drop in eGFR from baseline
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A sustained decline in eGFR of more than 5 mL/min/1.73 m 2
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Urinary red cell casts, RBC >20/hpf sustained and not readily explained
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CKD and hypertension (HTN) refractory to treatment with four or more antihypertensive agents
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Persistent abnormalities of serum potassium
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Recurrent or extensive nephrolithiasis
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Hereditary kidney disease
KDIGO “recommends timely referral for planning renal replacement therapy (RRT) in people with progressive CKD in whom the risk of kidney failure within 1 year is 10% to 20% or higher, as determined by validated risk prediction tools” as shown below.
11.2 Equations to calculate EGFR based on serum creatinine ,
For over 50 years, the Cockcroft-Gault equation was used to estimate creatinine clearance (CrCl) as a surrogate for GFR.
Cockcroft-Gault equation (to calculate estimated creatinine clearance) :
eCCr(mL/min)=(140−age)Scr(mg/dL)×Bodyweight(kg)72×(0.85iffemale)
where age is expressed in years, SCr in mg/dL, and weight in kg. The original formula used actual weight. Today, ideal body weight (IBW) is usually used because of erroneously high results in obese persons.
The Cockcroft-Gault equation is still used for some pharmacological dosing purposes, but has been largely replaced by one of the Modification of Diet in Renal Disease (MDRD) eGFR equations or its updated form, the CKD-EPI equation, which is more accurate and doesn’t require body weight.
MDRD eGFR equation :
eGFR=175×(SCr)−1.154×age−0.203×(0.742, if female)×(1.212 if Black)
where age is expressed in years, SCr in mg/dL, and weight in kg.
The MDRD GFR is an estimate of the GFR using serum creatinine (SCr) and demographic factors. It has not been studied extensively in populations that are not White or Black, while relying on a stable Cr. This estimate may be less accurate for GFR values above 60.
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation :
eGFR=141×min(SCr/κ, 1)α×max(SCr/κ, 1)−1.209×0.993Age×1.018[if female]×1.159[if Black]
where SCr is serum creatinine, κ is 0.7 for females and 0.9 for males, α is –0.329 for females and –0.411 for males, min indicates the minimum of SCr/κ or 1, and max indicates the maximum of SCr/κ or 1.
11.3 Additional equations to calculate EGFR (based on serum cystatin C alone or creatinine + cystatin C)
Since studies indicate that serum levels of cystatin C may offer a better estimate of eGFR and of adverse outcomes than Cr, a CKD-EPI-cystatin C formula was developed and is as follows:
eGFR=133×min(Scys/0.8, 1)−0.499×max(Scys/0.8, 1)−1.328×0.996age[×0.932 if female]
where Scys is serum cystatin C, min indicates the minimum of SCr/0.8 or 1, and max indicates the maximum of Scys/0.8 or 1.
Combining both serum markers, Cr and cystatin C, into a single CKD-EPI creatinine-cystatin C equation as shown below, appears to offer still better accuracy:
eGFR=135×min(SCr/κ, 1)α×max(SCr/κ, 1)−0.601×min(Scys/0.8, 1)−0.375×max(Scys/0.8, 1)−0.711×0.995age[×0.969 if female][×1.08 if Black]
where SCr is serum creatinine, Scys is serum cystatin C, κ is 0.7 for females and 0.9 for males, α is –0.248 for females and –0.207 for males, min indicates the minimum of SCr/κ or 1, and max indicates the maximum of SCr/κ or 1.
NB: Since the formulae shown above aren’t easy to use in practice, calculators are available online (e.g., https://www.kidney.org/professionals/kdoqi/gfr_calculator) and in the form of mobile devices. Furthermore, recent practice has often eliminated the use of the “Black race correction factor” and the authors advise using the updated “retrofit”equations without the race variable as described below in “11.6 Controversies about the use of ‘race’ in the estimation of GFR”.
11.4 Problems with using EGFR
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Creatinine, a product of the metabolism of creatine and phosphocreatine in skeletal muscle, is not specific to kidney function. Serum creatinine will be increased due to higher production in younger individuals with more muscle mass, and in males compared to females, and will depend on dietary intake (e.g., lower in vegetarians).
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In addition to glomerular filtration, creatinine has some renal tubular secretion. Certain medications can decrease tubular secretion and increase serum creatinine (e.g., trimethoprim, cimetidine). Some other medications may increase creatinine measurement (e.g., flucytosine, cephalosporins, and perhaps tenofovir), while others may decrease it (e.g., methyldopa, ethamsylate).
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Creatinine assay is not consistent between various laboratories and needs to be calibrated.
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The estimating equations perform poorly in numerous patient populations, including the very old and very young, normal renal function and very low renal function, very large and very small individuals, and many kidney transplant recipients.
11.5 Comparison of methods to measure or estimate GFR
| Advantages | Problems/Disadvantages | |
|---|---|---|
| Creatinine clearance based on 24-hour urine collection | Easy to do, as creatinine is an endogenous product | Inaccurate collection by patient may underestimate or overestimate GFR Clearance is often overestimated because of tubular secretion of creatinine |
| Mean of urea and creatinine clearance based on 24-hour urine collection | Might be more accurate than creatinine clearance, especially in advanced renal insufficiency | Same problem as above |
| Cystatin C (serum measurement) | A protein from all nucleated cells which undergoes glomerular filtration with reabsorption and catabolism by renal tubular cells | High variability of serum level between patients; is increased in malignancy, HIV, and steroid therapy |
| Inulin clearance | Gold standard (a 5200-dalton polymer of fructose) | Inulin is difficult to measure and a time-consuming, expensive method |
| Radioisotopic methods (e.g., 99mTc-labeled diethylenetriaminepentaacetic acid [DTPA], 51Cr-EDTA, 125I-iothalamate) | Accurate and easy to perform | Not readily available and requires infusion of the radionuclide and radioactive precautions; material is expensive, cannot be used in pregnancy, and is less accurate in advanced renal failure |
| Radiocontrast agents (e.g., iothalamate, diatrizoate, iohexol) | Accurate and easy to perform | Requires infusion of the contrast agent |
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