CONTENTS

• Some basics:
  • Indexed vs nonindexed GFR
  • Race and GFR estimation
  • Limitations of creatinine-based GFR estimation
• Key estimation formulae:
  • Crockcroft-Gault equation
  • CKD-EPI 2021 creatinine
• GFR estimation in obesity
• Augmented Renal Clearance (ARC)
• Estimating GFR from vancomycin clearance
• Measured GFR using timed urine collection

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indexed versus nonindexed GFR

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indexed GFR (ml/min/1.73m2)

• Normally, renal mass is roughly proportional to body surface area (BSA).
• Indexed GFR expresses the GFR in proportion to the patient's body surface area. This is the preferred measurement for diagnosis and staging of chronic kidney disease.

nonindexed GFR (ml/min)

• Nonindexed GFR is the correct approach to medication dosing.
• Medications are generally dosed in absolute measurements (not weight-based or body-surface-area-based). The GFR should be indexed in the same way so that they match. Drug filtration depends on absolute clearance, not indexed clearance.
• This is not controversial, for example:
  • KDIGO 2024 guidelines recommend using the nonindexed GFR: “Because clearance is more strongly associated with nonindexed eGFR (ml/min) than indexed eGFR (ml/min per 1.73 m2), in very small or large individuals, this can result in over- or underdosing, respectively, as well as noninitiation of certain medications.” (38490803)
  • The FDA and European Medicines Agency also recommend dosing medications based on the nonindexed GFR.
• ⚠️ Electronic medical records will often display the indexed GFR. This will be inadequate for dosing medications in patients with unusual body surface area (e.g., morbid obesity).

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race and GFR estimation

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• Race-based GFR estimation should not be utilized.
• None of the equations discussed in this chapter are race-based.
• For further discussion of this topic, please see Kasozi et al.

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limitations of creatinine-based GFR estimation

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• [1] Abnormal muscle mass, e.g.:
  • Cachexia (including cirrhosis).
  • Status post amputation.
  • Neuromuscular disease.
  • Bodybuilders.
• [2] Diet:
  • A high-protein diet may increase creatinine.
  • NPO status may reduce creatinine.
• [3] Medications that decrease tubular creatinine secretion will increase the serum creatinine, thereby appearing to reduce GFR without actually harming the kidneys (“pseudonephrotoxins”):
  • Trimethoprim.
  • Piperacillin.
  • Fenofibrate.
  • Dronedarone.
  • HIV medications: dolutegravir, cobicistat, rilpivirine.
  • PARP inhibitors: olaparib, rucaparib.
  • Tyrosine kinase inhibitors (including imatinib, bosutinib, and sorafenib).
• [4] Nonsteady state:
  • Acute kidney injury.
  • Acute fluid resuscitation may dilute creatinine.
• [5] Assay interference:
  • Acetoacetate may artificially elevate creatinine (e.g., in DKA).
  • Bilirubin may artificially elevate creatinine.
  • Some medications may artificially elevate creatinine levels (e.g., cefoxitin, flucytosine).

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Cockcroft-Gault equation

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The Cockcroft-Gault equation is one of the oldest formulas used to estimate glomerular filtration rate (GFR).

advantages of the Cockcroft-Gault equation

• The Cockcroft-Gault equation has been historically utilized in many clinical trials, making it clinically applicable for dosing some medications.
• However, more recent recommendations suggest using the most accurate GFR formula (rather than the Cockcroft-Gault equation).

limitations of the Cockcroft-Gault equation

• Cockcroft-Gault tends to under-estimate GFR in elderly patients.
• Issues regarding weight:
  • If the actual body weight is used, the Cockcroft-Gault equation will overestimate GFR in obese individuals. This problem can be addressed to some extent by using an adjusted body weight for obese patients (as discussed below: ⚡️).
  • Cockcroft-Gault will overestimate GFR in edematous states, where the absolute weight may overestimate endogenous muscle mass.
• Cockcroft-Gault was designed based on 249 men admitted to a single veterans hospital in Canada. It was subsequently estimated that women have ~15% lower muscle mass than men on average. It wasn't designed to estimate GFR across a diverse patient population.
• Cockcroft-Gault was developed before the advent of modern creatinine assays that are properly standardized. This may result in a ~10% over-estimation of the actual creatinine clearance. (39873963)
• Cockcroft-Gault was designed using 24-hour creatinine clearance as its gold standard, rather than glomerular filtration rate (GFR). Due to renal creatinine secretion, creatinine clearance will overestimate the true GFR.

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CKD-EPI 2021 creatinine

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CKD-EPI 2021 creatinine is the preferred formula for indexed GFR

• The CKD-EPI equation is more accurate than the Cockcroft-Gault equation. (20299365, 37664574)
• The CKD-EPI 2021 creatinine equation has recently replaced prior equations as the preferred estimator of GFR, partially because it is race-neutral. It is currently recommended by numerous organizations, including the American Society of Nephrology (ASN) and the National Kidney Foundation (NKF).
• For everyday clinical management in the ICU, the differences between the CKD-EPI 2021 and the CKD-EPI 2009 or MDRD equations are small and unlikely to affect management.
• The CKD-EPI equation may overestimate GFR in younger patients (18-30 years old). (37664574)

CKD-EPI 2021 creatinine may need to be converted to the nonindexed GFR for dosing medications

• For medication dosing, the indexed GFR needs to be multiplied by the (patient's BSA)/(1.73), as discussed further above: ⚡️
• For patients with a body surface area close to 1.73 m², this will have minimal impact. However, many ICU patients will have extremes of body surface area that need to be adequately accounted for.

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GFR estimation in obesity

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[1] nonindexed CKD-EPI 

• This may become the increasingly preferred strategy. (37947985)
• The CKD-EPI equation is used to estimate the indexed GFR. This value is subsequently converted from an indexed GFR to a nonindexed GFR, as discussed in the section above.

[2] Crockcroft-Gault equation using an adjusted body weight

• Using the patient's actual weight will overestimate creatinine production, since most added weight is in the form of adipose tissue (not muscle). Consequently, the most accurate approach to a Cockroft-Gault calculation is to use the adjusted body weight. (22576791)

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augmented renal clearance

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basics

• Augmented Renal Clearance (ARC) refers to supranormal kidney function (GFR >130 ml/min/1.73 m2). This may result from hyperdynamic circulation in the context of physiological stress. ARC may also be known as “renal hyperfiltration.”
• ARC leads to occult underdosing of renally cleared medications (especially antibiotics). The significance of antibiotic underdosing can be challenging to prove because ARC also correlates with patients who have robust organ function reserves who tend to fare well regardless. (32055559)

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epidemiology

ARC is relatively common if this is rigorously sought out. One prospective study found that ARC may occur in most patients during their first week of critical illness. (24201175)

risk factors for ARC

• Age <50 years.
• Male sex.
• Less profound illness (e.g., absence of multiorgan failure).
• Renal parameters:
  • Absence of chronic renal insufficiency.
  • Absence of diabetes.
  • Absence of oliguria.
  • Low serum creatinine (<0.7 mg/dL or <62 uM).
• Certain diseases associated with a hypermetabolic state:
  • Sepsis.
  • Burns.
  • Trauma.
  • Severe neurologic injury, especially:
    • Traumatic brain injury.
    • Subarachnoid hemorrhage.
    • CNS infections. (30723936)

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diagnosis of ARC

🥇 directly measure GFR

• Urine collection for 8 hours allows measurement of the actual creatinine clearance.
• This is the most definitive approach to diagnosing ARC. (Baptista 2023)

🥈 measurement of drug clearance

• If you are using a renally-cleared medication with measurement of levels (e.g., vancomycin, aminoglycoside), it is possible to quantitatively measure drug clearance.
• For example: if two vancomycin levels are known, these may be used to determine the effective glomerular filtration rate using pharmacokinetic formulas. 🌊
• 💡 The most common “clinical presentation” of ARC is a patient whose vancomycin levels are extremely low.

🥉 GFR estimation using CKD-EPI formula

• The fastest approach is usually to estimate the GFR using the CKD-EPI formula. This isn't perfect, but in many cases it may help rule-in or rule-out ARC. Attention should be paid to factors which may cause spurious increases or decreases in creatinine, some of which are listed below.
• Using the CKD-EPI formula for creatinine 🧮 : (32552817)
  • GFR >87 ml/min/1.73m2 was 96% sensitive & 58% specific for ARC.
  • GFR >96.5 ml/min/1.73m2 was 86% sensitive & 71% specific for ARC.
  • GFR >125 ml/min/1.73m2 was 31% sensitive & 95% specific for ARC.
  • So:
    • GFR <85 ml/min: ARC is unlikely.
    • GFR >100-125: ARC is increasingly likely.
• Consider causes of spuriously high creatinine:
  • Rhabdomyolysis, fenofibrate therapy.
  • Impaired secretion (e.g., trimethoprim, dronedarone, pyrimethamine, dapsone).
• Consider causes of spuriously low creatinine:
  • Low muscle mass (cachexia, amputation).

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management of ARC

Review the medication list, and consider the possibility that any renally-cleared medication may be underdosed. Aside from antibiotics, ARC may cause subtherapeutic dosing of other medications (especially enoxaparin and levetiracetam). (Baptista 2023)

if using a renally cleared antibiotic

• [1] Use the maximal approved dosage. (32659898)
• [2] Monitor drug levels, if possible (e.g., vancomycin).
• [3] Administer doses in a prolonged infusion (for antibiotics with time-dependent pharmacodynamics, such as beta-lactams).

consider switching to an antibiotic less dependent on renal clearance

• Beta-lactams:
  • Nafcillin.
  • Ceftriaxone: performs OK, but a higher dose may be required.
• Atypical coverage:
  • Doxycycline.
  • Azithromycin.
• Anaerobic coverage:
  • Clindamycin.
  • Metronidazole.
• Linezolid: performance is unclear; using higher doses is probably adequate in mild ARC.
• (Other less useful agents: tigecycline, rifampin, moxifloxacin.)

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estimating GFR based on vancomycin clearance

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There are two methods to estimate GFR based on vancomycin clearance. 

method #1: single compartment model

• Baseline assumptions:
  • Vancomycin clearance = 0.82(creatinine clearance). (19933799) Various studies have reported a ratio between 0.75-0.9, so 0.82 seems reasonable.  
  • Volume of distribution = 0.7 L/kg.  This factor is subject to greater variation between studies, but 0.7 L/kg seem to be a reasonable figure that is often quoted in pharmacokinetic textbooks.
  • Vancomycin is modeled using single-compartment pharmacokinetics.
• Based on these assumptions, GFR (creatinine clearance) may be estimated based on the concentration at two time points, the time elapsed between measurements, and the patient's weight:
  • GFR in ml/min = 14*ln(C2/C1)*(wt in kg)/(Δ time in hours)

method #2: Creighton equation

• The elimination constant (Kel) of vancomycin is linearly related to the creatinine equation based on the following equation: (6732213)
  • Kel (/hr) = 0.00083(Creatinine clearance in ml/min) + 0.0044
  • Kel = ln (C2/C1)/(Δ time in hours)
• This equation is widely cited in pharmacokinetic literature and has been the basis of some studies on vancomycin pharmacokinetics. (32166646) However, when various authors try to replicate this equation, the results are somewhat variable.

comparison of methods

• The online calculator below will estimate GFR using both methods.
• For weights around 70 kg, the results are similar. For higher weights, the 1-compartment model will produce a higher GFR (since it's calculating an absolute creatinine clearance).  Alternatively, the Creighton equation yields the same GFR regardless of weight (effectively calculating a GFR corrected for body surface area).

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measured GFR using timed urine collection

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role of timed urine collection

• Timed urine collection may be helpful when GFR estimation equations are considered less accurate, for example:
  • Very unusual muscle mass (e.g., amputations, severe cachexia).
  • Dynamic creatinine levels over time.

nuts and bolts of timed urine collection

• Timed urine collection may be utilized.
  • 24 hours might be ideal.
  • 8-12 hours may be adequate for patients with a Foley catheter, which allows for very accurate timing of urine collection. (37259709)
• Urine levels of creatinine, urea, and albumin may be checked.
• Measured creatinine clearance may overestimate the actual GFR by ~25% due to proximal renal tubular creatinine secretion. (37909162) Meanwhile, the urea clearance will substantially underestimate the GFR, due to reabsorption of urea. In severe renal disease, it is sometimes helpful to average the measured creatinine clearance and the measured urea clearance.
• (Formulas for calculating GFR are here.)

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questions & discussion

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

Guide to emoji hyperlinks 

•  = Link to online calculator.
•  = Link to Medscape monograph about a drug.
•  = Link to IBCC section about a drug.
•  = Link to IBCC section covering that topic.
•  = Link to FOAMed site with related information.
• 📄 = Link to open-access journal article.
• = Link to supplemental media.