Mapping eGFR and Creatinine Clearance to Renal PBPK Inputs

From a Clinical Measure to a PBPK Input

Renal function is often reported as an indexed estimated glomerular filtration rate (eGFR), whereas a PBPK model may require an absolute filtration rate for an individual. Creatinine clearance (CrCl) is another common measure, but it is not the same quantity as GFR. A defensible mapping therefore involves more than copying a laboratory value into a model: identify what the measure represents, put it on the model's scale, and retain its limitations.

The introductory material on translating renal and hepatic disease phenotypes into PBPK changes establishes the modeling principle that clinical phenotype must be connected to the relevant physiological process. Here the focus is the numerical conversion of eGFR and CrCl into renal covariates. These measures can inform filtration-related processes; neither alone specifies every mechanism of renal drug handling.

De-indexing eGFR and Matching Model Units

To convert an indexed eGFR to an absolute estimate, multiply by the person's BSA and divide by 1.73 m². If BSA is not already available, the Mosteller equation is one common estimate, using height in centimeters and weight in kilograms. De-indexing changes the scale of the reported value; it does not make the underlying estimate more precise or turn it into a measured GFR.

PBPK implementations may express flow or clearance in L/h rather than mL/min. Since 1 L = 1000 mL and 1 h = 60 min, multiply mL/min by \(60/1000=0.06\) to obtain L/h. Convert only after establishing whether the model input is absolute; do not convert an indexed value directly as though it were a person's total filtration rate.

Creatinine Clearance: Measured and Estimated

A timed-urine CrCl estimate is calculated as urine creatinine concentration multiplied by urine flow rate, divided by serum creatinine concentration. With urine concentration and serum concentration in matching units, the concentration ratio is dimensionless, so the result has the units of urine flow. The calculation assumes that urine was collected over the stated interval and that the serum creatinine concentration represents the collection period.

Here \(U_{\mathrm{Cr}}\) is urine creatinine concentration, \(P_{\mathrm{Cr}}\) is serum or plasma creatinine concentration, \(V\) is the collected urine volume, and \(t\) is collection duration. For example, if \(V\) is in mL and \(t\) in minutes, the calculated clearance is in mL/min. Incomplete collection, incorrect timing, or a nonrepresentative serum value can undermine the result.

A commonly used estimated CrCl equation for adults is Cockcroft–Gault. In its conventional form, age is in years, body weight in kg, and serum creatinine in mg/dL; the result is mL/min. The factor 0.85 is applied for females in this equation. This is an equation-based estimate, not a timed urine measurement. Its output depends on the equation's assumptions and on the chosen weight, which may require clinical judgment in unusual body composition.

Mapping the Measure to a Filtration-Related PBPK Process

An absolute filtration estimate can be used directly when a PBPK model represents GFR as an absolute physiological input and the chosen clinical measure is an appropriate estimate of it. If a model instead uses a renal-function multiplier relative to a reference condition, define the multiplier explicitly as the patient's selected absolute estimate divided by the reference GFR. The reference and patient values must have matching units and must represent compatible quantities.

For a drug filtered at the glomerulus, a simplified filtration clearance is \(f_{u,p}\times\mathrm{GFR}\), where \(f_{u,p}\) is the unbound fraction in plasma. This relation assumes filtration of the unbound drug and does not include secretion, reabsorption, or other renal processes. Consequently, applying a GFR multiplier to a model's entire renal clearance is only justified if that model's renal clearance is wholly GFR-dependent. The input must follow the model's structural meaning, not merely a convenient clinical label.

The ratio formula follows directly from proportional scaling. If the model's reference GFR is \(G_{\mathrm{ref}}\), and its patient input is \(G_{\mathrm{patient}}\), then the multiplier \(f_{\mathrm{GFR}}\) must satisfy \(G_{\mathrm{patient}}=f_{\mathrm{GFR}}G_{\mathrm{ref}}\). Dividing both sides by \(G_{\mathrm{ref}}\), for \(G_{\mathrm{ref}}>0\), gives \(f_{\mathrm{GFR}}=G_{\mathrm{patient}}/G_{\mathrm{ref}}\). This is a scale conversion, not evidence that all renal drug clearance scales linearly with GFR.

Choosing Between eGFR and CrCl

Creatinine is filtered and also secreted by renal tubules. As a result, CrCl can exceed GFR, although the size of the difference is not fixed for every person or clinical circumstance. eGFR and CrCl can also differ because their equations, inputs, and normalization differ. When a clinical protocol, drug-development analysis, or model calibration specifies one measure, preserve that definition rather than substituting another without justification.

Diagnostics, Pitfalls, and Limits

A basic diagnostic is dimensional: indexed eGFR has a BSA denominator, so it cannot be inserted as an absolute rate without accounting for that denominator. Another is arithmetic: \(1\ \mathrm{mL/min}=0.06\ \mathrm{L/h}\), and the conversion factor should make the numerical value in L/h smaller. Check whether height and weight are in the units required by the BSA formula and whether the creatinine concentrations use compatible units in timed-urine calculations.

A frequent mistake is to take an indexed eGFR of 40 mL/min/1.73 m², label it 40 mL/min for an individual, and enter it directly into a model. That ignores body size. The correction is to calculate \(40\times\mathrm{BSA}/1.73\) before treating it as an absolute estimate. A separate mistake is to call a CrCl value “the GFR.” The correction is to retain its identity as CrCl, explain why it is being used as a proxy if the model requires GFR, and report the resulting uncertainty rather than implying equivalence.

These conversions do not resolve limitations in the underlying clinical estimate. Creatinine-based estimates may be less representative when creatinine production or concentration is changing rapidly, and a timed urine result may be unreliable if collection is incomplete. BSA itself is estimated from height and weight. Finally, the conversion only addresses filtration-scale inputs; it does not determine how tubular processes or other renal changes should be represented. Those require separate mechanistic decisions.