FDA Renal Impairment Categories (2024 Guidance)

The FDA’s final March 2024 guidance sorts adult renal function into four groups, all in mL/min: control (normal renal function) at 90 or more, mild impairment at 60 to less than 90, moderate impairment at 30 to less than 60, and severe impairment and kidney failure not receiving dialysis below 30. Renal function can be an eGFR expressed in mL/min or a Cockcroft-Gault creatinine clearance (CrCl). The groups exist to enroll drug studies; the FDA states they are not meant for classifying kidney disease.

What the FDA Guidance Covers

The document is the FDA guidance for industry Pharmacokinetics in Patients with Impaired Renal Function: Study Design, Data Analysis, and Impact on Dosing, issued as a final guidance in March 2024 by the Center for Drug Evaluation and Research. It is written for drug sponsors and explains how to study the effect of impaired kidney function on a drug’s pharmacokinetics (PK), how to derive a recommended dosage, and how the results should inform the label. Like all FDA guidance, it is not binding: “should” means recommended, not required.

A dedicated renal impairment study is recommended when a drug or active metabolite is substantially eliminated by the kidneys, defined as a fraction excreted unchanged in urine of 0.3 or greater, and for therapeutic proteins and peptides under 69 kDa unless that fraction is below 0.3. For drugs cleared mainly by other routes, a reduced study in participants with severe impairment or kidney failure not on dialysis can represent the worst case.

The FDA Renal Function Groups

The labels and cut points below are reproduced from Table 1 of the guidance.

The four footnotes to the table carry most of its meaning:

• eGFR is an estimate of GFR expressed in mL/min, converted from mL/min/1.73 m² with the individual’s body surface area (BSA).
• eCLcr is estimated creatinine clearance from the Cockcroft-Gault equation.
• The classification is strictly for conducting a dedicated renal impairment study and is not intended to be used for classifying kidney disease.
• Participants should be enrolled using one common estimation method in the control and renal impairment groups.

Dialysis is not a group in Table 1. The guidance covers renal replacement therapy separately and recommends studying patients on intermittent hemodialysis, the most common modality in the United States, during both on-dialysis and off-dialysis periods. Participants with impaired renal function should also have stable renal function; patients with acute changes should not be included. The groups describe steady kidney function, not acute kidney injury.

eGFR in mL/min Versus Cockcroft-Gault CrCl

The guidance names two estimating approaches for adults: eGFR from a contemporary, widely accepted equation, and estimated CrCl in mL/min from the Cockcroft-Gault equation. In clinical practice eGFR is usually reported in mL/min/1.73 m². Because the renal clearance of a drug is proportional to the individual’s GFR in mL/min, the guidance says adult dosage recommendations should use eGFR expressed in mL/min, not the indexed value.

eGFR (mL/min) = eGFR (mL/min/1.73 m²) × BSA ÷ 1.73

Get the BSA from the BSA calculator and do the conversion with the GFR unit converter. The step matters most at the extremes of body size. For example, an indexed eGFR of 50 in a patient with a BSA of 2.2 m² becomes 50 × 2.2 ÷ 1.73, or about 64 mL/min, which falls in the mild group rather than the moderate one. The same indexed value with a BSA of 1.5 m² becomes about 43 mL/min.

On the choice of method, the guidance recommends eGFR over estimated CrCl in PK studies because of its widespread availability and use in current clinical practice, while still accepting measured GFR, measured CrCl, or any contemporary, widely accepted equation. The National Kidney Foundation advocates moving from Cockcroft-Gault CrCl to race-free eGFR, adjusted for BSA, for medication decisions in adults, using equations such as CKD-EPI 2021. See CrCl vs eGFR for how the two differ.

Body Weight in Overweight or Obese Participants

Because Cockcroft-Gault uses body weight, the guidance addresses it directly: in overweight or obese individuals, using alternative body weight metrics such as ideal body weight (IBW) or adjusted body weight (ABW) is likely to give a more accurate estimate of renal function than actual body weight.

Winter and colleagues compared Cockcroft-Gault estimates with measured 24-hour CrCl in 3,678 patients with stable renal function. Actual body weight gave an unbiased result in underweight patients and ideal body weight in patients of normal weight. In overweight, obese, and morbidly obese patients, adjusted body weight with a factor of 0.4 was the least biased and most accurate. The National Kidney Foundation also notes that weight choices are applied inconsistently across clinicians and institutions, which adds variability. Recording which weight was used makes a CrCl easier to check and repeat.

Why These Groups Are Not CKD Stages

The cut points of 90, 60, and 30 look familiar because they also appear in chronic kidney disease staging. The two systems answer different questions. KDIGO classifies CKD by cause, GFR category (G1 to G5), and albuminuria category (A1 to A3), and its GFR categories are in mL/min/1.73 m². Categories G1 and G2 do not meet the criteria for CKD without evidence of kidney damage. The FDA groups use absolute mL/min, do not include albuminuria, and serve only to enroll PK studies.

Use the CKD stages for diagnosis and follow-up, and the drug’s own label for dosing.

Reading Older Drug Labels

The Cockcroft-Gault equation has informed medication dosing for close to 50 years, so many labels written before the 2024 guidance state renal dose changes as CrCl bands in mL/min. Each label sets its own cut points, and they do not have to match Table 1. The practical rule is to apply the estimate the label names: if it gives Cockcroft-Gault CrCl bands, calculate CrCl with the Cockcroft-Gault equation; if it gives eGFR in mL/min, de-index the eGFR first. Current labels can be checked on DailyMed, and the renal drug dosing hub lists the estimate each drug page uses.

One caution applies to older CrCl bands. By 2011 most serum creatinine assays had been standardized to an isotope dilution mass spectrometry (IDMS) reference method, and the average creatinine value fell by 12%. As a result, Cockcroft-Gault values today run higher than the values in PK studies used to build dosing advice before 2011. A result close to a label’s cut point deserves extra care.

Using One Method Across All Groups

The guidance asks sponsors to enroll every group with one common estimation method and to use the same equation when data are pooled across studies. It prefers a regression approach that treats renal function as a continuous variable over analysing the four groups as categories, because that can reveal thresholds more meaningful for dose changes, so a label’s cut points need not follow Table 1. Because dose recommendations can differ significantly between estimating equations, the guidance calls it good practice to test how each contemporary equation affects them.

On labeling, the Prescribing Information should summarise PK and pharmacodynamics in renal impairment, including patients receiving dialysis, the renal elimination of the drug and active metabolites, the clinical effects of those changes, and recommendations such as a different dosage or monitoring. In practice:

• Check which estimate the label uses, since different equations can change the recommendation.
• Compare readings made with the same method, and de-index eGFR to mL/min when the dose depends on mL/min.
• In overweight or obese patients, consider ideal or adjusted body weight in Cockcroft-Gault.