Measurement of renal function and estimation of glomerular filtration rate (eGFR) using creatinine clearance

GFR as the index

GFR is the best single index of renal function - but it is never measured in routine practice

Method	What it is	Use
Measured GFR (mGFR)	Clearance of an exogenous filtration marker - inulin, iohexol, 51Cr-EDTA, 99mTc-DTPA	Reference standard. Living donor workup, chemotherapy dosing, discordant estimates
Creatinine clearance (24 h urine)	(U_Cr x V) / P_Cr	*Overestimates GFR by 10-20%* - creatinine is secreted as well as filtered
eGFRcr (CKD-EPI 2021)	Creatinine, age, sex. No race coefficient	The number Australian labs report on every UEC
eGFRcr-cys	Creatinine + cystatin C	More accurate than either alone - confirmatory test when eGFRcr is unreliable
Cockcroft-Gault	Creatinine clearance from actual weight, uncorrected for BSA	Drug dosing - the equation most drug licensing was built on

eGFR is indexed to 1.73 m2 BSA - must be de-indexed for drug dosing at extremes of body size

CKD ~1 in 10 Australian adults; ~90% unaware
Aboriginal and Torres Strait Islander peoples: ESKD rate up to ~4x, and far higher in remote communities
Automatic eGFR reporting on every serum creatinine in Australia since 2005
- Values >90 reported as ">90" - the equations are imprecise in the normal range

Creatinine = product of muscle creatine turnover -> production tracks muscle mass, not renal function
Freely filtered, but also actively secreted by proximal tubular OCT2/MATE transporters (~10-20% of clearance)
- -> creatinine clearance > true GFR
- Secretion blocked by trimethoprim, cimetidine, cobicistat, dolutegravir, ritonavir, tyrosine kinase inhibitors -> creatinine rises with NO change in GFR
Creatinine-blind range: GFR must fall ~50% before creatinine leaves the reference interval
- Halving of GFR from 120 to 60 may move creatinine only from 60 to 100 umol/L

inc creatinine (eGFR falsely low)	dec creatinine (eGFR falsely high)
High muscle mass, bodybuilders	Sarcopenia, frailty, elderly
Cooked meat load, creatine supplements	Cirrhosis (dec hepatic creatine synthesis, muscle wasting)
Trimethoprim, cimetidine, fenofibrate	Amputation, paraplegia, malnutrition
Ketoacidosis (Jaffe assay interference)	Pregnancy (inc GFR + inc volume)

Cystatin C - produced by all nucleated cells, freely filtered, catabolised in tubule
- Independent of muscle mass -> the test of choice when muscle mass is abnormal
- Own non-GFR determinants: corticosteroids, thyroid dysfunction, obesity, smoking, inflammation, malignancy

Non-steady state - AKI, rapidly changing creatinine. eGFR assumes a stable creatinine; in evolving AKI it is meaningless
Extremes of body size or muscle mass, amputees, paraplegia, malnutrition
Cirrhosis - eGFR substantially overestimates true GFR
Pregnancy - equations not validated
Children <18 (use a paediatric equation)
Where an exact number changes therapy - carboplatin dosing, living donation, discordant clinical picture

CKD staging - G and A categories are BOTH required

Chronicity required: abnormality present >=3 months
- Never diagnose CKD from a single result - repeat to confirm and exclude resolving AKI
G3a A1 and G1 A3 are not the same risk - albuminuria and eGFR contribute independently to CV and kidney outcomes

Staging, referral, risk prediction -> indexed eGFRcr (or eGFRcr-cys)
Drug dosing -> depends on the drug
- Cockcroft-Gault or de-indexed eGFR for narrow-therapeutic-index and renally cleared drugs
- DOACs - dosing thresholds derived from Cockcroft-Gault CrCl, not eGFR
- Carboplatin (Calvert formula) - use measured GFR
Confirmatory cystatin C when eGFRcr and the clinical picture disagree, or muscle mass is abnormal
Measured GFR for living kidney donation, oncology dosing, and unresolved discordance

Standardised (IDMS-traceable) enzymatic creatinine assay
Avoid checking creatinine after a large cooked-meat meal or heavy exercise
Recognise the drug-induced creatinine rise (trimethoprim, cobicistat, dolutegravir) - no fall in eGFR-independent markers such as urea or cystatin C
Report and act on eGFR + ACR together

Sarcopenia and frailty - the commonest cause of a falsely reassuring eGFR
Cirrhosis, heart failure, anorexia nervosa
Obesity - BSA indexing distorts both drug dosing and staging
Aboriginal and Torres Strait Islander peoples - no race coefficient applies; the 2021 equations are race-free
Kidney donation assessment, chemotherapy dosing, DOAC prescribing
Amputation, spinal cord injury, neuromuscular disease

Normal age-related decline ~0.5-1 mL/min/1.73 m2 per year after age 40
Rapid progression = sustained fall >5 mL/min/1.73 m2/yr, or a >=25% drop with a change in G category
A single eGFR is a snapshot; the trajectory is the prognostic variable
Initial dip after starting ACEi/ARB or SGLT2i (up to ~30% creatinine rise) is haemodynamic and expected
- Not a reason to stop; predicts long-term benefit
Kidney failure risk equation (KFRE) integrates age, sex, eGFR and ACR - used to time nephrology referral, access planning and transplant workup

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