GFR and renal clearance
GFR, renal blood flow, autoregulation and renal clearance (with worked calculations)
The kidneys get a fifth of cardiac output and filter about 180 L of plasma a day; inulin measures GFR and PAH measures renal plasma flow. Covers Starling forces, arteriolar tone, autoregulation, clearance sums, creatinine, prerenal injury and free water clearance.
Renal blood flow
- Kidneys receive about 20–25% of cardiac output (1.1–1.2 L/min), far more than their metabolism needs. Most goes to the cortex; the medulla receives under 10%, which preserves its concentration gradient but makes it vulnerable to ischaemia.
- Renal plasma flow (RPF) is about 600–650 mL/min, measured by para-aminohippuric acid (PAH) clearance (effective RPF).
- RBF = RPF ÷ (1 − haematocrit). With RPF 600 mL/min and haematocrit 0.40: 600 ÷ 0.6 = 1,000 mL/min. Divide by the plasma fraction, not by the haematocrit.
The filtration barrier
- Three layers: fenestrated endothelium, the glomerular basement membrane (type IV collagen, laminin, and heparan sulphate proteoglycan, which gives the negative charge) and the slit diaphragms between podocyte foot processes (nephrin, podocin).
- It restricts by size (molecules above about 70 kDa barely pass; albumin is 69 kDa) and charge (negative charge repels anionic albumin). Loss of the charge barrier, as in minimal change disease, causes selective albuminuria, often heavy enough to be nephrotic (above 3.5 g/day); severe structural damage gives non-selective proteinuria.
Starling forces in the glomerulus
| Force | Value (approx.) | Direction |
|---|---|---|
| Glomerular capillary hydrostatic pressure | About 45–60 mmHg | Favours filtration |
| Bowman's space hydrostatic pressure | About 10–18 mmHg | Opposes |
| Glomerular oncotic pressure | About 25 mmHg, rising to about 35 along the capillary | Opposes |
| Bowman's space oncotic pressure | About 0 | Favours (negligible) |
Net filtration pressure is about 10–15 mmHg. Glomerular capillaries lie between two arterioles, so hydrostatic pressure stays high along their length. GFR = Kf × net filtration pressure, about 125 mL/min (180 L/day).
Changing GFR with arteriolar tone
| Change | Glomerular pressure | GFR | RPF | Filtration fraction |
|---|---|---|---|---|
| Afferent constriction (NSAIDs, sympathetic, severe angiotensin II) | ↓ | ↓ | ↓ | Unchanged |
| Afferent dilatation (prostaglandins, high-protein meal) | ↑ | ↑ | ↑ | Unchanged |
| Efferent constriction (angiotensin II) | ↑ | ↑ (modest) | ↓ | ↑ |
| Efferent dilatation (ACE inhibitor, ARB) | ↓ | ↓ | ↑ | ↓ |
| Raised plasma protein (dehydration, myeloma) | — | ↓ | — | ↓ |
| Ureteric obstruction (↑ Bowman's pressure) | — | ↓ | — | ↓ |
- Filtration fraction = GFR ÷ RPF, normally about 20% (125 ÷ 625).
- In bilateral renal artery stenosis (or a single kidney with stenosis), GFR depends on angiotensin II constricting the efferent arteriole; an ACE inhibitor removes this and GFR falls sharply.
- NSAIDs remove prostaglandin dilatation of the afferent arteriole, which matters in volume depletion, heart failure and cirrhosis. ACE inhibitor + diuretic + NSAID is the classic harmful combination.
- GFR rises in pregnancy (by about 50%) and after a protein meal.
Autoregulation
RBF and GFR stay nearly constant over a mean arterial pressure of about 80–180 mmHg, through two mechanisms:
- Myogenic response: stretch of the afferent arteriole wall causes contraction (stretch-activated cation channels, depolarisation, Ca²⁺ entry). It does not relax.
- Tubuloglomerular feedback: the macula densa (part of the juxtaglomerular apparatus in the early distal tubule) senses NaCl delivery. High NaCl (from high GFR) releases adenosine, which constricts the afferent arteriole and lowers GFR; low NaCl dilates the afferent arteriole and stimulates renin release from juxtaglomerular cells. After haemorrhage, this juxtaglomerular mechanism, with angiotensin II on the efferent arteriole, works to restore GFR.
Below about 80 mmHg GFR falls with pressure and sympathetic afferent constriction overrides autoregulation, so oliguria is an early sign of shock.
Clearance
Clearance C = (U × V) ÷ P: the volume of plasma completely cleared of a substance per minute. U and P must be in the same units. Filtered load = GFR × plasma concentration.
| Substance | Clearance | Reason |
|---|---|---|
| Inulin | = GFR (about 125 mL/min) | Freely filtered, not reabsorbed, secreted or metabolised: gold standard |
| Creatinine | Slightly > GFR | Small amount secreted; best clinical estimate |
| PAH | ≈ RPF (about 625 mL/min) | Filtered and secreted almost completely in one pass |
| Urea | < GFR (about half) | Partly reabsorbed |
| Na⁺ | About 1 mL/min | 99% reabsorbed |
| Glucose, amino acids | 0 normally | Filtered then fully reabsorbed |
- Order of clearance: PAH > creatinine > inulin > urea > Na⁺ > glucose.
- Clearance less than inulin means net reabsorption; more than inulin means the substance is filtered and also secreted.
Worked calculations
- Inulin: plasma 1 mg/mL, urine 60 mg/mL, urine flow 2 mL/min. GFR = 60 × 2 ÷ 1 = 120 mL/min.
- Creatinine clearance: 24-hour urine 1.5 L with creatinine 8 mmol/L (8,000 µmol/L); plasma 100 µmol/L. C = 8,000 × 1.5 ÷ 100 = 120 L/day = 120,000 ÷ 1,440 = about 83 mL/min. An incomplete collection falsely lowers the result.
- Transport maximum: GFR 125 mL/min, plasma level 200 mg/100 mL (2 mg/mL), Tm 125 mg/min. Filtered load = 250 mg/min; reabsorbed = 125 mg/min (Tm); excreted = 125 mg/min.
Creatinine, urea and cystatin C
- Creatinine comes from muscle at a steady rate. Plasma creatinine roughly doubles each time GFR halves, but on this hyperbolic curve it can stay "normal" until about half of function is lost. eGFR equations (CKD-EPI) adjust for age and sex; normal creatinine clearance is about 100–125 mL/min.
- Because a little creatinine is secreted by the proximal tubule (organic cation transporters), creatinine clearance overestimates GFR. Trimethoprim and cimetidine block this secretion and raise creatinine by 10–30% without changing true GFR; an unchanged cystatin C or urea confirms it.
- Cystatin C is produced by all nucleated cells, is independent of muscle mass and is a useful second marker.
Prerenal versus intrinsic injury
| Finding | Prerenal | Acute tubular necrosis |
|---|---|---|
| Urine sodium | < 20 mmol/L | > 40 mmol/L |
| Fractional excretion of Na⁺ | < 1% | > 2% |
| Urine osmolality | > 500 mOsm/kg | About 300 (isosthenuria) |
| BUN:creatinine ratio | > 20:1 (urea reabsorbed with water) | < 15:1 |
- Postoperative oliguria (15 mL/h) with tachycardia and a freely flushing catheter is hypovolaemia: give fluid, never a diuretic. Prolonged prerenal injury progresses to ATN.
- Crush injury and rhabdomyolysis (dark urine, CK 60,000 U/L): myoglobin is toxic to tubules and forms casts. Generous IV fluids early protect the kidneys; release of the crush can cause sudden hyperkalaemic arrest.
- Contrast-associated kidney injury in diabetics with low eGFR is best reduced by IV isotonic fluid before and after the scan.
Free water clearance
Free water clearance = urine flow − osmolar clearance (C_osm = U_osm × V ÷ P_osm). It is positive when dilute urine is passed (water excess, diabetes insipidus) and negative when concentrated urine is passed (dehydration, SIADH, where water is retained inappropriately).
Remember Inulin for GFR, PAH for RPF; C = UV/P; angiotensin II squeezes the efferent arteriole.
Exam trap Angiotensin II constricts mainly the efferent arteriole; NSAIDs remove afferent dilatation.
Exam trap The myogenic response is contraction when stretched, not relaxation.
How FCPS asks about this
- Best measure of GFR: inulin clearance; best clinical estimate: creatinine clearance or eGFR; RPF: PAH.
- Clearance greater than inulin: the substance is filtered and secreted.
- RBF from RPF 600 and haematocrit 0.40: 1,000 mL/min.
- Autoregulation of GFR: myogenic response and tubuloglomerular feedback (macula densa), MAP about 80–180 mmHg.
- Negative charge of the GBM: heparan sulphate.
- BUN:creatinine above 20:1 and FENa under 1%: prerenal azotaemia.
- Creatinine rises on trimethoprim with unchanged cystatin C: blocked tubular secretion of creatinine.
Test yourself on this topic
5 of the 39 questions in our bank on this topic. Choose an answer to see why every option is right or wrong.
A 65-year-old man with heart failure has a markedly reduced renal plasma flow, but his GFR has fallen much less. What happens to his filtration fraction, and why?
Answer: It rises because efferent arterioles constrict
Filtration fraction is GFR divided by renal plasma flow, normally about 20%. In heart failure, low cardiac output activates the renin–angiotensin system, and angiotensin II constricts the efferent arteriole more than the afferent. This raises glomerular capillary pressure and keeps GFR relatively stable while plasma flow falls, so the filtration fraction rises. The higher oncotic pressure of the blood leaving the glomerulus then favours sodium and water reabsorption in the proximal tubule. ACE inhibitors remove this support.
Filtration fraction
- FF = GFR ÷ RPF (~20%)
- Angiotensin II: efferent constriction
- RPF falls, GFR kept: FF rises
- Peritubular oncotic pressure up: Na⁺ retained
Remember Squeeze the outflow and more plasma is filtered.
Exam trap In low-flow states GFR depends on angiotensin II; ACE inhibitors can then cause a sudden fall.
Why the other options are wrong
- It falls because afferent arterioles constrict Afferent constriction would lower both GFR and the fraction.
- It is unchanged because both arterioles dilate The arterioles are constricted, not dilated.
- It rises because Bowman's pressure falls Bowman's pressure is not the main change.
- It falls because plasma oncotic pressure rises Not the main mechanism.
Eight hours after a bowel resection, a patient's urine output has been 15 mL/h. The catheter flushes freely, pulse is 110/min and BP 100/65 mmHg. What is the most likely cause?
Answer: Hypovolaemia (prerenal)
Postoperative oliguria (under 0.5 mL/kg/h) is most often prerenal: fluid losses, bleeding, third-space shifts and stress hormones (ADH, aldosterone). After checking the catheter, the patient is assessed for hypovolaemia (tachycardia, low BP, cool peripheries) and given a fluid challenge, with review of losses and drugs. Prolonged hypoperfusion can lead to acute tubular necrosis.
Postoperative oliguria
- Check catheter first
- Commonest: prerenal (hypovolaemia)
- Signs: tachycardia, low BP
- Give fluid challenge, reassess
- Untreated: ATN
Remember Low urine after surgery: fill the tank first.
Exam trap Do not give diuretics to an oliguric hypovolaemic patient.
Why the other options are wrong
- Bladder outlet obstruction Catheter is patent.
- Acute tubular necrosis from the start Possible if hypoperfusion persists, not first.
- Glomerulonephritis Not likely here.
- Syndrome of inappropriate ADH alone Contributes, but tachycardia and low BP point to hypovolaemia.
At 28 weeks of pregnancy, a woman's creatinine is 85 µmol/L (0.96 mg/dL), within the non-pregnant range. Why is this result worrying?
Answer: GFR normally rises by about 50% in pregnancy
From early pregnancy, renal plasma flow rises by about 50–80% and GFR by about 50%, driven by systemic vasodilatation and the expanded plasma volume. Serum creatinine and urea therefore fall, and a creatinine of around 35–70 µmol/L (0.4–0.8 mg/dL) is usual. A value that would be normal outside pregnancy can indicate significant renal impairment, for example from pre-eclampsia. The higher filtered load also contributes to glycosuria in pregnancy.
Kidney in pregnancy
- RPF up 50–80%, GFR up ~50%
- Creatinine normally falls
- Usual ~35–70 µmol/L
- 'Normal' adult value may be abnormal
Remember In pregnancy, a normal creatinine can be a high creatinine.
Exam trap Interpret creatinine in pregnancy against pregnancy ranges, not the general adult range.
Why the other options are wrong
- Creatinine production doubles in pregnancy Production does not double.
- The placenta secretes creatinine The placenta does not secrete creatinine.
- Pregnancy lowers tubular creatinine secretion Not the reason.
- Plasma volume falls in pregnancy Plasma volume rises in pregnancy.
Creatinine clearance slightly overestimates the true GFR. Why?
Answer: Some creatinine is secreted by the tubules
Creatinine is freely filtered and not reabsorbed, but about 10–20% of urinary creatinine is added by proximal tubular secretion, so its clearance runs a little higher than GFR. Inulin is filtered and neither secreted nor reabsorbed, so inulin clearance is the gold standard. In practice eGFR from serum creatinine is used. Drugs such as trimethoprim block creatinine secretion and raise serum creatinine without harming the kidney.
Measuring GFR
- Gold standard: inulin clearance
- Creatinine: filtered + secreted
- So clearance overestimates GFR
- Trimethoprim blocks secretion
- PAH clearance = renal plasma flow
Remember Secretion adds a little extra creatinine.
Exam trap PAH clearance measures renal plasma flow, not GFR.
Why the other options are wrong
- Creatinine is partly reabsorbed Reabsorption would make it underestimate GFR.
- Creatinine is bound to plasma protein It is freely filtered.
- Creatinine is made by the kidney Made by muscle.
- Creatinine is filtered only partly It is freely filtered.
During a measurement study, inulin is infused to a steady plasma concentration of 1 mg/mL. Urine flow is 2 mL/min and urinary inulin concentration is 60 mg/mL. What is the glomerular filtration rate?
Answer: 120 mL/min
Clearance is the volume of plasma completely cleared of a substance per minute: C = (U × V) ÷ P, where U is urine concentration, V urine flow and P plasma concentration. Here (60 × 2) ÷ 1 = 120 mL/min. Inulin is freely filtered and neither reabsorbed nor secreted, so all inulin in the urine came from filtration and its clearance equals GFR. Creatinine is used clinically but is slightly secreted, so creatinine clearance slightly overestimates GFR. PAH is filtered and secreted almost completely, so its clearance approximates renal plasma flow (about 625 mL/min). A substance with a clearance lower than inulin is net reabsorbed; higher, net secreted.
Clearance
- C = U × V ÷ P
- Inulin clearance = GFR
- PAH clearance ≈ RPF
- Creatinine slightly overestimates GFR
Remember Urine times flow over plasma.
Exam trap Check the units: urine and plasma concentrations must be in the same units.
Why the other options are wrong
- 30 mL/min This is U ÷ P ÷ V, an incorrect formula.
- 60 mL/min Forgets to multiply by urine flow.
- 240 mL/min Doubles the result incorrectly.
- 600 mL/min Closer to renal plasma flow (PAH clearance).
Where this sits in the CPSP syllabus
- Paper 1: Renal physiology, body fluids and acid-base, Glomerular filtration, renal blood flow and clearance
- Surgery & Allied, Paper 2: Renal physiology, body fluids and acid-base, Glomerular filtration, renal blood flow and clearance
- Medicine & Allied, Paper 2: Renal physiology, body fluids and acid-base, Glomerular filtration, renal blood flow and clearance
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