Glomerular Filtration & GFR

Glomerular filtration is the first and rate-limiting step of urine formation, in which a near protein-free ultrafiltrate of plasma crosses the glomerular barrier into Bowman's space. Understanding the filtration barrier, the Starling forces, the determinants of GFR, and its autoregulation is one of the highest-yield blocks in renal physiology for NEET PG, and it links directly to clearance-based MCQs.

Overview & definitions

Glomerular filtration rate (GFR) = the volume of plasma filtered by both kidneys per unit time. Normal value ≈ 125 mL/min (≈ 180 L/day) in a healthy young adult male; slightly lower (~110 mL/min) in females. Since ~180 L is filtered but only ~1.5 L is excreted, >99% of the filtrate is reabsorbed.

Parameter	Typical value	Note
GFR	125 mL/min (180 L/day)	Both kidneys
Renal plasma flow (RPF)	625 mL/min	Effective RPF measured by PAH
Renal blood flow (RBF)	1100–1200 mL/min	~20–25% of cardiac output
Filtration fraction (FF)	0.20 (≈ 20%)	FF = GFR ÷ RPF
Filtration coefficient (Kf)	high	Surface area × permeability

High-yield: Filtration fraction = GFR/RPF = 125/625 = 0.2. Roughly one-fifth of plasma reaching the glomerulus is filtered.

The glomerular filtration barrier

The barrier is size-selective and charge-selective. From blood to Bowman's space, the three layers are:

Fenestrated endothelium → Glomerular basement membrane (GBM) → Podocyte foot processes (filtration slits)

Layer	Key structural feature	Function / charge
1. Capillary endothelium	Fenestrae 70–100 nm, no diaphragm	Blocks cells; glycocalyx is negatively charged
2. GBM	Type IV collagen, laminin, heparan sulfate	Main size + charge barrier (anionic)
3. Podocytes	Foot processes + slit diaphragm (nephrin, podocin)	Final size barrier; slit ~25–40 nm

High-yield: The negative charge of the barrier (heparan sulfate in GBM + glycocalyx) repels anionic plasma proteins like albumin. Loss of this charge (as in minimal change disease) causes selective albuminuria even with normal-looking podocytes on light microscopy.

• Nephrin mutation → congenital nephrotic syndrome of the Finnish type (NPHS1).
• Podocin mutation → steroid-resistant nephrotic syndrome / FSGS (NPHS2).
• Effacement (fusion) of foot processes on electron microscopy is the hallmark of nephrotic syndrome.

Filterability by molecular weight / radius:

• Freely filtered: water, glucose, amino acids, urea, Na⁺, inulin (5.2 kDa).
• Restricted: albumin (~69 kDa, anionic) — barely filtered.
• Not filtered: cells, large globulins, protein-bound substances (e.g., ~40% of plasma Ca²⁺, most drugs bound to albumin).

High-yield: A positively charged molecule is filtered more easily than a neutral or negatively charged molecule of the same size, because the barrier is anionic.

Starling forces at the glomerulus

Filtration is driven by the same Starling forces as systemic capillaries, but the glomerular capillary is a high-pressure, filtration-only bed.

Net filtration pressure (NFP):

NFP = (P_GC − P_BS) − (π_GC − π_BS)

Since Bowman's space is essentially protein-free, π_BS ≈ 0, so:

NFP = P_GC − P_BS − π_GC

Force	Symbol	Approx value (mmHg)	Direction
Glomerular capillary hydrostatic pressure	P_GC	60	Favours filtration
Bowman's space hydrostatic pressure	P_BS	18	Opposes filtration
Glomerular capillary oncotic pressure	π_GC	32 (avg)	Opposes filtration
Bowman's space oncotic pressure	π_BS	~0	(negligible)

Net ≈ 60 − 18 − 32 = +10 mmHg (always favours filtration along the entire capillary).

GFR = Kf × NFP, where Kf = hydraulic permeability × filtration surface area. Kf at the glomerulus is very high (~12.5 mL/min/mmHg) — far greater than in systemic capillaries.

High-yield: As blood flows along the glomerular capillary, plasma is filtered out → proteins concentrate → π_GC rises from ~28 to ~36 mmHg. NFP therefore falls toward the efferent end and may reach filtration equilibrium. Increasing renal plasma flow shifts equilibrium downstream → GFR rises (RPF is a positive determinant of GFR).

Determinants of GFR and the afferent/efferent arteriole logic

The two key resistance vessels are the afferent and efferent arterioles. Their selective constriction differentially changes P_GC, RPF, GFR and FF — a near-guaranteed MCQ.

Change	RBF/RPF	P_GC	GFR	FF
Afferent constriction	↓	↓	↓	~unchanged / ↓
Afferent dilation	↑	↑	↑	~unchanged / ↑
Efferent constriction (mild, e.g. Ang II)	↓	↑	↑ then ↓ if severe	↑
Efferent dilation	↑	↓	↓	↓
↑ Kf	—	—	↑	—
↑ Bowman's pressure (ureteric obstruction)	—	—	↓	—
↑ Plasma oncotic pressure	—	—	↓	—

High-yield: Angiotensin II preferentially constricts the EFFERENT arteriole → maintains P_GC and GFR when renal perfusion falls. This is why ACE inhibitors/ARBs drop GFR (efferent dilation, ↓ P_GC) — protective long-term in diabetic nephropathy but can precipitate acute kidney injury in bilateral renal artery stenosis.

High-yield: NSAIDs block prostaglandin-mediated afferent dilation → afferent constriction → ↓ GFR. Dangerous when combined with volume depletion or ACE-I ("triple whammy": ACE-I + diuretic + NSAID → AKI).

Mnemonic — "AFferent Affects Flow, EFferent Elevates pressure": afferent tone is the main controller of RBF; efferent constriction is the main way to raise P_GC/GFR selectively.

Autoregulation of GFR and RBF

GFR and RBF are kept remarkably constant over a mean arterial pressure of ~80–180 mmHg. Two intrinsic mechanisms operate:

1. Myogenic mechanism — ↑ arterial pressure stretches the afferent arteriole → stretch-activated Ca²⁺ channels open → smooth muscle contracts → afferent constriction → flow held constant. Fast (seconds).

2. Tubuloglomerular feedback (TGF) — mediated by the macula densa (specialised distal tubule cells of the thick ascending limb at the vascular pole). When GFR rises → more NaCl delivered to the macula densa → sensed via the NKCC2 (Na-K-2Cl) cotransporter → release of adenosine (ATP) → afferent vasoconstriction → GFR falls back. (Conversely, low NaCl → renin release from granular cells.)

Flow of TGF: ↑GFR → ↑NaCl at macula densa → ↑uptake via NKCC2 → adenosine release → afferent arteriole constricts → ↓GFR (negative feedback).

High-yield: Loop diuretics (furosemide) block NKCC2 at the macula densa → the macula densa "thinks" NaCl delivery is low → blunts TGF and stimulates renin release. This explains diuretic-induced activation of RAAS.

High-yield: Autoregulation fails below MAP ~70–80 mmHg → GFR falls steeply → prerenal AKI / oliguria in hypotension/shock.

Filtration fraction — clinical correlation

FF = GFR/RPF. Changes in FF affect the peritubular capillary oncotic pressure, which drives proximal tubule reabsorption.

• ↑ FF (e.g., efferent constriction by Ang II, mild volume depletion) → ↑ protein concentration in efferent/peritubular blood → ↑ peritubular oncotic pressure → ↑ proximal Na⁺ and water reabsorption (glomerulotubular balance).
• ↓ FF → ↓ proximal reabsorption.

High-yield: In early/mild haemorrhage, Ang II raises FF to preserve GFR while enhancing Na⁺ retention — a key compensatory loop.

Measurement of GFR — clearance

Clearance (C_x) = (U_x × V) / P_x, where U = urine conc, V = urine flow rate, P = plasma conc.

A substance estimates GFR accurately if it is freely filtered, not reabsorbed, not secreted, not metabolised, and not synthesised by the kidney.

Marker	Use	Comment
Inulin	Gold standard for GFR	Freely filtered, neither reabsorbed nor secreted; needs IV infusion → research
Creatinine	Clinical GFR estimate	Freely filtered but ~10–15% secreted by tubules → overestimates GFR
PAH (para-aminohippuric acid)	Effective RPF	Filtered + almost completely secreted; clearance ≈ RPF at low doses
Cystatin C	eGFR (alternative)	Not affected by muscle mass
Urea	Poor — reabsorbed	Underestimates GFR
Cr-EDTA, iohexol, iothalamate	Research GFR markers	—

High-yield: Inulin clearance = GFR (gold standard). PAH clearance = effective renal plasma flow. Creatinine clearance slightly overestimates true GFR because of tubular secretion of creatinine (this offsets the slight overestimation of plasma creatinine by chromogens — a happy coincidence historically).

Cockcroft–Gault (estimates creatinine clearance):

CrCl = [(140 − age) × weight (kg)] / (72 × serum creatinine) ; × 0.85 for females.

CKD-EPI / MDRD are the currently preferred eGFR equations. CKD staging:

CKD stage	eGFR (mL/min/1.73 m²)
G1	≥ 90 (with kidney damage)
G2	60–89
G3a	45–59
G3b	30–44
G4	15–29
G5 (failure)	< 15

High-yield: Serum creatinine is an insensitive early marker — GFR can halve before creatinine rises appreciably (the "creatinine-blind range"). Plasma creatinine is inversely proportional to GFR: when GFR halves, creatinine roughly doubles at steady state.

GFR in disease states

Condition	Effect on GFR	Mechanism
Hypotension/shock	↓	P_GC falls below autoregulatory range
Renal artery stenosis	↓ (on ACE-I, sharply ↓)	↓ perfusion; efferent tone is compensating
Ureteric obstruction	↓	↑ Bowman's hydrostatic pressure
Acute glomerulonephritis	↓	↓ Kf (capillary inflammation, ↓ surface area)
Severe hypoproteinaemia	↑ (theoretically)	↓ π_GC
Early diabetes mellitus	↑ (hyperfiltration)	Afferent dilation, ↑ P_GC
Pregnancy	↑ (~50%)	↑ RPF and GFR; ↓ serum creatinine
NSAID use	↓	Afferent constriction (loss of PGE2)
ACE-I/ARB	↓ (acutely)	Efferent dilation, ↓ P_GC

High-yield: Diabetic hyperfiltration (early ↑ GFR from afferent dilation and raised P_GC) is the earliest functional change in diabetic nephropathy and drives later glomerulosclerosis; SGLT2 inhibitors restore TGF (↑ distal NaCl sensing → afferent constriction) and reduce intraglomerular pressure — renoprotective.

Hormonal / vasoactive modulators (quick table)

Agent	Afferent	Efferent	Net GFR
Angiotensin II	(mild ↑)	↑↑ constrict	↑ (and ↑FF)
Prostaglandins (PGE2, PGI2)	dilate	—	↑ / protective
Atrial natriuretic peptide (ANP)	dilate	constrict	↑ GFR
Endothelin	constrict	constrict	↓
Nitric oxide	dilate	dilate	↑ RBF
Sympathetic / noradrenaline	constrict	constrict	↓ (afferent > efferent)

High-yield: ANP increases GFR by dilating the afferent and constricting the efferent arteriole (and by relaxing mesangial cells → ↑ Kf) → promotes natriuresis.

Mesangial cells & Kf

Mesangial cells contract in response to Ang II, endothelin, ADH → reduce the glomerular surface area → ↓ Kf → ↓ GFR. Relaxation (ANP, PGE2, dopamine) ↑ Kf.

Key differentials / commonly confused concepts

• GFR vs RBF: RBF includes blood not filtered; GFR is plasma filtered. FF connects them.
• Inulin (filtration marker) vs insulin (hormone) — classic spelling trap.
• Clearance > GFR ⇒ net secretion (e.g., PAH, creatinine); clearance < GFR ⇒ net reabsorption (e.g., glucose, Na⁺, urea); clearance = GFR ⇒ marker (inulin).
• Selective vs non-selective proteinuria: charge-barrier loss (MCD) → selective (albumin); size-barrier loss → non-selective (albumin + globulins).

Recently asked / exam angle

• "Which substance clearance equals GFR?" → Inulin (PAH = ERPF).
• "Effect of efferent arteriolar constriction on FF?" → Increases FF.
• Mechanism by which ACE-I lowers GFR and contraindication in bilateral renal artery stenosis.
• NSAID-induced afferent constriction and the "triple whammy" of AKI.
• Macula densa / NKCC2 / adenosine as the basis of tubuloglomerular feedback; furosemide blunting TGF and ↑ renin.
• Charge selectivity loss in minimal change disease → selective albuminuria; EM foot-process effacement.
• Calculation MCQs using clearance formula (U×V/P) and FF = GFR/RPF.
• Diabetic hyperfiltration and the renoprotective mechanism of SGLT2 inhibitors (restoring TGF).
• Genetic: nephrin → Finnish congenital nephrotic syndrome, podocin → FSGS.
• "Pressure that opposes filtration the most along the capillary" → rising π_GC.

Rapid revision

1. GFR ≈ 125 mL/min (180 L/day); FF = GFR/RPF = 0.2.
2. Barrier layers: fenestrated endothelium → GBM (heparan sulfate, anionic) → podocyte slit diaphragm (nephrin/podocin).
3. Negatively charged barrier repels albumin; charge loss → selective albuminuria (MCD).
4. NFP = P_GC − P_BS − π_GC ≈ 60 − 18 − 32 = +10 mmHg; GFR = Kf × NFP.
5. Ang II constricts the efferent arteriole → ↑P_GC, ↑GFR, ↑FF; ACE-I reverses this.
6. NSAIDs cause afferent constriction → ↓GFR; dangerous with ACE-I + diuretic.
7. Autoregulation MAP ~80–180 mmHg via myogenic + tubuloglomerular feedback.
8. Macula densa senses NaCl via NKCC2 → releases adenosine → afferent constriction (TGF). Furosemide blunts this → ↑renin.
9. Inulin clearance = GFR (gold standard); PAH clearance = effective RPF.
10. Creatinine clearance overestimates GFR (tubular secretion); creatinine is inversely related to GFR.
11. ANP ↑ GFR (afferent dilation + efferent constriction + ↑Kf).
12. Early diabetes = hyperfiltration; SGLT2 inhibitors restore TGF and reduce intraglomerular pressure.