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PY7.1-9 | Renal Physiology — Part 1
CLINICAL SCENARIO
A 52-year-old farmer from Vellore district is brought to the PHC by his family. He complains of puffiness around the eyes in the morning that disappears by evening, and swelling of both feet that has gradually crept up to his knees over 3 months. He has been diabetic for 8 years on irregular treatment. On examination: BP 160/100 mmHg, urine dipstick shows 3+ protein, serum creatinine 3.4 mg/dL (normal < 1.2), eGFR 18 mL/min (severely reduced).
The diagnosis is diabetic nephropathy — a failure of glomerular filtration caused by decades of uncontrolled blood sugar damaging the delicate capillary tuft that filters blood. Understanding why this patient has proteinuria, hypertension, and salt retention requires understanding the physiology you will learn today: how the glomerulus works, how the tubules regulate composition, and how the kidney maintains blood pressure and acid-base balance.
WHY THIS MATTERS
Chronic kidney disease affects an estimated 17% of Indians — nearly 220 million people — making it one of the most prevalent non-communicable diseases in the country. As a doctor, kidney physiology underpins:
- Interpreting investigations: Every serum creatinine, BUN, and urine report you will order for the rest of your career requires understanding of GFR and tubular function.
- Prescribing safely: Dose adjustments for antibiotics, NSAIDs, metformin, and ACE inhibitors depend on renal function.
- Managing fluids and electrolytes: IV fluid therapy, hyponatraemia, hyperkalaemia — all governed by renal physiology.
- Understanding hypertension: RAAS, pressure natriuresis, and renal mechanisms are central to 90% of hypertension management.
- Cross-subject integration: Biochemistry gave you the chemistry of acid-base; physiology now gives you the organ that defends pH.
RECALL
Before diving in, anchor the new material to what you have already studied:
From Anatomy (AN): You have studied the kidney's gross structure — hilum, cortex, medulla, pyramids, pelvis — and its blood supply (renal artery → interlobar → arcuate → interlobular arteries). You know the nephron has a glomerulus inside Bowman's capsule and a tubular system (PCT → loop of Henle → DCT → collecting duct).
From Biochemistry (BI): You studied acid-base chemistry — Henderson-Hasselbalch equation, buffer systems (bicarbonate, phosphate, protein). You also covered glucose metabolism, which explains why diabetics develop glycosuria when plasma glucose exceeds the renal threshold.
From last module (Cardiovascular): You understand hydrostatic and oncotic pressures (Starling forces) — the same forces govern glomerular filtration.
Now we will see these structures in action.
The Glomerulus: A Pressure-Driven Ultrafilter
The glomerulus is a knot of fenestrated capillaries wrapped inside Bowman's capsule. Blood enters via the afferent arteriole and exits via the efferent arteriole — a unique arrangement that makes the capillary bed a high-pressure zone, unlike any other capillary bed in the body.
Figure: The Glomerulus: A Pressure-Driven Ultrafilter
The filtration membrane has three layers:
1. Fenestrated endothelium — pores 70–100 nm wide; blocks cells and large proteins
2. Basement membrane (GBM) — a negatively charged meshwork that repels albumin (also negatively charged)
3. Slit diaphragm of podocytes — final barrier; its protein nephrin is mutated in congenital nephrotic syndrome
What crosses freely: Water, urea, glucose, amino acids, creatinine, small ions (Na⁺, K⁺, Cl⁻, HCO₃⁻)
What does NOT cross: Red blood cells, white blood cells, platelets, albumin and larger proteins
In diabetic nephropathy (our opening case), glycation of the GBM increases its permeability — albumin leaks through, causing proteinuria. The massive protein loss reduces plasma oncotic pressure, promoting oedema.
Starling Forces and GFR
Starling Forces at the Glomerulus
| Force | Value (mmHg) | Direction | Effect on Filtration |
|---|---|---|---|
| Glomerular capillary hydrostatic pressure (Pgc) | 55 | Out of capillary | Favours filtration (main driver) |
| Bowman's capsule hydrostatic pressure (Pbs) | 15 | Opposes filtration | Opposes filtration (increases in ureteral obstruction) |
| Glomerular oncotic pressure (pi-gc) | 30 | Opposes filtration | Opposes filtration (increases along capillary length) |
| Bowman's capsule oncotic pressure | ~0 | Negligible | Normally negligible (increases in proteinuria) |
| Net Filtration Pressure | 10 | Net outward | Drives GFR of 125 mL/min |
Starling Forces at the Glomerulus
Figure: Starling Forces and GFR
| Force | Value (mmHg) | Direction | Effect on Filtration |
|---|---|---|---|
| Glomerular capillary hydrostatic pressure (Pgc) | 55 | Out of capillary | Favours filtration (main driver) |
| Bowman's capsule hydrostatic pressure (Pbs) | 15 | Opposes filtration | Opposes filtration (increases in ureteral obstruction) |
| Glomerular oncotic pressure (pi-gc) | 30 | Opposes filtration | Opposes filtration (increases along capillary length) |
| Bowman's capsule oncotic pressure | ~0 | Negligible | Normally negligible (increases in proteinuria) |
| Net Filtration Pressure | 10 | Net outward | Drives GFR of 125 mL/min |
Starling Forces at the Glomerulus
| Force | Value (mmHg) | Direction | Effect on Filtration |
|---|---|---|---|
| Glomerular capillary hydrostatic pressure (Pgc) | 55 | Out of capillary | Favours filtration (main driver) |
| Bowman's capsule hydrostatic pressure (Pbs) | 15 | Opposes filtration | Opposes filtration (increases in ureteral obstruction) |
| Glomerular oncotic pressure (pi-gc) | 30 | Opposes filtration | Opposes filtration (increases along capillary length) |
| Bowman's capsule oncotic pressure | ~0 | Negligible | Normally negligible (increases in proteinuria) |
| Net Filtration Pressure | 10 | Net outward | Drives GFR of 125 mL/min |
GFR (Glomerular Filtration Rate) is the volume of filtrate formed per minute across ALL glomeruli. Normal GFR = 125 mL/min (180 L/day).
Figure: Starling Forces and GFR
GFR is determined by Starling forces — specifically the net filtration pressure (NFP):
Forces favouring filtration:
- Glomerular capillary hydrostatic pressure (Pgc): 55 mmHg — the main driver; high because efferent arteriole is narrower than afferent
Forces opposing filtration:
- Bowman's capsule hydrostatic pressure (Pbs): 15 mmHg (backs up if ureter blocked)
- Glomerular oncotic pressure (πgc): 30 mmHg (increases along the capillary as protein is left behind)
NFP = Pgc − Pbs − πgc = 55 − 15 − 30 = +10 mmHg → net filtration
GFR also depends on Kf (filtration coefficient) = capillary permeability × surface area.
GFR = Kf × NFP
Clinically, GFR is estimated using serum creatinine and the CKD-EPI or MDRD formulas, or measured directly using inulin clearance (gold standard) or creatinine clearance.
Autoregulation of GFR
Despite changes in mean arterial pressure between 80–180 mmHg, GFR remains nearly constant. This is autoregulation, achieved by two mechanisms:
Figure: Autoregulation of GFR
- Myogenic mechanism: When pressure rises, the afferent arteriole smooth muscle stretches and constricts — reducing blood flow and preventing a rise in GFR. When pressure falls, it relaxes.
2. Tubuloglomerular feedback (TGF) via the juxtaglomerular apparatus (JGA):
- The macula densa (specialised cells of the DCT) senses Na⁺/Cl⁻ concentration in tubular fluid
- High NaCl (↑ GFR) → macula densa releases adenosine → constricts afferent arteriole → ↓ GFR
- Low NaCl (↓ GFR) → macula densa signals JG cells → release renin → activates RAAS → ↑ GFR
Filtration fraction (FF) = GFR ÷ Renal plasma flow = 125 ÷ 625 = 0.20 (20%). This means 20% of plasma that enters the glomerulus is filtered. The remaining 80% flows into the peritubular capillaries and vasa recta — it is protein-rich and drives reabsorption.
SELF-CHECK — : Glomerular Filtration
A patient with ureteric stone causing complete obstruction has Bowman's capsule pressure of 45 mmHg (instead of normal 15 mmHg). Glomerular capillary pressure is 55 mmHg and oncotic pressure is 30 mmHg. What happens to GFR?
A. GFR increases because more pressure is generated
B. GFR stops because NFP = 0 or negative
C. GFR is unchanged due to autoregulation
D. GFR falls by 50% due to myogenic reflex
Reveal Answer
Answer: B. GFR stops because NFP = 0 or negative
Which structure in the filtration membrane is responsible for the charge-selective barrier that repels albumin?
A. Fenestrated endothelium
B. Glomerular basement membrane (GBM)
C. Slit diaphragm of podocytes
D. Mesangial cells
Reveal Answer
Answer: B. Glomerular basement membrane (GBM)