Renal artery → branches down → afferent arteriole carries blood INTO the glomerulus.
Key job: Deliver blood at the RIGHT pressure for filtration. Too little pressure = no filtration. Too much = glomerular damage.
Who controls its width?
— Prostaglandins DILATE it → keeps blood flowing in, especially when BP drops (autoregulation). This is why prostaglandins are "renal protective."
— NSAIDs BLOCK prostaglandins → afferent CONSTRICTS → less blood enters → GFR drops. This is why NSAIDs cause AKI in dehydrated patients and are avoided in CKD.
Blood is pushed through the glomerular capillary tuft inside Bowman's capsule. Hydrostatic pressure forces fluid out of blood into Bowman's space. This fluid = ultrafiltrate (= plasma minus proteins).
What gets filtered? Everything small: water, Na⁺, K⁺, glucose, amino acids, HCO₃⁻, urea, creatinine, uric acid, PO₄, drugs. NOT filtered: albumin, globulins, RBCs (too big).
GFR = ~120 mL/min = ~180 L/day. You filter your ENTIRE blood volume 60 times/day. 99% is reabsorbed — only 1-2L becomes urine.
What maintains filtration pressure? The balance between afferent (in) and efferent (out). The efferent arteriole is the EXIT — its constriction is critical:
— Angiotensin II CONSTRICTS the efferent → blood can't leave easily → pressure BUILDS inside glomerulus → GFR maintained even when BP is low. This is a rescue mechanism.
— ACEi/ARB BLOCK Ang II → efferent DILATES → pressure inside glomerulus DROPS → GFR falls acutely.
But wait — this drop in pressure is actually GOOD long-term. High glomerular pressure damages the filtration membrane (especially in DM). By LOWERING it, ACEi/ARB protect the kidney from hyperfiltration damage.
The ultrafiltrate (180L/day) enters the proximal convoluted tubule. PCT's job is simple: grab back everything valuable before it's lost.
What comes back and HOW:
— Na⁺ (65%): Via NHE3 (Na⁺/H⁺ exchanger) on apical side. Na⁺ in, H⁺ out. The H⁺ that goes out combines with filtered HCO₃⁻ in the lumen → H₂CO₃ → CO₂ + H₂O (via carbonic anhydrase IV on brush border). CO₂ diffuses back into cell → carbonic anhydrase II regenerates HCO₃⁻ inside → HCO₃⁻ exits basolateral into blood. Net result: ALL filtered HCO₃⁻ is reclaimed.
— Glucose (100%): Via SGLT2 (90%) in early PCT and SGLT1 (10%) in late PCT. Cotransported WITH Na⁺. Normally ALL glucose reabsorbed — none in urine.
— Amino acids (100%): Multiple specific cotransporters with Na⁺.
— PO₄ (85%): Na⁺/PO₄ cotransporter (NaPi-IIa). PTH INHIBITS this → more PO₄ wasted in urine (why PTH lowers serum PO₄).
— Uric acid (90%): Via URAT1 on apical membrane. Reabsorbed back into blood. Also secreted via OAT transporters. Net = 90% reabsorbed.
— Water (65%): Follows Na⁺ passively (osmotic gradient). PCT is freely water-permeable — no hormone needed.
When SGLT2i (dapagliflozin/empagliflozin) blocks SGLT2:
1. Glucose stays in lumen → glucosuria (HbA1c drops 0.5-0.8%)
2. Na⁺ that would have cotransported with glucose ALSO stays in lumen → natriuresis → osmotic diuresis → ↓BP, ↓preload
3. More Na⁺ reaches macula densa (at junction of LOH and DCT) → macula densa senses "too much Na⁺ arriving" → triggers tubuloglomerular feedback (TGF) → afferent arteriole CONSTRICTS → intraglomerular pressure DROPS → renoprotection
4. Changed intracellular dynamics at PCT → URAT1 interaction disrupted → uric acid excretion increases → serum urate drops → gout protective
When PCT globally fails = Fanconi syndrome:
Everything PCT reabsorbs is lost: glucose + amino acids + PO₄ + HCO₃⁻ + uric acid all appear in urine. Causes: multiple myeloma (light chains damage PCT), ifosfamide, tenofovir, Wilson's disease. Think Fanconi when you see "glycosuria with normal blood glucose + aminoaciduria + phosphaturia + type 2 RTA" together.
RTA Type 2 (proximal): Isolated HCO₃⁻ reabsorption failure at PCT. Carbonic anhydrase doesn't work → HCO₃⁻ floods downstream → lost in urine → metabolic acidosis. The HCO₃⁻ loss carries Na⁺ with it → more Na⁺ delivered to CD → more K⁺ secreted at CD → hypoK⁺. Urine pH: initially >5.5 when serum HCO₃⁻ is above the new (lower) threshold, but once serum HCO₃⁻ drops below threshold, distal acidification works → pH can drop <5.5. This is why RTA2 urine pH is "variable" — unlike RTA1 which is ALWAYS >5.5.
The filtrate descends into the Loop of Henle — a hairpin turn that dips deep into the medulla and comes back up.
Descending limb: Thin. Water-PERMEABLE, solute-impermeable. Water leaves (drawn out by the hypertonic medullary interstitium) → fluid becomes concentrated as it descends.
Ascending limb (thick): The action segment. Water-IMPERMEABLE. NKCC2 transporter (Na⁺/K⁺/2Cl⁻) on the apical membrane actively pumps Na⁺, K⁺, and 2Cl⁻ OUT of the lumen into the cell, then into the interstitium.
Why this matters:
1. Na⁺/K⁺/2Cl⁻ removal from the lumen → makes the INTERSTITIUM hypertonic (this is what creates the medullary concentration gradient that AVP/ADH will later use at the collecting duct to concentrate urine)
2. K⁺ that enters the cell via NKCC2 recycles back into the lumen via ROMK channel → creates a lumen-positive voltage → this drives paracellular (between cells) reabsorption of Ca²⁺ and Mg²⁺
3. Fluid leaving the ascending limb is now DILUTE (solute removed, water kept) → "diluting segment"
Furosemide blocks NKCC2:
— Na⁺/K⁺/2Cl⁻ stay in lumen → massive natriuresis (most potent diuretic)
— No K⁺ recycling → no lumen-positive voltage → Ca²⁺ and Mg²⁺ NOT reabsorbed → lost in urine
— More Na⁺ delivered to CD → exchanged for K⁺ at ENaC/ROMK → hypoK⁺
— Volume loss → contraction alkalosis + H⁺/K⁺ loss → metabolic alkalosis
— Volume depletion → PCT ramps up reabsorption of everything including uric acid → hyperuricemia
Bartter syndrome = born without working NKCC2:
Exact same picture as chronic furosemide: hypoK⁺ + metabolic alkalosis + hypercalciuria + polyuria. Severe — presents in neonates/infants. Polyhydramnios in utero (fetal polyuria). Bartter = Big (severe), Baby, Big loop.
Specialized cells at the junction between ascending LOH and DCT. They sense Na⁺/Cl⁻ concentration in the tubular fluid passing by.
Low Na⁺ at macula densa (= "not enough filtered, kidneys underperfused") → signals JG cells on afferent arteriole → RENIN released → starts RAAS cascade → Ang II → efferent constriction + aldosterone → save Na⁺ and water.
High Na⁺ at macula densa (= "too much filtered") → tubuloglomerular feedback (TGF) → afferent arteriole CONSTRICTS → GFR drops → less filtered → protection from hyperfiltration.
Only 5% of Na⁺ reabsorption happens here via NCC (Na⁺/Cl⁻ cotransporter). Sounds trivial — but the SIDE EFFECTS of blocking it are enormous.
Ca²⁺ reabsorption — the thiazide paradox:
At DCT, Ca²⁺ enters the cell via TRPV5 channel (apical), shuttled by calbindin, exits via NCX (Na⁺/Ca²⁺ exchanger, basolateral) and Ca²⁺-ATPase.
When thiazide blocks NCC → less Na⁺ enters cell → intracellular Na⁺ drops → the basolateral Na⁺/Ca²⁺ exchanger works HARDER (more Na⁺ in, more Ca²⁺ out) → cell Ca²⁺ drops → more Ca²⁺ pulled in from lumen via TRPV5 → net: MORE Ca²⁺ reabsorbed.
This is why thiazide causes mild hypercalcemia and is used to TREAT idiopathic hypercalciuria (recurrent kidney stones). Opposite of furosemide which WASTES Ca²⁺.
Thiazide side effects — the full list mapped to mechanism:
— HypoNa⁺: #1 drug cause of hyponatremia, especially in elderly. Mechanism debated: impaired dilution (blocks NCC in diluting segment) + continued water intake + possible AVP-like effect.
— HypoK⁺: More Na⁺ delivered to CD → exchanged for K⁺ via ROMK.
— Hyperuricemia: Thiazide-induced volume contraction → ↑PCT urate reabsorption. Also: competition at OAT secretory pathway. → precipitates gout.
— HypoMg²⁺: Impaired Mg²⁺ reabsorption at DCT (mechanism less clear).
— HyperCa²⁺: As explained above (paradoxical).
— Hyperglycemia: HypoK⁺ impairs insulin secretion.
— Hyperlipidemia: Mild, mechanism unclear.
Gitelman syndrome = born without working NCC:
= "genetic thiazide." Milder than Bartter. Adolescent/adult onset. Triad: hypoK⁺ + hypoMg²⁺ (the distinguishing feature) + hypocalciuria (like thiazide saves Ca²⁺). Gitelman = Gentle, low maGnesium.
Everything upstream was mostly autonomous — transporters doing their job. The CD is different: it waits for hormonal instructions before deciding what to do with the remaining fluid.
MASTER 1 — ALDOSTERONE (controls Na⁺/K⁺ balance)
Source: zona glomerulosa of adrenal cortex. Mnemonic: "GFR" = Glomerulosa (mineralocorticoid/salt), Fasciculata (glucocorticoid/sugar), Reticularis (androgen/sex). "Deeper you go, sweeter it gets" — salt → sugar → sex.
Stimuli: Angiotensin II (from RAAS — primary), Hyperkalemia (direct — independent of RAAS, the safety valve), ACTH (minor).
What it does at CD principal cell:
Binds mineralocorticoid receptor (MR) → nuclear → transcription → upregulates:
1. ENaC (epithelial Na⁺ channel, apical) → Na⁺ reabsorbed from lumen
2. ROMK (renal outer medullary K⁺ channel, apical) → K⁺ secreted into lumen
3. Na⁺/K⁺-ATPase (basolateral) → drives the gradient
4. H⁺-ATPase → H⁺ secretion (minor contribution → metabolic alkalosis when excess aldo)
Net: Na⁺ IN, K⁺ OUT, H⁺ OUT → volume expansion + hypoK⁺ + metabolic alkalosis
Too much aldosterone (Conn's syndrome): Adrenal adenoma → autonomous aldo → Na⁺ retention → resistant HTN + hypoK⁺ + metabolic alkalosis. Renin is SUPPRESSED (volume-expanded). Screen: aldosterone:renin ratio (ARR) >30. Indian: underdiagnosed cause of secondary HTN.
Too little aldosterone (= RTA Type 4): ENaC/ROMK underactive → can't secrete K⁺ or H⁺ → hyperK⁺ + mild metabolic acidosis. But α-intercalated cells still work → can still acidify urine → pH <5.5 (this distinguishes from Type 1). The problem is ↓NH₃ buffer production (needs aldosterone signal), not H⁺ pump failure.
#1 cause: DM nephropathy (damages JG cells → ↓renin → ↓Ang II → ↓aldo = "hyporeninemic hypoaldosteronism"). Also caused by ACEi/ARB (↓Ang II → ↓aldo), spironolactone (blocks MR), NSAIDs (↓renin).
Commonest RTA in clinical practice. Every DM patient on ACEi with mild hyperK⁺ = think Type 4.
Aldosterone escape: In CHF and cirrhosis, RAAS is chronically activated → aldo → Na⁺ retention. But after a few days, ANP/BNP rise and cause "escape" from Na⁺ retention. However, K⁺ wasting does NOT escape → persistent hypoK⁺ risk. This is why spironolactone works in CHF (RALES trial — 30% ↓mortality) and cirrhotic ascites — it blocks the aldo that continues to cause harm even after Na⁺ escape.
MASTER 2 — AVP/ADH/VASOPRESSIN (controls water balance)
Same molecule, three names: Arginine Vasopressin (AVP) = Antidiuretic Hormone (ADH) = Vasopressin. 9 amino acid peptide.
Source: Synthesized in supraoptic nucleus (mainly) + paraventricular nucleus of hypothalamus. Transported down axons. Stored in posterior pituitary.
Release triggers:
— Osmotic: ↑serum osmolality >285 mOsm/kg → osmoreceptors in hypothalamus fire → AVP released. Steep response above 290.
— Non-osmotic: ↓blood volume (baroreceptors in carotid/aorta — this OVERRIDES the osmostat, which is why hypovolemic patients retain water even if hypo-osmolar), pain, nausea, stress, Ang II, drugs.
— Ang II stimulates AVP release — this links RAAS to water retention. In CHF: ↑RAAS → ↑Ang II → ↑AVP → water retention → dilutional hypoNa⁺. This is why CHF patients are hyponatremic.
Receptors:
— V1a (vascular smooth muscle) → Gq → vasoconstriction. This is the "vasopressin" action. Used therapeutically: vasopressin drip in septic shock (V1a-mediated vasoconstriction).
— V2 (CD principal cell, basolateral) → Gs → cAMP → PKA → aquaporin-2 (AQP2) insertion into apical membrane → water channels open → water reabsorbed from lumen → concentrated urine.
— V1b/V3 (anterior pituitary) → ACTH release (stress response link).
Thirst: Activates at ~295 mOsm/kg (HIGHER than AVP threshold of 285). AVP is the first defense; thirst is backup. This is why elderly with impaired thirst are vulnerable to hypernatremia.
AVP disorders at the CD — the decision tree:
1. SIADH (too much AVP): AQP2 always ON → water pours back in → dilutes serum → euvolemic hyponatremia. Diagnosis: serum Na⁺ <135, serum osm <275, urine osm >100 (inappropriately concentrated), urine Na⁺ >40, euvolemic (no edema, no dehydration). Causes: SCLC (ectopic AVP), pneumonia, CNS disorders (meningitis, SAH, stroke), drugs (SSRIs, carbamazepine, cyclophosphamide, ecstasy). Rx: fluid restriction first-line → tolvaptan (V2 antagonist, "aquaretic") if refractory → 3% hypertonic saline if seizures/severe. Correct ≤8-10 mEq/L/24h or risk ODS (osmotic demyelination = central pontine myelinolysis → locked-in syndrome).
2. Central DI (no AVP production): Posterior pituitary damaged → no AVP → AQP2 never inserted → water NOT reabsorbed → massive dilute polyuria (>3L/day, urine osm <300). Causes: pituitary surgery (#1), craniopharyngioma, Sheehan syndrome, autoimmune, idiopathic. Water deprivation test: urine does NOT concentrate. Desmopressin (DDAVP) test: urine DOES concentrate → proves kidney is fine, problem is no AVP. Rx: desmopressin (synthetic V2 agonist, intranasal or oral).
3. Nephrogenic DI (kidney ignores AVP): V2 receptor or AQP2 defect → same polyuria/polydipsia. Desmopressin test: urine does NOT concentrate → kidney is the problem. Causes: lithium (#1 drug — accumulates in CD via ENaC, damages AQP2 signaling), hypercalcemia, chronic hypokalemia, sickle cell (medullary damage). Rx: remove cause + thiazide (paradoxical antidiuresis — volume depletion → PCT reabsorbs more → less delivered to CD → less urine) + amiloride (blocks ENaC → blocks lithium entry into cell, specific for lithium-induced).
α-Intercalated cells (the acid secretors):
These sit alongside principal cells in the CD. Their job: secrete H⁺ via H⁺-ATPase (apical) → acidify urine. Simultaneously, HCO₃⁻ exits basolateral (via AE1/Band 3) into blood → regenerates buffer.
RTA Type 1 (distal): These cells fail → cannot secrete H⁺ → urine stays alkaline (pH >5.5 — THE diagnostic clue). Systemic acidosis accumulates. K⁺ is wasted (H⁺ can't compete for secretion → K⁺ secreted instead → hypoK⁺). Alkaline urine → calcium phosphate precipitates → nephrocalcinosis + kidney stones. Causes: Sjögren's, SLE, amphotericin B, toluene/glue sniffing, medullary sponge kidney. Indian: Sjögren's underdiagnosed in South India. Amphotericin for mucormycosis or kala-azar → iatrogenic Type 1.
RAAS pathway (sequential):
↓ Renal perfusion / ↓ Na⁺ at macula densa / ↑ sympathetic → JG cells (afferent arteriole) release RENIN
→ Renin cleaves angiotensinogen (made by liver, always circulating) → Angiotensin I (inactive)
→ ACE (angiotensin-converting enzyme, mainly in lung endothelium) converts Ang I → Angiotensin II (active)
→ Ang II does 6 things: (1) vasoconstriction, (2) aldosterone release from adrenal, (3) efferent arteriole constriction, (4) AVP/ADH release, (5) thirst stimulation, (6) sympathetic activation
→ Aldosterone → CD → ENaC → Na⁺ retention + K⁺ excretion
ACE also degrades bradykinin. Block ACE → bradykinin accumulates → cough (15-20% of patients), angioedema (rare but dangerous). This is why ARBs (block AT1 receptor, don't affect bradykinin) don't cause cough. This is also why you need a 36-hour washout from ACEi before starting ARNi — sacubitril ALSO increases bradykinin (via neprilysin inhibition) → double bradykinin → angioedema risk.
Natriuretic Peptide System (NPS) — the counter-RAAS:
Atrial stretch → ANP (atrial natriuretic peptide). Ventricular stretch → BNP (B-type/brain natriuretic peptide).
ANP/BNP → natriuresis + vasodilation + ↓aldosterone + ↓ADH = exact opposite of RAAS.
Problem: an enzyme called neprilysin rapidly degrades ANP/BNP → RAAS wins.
Solution: Sacubitril inhibits neprilysin → ANP/BNP SURVIVE → enhanced counter-RAAS effect.
ARNi = Sacubitril + Valsartan (Entresto):
Dual mechanism: sacubitril (↑NPS) + valsartan (↓RAAS) = simultaneous brake on RAAS + boost to NPS.
Trial: PARADIGM-HF (2014) — sacubitril/valsartan vs enalapril in HFrEF (EF ≤40%). 20% ↓ CV death + HF hospitalization. Stopped early for benefit.
Indication: HFrEF, NYHA II-IV, replacing ACEi/ARB.
36-hour ACEi washout rule. ARB with ARNi = fine (valsartan IS the ARB component).
Side effects: hypotension (dual vasodilation — careful in low-BMI Indian patients), hyperK⁺ (↓aldo), angioedema (if ACEi overlap).
Indian: young HFrEF from RHD + DM cardiomyopathy. Cost barrier but PMJAY may cover.