Step 1 · Renal

Sodium, Potassium & Volume Regulation

Name: Sodium, Potassium & Volume Regulation
Creator: Veli Bakalov, MD

RAAS, ADH, and ANP set the balance; SIADH and DI are the mirror-image failures

Renal·Physiology·5 min read·9 high-yield points·Reviewed by Veli Bakalov, MD @HemeOncBuddy

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Renin (JG cells) is released for ↓ renal perfusion pressure, ↓ NaCl at the macula densa, and β1 stimulation; ACE in the lung converts angiotensin I to angiotensin II.
Angiotensin II: systemic vasoconstriction, efferent constriction (↑ GFR and FF), aldosterone and ADH release, ↑ PCT Na⁺/H⁺ exchange, thirst; ACE inhibitors raise bradykinin (cough, angioedema).
Aldosterone (zona glomerulosa; stimulated by angiotensin II and hyperkalemia) raises ENaC and Na⁺/K⁺-ATPase activity; excess (Conn syndrome) = hypertension, hypokalemia, metabolic alkalosis.
ADH responds mainly to ↑ plasma osmolality (and large volume loss): V2 → aquaporin-2 water reabsorption, V1 → vasoconstriction; ANP/BNP from stretched atria/ventricles cause natriuresis, afferent dilation, and ↓ renin and aldosterone.
K⁺ shifts out of cells with acidosis, insulin deficiency, β-blockers, digoxin, cell lysis, hyperosmolality, and succinylcholine; it shifts in with alkalosis, insulin, β2-agonists, and hypothermia.
Hyperkalemia with ECG changes: calcium gluconate first to stabilize the myocardium, then insulin + glucose and albuterol to shift K⁺ into cells, then removal.
Hyponatremia: check serum osmolality, then volume status (hypovolemic: GI loss, diuretics; euvolemic: SIADH, hypothyroidism, adrenal insufficiency; hypervolemic: heart failure, cirrhosis, nephrotic syndrome); FENa below 1% = volume-avid state.
Correct chronic hyponatremia by no more than ~8–10 mEq/L per 24 h to avoid osmotic demyelination; correcting hypernatremia too fast causes cerebral edema.
SIADH = euvolemic hyponatremia with inappropriately concentrated urine (osmolality above 100) and urine Na⁺ above 20–40; DI = dilute polyuria; desmopressin raises urine osmolality more than 50% in central but not nephrogenic DI (lithium, hypercalcemia).

The renin-angiotensin-aldosterone system

Renin. Juxtaglomerular (granular) cells of the afferent arteriole release renin when renal perfusion pressure falls, when the macula densa senses less NaCl, and with β1-sympathetic stimulation. Renin cleaves angiotensinogen (made by the liver) to angiotensin I, and ACE, mainly in the pulmonary endothelium, converts it to angiotensin II.

Low BP, low NaCl, β1 toneRenin from JG cells
Angiotensinogen → angiotensin IRenin
Angiotensin I → angiotensin IIACE (lung)
Angiotensin II actsVasoconstriction, aldosterone, ADH, thirst

The RAAS cascade

Angiotensin II actions.

Systemic arteriolar vasoconstriction (AT1 receptors) raises blood pressure.
Efferent arteriolar constriction raises GFR and filtration fraction.
Aldosterone release from the adrenal zona glomerulosa.
ADH release and thirst.
Increased PCT Na⁺/H⁺ exchange (the basis of contraction alkalosis).

ACE also degrades bradykinin, so ACE inhibitors raise bradykinin and cause cough and angioedema; ARBs block AT1 receptors instead and rarely cause cough.

Aldosterone, ADH, and natriuretic peptides

Aldosterone. The zona glomerulosa releases it in response to angiotensin II and hyperkalemia. On collecting duct principal cells it increases ENaC and Na⁺/K⁺-ATPase activity, retaining Na⁺ and water while secreting K⁺ and H⁺. Excess (Conn syndrome, usually an aldosterone-secreting adenoma) causes hypertension, hypokalemia, and metabolic alkalosis with suppressed renin.

ADH (vasopressin). Made in the hypothalamus (supraoptic and paraventricular nuclei) and released from the posterior pituitary, mainly in response to rising plasma osmolality and also to large drops in blood volume. V2 receptors on the collecting duct insert aquaporin-2 for water reabsorption and concentrated urine; V1 receptors cause vasoconstriction.

ANP and BNP. Released by atrial (ANP) and ventricular (BNP) myocytes stretched by volume overload. Acting through cGMP, they dilate the afferent arteriole (raising GFR), promote natriuresis, and inhibit renin and aldosterone. BNP levels help diagnose heart failure.

Hormones of volume and water balance

Hormone	Main stimulus	Key renal action	Net result
Angiotensin II	↓ Renal perfusion, ↓ macula densa NaCl, β1 (via renin)	Efferent constriction; ↑ PCT Na⁺/H⁺ exchange	↑ BP; GFR preserved
Aldosterone	Angiotensin II, hyperkalemia	↑ ENaC and Na⁺/K⁺-ATPase in principal cells	Na⁺ retention; K⁺ and H⁺ loss
ADH	↑ Plasma osmolality; large ↓ volume	V2 → aquaporin-2	Free water retention
ANP/BNP	Atrial/ventricular stretch	Afferent dilation, natriuresis; ↓ renin and aldosterone	Na⁺ and water loss

Potassium balance and shifts

Where K⁺ lives. About 98% of body K⁺ is intracellular, held there by the Na⁺/K⁺-ATPase, so small shifts across cell membranes change serum K⁺ quickly. Long-term balance depends on aldosterone-driven secretion by principal cells.

Transcellular potassium shifts

Factor	K⁺ moves	Mechanism
Acidosis / alkalosis	Out / in	H⁺ and K⁺ exchange across cell membranes
Insulin deficiency / insulin	Out / in	Insulin stimulates Na⁺/K⁺-ATPase
β-blockers / β2-agonists (albuterol)	Out / in	β2 stimulation drives Na⁺/K⁺-ATPase
Digoxin	Out	Blocks Na⁺/K⁺-ATPase
Cell lysis	Out	Releases intracellular K⁺ (rhabdomyolysis, tumor lysis, hemolysis)
Hyperosmolality	Out	Water leaves cells and drags K⁺ with it
Succinylcholine	Out	Depolarizing block releases K⁺ from muscle
Hypothermia	In	Intracellular shift

Treating hyperkalemia. Peaked T waves or arrhythmias call for membrane stabilization first, then shifting, then removal:

Calcium gluconateStabilizes the cardiac membrane at once; does not lower K⁺
Insulin + glucose, albuterolShift K⁺ into cells
Remove K⁺Diuretics, binders, or dialysis

Hyperkalemia emergency

Sodium, water, and volume

Two different questions. ECF volume tracks total-body Na⁺ content, whereas serum [Na⁺] reflects water balance. Volume is judged by exam (skin turgor, JVP, edema, orthostatic vital signs) and urine studies: a fractional excretion of Na⁺ (FENa) <1% signals a volume-avid, prerenal state, and a urine Na⁺ <20 mEq/L suggests hypovolemia.

Approach to hyponatremia. First check serum osmolality: hypertonic hyponatremia (hyperglycemia, mannitol) and isotonic pseudohyponatremia (severe hyperlipidemia or hyperproteinemia) are not true water excess. True hypotonic hyponatremia is then sorted by volume status:

Hypovolemic: diarrhea, vomiting, diuretics (especially thiazides); primary adrenal insufficiency with aldosterone loss also fits here.
Euvolemic: SIADH, hypothyroidism, glucocorticoid deficiency (adrenal insufficiency), primary polydipsia.
Hypervolemic: heart failure, cirrhosis, nephrotic syndrome, where low effective circulating volume drives ADH and RAAS.

Correct slowly, both ways. Brain cells adapt to chronic hyponatremia by shedding osmolytes, so raising Na⁺ faster than ~8–10 mEq/L per 24 h shrinks them and causes osmotic demyelination (central pontine myelinolysis): dysarthria, dysphagia, quadriparesis. In chronic hypernatremia the brain has gained osmolytes, so lowering Na⁺ too fast pulls water in and causes cerebral edema.

SIADH vs diabetes insipidus

SIADH. Excess ADH causes euvolemic hypotonic hyponatremia with low serum osmolality, inappropriately concentrated urine (urine osmolality >100, often >300 mOsm/kg), and urine Na⁺ >20–40 mEq/L. Causes include small cell lung cancer (ectopic ADH), CNS disease, pulmonary disease, and drugs (carbamazepine, SSRIs, cyclophosphamide). Treat with fluid restriction and salt, then V2 antagonists (vaptans) or demeclocycline.

Diabetes insipidus. Too little ADH (central DI: pituitary surgery, head trauma, tumors) or renal resistance to it (nephrogenic DI: lithium, hypercalcemia) produces large volumes of dilute urine, polyuria, polydipsia, and hypernatremia when water intake cannot keep up.

Water deprivation test. Withholding water fails to concentrate the urine in either form of DI (it does in primary polydipsia). Desmopressin then separates them: urine osmolality rises >50% in central DI but barely changes in nephrogenic DI.

SIADH vs diabetes insipidus

Feature	SIADH	Central DI	Nephrogenic DI
Defect	Too much ADH	Too little ADH	Renal ADH resistance
Serum Na⁺	↓	↑ or high-normal	↑ or high-normal
Urine	Concentrated, low volume	Dilute, high volume	Dilute, high volume
After desmopressin	Not used (worsens hyponatremia)	Urine osmolality ↑ >50%	Little change
Treatment	Fluid restriction, salt, vaptans, demeclocycline	Desmopressin	Thiazides; amiloride for lithium