ADH, RAAS and potassium

ADH (vasopressin) is made in the supraoptic and paraventricular nuclei of the hypothalamus and released from the posterior pituitary. Its main trigger is a rise in plasma osmolality, sensed by hypothalamic osmoreceptors, which respond to changes of 1–2%. A large fall in blood volume or pressure (more than about 5–10%) also releases ADH and overrides osmolality, which is why hypovolemic patients retain water even when their sodium is already low. Nausea, pain and many drugs release it too.

How the kidney handles water. About two-thirds of filtered water is reabsorbed with sodium in the proximal tubule whatever the body needs. The thick ascending limb then pumps NaCl out without water: this dilutes the tubular fluid (to roughly 100 mOsm/kg) and, through countercurrent multiplication, builds a medullary interstitium of up to about 1200 mOsm/kg. Whether that dilute fluid leaves as dilute urine or is concentrated depends only on whether the collecting duct is permeable to water, which is what ADH decides. Urine osmolality can therefore range from about 50 to 1200 mOsm/kg: a low value means ADH is absent or ignored, a high one means it is acting.

ADH binds V2 receptors on collecting-duct principal cells. Through cAMP it inserts aquaporin-2 channels into the luminal membrane, and water flows out of the tubule into the concentrated medullary interstitium. Urine becomes concentrated; the body keeps free water, which lowers plasma osmolality and sodium. On V1 receptors in arterioles it causes vasoconstriction.

The renin–angiotensin–aldosterone system responds to low renal perfusion, low NaCl at the macula densa and sympathetic (β1) stimulation. Renin cleaves angiotensinogen to angiotensin I; ACE converts it to angiotensin II, which constricts arterioles, stimulates thirst and ADH, increases proximal sodium reabsorption and releases aldosterone. Aldosterone acts on principal cells (more ENaC channels and Na⁺/K⁺-ATPase): sodium is reabsorbed and K⁺ and H⁺ are secreted in exchange. Water follows the sodium, so aldosterone expands the ECF without changing sodium concentration.

In diabetes insipidus the kidney cannot keep free water. In central DI the pituitary does not release ADH (head trauma, pituitary or hypothalamic surgery, tumors such as craniopharyngioma, infiltrative disease, idiopathic). In nephrogenic DI ADH is present but the collecting duct does not respond: lithium, hypercalcemia, hypokalemia (vacuolar nephropathy), demeclocycline, or inherited V2-receptor or aquaporin-2 mutations. Either way the patient passes large volumes of dilute urine (polyuria), plasma osmolality and sodium rise (pure water loss, TBNa⁺/↓↓TBW), and thirst drives polydipsia. With free access to water the sodium may stay high-normal; without it, hypernatremia develops quickly.

The water deprivation test asks two questions in order. First, withhold water: does the urine concentrate by itself? If it does, the ADH axis works, and the patient was simply drinking too much (primary polydipsia). If urine stays dilute (< 300 mOsm/kg) while plasma osmolality rises, the patient has DI. Second, give desmopressin (synthetic ADH): if the urine now concentrates, the kidney could respond and ADH was missing (central); if it stays dilute, the kidney cannot respond (nephrogenic).

In SIADH, ADH is released although plasma osmolality is low and volume is not reduced. The lecture names the commonest cause it emphasizes: ectopic ADH from small cell carcinoma of the lung. Others are CNS disease (meningitis, hemorrhage, trauma), lung disease (pneumonia, tuberculosis), drugs (SSRIs, carbamazepine, cyclophosphamide, vincristine) and postoperative pain and nausea.

Primary (psychogenic) polydipsia produces hyponatremia the other way: the patient drinks more than the kidney can excrete, while ADH is correctly switched off. The urine is therefore maximally dilute, urine osmolality < 100 mOsm/kg. The single number that separates the two is the urine osmolality: above 100 means ADH is acting (SIADH, or ADH released by low volume); below 100 means it is not.

Brain cells defend their volume. Over about 48 hours of hyponatremia they export potassium, chloride and organic osmolytes (glutamine, taurine, myo-inositol), so they shrink back toward normal despite the dilute ECF. Re-importing those osmolytes takes days. If the serum sodium is then raised quickly, the ECF becomes hypertonic relative to the adapted cells, water leaves them, and oligodendrocytes in the densely packed white matter of the central pons are injured: osmotic demyelination syndrome (central pontine myelinolysis). Signs appear 2–6 days after the correction: dysarthria, dysphagia, diplopia, spastic quadriparesis, falling consciousness, and sometimes a locked-in state.

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In chronic hypernatremia the reverse adaptation happens: brain cells accumulate osmolytes (sometimes called idiogenic osmoles) to hold on to water. Lower the sodium too fast with free water and water rushes into those cells: cerebral edema, seizures and herniation, most often in children.

About 98% of body potassium is inside cells (about 140 mEq/L, against 3.5–5.0 mEq/L in plasma), held there by the Na⁺/K⁺-ATPase. That steep gradient sets the resting membrane potential of nerve and muscle. Because so little potassium is outside, a small shift of intracellular K⁺ across the membrane changes the serum level a lot, before any potassium has been gained or lost.

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Hypokalemia is serum K⁺ < 3.5 mEq/L. Causes: low intake (rarely alone), GI loss (diarrhea, laxatives), renal loss (loop and thiazide diuretics, mineralocorticoid excess, vomiting through secondary aldosteronism and alkalosis, hypomagnesemia, some renal tubular acidoses) and shift into cells (insulin, β2-agonists, alkalosis).

Low extracellular K⁺ makes the resting membrane potential of skeletal and smooth muscle more negative (hyperpolarized), so it is harder to fire: muscle weakness, fatigue, cramps, constipation or ileus. In the heart, repolarization is delayed: the T wave flattens, the ST segment sags and a U wave appears after the T wave; arrhythmias follow, especially with digoxin. In the kidney, severe hypokalemia vacuolates collecting-duct cells and makes them resistant to ADH (polyuria, a nephrogenic DI). Rhabdomyolysis can occur during exertion.

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Hyperkalemia is serum K⁺ > 5 mEq/L. Causes: decreased renal excretion (kidney failure; low aldosterone from Addison disease, ACE inhibitors, angiotensin receptor blockers, spironolactone), shift out of cells (acidosis, insulin deficiency, β-blockers, digoxin toxicity), tissue breakdown (rhabdomyolysis, tumor lysis, hemolysis, crush injury) and increased intake when excretion is impaired. Rule out pseudohyperkalemia first: a hemolyzed sample, fist clenching or very high platelet or white cell counts release K⁺ in the tube.

High extracellular K⁺ makes the resting potential less negative (partial depolarization). That sounds excitatory, but sustained depolarization inactivates the fast sodium channels, so cells become less excitable: muscle weakness and depressed or absent tendon reflexes. In the heart, potassium conductance rises and repolarization speeds up, giving tall, narrow, peaked T waves. As K⁺ rises further, P waves flatten, PR and QRS widen, the complex merges into a sine wave, and the heart stops in diastole (severe hyperkalemia, about 7–8 mEq/L).

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