Juxtaglomerular apparatus

What it normally does

• Granular cells (juxtaglomerular cells) in the wall of the incoming arteriole (afferent arteriole) store renin and release it in response to three main stimuli: pressure inside that arteriole falls, sympathetic nerves fire on their beta-1 receptors, or the tubule beside them delivers less salt.

  the kidney reacts to its own perfusion pressure, not to whole-body volume — so a kidney behind a narrowed artery screams for salt and pressure even when the patient is overloaded.

• Renin cuts angiotensinogen from the liver into angiotensin I; angiotensin converting enzyme (ACE), mostly on lung capillary lining, cuts that into angiotensin II. Angiotensin II constricts arterioles and tells the adrenal cortex (zona glomerulosa) to make aldosterone, which drives sodium reabsorption and potassium excretion in the late distal tubule and collecting duct.

  one enzyme released here raises blood pressure two ways — squeeze now, salt and water later — and blocking the cascade at any level tends to drop pressure and to raise potassium.

• Angiotensin II constricts the outgoing arteriole (efferent) harder than the incoming one, which holds pressure up inside the glomerulus. Locally made prostaglandins (PGE2, PGI2) keep the incoming arteriole open.

  when flow into the kidney falls, filtration is propped up by angiotensin II squeezing the exit and prostaglandins holding the entrance open — in a kidney already leaning on those two, removing either can make filtration fall sharply.

• The macula densa is a plaque of tubular cells at the end of the thick ascending limb, tasting the filtrate through the NKCC2 salt transporter. Too much salt arriving means the glomerulus above is over-filtering, so it releases ATP, rapidly broken down to adenosine, which constricts the incoming arteriole and turns filtration down (tubuloglomerular feedback). Too little salt means the opposite: dilate, and release renin.

  each nephron self-regulates, and a drug that changes salt delivery to this point tends to move filtration and renin whether or not that was the intention.

What goes wrong

• Renovascular hypertension (renal artery narrowing)← from “Granular cells (juxtaglomerular cells) in the …”

  Atherosclerosis narrows the renal artery, so pressure at the granular cells is low even though systemic pressure is high. They read this as shock and release renin continuously. Angiotensin II constricts everything and aldosterone holds onto sodium, pushing systemic pressure higher still — which never reaches the sensor behind the stenosis, so the loop never switches off.

  Low pressure at the sensor, high pressure everywhere else. Resistant hypertension plus a steep creatinine rise on an ACE inhibitor means think bilateral renal artery stenosis, or stenosis supplying a single functioning kidney — those are the situations where the whole kidney was living on angiotensin II.

  You would find: Blood pressure that will not come down on three agents, sudden pulmonary oedema without a new cardiac cause, or a creatinine that jumps more than 30% within a week or two of starting an ACE inhibitor. An abdominal bruit if you listen for it — specific but insensitive, so its absence proves nothing.

• Neurohormonal activation in heart failure← from “Renin cuts angiotensinogen from the liver into…”

  A failing left ventricle delivers less blood to the kidney. The granular cells sense the low perfusion and pour out renin. Angiotensin II raises afterload, so the weak ventricle has to push against more resistance, and aldosterone retains sodium and water, so preload rises too. Both drive fibrosis in the myocardium. The response evolved for haemorrhage, and applied to a failing pump it makes things worse.

  Low output is misread as low volume. Renin-angiotensin-aldosterone blockade in heart failure is disease-modifying, not just symptom relief. Two of the four foundational drug classes in HFrEF are RAAS blockade (an ACE inhibitor or ARNI, and a mineralocorticoid receptor antagonist); the other two are a beta blocker and an SGLT2 inhibitor. Loop diuretics relieve congestion but have not been shown to reduce mortality.

  You would find: Raised jugular venous pressure, ankle and sacral oedema, crackles at the lung bases, and low urinary sodium — the kidney is hoarding salt in a patient who is visibly overloaded.

• Primary aldosteronism← from “Renin cuts angiotensinogen from the liver into…”

  An adrenal adenoma or bilateral adrenal hyperplasia makes aldosterone without being asked. Sodium is retained and potassium dumped, blood pressure rises, and the resulting volume expansion and high perfusion pressure feed back on the granular cells and shut renin off. So aldosterone is high while renin is suppressed — the mirror image of the causes driven by the kidney's own under-perfusion, where renin runs high.

  Common, and commonly missed: figures range from about 5% of all hypertension upward, and an Australian primary care study reported it in around 14% of treatment-naive hypertensive patients. It is generally regarded as the commonest specifically treatable cause of secondary hypertension. High aldosterone plus suppressed renin puts the problem in the adrenal, not the kidney.

  You would find: Hypertension with a low or low-normal potassium, though potassium is normal in most cases, so normokalaemia does not exclude it. Diagnosed on a high aldosterone-to-renin ratio. The ratio is only interpretable under conditions that do not distort it: a mineralocorticoid antagonist or a potassium-wasting diuretic is the main offender and is usually withdrawn about four weeks beforehand, potassium is corrected first, and beta blockers, ACE inhibitors and sartans shift the ratio enough that a borderline result on them is repeated. A positive ratio is confirmed with a suppression test before anyone talks about surgery.

• Haemodynamic acute kidney injury (the triple whammy)← from “Angiotensin II constricts the outgoing arterio…”

  Three common drugs together dismantle glomerular pressure. A diuretic drops the volume arriving. An NSAID blocks prostaglandins, so the incoming arteriole cannot stay dilated. An ACE inhibitor or sartan removes angiotensin II, so the outgoing arteriole cannot stay constricted. Little is left holding pressure across the filter, and filtration falls off a cliff.

  Diuretic plus NSAID plus ACE inhibitor or sartan. Add an intercurrent gastroenteritis and it is one of the commonest avoidable causes of acute kidney injury in general practice — which is why sick-day advice about which drugs to hold matters more than any of them individually.

  You would find: Creatinine climbing within days of a new prescription in an otherwise stable patient, urine output falling, and a urine dipstick that is unremarkable — the kidney tissue is fine, the pressure across it is not.

• Diabetic kidney disease and glomerular hyperfiltration← from “The macula densa is a plaque of tubular cells …”

  High glucose is reabsorbed with sodium in the proximal tubule, so less sodium reaches the macula densa. It reads this as under-filtration and dilates the incoming arteriole. Pressure inside the glomerulus rises, filtration runs above normal for years, protein leaks through the strained barrier, and the sustained pressure scars the glomerulus.

  Hyperfiltration is the injury, not a sign of a healthy kidney. Diabetic and hypertensive kidney disease fall hardest on Aboriginal and Torres Strait Islander Australians, whose rates of treated end-stage kidney disease run several times the non-Indigenous rate and higher again in remote communities.

  You would find: Rising albumin-to-creatinine ratio on a spot urine, sometimes a supranormal eGFR early on, and a falling eGFR much later. A kidney health check — eGFR plus urine ACR — is recommended at least annually for adults with diabetes.

What we give, and how it works

Open a drug to see what it binds, what that does to the cell, and what you then see in the patient.