Proximal convoluted tubule
The workhorse of the nephron: it takes back about two thirds of everything the glomerulus filtered — salt, water, essentially all of the filtered glucose, most of the bicarbonate — before the fluid ever reaches the loop.
What it normally does
It reabsorbs in bulk, not in fine detail: roughly 65% of the filtered sodium and water. The whole operation is powered by one pump on the blood side of the cell that pushes sodium out (Na+/K+-ATPase), creating a low intracellular sodium that everything else rides on.
almost every uptake pathway on the brush border depends on that sodium gradient, directly (sodium-coupled carriers) or indirectly (the H+ gradient NHE3 sets up) — knock out the cell's energy supply and they fail together — and a drug that blocks reabsorption here loses much of its effect because the loop and distal tubule downstream simply take the sodium back.
All of the filtered glucose is normally reabsorbed here, about 90% of it by a sodium-glucose cotransporter in the first segment (SGLT2, low affinity but high capacity) and the rest by a higher-affinity, lower-capacity one further along in S3 (SGLT1). The system has a ceiling — it saturates once blood glucose passes roughly 10 to 11 mmol/L.
glucose appearing in the urine means either the blood level has overwhelmed a normal transporter, or the transporter itself is broken or blocked.
This is where filtered bicarbonate is reclaimed — around 80% of it. The cell secretes H+ into the lumen (sodium-hydrogen exchanger, NHE3); that H+ joins filtered bicarbonate to make CO2 and water under brush border carbonic anhydrase; the CO2 diffuses into the cell, where carbonic anhydrase runs the reaction backwards and the regenerated bicarbonate leaves across the basolateral membrane into the blood.
bicarbonate is not absorbed as a molecule, it is dismantled and rebuilt — so blocking the enzyme in the middle of that loop dumps bicarbonate into the urine and acidifies the blood.
The same brush border reclaims amino acids, phosphate, urate and small filtered proteins, and the cells are packed with mitochondria to pay for it. The straight segment running into the outer medulla (S3) sits in the region of the kidney with the lowest oxygen supply, alongside the medullary thick ascending limb, while still running a high ATP demand.
one cell, many jobs, one power source: poison or starve these cells and you lose glucose, amino acids, phosphate and bicarbonate simultaneously — and the S3 segment is among the first parts of the kidney to be injured when perfusion drops.
What goes wrong
- Glycosuria and osmotic diuresis← from “All of the filtered glucose is normally reabso…”
When blood glucose climbs past about 10 to 11 mmol/L, the filtered load exceeds what SGLT2 and SGLT1 can carry. The excess glucose stays in the tubular fluid and holds water with it osmotically, so the patient loses litres of urine plus the salt and potassium dissolved in it. This is why uncontrolled type 2 diabetes presents as thirst and passing urine all night, rather than as a number on a meter.
Filtered load beats transport maximum (threshold about 10 to 11 mmol/L) → glucose stays in the lumen → osmotic diuresis → polyuria, thirst, volume depletion.
You would find: Polyuria, nocturia and thirst, with glucose on the urine dipstick and a raised blood glucose. In a hyperglycaemic, dehydrated patient this same osmotic loss is what creates the huge fluid deficit. Type 2 diabetes and its complications fall disproportionately on Aboriginal and Torres Strait Islander communities, where rates of kidney failure are several times the national figure.
- Fanconi syndrome (generalised proximal tubule failure)← from “The same brush border reclaims amino acids, ph…”
Anything that cripples the energy supply of these cells — a drug, light chains from myeloma, copper in Wilson disease, cystine in children with cystinosis — drops ATP, the sodium pump slows, and the whole brush border fails at once. Glucose, amino acids, phosphate, bicarbonate, urate and small proteins all leak into the urine together. The phosphate loss is the one that shows up in bone, and it is compounded because the proximal tubule is also where 1-alpha-hydroxylase converts 25-hydroxyvitamin D to calcitriol: the patient loses phosphate and loses the hormone that would help them absorb more.
Everything leaks at once: glycosuria with normal blood glucose, aminoaciduria, hypophosphataemia, type 2 RTA, low urate. Adults — think drugs or myeloma. Children — think cystinosis.
You would find: Glucose on the dipstick with a normal blood glucose — once an SGLT2 inhibitor has been excluded from the medication list, that pairing points hard at the proximal tubule. Add low phosphate, low potassium, low bicarbonate, low urate, and bone pain or difficulty rising from a chair (osteomalacia in adults, rickets in children). Dipstick protein is often negative, because the proteins being lost are small and the stick detects albumin.
- Type 2 (proximal) renal tubular acidosis← from “This is where filtered bicarbonate is reclaime…”
The bicarbonate reclamation machinery is blocked or broken, so the tubule can only hold bicarbonate up to a lowered threshold. Bicarbonate spills into the urine until plasma bicarbonate falls to that new set point — commonly quoted as around 12 to 18 mmol/L — and then the leak stops. The bicarbonate carries sodium with it to the distal nephron, where the extra sodium delivery (helped by the volume depletion and secondary aldosterone that go with it) drives distal sodium reabsorption through ENaC, leaving the lumen more negative and driving potassium secretion — so the patient becomes hypokalaemic as well as acidotic.
Leaky reclamation, not failed acidification. Normal gap acidosis, hypokalaemia, plasma bicarbonate plateaus low, urine can still reach pH <5.5. Usually part of Fanconi syndrome rather than isolated.
You would find: A normal anion gap metabolic acidosis with a low potassium. Early on, and whenever plasma bicarbonate is above the tubule's threshold, the urine is alkaline; once plasma bicarbonate has dropped below that threshold the urine can acidify normally (pH under 5.5) — that is what separates it from distal (type 1) RTA, where the urine cannot be acidified below about pH 5.5 even under an acid load. Give bicarbonate and the potassium falls further.
- Acute tubular necrosis← from “The same brush border reclaims amino acids, ph…”
The S3 segment sits in the outer medulla with a high ATP demand and a marginal oxygen supply. Sepsis, haemorrhage, major surgery or sustained hypotension drop perfusion below what those cells survive; nephrotoxins (aminoglycosides, contrast, myoglobin from rhabdomyolysis) do the same by direct injury. Dead cells slough into the lumen, obstruct the tubule, and stop reabsorbing sodium — so the kidney fails and the urine sodium goes up rather than down.
Commonest cause of acute kidney injury arising in hospital. Ischaemic or toxic, S3 segment first. Muddy brown casts, FENa >2%, isosthenuric urine. No drug has been shown to reverse established ATN — the management is restoring perfusion, removing the toxin and supporting the patient while the epithelium regenerates.
You would find: Creatinine climbing over days after a septic or hypotensive episode, urine output falling, muddy brown granular casts on microscopy, and a fractional excretion of sodium above 2% — the opposite of the avid sodium retention of pre-renal failure (FENa under 1%). The FENa is only interpretable if the patient is not on a diuretic.
- Hyperuricaemia and gout← from “It reabsorbs in bulk, not in fine detail: roug…”
About 90% of filtered urate is taken back in the proximal tubule, largely by an exchanger that takes urate up from the lumen in exchange for an intracellular organic anion (URAT1). Anything that increases proximal reabsorption raises blood urate: volume depletion and diuretics, because more sodium and water reabsorbed here means more urate reabsorbed with it, and lactate or ketoacids from alcohol or starvation, which supply extra counter-anion and so pull more urate back into the cell. Once plasma urate stays high, monosodium urate crystallises in cooler peripheral joints.
Urate is largely a proximal tubule handling problem rather than an overproduction problem in most patients. Volume depletion and diuretics → more proximal reabsorption → higher urate → gout. The usual urate-lowering target in Australian practice is under 0.36 mmol/L (lower again with tophi).
You would find: A hot, exquisitely tender first metatarsophalangeal joint coming on overnight, often after alcohol, a diuretic or dehydration. Serum urate is usually raised — plasma is saturated somewhere around 0.40 to 0.42 mmol/L — though it can read normal or low during the attack itself, so a normal level does not exclude gout; joint aspiration showing negatively birefringent needle-shaped crystals is the definitive test. Gout is more common, earlier and more severe in Aboriginal and Torres Strait Islander people and in Māori and Pacific Islander communities in Australia, and is under-treated in all of them.
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.
- Binds
- SGLT2 in the S1/S2 brush border
- Which does
- Blocks sodium-coupled glucose uptake, so filtered glucose stays in the lumen. SGLT1 further along recaptures some of it, which is why only a fraction of the filtered glucose is actually excreted rather than all of it — and why these drugs do not by themselves cause hypoglycaemia: as blood glucose falls, so does the filtered load, and the effect switches itself off.
- So you see
- Glucose and the water it holds leave in the urine: HbA1c falls, weight drops a few kilograms, and the mild osmotic diuresis lowers blood pressure. Be honest about the big benefit — it is not the sugar. The extra sodium now reaching the macula densa restores tubuloglomerular feedback, constricting the afferent arteriole and taking pressure off the glomerulus. That happens at a different structure, and it is what protects the kidney and the failing heart.
- And the same mechanism causes
- You have deliberately put sugar in the urine, so you have fed the organisms that live in it — genital candidiasis (thrush in women, balanitis, more often in uncircumcised men) is the direct and common consequence, and the osmotic diuresis on top of it causes volume depletion and postural dizziness, especially in an older patient already on a diuretic.
- Handling
- The same tubuloglomerular feedback that protects the glomerulus produces a small expected dip in eGFR in the first weeks — that is the drug working, not the drug failing, and it plateaus and recovers. Glucose lowering depends on filtering glucose, so it fades as GFR falls, but the kidney and heart protection persists, which is why they are continued at eGFR levels where they no longer do much for the sugar.
Catches people out: Euglycaemic ketoacidosis. Losing glucose lowers insulin and pushes metabolism towards fat, so ketoacidosis can develop with a nearly normal blood glucose and get missed. These agents are therefore withheld during acute illness, prolonged fasting and around surgery — Australian Diabetes Society guidance sets the pre-operative withholding period — and in an unwell patient it is ketones, not the glucose, that answer the question.
- Binds
- Carbonic anhydrase — membrane-bound type IV facing the lumen and cytoplasmic type II inside the cell
- Which does
- Without the enzyme, filtered bicarbonate cannot be turned into CO2 to cross the membrane, and the cell cannot regenerate the H+ that NHE3 needs to secrete. Bicarbonate is stranded in the lumen and takes sodium and water with it.
- So you see
- An alkaline, bicarbonate-loaded urine and a falling plasma bicarbonate, with a modest diuresis that peters out within days because plasma bicarbonate reaches the new threshold and the loop and distal tubule reclaim the sodium. Say it plainly: this is a poor diuretic, used for what it does to acid-base rather than to volume.
- And the same mechanism causes
- The bicarbonate being dumped is the body's buffer, so the blood acidifies (normal anion gap metabolic acidosis) and the patient hyperventilates to compensate — which is exactly why the same drug helps at altitude — and the tingling in the fingers and around the mouth that patients report goes with that acidosis and hypocapnia rather than being an allergy.
- Handling
- The sodium and bicarbonate delivered downstream drive distal potassium secretion, so potassium falls — further still if a loop diuretic has already lowered it.
Catches people out: Carbonic anhydrase is not confined to the kidney. The same enzyme family in the ciliary body makes aqueous humour, which is why it lowers intraocular pressure, and it sits in taste buds, which is why patients say carbonated drinks taste flat or metallic. It is a non-antibiotic sulfonamide, and its diuretic effect self-limits once plasma bicarbonate reaches the new threshold.
- Binds
- Organic anion and organic cation transporters on the blood side of the cell — OAT1/OAT3 for tenofovir, OCT2 for cisplatin — which pull the drug in faster than the apical pumps can push it out
- Which does
- The drug accumulates inside the cell at concentrations the rest of the body never sees. Tenofovir depletes mitochondrial DNA through inhibition of DNA polymerase gamma; ifosfamide's metabolite chloroacetaldehyde and cisplatin injure mitochondria and DNA directly. ATP falls, and the sodium pump driving the entire brush border runs down.
- So you see
- Generalised proximal failure: glycosuria with a normal blood glucose, phosphate wasting, normal anion gap acidosis, hypokalaemia and small-protein leak. Heavier injury kills the cells outright and appears as acute tubular necrosis with a rising creatinine.
- And the same mechanism causes
- The kidney is harmed precisely because it is the organ doing the clearing — transporters designed to excrete the drug deliver these cells a dose no other tissue receives. That is why proximal tubular toxicity is so often the dose-limiting problem with these agents (classically with cisplatin and tenofovir disoproxil), even where each drug also carries toxicities of its own elsewhere.
- Handling
- Serum phosphate and the urine dipstick move before creatinine does — phosphate falls and glucose appears in the urine while the creatinine is still normal, so monitoring only creatinine misses the early picture. Tenofovir alafenamide delivers the same active antiviral metabolite to lymphocytes at far lower plasma tenofovir exposure, so far less reaches the proximal tubule and it largely spares it.
Catches people out: Caught early it usually reverses over weeks to months after withdrawal. Missed, the phosphate wasting produces osteomalacia — bone pain and difficulty rising from a chair — and the bone complaint may be what brings the patient in.
- Binds
- URAT1 and related urate transporters on the luminal membrane of the proximal tubule
- Which does
- Blocks urate reabsorption, so filtered urate stays in the tubular fluid and leaves in the urine instead of returning to the blood.
- So you see
- Serum urate falls, and if it is held below the saturation point the crystal deposits in joints and tophi dissolve over months, so flares become less frequent and eventually stop.
- And the same mechanism causes
- You are now running concentrated urate down the tubule, so it can crystallise on the way out — urate stones and crystal nephropathy follow directly from the mechanism, which is why fluid intake matters and why it is avoided in anyone who already forms urate stones.
- Handling
- It works by leaving filtered urate unreabsorbed, so it loses effect once GFR is substantially reduced. It also blocks the organic anion transporters that secrete other drugs, holding methotrexate in the body — a dangerous interaction — and historically holding penicillin there on purpose.
Catches people out: Be clear where the first-line drug acts: allopurinol is not a tubular drug at all. It blocks xanthine oxidase and cuts urate production upstream; febuxostat does the same and is the usual next choice in Australia ahead of probenecid. Probenecid works on the plumbing, allopurinol on the factory. Urate-lowering therapy is not treatment for the acute flare itself — it is started once the flare has settled, or started alongside anti-inflammatory prophylaxis, because dropping urate abruptly can precipitate a flare; and urate-lowering therapy already established is continued through a flare rather than stopped, then titrated long term to a urate target.
Glucose in the urine is not one disease, it is three. A normal transporter overwhelmed by a high blood glucose (diabetes), a broken transporter with a normal blood glucose (Fanconi syndrome, or inherited familial renal glycosuria), or a normal transporter deliberately blocked (an SGLT2 inhibitor). Read the dipstick next to the blood glucose and the medication list — that one pairing separates all three.
Now test whether it stuck
Reading this through is not the same as being able to reconstruct it. Every question in the bank is free, with a full debrief on each option.