Measuring renal function
The kidney's core job is filtering plasma, but filtration cannot be seen or directly measured — so we infer it from a muscle waste product in the blood, and read the urine for everything that number misses.
What it normally does
The two kidneys filter roughly 180 litres of plasma a day and hand almost all of it back. The rate of that filtering (glomerular filtration rate, GFR) is the best overall summary of how much kidney is working — normally about 90 to 120 mL/min/1.73 m2.
chronic kidney disease is defined and staged largely by how far GFR has fallen (alongside albuminuria), yet true GFR cannot be measured at the bedside — it needs a clearance study — so the GFR a lab reports is an estimate (eGFR), not a measurement.
Creatine and phosphocreatine in muscle convert to creatinine at a near-constant rate. Creatinine is filtered freely and only a small share (about 10 to 15%) is secreted by the proximal tubule, so the blood level settles where production and clearance balance (creatinine is roughly production divided by GFR).
the relationship is a curve, not a straight line — roughly half of filtration can be gone before creatinine leaves the reference range, and someone with very little muscle can have a normal creatinine and a badly damaged kidney.
The glomerulus is a three-layer sieve — fenestrated endothelium, glomerular basement membrane, podocyte foot processes — and its surfaces carry a net negative charge, so it holds back cells and albumin.
albumin or blood appearing in the urine points to damage at the filter itself, and albuminuria typically appears years before GFR falls — but the pattern has to fit, because proteinuria can also be tubular or overflow, and most haematuria is urological rather than glomerular.
Downstream, the tubules reclaim sodium and water and concentrate the urine, and they respond to underperfusion by reabsorbing harder — driven by angiotensin II, aldosterone and antidiuretic hormone.
the urine often helps separate a kidney that is underperfused but intact from one whose tubule cells have died — though the urine indices are unreliable once diuretics are on board, in established chronic disease, or when the picture is mixed.
What goes wrong
- Acute kidney injury← from “Downstream, the tubules reclaim sodium and wat…”
Something drops perfusion — vomiting, sepsis, bleeding, heart failure. Filtration pressure falls, GFR falls, and creatinine piles up because muscle keeps making it while the kidney stops clearing it. Intact tubules react by clamping down on sodium and water, so the urine is scanty and concentrated (prerenal). If the underperfusion continues, the tubular cells with the highest oxygen demand and the lowest oxygen supply — the S3 proximal tubule and the medullary thick ascending limb — die, slough into the lumen and stop reabsorbing anything. Now the urine is dilute and full of debris (acute tubular necrosis). Not all AKI is haemodynamic: obstruction and intrinsic causes such as glomerulonephritis and interstitial nephritis produce the same rising creatinine and must be excluded.
AKI is a rate of change, not a number. Creatinine lags a day or two behind the insult, so urine output falls first. eGFR is invalid here — it assumes a steady state that by definition does not exist.
You would find: KDIGO: creatinine rising by at least 26 micromol/L within 48 hours, or to 1.5 times a baseline known or presumed to be from the previous 7 days, or urine output under 0.5 mL/kg/h for 6 hours. Prerenal: small volumes of concentrated urine, urea raised out of proportion to creatinine (though GI bleeding, steroids and catabolism do that too), a bland dipstick. Tubular necrosis: dilute urine that will not concentrate, and muddy brown granular casts.
- Chronic kidney disease← from “The two kidneys filter roughly 180 litres of p…”
Nephrons are lost and never replaced. The survivors hyperfilter to compensate, so total GFR holds up while the tissue quietly disappears — which is exactly why creatinine can sit in the normal range until around half the kidney is gone. When it finally rises it rises over months and years, and by then the kidney has failed at its other jobs too: erythropoietin (anaemia), vitamin D activation and phosphate excretion (high phosphate, high parathyroid hormone), and acid excretion (metabolic acidosis).
Diabetes is the leading cause of treated kidney failure in Australia, behind roughly a third of people starting dialysis or transplantation. Aboriginal and Torres Strait Islander Australians start kidney replacement therapy at several times the rate of other Australians — of the order of four to five times nationally, and up to roughly twenty times in remote and very remote areas — which is why Kidney Health Australia recommends an annual Kidney Health Check (eGFR, urine ACR, blood pressure) for Aboriginal and Torres Strait Islander adults from age 18, not only those with an extra risk factor.
You would find: eGFR under 60 mL/min/1.73 m2, or albuminuria, or another marker of kidney damage such as glomerular haematuria or a structural abnormality — present for at least three months. Old results are among the most valuable tests you have: a creatinine drifting up over years is chronic. So are anaemia, high phosphate, high PTH and small echogenic kidneys — though diabetic, amyloid and polycystic kidneys can be normal-sized or large.
- Albuminuria in diabetic and hypertensive kidney disease← from “The glomerulus is a three-layer sieve — fenest…”
High glucose and high pressure inside the glomerular capillary injure podocytes and degrade the negatively charged heparan sulphate of the basement membrane. Albumin is negatively charged and sits close to the size cut-off, so it is among the first proteins to slip through. The proximal tubule reabsorbs what it can and is then overwhelmed. All of this happens while GFR is still normal or even raised (hyperfiltration), so the creatinine is reassuring and wrong.
Albuminuria predicts progression and cardiovascular death independently of eGFR. Stage kidney disease with both axes — eGFR and ACR together, not eGFR alone.
You would find: Urine albumin-to-creatinine ratio (ACR), ideally on a first-morning sample: raised above 2.5 mg/mmol in men, 3.5 mg/mmol in women, and confirmed on repeat testing (two of three samples over three months) because exercise, fever, infection and menstruation all raise it transiently. The dipstick usually stays negative until ACR is roughly ten times those thresholds, so the dipstick is not a screening test for this.
- Glomerulonephritis← from “The glomerulus is a three-layer sieve — fenest…”
Immune complexes or antibodies inflame the glomerulus. Holes open in the filter, red cells are forced through and deformed by the squeeze (dysmorphic), then set in the tubule with Tamm-Horsfall protein (uromodulin) into a red cell cast. The inflamed glomerulus also filters less and retains sodium, which is where the hypertension and oedema come from.
Blood alone means stone, tumour or infection until proven otherwise. Blood plus protein plus casts means glomerulus. Post-streptococcal glomerulonephritis following skin sores or throat infection remains far more common in remote Aboriginal and Torres Strait Islander communities than elsewhere in Australia, and presents as a child with tea-coloured urine, puffy eyes and a high blood pressure.
You would find: Blood and protein together on dipstick, with dysmorphic red cells and red cell casts on microscopy. A cast is moulded inside a tubule, so a red cell cast places the bleeding upstream in the kidney itself rather than in a stone, the bladder or the prostate.
- A creatinine that rises without any kidney injury← from “Creatine and phosphocreatine in muscle convert…”
About 10 to 15% of creatinine clearance is tubular secretion rather than filtration. Block those transporters and creatinine backs up in the blood while filtration is completely unchanged. The production side of the equation misleads in the same way: a body builder or someone eating a lot of cooked meat makes far more creatinine, while a frail elderly woman, an amputee or someone with cirrhosis makes far less. (Rhabdomyolysis also floods the blood with creatinine from damaged muscle — but there the released creatinine usually sits alongside genuine tubular injury, so it is not a clean example of a falsely raised value.)
eGFR assumes average muscle mass and a steady state. It is unreliable in AKI, pregnancy, extremes of body size and amputees. Cystatin C, produced by nucleated cells generally rather than by muscle, sidesteps the muscle problem when the creatinine does not fit the patient in front of you — though it is not routinely available or rebated in every Australian setting.
You would find: Creatinine up 10 to 20% within days of starting trimethoprim, with no fall in urine output, a flat urea, and a return to baseline when the drug stops. The mirror image is the 45 kg nursing home resident whose creatinine of 70 micromol/L is not the reassurance it looks like.
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
- Cyclo-oxygenase (COX-1 and COX-2), the enzyme that makes prostaglandins
- Which does
- Less prostaglandin E2 and prostacyclin means less vasodilator tone on the afferent arteriole, so it constricts. Less blood reaches the glomerulus and filtration pressure falls.
- So you see
- In a well-perfused, euvolaemic person, usually very little. In someone dry, septic, elderly or on the wrong combination, GFR drops, urine output falls and creatinine climbs over the next few days.
- And the same mechanism causes
- The kidney injury is the mechanism, not a separate toxicity — the same prostaglandin blockade that relieves the pain removes the vasodilation an underperfused kidney was leaning on. Gastric ulceration follows from the identical fact: prostaglandins protect the gastric mucosa too. Sodium and water retention, and the blood pressure rise that goes with it, come from the same loss of renal prostaglandins. (Acute interstitial nephritis is also seen with NSAIDs, but that is an idiosyncratic immune reaction, not a prostaglandin effect.)
Catches people out: The triple whammy: an ACE inhibitor or ARB dilating the efferent side, a diuretic dropping the volume, and an NSAID constricting the afferent side. Each is usually tolerated alone; together they remove most of the compensation the glomerulus has left. Over-the-counter ibuprofen and diclofenac count, so ask about them by name.
- Binds
- Angiotensin converting enzyme, so less angiotensin II is generated (the inhibitors), or the AT1 receptor on vascular smooth muscle and adrenal cortex, so the angiotensin II present cannot signal (the blockers)
- Which does
- Less angiotensin II signalling lets the efferent arteriole relax. Pressure inside the glomerular capillary falls, so the filter is no longer being pushed to leak.
- So you see
- Albuminuria falls within weeks and the long-run slope of GFR decline flattens. Blood pressure falls as well.
- And the same mechanism causes
- Dropping efferent tone drops filtration pressure, so creatinine rises and eGFR dips as soon as the drug is started. Guidelines accept a creatinine rise of up to about 30% (an eGFR fall of up to about 25%) as the drug working rather than a reason to stop; a larger or continuing rise prompts review for volume depletion, an NSAID or renovascular disease. In someone volume-depleted, or with bilateral renal artery stenosis whose GFR was being propped up by angiotensin II, the same effect tips into frank AKI. Two further adverse effects fall straight out of the mechanism and separate the classes: ACE also degrades bradykinin, so ACE inhibitors cause the dry cough and (rarely) angioedema that ARBs largely do not.
- Handling
- Because the same loss of angiotensin II signalling removes the main stimulus to aldosterone, potassium is retained — potassium and creatinine are conventionally rechecked one to two weeks after starting or increasing the dose.
Catches people out: Sick day rules: these are withheld during an illness with vomiting, diarrhoea or fever — precisely when the kidney is leaning on angiotensin II. Routine dual blockade with an ACE inhibitor plus an ARB is avoided, because the combination worsens hyperkalaemia and AKI without improving outcomes.
- Binds
- SGLT2 in the S1/S2 segment of the proximal convoluted tubule, which reabsorbs most filtered glucose along with sodium
- Which does
- Blocking reabsorption leaves more sodium chloride in the filtrate reaching the macula densa. Tubuloglomerular feedback then constricts the afferent arteriole. Intraglomerular pressure falls and the surviving nephrons stop hyperfiltering themselves to death.
- So you see
- An immediate dip in eGFR of a few mL/min/1.73 m2, then a distinctly slower decline than without the drug, and less albuminuria.
- And the same mechanism causes
- The glucose that is not reabsorbed ends up in the urine. Sugary urine feeds yeast, so genital thrush is the predictable adverse effect, and the osmotic pull of that same glucose drags water with it and can leave the patient volume-depleted — the reason a co-prescribed diuretic may need reviewing. The same urinary glucose loss lowers insulin and shifts metabolism towards ketones, which is why ketoacidosis can occur at a near-normal blood glucose.
Catches people out: Glycosuria on the dipstick is the expected finding in someone taking one — that is the drug working, not diabetes out of control. The early eGFR dip is expected too; the error is stopping the drug because of it. The error in the other direction is missing euglycaemic ketoacidosis: ketones, not just glucose, are the test in anyone on one of these who is acutely unwell, and these drugs are withheld during acute illness and around surgery. Note also that in Australia PBS subsidy for the chronic kidney disease indication is agent-specific rather than class-wide, so the two examples are not interchangeable on paper.
- Binds
- The organic cation secretory pathway of the proximal tubule — OCT2 (with OCT3) on the basolateral membrane carries creatinine from blood into the cell, and MATE1 and MATE2-K on the apical membrane push it out into the urine. Trimethoprim inhibits this pathway, principally the apical MATE transporters. Cimetidine does the same and is the classic textbook example, though it is now little used in Australia.
- Which does
- Blocking secretion means the 10 to 15% of creatinine clearance that normally takes that route is lost, so creatinine accumulates in the blood while filtration itself is untouched.
- So you see
- Serum creatinine rises and the reported eGFR falls within days, with normal urine output and no real loss of filtration; both return to baseline after the course finishes.
- And the same mechanism causes
- A second, separate mechanism runs alongside: trimethoprim is structurally like amiloride and blocks the epithelial sodium channel in the collecting duct. Less sodium in means less of the electrical gradient driving potassium out — so the drug that fakes a kidney injury causes a genuine hyperkalaemia, and sometimes a mild type 4-like acidosis, especially alongside an ACE inhibitor, ARB or spironolactone.
Catches people out: Recognising the pattern saves a needless fluid challenge and ultrasound — but only if it genuinely fits: stable urine output, a flat urea, a rise that plateaus and reverses on stopping. Trimethoprim and co-trimoxazole can also cause real injury through acute interstitial nephritis, so oliguria, a rising urea, a rash, eosinophilia or a rise that keeps climbing means investigate, not reassure. The potassium is worth checking either way — that hazard is real whether or not the creatinine rise is.
Ask three questions of every abnormal kidney result. How fast — today's creatinine against the old ones, because acute and chronic are the same number on different timelines. What does the urine say — ACR, dipstick and microscopy tell you about the filter, which creatinine cannot. Does the number fit this patient — muscle mass, steady state, new drugs. eGFR answers only the first question, and only in someone stable.
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.