Calcium, phosphate and vitamin D
The kidney performs the final activating step of vitamin D and is where parathyroid hormone does much of its work — so the kidney sets the calcium and phosphate the skeleton is built from.
What it normally does
Essentially all circulating calcitriol is made in the kidney. The liver makes 25-hydroxyvitamin D (the storage form, and the one actually measured), then 1-alpha-hydroxylase in the proximal tubule adds the 1-hydroxyl to make the active hormone 1,25-dihydroxyvitamin D (calcitriol). Calcitriol drives active transcellular calcium absorption in the duodenum. (Macrophages in granulomatous disease can also 1-hydroxylate, which is why sarcoidosis causes hypercalcaemia — but they contribute essentially nothing normally.)
as nephrons are lost, calcitriol production falls and calcium absorption from food falls with it. Colecalciferol still has to be 1-hydroxylated by the kidney, so it cannot replace that step in advanced CKD — 25(OH)D deficiency is still corrected, because it is the substrate and cheap to replace, but an already 1-hydroxylated analogue is what substitutes for the missing enzyme.
Parathyroid hormone (PTH) does three things at the kidney: it increases calcium reabsorption in the distal convoluted tubule and connecting tubule (via TRPV5), it inhibits phosphate reabsorption in the proximal tubule (it internalises the NaPi-IIa/IIc cotransporters) so phosphate is lost into the urine, and it switches on 1-alpha-hydroxylase.
an intact PTH-kidney axis means calcium up and phosphate down together — and when PTH is absent you get the mirror image, low calcium with high phosphate.
Phosphate balance is set by the kidney. Roughly 60-70% of dietary phosphate is absorbed, and the kidney excretes essentially all of that absorbed load; the unabsorbed remainder simply passes in the stool (which is exactly what phosphate binders exploit). As nephrons are lost, osteocytes release more FGF23, which — with its co-receptor Klotho — suppresses proximal tubule phosphate reabsorption so each surviving nephron excretes more; FGF23 also switches 1-alpha-hydroxylase off and switches 24-hydroxylase (which degrades calcitriol) on.
FGF23 rises first and active vitamin D falls early in kidney disease while serum phosphate still looks normal; phosphate only climbs late, once too few nephrons remain for that compensation to work.
The parathyroid chief cell reads ionised calcium through a calcium-sensing receptor (CaSR) on its surface: a fall in ionised calcium takes the brake off and PTH is released within minutes. Low calcitriol also drives PTH (calcitriol normally suppresses transcription of the PTH gene through the vitamin D receptor), and so does high phosphate — phosphate acts on the gland directly, stabilising PTH mRNA and promoting gland growth, and also indirectly, by lowering ionised calcium for the CaSR to read.
years of continuous drive do not just raise PTH — the glands become hyperplastic and then nodular, and eventually keep secreting even after the stimulus is corrected.
What goes wrong
- Secondary hyperparathyroidism of chronic kidney disease← from “Essentially all circulating calcitriol is made…”
Failing kidneys make less calcitriol, so the gut absorbs less calcium and serum calcium drifts down. Phosphate is retained as GFR falls. Low ionised calcium takes the brake off the calcium-sensing receptor, and low calcitriol and high phosphate act on the gland directly, so PTH is secreted continuously and the glands grow. PTH does defend serum calcium — largely by resorbing bone — so calcium often looks normal on the blood test while the skeleton pays for it.
CKD → loss of 1-alpha-hydroxylation + phosphate retention → low calcium → PTH driven up. High PTH with HIGH phosphate says the kidney is the problem.
You would find: PTH starts drifting up from CKD G3 and is usually clearly abnormal by G4-G5 (eGFR under about 30): PTH high, phosphate high, calcium low or deceptively normal, ALP often high. FGF23 rises earliest and 1,25-dihydroxyvitamin D falls early, but neither is measured routinely — PTH, corrected calcium, phosphate and ALP are what you actually order. Bone pain and proximal weakness getting out of a chair.
- Renal bone disease (renal osteodystrophy)← from “The parathyroid chief cell reads ionised calci…”
Sustained PTH acts on osteoblasts and osteocytes (osteoclasts do not carry the PTH1 receptor), driving RANKL expression and so osteoclastic resorption. Bone is resorbed and replaced by disorganised woven bone and marrow fibrosis faster than it can be laid down properly — high-turnover disease, osteitis fibrosa. Low calcitriol adds a second lesion: the new osteoid cannot mineralise properly, so it stays soft (osteomalacia). The mirror-image lesion matters just as much — over-suppressing PTH, with calcium load, active vitamin D or a calcimimetic, produces adynamic bone, in which turnover is too low to buffer a calcium load, and fracture and vascular calcification risk rise. This is why PTH in dialysis patients is generally kept in a range of roughly two to nine times the upper limit of normal rather than pushed to normal.
High PTH = resorption; low calcitriol = unmineralised osteoid; over-treated PTH = adynamic bone. Painful bone, high ALP, fractures at low trauma.
You would find: Bone and proximal muscle pain, fragility fractures, alkaline phosphatase high alongside the raised PTH. Dense end-plates with lucent mid-vertebrae on a lateral spine film — the rugger-jersey spine. Bone biopsy remains the only reliable way to separate high-turnover from adynamic disease, which is why PTH and ALP trends, not single values, guide treatment.
- Vascular calcification and calciphylaxis← from “Phosphate balance is set by the kidney. Roughl…”
Once phosphate can no longer be excreted it rises, and calcium and phosphate together exceed what stays in solution while the inhibitors of mineralisation (fetuin-A, matrix Gla protein) are depleted. Vascular smooth muscle cells exposed to high phosphate switch to an osteoblast-like phenotype and mineralise the media of the artery wall. In small dermal arterioles the lumen occludes and the overlying skin infarcts (calciphylaxis).
High phosphate is the main driver, not high calcium — which is why phosphate control matters as much as calcium in dialysis. Treat calcium and phosphate as separate targets; the calcium-phosphate product is a rough physicochemical idea and current KDIGO guidance no longer recommends managing patients by it. Aboriginal and Torres Strait Islander Australians begin kidney replacement therapy at several times the rate of other Australians, and higher again in remote central and northern Australia, so this burden falls unevenly.
You would find: Rigid, calcified arteries on a plain abdominal or hand X-ray in a dialysis patient. Calciphylaxis is exquisitely painful, dusky, necrotic plaques on the thighs, abdomen or other fatty areas — high mortality. Warfarin and obesity are recognised risk factors.
- Tertiary hyperparathyroidism← from “The parathyroid chief cell reads ionised calci…”
After years of continuous stimulation the parathyroid glands become nodular and hyperplastic, and the expanded clones down-regulate calcium-sensing and vitamin D receptors. Secretion becomes largely autonomous. Correct the underlying problem — usually a kidney transplant, which restores 1-alpha-hydroxylation and phosphate excretion — and the glands keep pouring out PTH anyway, so calcium now climbs.
Secondary = low or normal calcium, an appropriate response. Tertiary = high calcium, the glands no longer listen. Persistent, symptomatic tertiary disease is ultimately treated surgically (parathyroidectomy).
You would find: HIGH calcium with high PTH, classically persisting or appearing in the months after a successful transplant (it can also be seen on long-term dialysis). Stones, bone pain, constipation, thirst.
- Hypoparathyroidism after neck surgery← from “Parathyroid hormone (PTH) does three things at…”
The parathyroids sit on the posterior surface of the thyroid and may be removed or devascularised during thyroidectomy. With no PTH, the distal tubule stops reabsorbing calcium, the proximal tubule resumes reabsorbing phosphate, and 1-alpha-hydroxylase is not stimulated. Everything PTH does at the kidney runs in reverse.
Low calcium + high phosphate = either no PTH or a kidney that cannot respond to it. Phosphate is the discriminator: in vitamin D deficiency the PTH response wastes phosphate, so phosphate is low.
You would find: Low corrected (or ionised) calcium with HIGH phosphate and an inappropriately low or normal PTH, typically within one to three days of thyroid surgery — often transient. Perioral tingling, cramps, tetany, tapping over the facial nerve twitches the lip (Chvostek), a cuff inflated above systolic pressure produces carpal spasm (Trousseau), long QT on ECG. Check magnesium at the same time.
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
- The nuclear vitamin D receptor in duodenal enterocytes and in parathyroid chief cells
- Which does
- The activated receptor pairs with RXR and increases transcription of the apical calcium channel (TRPV6) and the calcium-binding proteins that ferry calcium across the enterocyte; in the parathyroid it suppresses transcription of the PTH gene.
- So you see
- Gut calcium absorption rises, serum calcium rises, and PTH falls — from two directions at once.
- And the same mechanism causes
- The same receptor also increases the gut's sodium-phosphate cotransporter (NaPi-IIb) alongside its calcium transporter, and falling PTH removes the phosphaturic drive. So the drug that lifts calcium also lifts phosphate — hypercalcaemia and hyperphosphataemia, feeding the vascular calcification you were trying to avoid. Over-suppressing PTH also risks adynamic bone.
- Handling
- Plain colecalciferol still needs the kidney's 1-alpha-hydroxylase, so it cannot correct calcitriol deficiency in advanced kidney disease (it is still used to correct 25(OH)D deficiency, the substrate). Alfacalcidol needs only hepatic 25-hydroxylation; calcitriol needs no further activation. Calcium, phosphate and PTH are monitored on treatment.
Catches people out: Not a routine treatment for every raised PTH in CKD — current guidance reserves active vitamin D for severe or progressive secondary hyperparathyroidism, after phosphate, calcium and vitamin D substrate have been addressed. Uncontrolled hyperphosphataemia and hypercalcaemia are reasons to hold it.
- Binds
- Phosphate in food within the gut lumen
- Which does
- The cation (calcium, lanthanum) or the non-absorbed polymer (sevelamer) binds dietary phosphate into a complex that cannot cross the enterocyte, so that phosphate leaves in the stool.
- So you see
- Serum phosphate falls, and one of the stimuli to PTH secretion and to vascular calcification is removed.
- And the same mechanism causes
- Because the drug sits unabsorbed in the lumen binding ions and altering the gut contents, gastrointestinal effects are intrinsic rather than incidental: constipation and bloating with the cation binders, and nausea, dyspepsia and altered bowel habit more typically with sevelamer. Calcium-based binders are absorbed enough to add a genuine calcium load, so they can tip a patient into hypercalcaemia and positive calcium balance.
- Handling
- They only work if swallowed with the meal. Taken between meals there is no dietary phosphate to bind — one of the commonest reasons phosphate stays high. They also bind other drugs in the lumen, so the timing of other medicines matters.
Catches people out: Non-calcium binders (sevelamer, lanthanum) are preferred when calcium is already high, PTH is suppressed, or calcification is established. Aluminium-containing binders are avoided because of aluminium toxicity.
- Binds
- The calcium-sensing receptor on parathyroid chief cells
- Which does
- It binds allosterically and makes the receptor more sensitive to the calcium already present, so the gland reads a normal calcium as a high one and reduces secretion.
- So you see
- PTH falls, and because it falls without administering calcium or vitamin D, serum calcium falls with it and phosphate tends to fall too — the opposite of what active vitamin D analogues do.
- And the same mechanism causes
- The gland has been made to read calcium as higher than it is, so it keeps secretion suppressed while calcium keeps dropping: hypocalcaemia, with perioral tingling, cramps and a prolonged QT. Nausea and vomiting are common; the calcium-sensing receptor is also expressed in the gastrointestinal tract, though this is better regarded as a well-documented class effect than a proven mechanism. Over-suppression of PTH risks adynamic bone.
Catches people out: Its effect depends on glands that still express a responsive receptor, so it works less well once they are nodular and have down-regulated it. In autonomous tertiary disease, particularly persistent hypercalcaemia after transplant, parathyroidectomy is the definitive treatment; in Australia cinacalcet's approved use is severe secondary hyperparathyroidism in patients on dialysis, not the post-transplant setting.
- Binds
- Calcium delivered to the gut lumen, absorbed through vitamin D receptor-driven transporters in the duodenum
- Which does
- Calcitriol opens the transcellular calcium pathway in the gut and the calcium salt supplies the substrate, so absorption makes up for the calcium the kidney is losing.
- So you see
- Serum calcium rises, tetany and the long QT resolve.
- And the same mechanism causes
- Without PTH the distal tubule cannot reabsorb filtered calcium, so much of what is absorbed goes straight into the urine. Pushing serum calcium up into the mid-normal range generates marked hypercalciuria — stones and nephrocalcinosis. This is why the aim is a low-normal serum calcium: enough to abolish symptoms, not enough to flood the tubule. Urinary calcium and renal function are monitored, not just serum calcium.
Catches people out: Check magnesium. Low magnesium impairs both PTH release and PTH action, and calcium will not correct until magnesium is replaced. Acute symptomatic hypocalcaemia (tetany, seizures, long QT) is an emergency treated with intravenous calcium rather than oral therapy.
Never read PTH against one other value — read PTH, calcium and phosphate together. High PTH + HIGH calcium + low or low-normal phosphate = primary hyperparathyroidism: the gland is autonomous and the kidney is obeying it perfectly. High PTH + high phosphate + low or normal calcium = the kidney cannot obey, because it can neither excrete phosphate nor activate vitamin D: secondary hyperparathyroidism of CKD. High PTH + LOW phosphate + low or normal calcium is NOT primary disease — it is the appropriate secondary response to vitamin D deficiency. Low or inappropriately normal PTH + low calcium + high phosphate = hypoparathyroidism.
Now test whether it stuck
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