NephrologyTier 1Disease (DEADMAN)

Electrolyte abnormalities - hypo- and hypercalcaemia

Description

Always correct or measure ionised calcium first

Corrected Ca = measured Ca + 0.02 x (40 - albumin g/L)
Ionised calcium is the physiologically active fraction (~50%) - measure it directly when albumin is abnormal, in critical illness, or in acid-base disturbance
*Alkalosis increases albumin binding -> ionised Ca falls with a normal total Ca* - the mechanism of tetany in hyperventilation

Reference points

	Total Ca (corrected)
Normal	~2.10-2.60 mmol/L
Hypocalcaemia	<2.10 (severe <1.90 or symptomatic)
Hypercalcaemia	>2.60; moderate 3.0-3.5; severe >3.5 = emergency

The renal angle: calcium disorders both cause and are caused by kidney disease - CKD-MBD, hypercalcaemic nephropathy, nephrolithiasis, nephrogenic DI

Epidemiology

Hypercalcaemia: ~1-2% of the population (primary hyperparathyroidism, mostly asymptomatic outpatients) and ~1% of inpatients (usually malignancy)
Primary hyperparathyroidism and malignancy account for ~90% of all hypercalcaemia
- Outpatient with a mildly raised Ca: hyperparathyroidism. Inpatient who is unwell: malignancy
Hypocalcaemia: ~15-20% of inpatients; up to 85% in ICU
Post-thyroidectomy hypoparathyroidism ~5-10% transient, ~1-3% permanent - the commonest cause of hypoparathyroidism

Aetiopathogenesis

Hypercalcaemia

PTH-mediated (PTH high or inappropriately normal)
- Primary hyperparathyroidism - adenoma ~85%, hyperplasia ~15%, carcinoma <1%; MEN1/MEN2A
- Tertiary hyperparathyroidism - long-standing CKD, or post-transplant
- Familial hypocalciuric hypercalcaemia (FHH) - inactivating CASR mutation; urine calcium:creatinine clearance ratio <0.01
- Lithium - shifts the CaSR set-point
PTH-independent (PTH suppressed)
- Malignancy - the sickest patients, highest calcium, fastest onset
  - PTHrP (humoral hypercalcaemia) - squamous cell (lung, head and neck), renal, breast, ovarian
  - Osteolytic metastases - breast, myeloma, lymphoma
  - 1,25-(OH)2 vitamin D production - lymphoma
- Granulomatous disease - sarcoidosis, TB, histoplasmosis, berylliosis; extrarenal 1-alpha-hydroxylase in macrophages
- Vitamin D or vitamin A toxicity
- Thyrotoxicosis, phaeochromocytoma, adrenal insufficiency
- Immobilisation (high-turnover states - Paget disease, adolescents)
- Milk-alkali / calcium-alkali syndrome - hypercalcaemia + metabolic alkalosis + AKI
Drugs: thiazide diuretics, lithium, theophylline, vitamin D, vitamin A/retinoids, calcium supplements, teriparatide

Hypocalcaemia

Low PTH
- Post-surgical (thyroidectomy, parathyroidectomy) - much the commonest
- Autoimmune (APS type 1), infiltration (haemochromatosis, Wilson, metastases), radiation
- DiGeorge (22q11 deletion), activating CASR mutation (autosomal dominant hypocalcaemia)
- Hypomagnesaemia - *both impairs PTH secretion and causes PTH resistance. Calcium will not correct until magnesium is replaced*
High PTH (secondary)
- Vitamin D deficiency - the commonest cause overall
- CKD - inc PO4 + dec calcitriol
- Pseudohypoparathyroidism - PTH resistance; Albright hereditary osteodystrophy: short stature, round face, short 4th/5th metacarpals
- Acute pancreatitis (saponification), rhabdomyolysis and tumour lysis (phosphate binding), osteoblastic metastases (prostate, breast)
- Massive transfusion (citrate), hungry bone syndrome, bisphosphonates and denosumab (severe and prolonged in CKD)
- Drugs: foscarnet, cinacalcet, phenytoin, phenobarbitone, proton pump inhibitors (via magnesium)

Diagnosis

Hypercalcaemia - the sequence

1. Confirm with a corrected or ionised calcium on a repeat sample
2. Measure PTH - this single test splits the differential in two

	PTH high or inappropriately normal	PTH suppressed
Think	Primary/tertiary hyperparathyroidism, FHH, lithium	Malignancy, granulomatous disease, vitamin D toxicity, thyrotoxicosis
Next test	24h urine calcium; calcium:creatinine clearance ratio	PTHrP, 1,25-(OH)2 vitamin D, 25-OH vitamin D, SPEP + free light chains, imaging

Ca:Cr clearance ratio <0.01 -> FHH (avoids a futile parathyroidectomy - this is the classic trap)
Also check: phosphate (low in hyperparathyroidism and PTHrP; high in vitamin D toxicity and osteolysis), ALP, magnesium, UEC, TSH, ACE, morning cortisol

Hypocalcaemia - the sequence

Confirm (ionised Ca), then measure: PTH, magnesium, phosphate, 25-OH vitamin D, creatinine, ALP

Ca	PTH	PO4	Diagnosis
dec	dec/normal	inc	Hypoparathyroidism
dec	inc	inc	CKD; pseudohypoparathyroidism
dec	inc	dec	Vitamin D deficiency; malabsorption
dec	dec	variable	Hypomagnesaemia (check it every time)

Clinical features

Hypercalcaemia - 'stones, bones, abdominal groans, psychic moans'
- Polyuria and polydipsia (nephrogenic DI) -> volume depletion -> worsening hypercalcaemia (the vicious cycle)
- Nausea, constipation, anorexia, peptic ulcer, pancreatitis
- Confusion, lethargy, weakness, coma
- AKI, nephrolithiasis, nephrocalcinosis, distal (type 1) RTA
- ECG: short QT, bradycardia, osborn-like J waves in severe cases
Hypocalcaemia - neuromuscular irritability
- Perioral and acral paraesthesiae, cramps, carpopedal spasm, tetany
- Chvostek sign (~10-25% of normal people - low specificity), Trousseau sign (more specific)
- Laryngospasm, bronchospasm, seizures
- ECG: prolonged QT -> torsades; hypotension, heart failure
- Chronic: cataracts, basal ganglia calcification, papilloedema, dry skin, brittle nails

Management

Severe hypercalcaemia (>3.5 mmol/L, or symptomatic)

1. IV isotonic saline - the first and most important step
- 3-6 L over 24 h (adjusted for cardiac and renal function); restores GFR and promotes calciuresis
- *Do not give a loop diuretic routinely* - only once euvolaemic, and for volume overload, not to lower calcium
2. Bisphosphonate - the definitive agent for malignancy
- Zoledronic acid 4 mg IV (or pamidronate 30-90 mg)
- Onset 24-48 h, nadir at 4-7 days - so it does not help the first day; that is what the saline is for
- Dose-reduce or avoid if eGFR <30; hydrate first
3. Calcitonin 4 units/kg SC/IM 12-hourly - onset 4-6 h, tachyphylaxis by 48 h; a bridge only
4. Denosumab - for bisphosphonate-refractory hypercalcaemia or severe renal impairment; watch for prolonged hypocalcaemia
5. Corticosteroids - for granulomatous disease, lymphoma and vitamin D toxicity (block extrarenal 1-alpha-hydroxylase)
6. Haemodialysis with low-calcium dialysate - for refractory hypercalcaemia, severe renal failure or heart failure
Stop the culprit: thiazides, lithium, calcium and vitamin D supplements, calcium-containing antacids

Primary hyperparathyroidism - parathyroidectomy criteria

Symptomatic disease, OR asymptomatic with any of:
- Ca >0.25 mmol/L above the upper limit of normal
- eGFR <60, 24h urine calcium >10 mmol/day, nephrolithiasis or nephrocalcinosis on imaging
- T-score <=-2.5 at any site, or a vertebral fracture
- Age <50
Cinacalcet if surgery is not possible; lowers calcium but does not improve bone density

Acute symptomatic hypocalcaemia

IV calcium gluconate 10% 10-20 mL over 10 min, then an infusion (10 mL/h of 10% in 5% glucose, titrated)
- Prefer gluconate peripherally - chloride is more sclerosant
- Cardiac monitoring; caution on digoxin
*Replace magnesium at the same time - hypocalcaemia will not correct until it is corrected*
Correct the calcium before the phosphate in CKD; avoid raising the Ca x PO4 product

Chronic hypocalcaemia

Oral calcium carbonate + activated vitamin D (calcitriol) if the PTH is low (plain vitamin D is not enough without PTH - 1-alpha-hydroxylation is PTH-dependent)
Target calcium at the low end of normal - hypoparathyroidism has no PTH-driven renal calcium reabsorption, so normalising serum calcium causes hypercalciuria, stones and nephrocalcinosis
Monitor urine calcium as well as serum calcium
Recombinant PTH (palopegteriparatide, teriparatide) for refractory hypoparathyroidism
Thiazide + low salt diet reduces hypercalciuria

Associations

CKD - both a cause (CKD-MBD, tertiary hyperparathyroidism) and a consequence (hypercalcaemic nephropathy, nephrocalcinosis)
Nephrolithiasis, nephrocalcinosis, distal (type 1) RTA, nephrogenic DI
Malignancy - myeloma, breast, lung, renal, lymphoma
Sarcoidosis and other granulomatous disease
MEN1 (parathyroid, pituitary, pancreas), MEN2A (parathyroid, medullary thyroid, phaeochromocytoma)
Post-thyroidectomy and post-parathyroidectomy (hungry bone syndrome)
Vitamin D deficiency, malabsorption, coeliac, bariatric surgery, pancreatic insufficiency
Denosumab and bisphosphonates in CKD - severe, prolonged hypocalcaemia
Acute pancreatitis, rhabdomyolysis, tumour lysis syndrome, massive transfusion
Thiazides, lithium, PPIs (via hypomagnesaemia), foscarnet, cinacalcet

Natural history & complications

Hypercalcaemia is self-perpetuating: nephrogenic DI -> polyuria -> volume depletion -> dec GFR -> dec calcium excretion -> higher calcium. Breaking the cycle with saline is why fluid comes first
Hypercalcaemia of malignancy carries a median survival of weeks to a few months - it is a marker of advanced disease and should trigger a goals-of-care conversation
Primary hyperparathyroidism is usually indolent; ~25% of those managed conservatively meet surgical criteria within 10-15 years - monitor calcium, eGFR and bone density annually
Hungry bone syndrome after parathyroidectomy for severe hyperparathyroidism: profound, prolonged hypocalcaemia, hypophosphataemia and hypomagnesaemia for weeks - anticipate and pre-load with calcium and calcitriol
Chronic hypoparathyroidism: lifelong treatment; complications are largely iatrogenic - nephrocalcinosis, stones and CKD from over-treatment, plus cataracts and basal ganglia calcification
Sustained hypercalcaemia causes irreversible nephrocalcinosis and CKD - the reason not to tolerate it in FHH-negative patients

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