NephrologyTier 2Disease (DEADMAN)

Chronic renal failure - mineral and bone disorder

Description

Systemic disorder of mineral and bone metabolism in CKD - not just a bone disease
Three components, any combination:
- 1. Biochemical - Ca, PO4, PTH, vitamin D, FGF-23 abnormalities
- 2. Bone - renal osteodystrophy (turnover, mineralisation, volume)
- 3. Vascular/soft-tissue calcification
The vascular component is what kills - calcification predicts cardiovascular mortality more strongly than fracture predicts anything

Biochemical abnormalities detectable from CKD G3a; near-universal by G5
Fracture risk ~2-4x general population at any given BMD; hip fracture in dialysis carries ~50% 1-yr mortality
Adynamic bone disease is now the commonest lesion in dialysis patients (was osteitis fibrosa)

The sequence

1. dec GFR -> dec filtered phosphate load -> phosphate retention (the likely initial trigger)
2. inc FGF-23 - the earliest measurable abnormality, rises before PO4 or PTH
- Secreted by osteocytes/osteoblasts in response to calcitriol, dietary PO4 load, PTH, Ca
- Acts with co-receptor Klotho in the kidney:
  - dec luminal Na-phosphate co-transporter -> phosphaturia
  - dec 1-alpha-hydroxylase -> dec calcitriol (this, not loss of renal mass, is the major driver of early calcitriol deficiency)
  - dec PTH secretion - but parathyroids become FGF-23/Klotho resistant in CKD, so this brake fails
3. dec calcitriol -> dec gut Ca absorption -> hypocalcaemia; loss of vitamin D receptor-mediated suppression of PTH gene
4. Secondary hyperparathyroidism - the major feature
- Driven by inc PO4 + dec Ca + dec calcitriol + dec Klotho/FGF-23 resistance
- Parathyroid hyperplasia: diffuse -> nodular -> monoclonal, with loss of CaSR and VDR -> autonomous (tertiary)
5. Metabolic acidosis - skeleton buffers the acid load
- Acid dissolves bone apatite -> releases alkaline Ca salts + bicarbonate
- -> osteomalacia/osteoporosis, hypercalciuria, stones

inc PTH -> inc bone turnover; too much PTH suppression -> adynamic bone. Both are bad

Biochemistry - measure from CKD G3a

	Frequency (KDIGO)
G3a-G3b	Ca, PO4 6-12 monthly; PTH by baseline and CKD progression
G4	Ca, PO4 3-6 monthly; PTH 6-12 monthly
G5/G5D	Ca, PO4 1-3 monthly; PTH 3-6 monthly; ALP 12 monthly

Interpret trends, not single values
Total ALP (bone-specific if available) - high with high turnover, low with adynamic bone
25-OH vitamin D - measure and replace as in the general population
Ca x PO4 product is no longer used

Imaging

Lateral abdominal X-ray for aortic calcification, echo for valvular calcification - reasonable alternatives to CT-based scoring
DEXA is now recommended in CKD G3a-G5D if results will change management (previous guidance said it did not predict fracture)
Bone biopsy (tetracycline-labelled) is the gold standard - indicated if the lesion is uncertain and treatment depends on it, e.g. before antiresorptive therapy with unexplained low PTH

Renal osteodystrophy - the TMV classification

Lesion	Turnover	PTH	Features
Osteitis fibrosa cystica	High	High	2ary hyperPTH; marrow fibrosis, brown tumours, subperiosteal resorption (radial side of middle phalanges), rugger jersey spine
Adynamic bone disease	Low	Low/normal	Commonest in dialysis; over-suppression of PTH (Ca load, calcitriol, calcimimetics), diabetes, age, peritoneal dialysis. Hypercalcaemia + vascular calcification + fracture
Osteomalacia	Low	Variable	Defective mineralisation - vitamin D deficiency, acidosis, historically aluminium
Mixed uraemic osteodystrophy	High	High	Osteitis fibrosa + defective mineralisation

Phosphate

*Lower elevated PO4 toward the normal range* - treat persistent elevation, not a single result
- Do not treat mildly high PO4 prophylactically in G3a-G4
Dietary PO4 restriction - target additives and processed food (near-100% absorbed) before protein
Restrict the dose of calcium-based binders in all CKD stages (calcium carbonate, calcium acetate)
Non-calcium binders: sevelamer, lanthanum carbonate
Dialysis: adequate clearance; conventional HD removes little total phosphate

PTH

Non-dialysis CKD (G3a-G5)
- Optimal PTH level not established
- Progressively/persistently high PTH -> correct modifiable factors first: hyperphosphataemia, hypocalcaemia, high phosphate intake, vitamin D deficiency
- *Calcitriol and vitamin D analogues NOT recommended routinely* - reserve for severe progressive hyperparathyroidism
Dialysis (G5D)
- Target PTH 2-9x the upper limit of normal
- Calcimimetic (cinacalcet, IV etelcalcetide), calcitriol, or a vitamin D analogue - no preferred first-line agent
- Dialysate calcium 1.25-1.50 mmol/L
Parathyroidectomy if severe hyperparathyroidism refractory to medical therapy
- Watch for hungry bone syndrome - profound prolonged hypocalcaemia

Acidosis

Antiresorptives in CKD

Bisphosphonates contraindicated if eGFR <30 (and avoid where adynamic bone is likely)
Denosumab - not renally cleared, but *severe hypocalcaemia risk in advanced CKD - correct vitamin D and calcium first and monitor closely*
Never give an antiresorptive without knowing the turnover state

Calciphylaxis (calcific uraemic arteriolopathy)

Painful violaceous retiform necrotic skin lesions, very high mortality
Stop warfarin and calcium/vitamin D; sodium thiosulfate, cinacalcet, intensified dialysis, wound care, analgesia

Vascular and valvular calcification - medial (Monckeberg) arterial calcification, aortic stenosis
Cardiovascular mortality - the dominant outcome
Calciphylaxis - warfarin, obesity, female sex, diabetes, high Ca x PO4
Fracture, bone pain, proximal myopathy, pruritus
Tumoral calcinosis, red eye from conjunctival calcification
Tertiary hyperparathyroidism post-transplant - persistent hypercalcaemia + hypophosphataemia
Anaemia of CKD, protein-energy wasting - the wider uraemic syndrome

Begins at CKD G3a and is essentially universal by G5
Progression: FGF-23 rise -> calcitriol deficiency -> secondary hyperPTH -> parathyroid nodular hyperplasia -> autonomous (tertiary) hyperparathyroidism
Over-treatment produces adynamic bone - hypercalcaemia, accelerated vascular calcification, fracture
- The therapeutic window is narrow in both directions
Transplantation corrects most of the biochemistry but hyperparathyroidism can persist for years; post-transplant bone loss is fastest in the first 6-12 months
Fracture and vascular calcification are largely irreversible - the case for early phosphate and PTH control

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