Renal Osteodystrophyx

Renal Osteodystrophy/CKDMBD KDIGO (Kidney Disease: Improving Global Outcomes sponsored a controversies conference in 2005 to: • Develop a clear, clinically relevant and internationally acceptable definition and classification system • Develop a consensus for bone biopsy evaluation and classification • Evaluate laboratory and imaging markers for the clinical assessment of patients with CKD Systemic disorder of mineral and bone metabolism due to CKD manifested through combinations of the following: • Abnormalities of Ca, P, PTH or vitamin D metabolism • Abnormalities in bone turnover, mineralisation volume, linear growth or strength • Extraskeletal calcification • Note: most elements of CKD-MBD present when GFR <40mL/ min Abnormalities that lead to Secondary HyperPTism • Phosphate retention • ↓Free Ca concentration • ↓1,25-dihydroxyitamin D (calcitriol) concentration • ↑FGF-23 concentration • ↓Expression of vitamin D receptors (VDRs), CaSRs, FGF receptors and klotho in PT gland Vessel Calcification Decline in Calcitriol Concentration • Initially due to ↑FGF-23 concentration o Renal injury  ↑FGF23 and continues to increase with CKD o This is to maintain normal serum phosphate by increasing excretion in urine o FGF-23 inhibits 1-α-hydroxylase • In advanced CKD, hyperphosphataemia + ↓renal mass  ↓calcitriol synthesis Effects of Low Calcitriol Concentration on PTH Secretion • Indirect effect: ↓Ca intestinal absorption + ↓Ca release from bone  hypocalcaemia • Direct effect: calcitriol acts on VDRs in PT to suppress PTH transcription but not secretion o Reduced number of VDRs in PT  promote PT chief cell hyperplasia + nodule formation • Calcitriol administration can partially reverse hyperPTism Hypocalcaemia and CaSRs in CKD • Hypocalcaemia: ↑PTH + abnormal bone remodelling o Due to:  Phosphate retention  ↓Calcitriol concentration  Resistance to calcaemic actions of PTH on bone • Hypercalcaemia: extraskeletal calcifications o Tertiary hyperPTism • Number of CaSRs reduced in hypertrophied PT o  inadequate suppression of PTH secretion by Ca o Calcimimetic agent:  ↑Sensitivity of receptor to EC calcium  ↓PTH secretion  ↓PTH gene expression  ↑VDR expression in PT FGF-23 • Circulating peptide and phosphaturic agent • Secreted by osteocytes and osteoblasts in response to o Calcitriol, PTH, phosphate and calcium • Primary function is to maintain serum phosphate by o Reducing renal phosphate reabsorption  Inhibition of NaPiIIa and IIc cotransporters in PCT o ↓Calcitriol production  ↓intestinal phosphate absorption  Inhibits 1-α-hydroxylase • FGF-23 suppresses PTH secretion through klotho Klotho • Transmembrane protein produced by osteocytes • Required for FGF-23 receptor activation o Klotho expression declines early in CKD and progressive with GFR loss o ↓Klotho coincides with ↑FGF-23 o ↓klotho expression on hyperplastic PT glands may contribute to resistance and impaired PT suppression by FGF-23 Tertiary HyperPTism • ↑PTH concentration associated with hypercalcaemia in ESKD o Reflects severe PT hyperplasia with autonomous secretion of PTH no longer responsive to plasma Ca o Low calcitriol + high phosphate + low calcium  prolonged stimulation of PT cell growth o ↓Expression of CaSRs and VDRs  ↓suppression of PTH by increasing Ca or vitamin D analogues o Nodular PT glands do not undergo involution despite resolution of some of the triggering mechanisms (e.g. high PTH and hypercalcemia in CKD patients after receiving renal transplant) o Medical therapy often fails, parathyroidectomy required TMV (Turnover-Mineralisation-Volume) Characteristics of CKD-related Bone Diseases • Osteitis Fibrosa Cystica: high bone turnover due to secondary hyperPTism • Adynamic bone disease: low bone turnover o Result from excess PT gland suppression o Major bone lesion in peritoneal and haemodialysis patients • Osteomalacia: low bone turnover + abnormal mineralisation o Mineralisation lag time prolonged: >100days (normal: 35 days) o Now uncommon; used to use aluminium-based phosphate binders  aluminium deposition in bone • Mixed uraemic osteodystrophy: high or low bone turnover + abnormal mineralisation • β2-microglobulin-associated amyloid deposits: unique pathogenesis; occurs in patients with long term dialysis, presents as bone cysts Bone histology • Osteoid: red-brown with trichrome stain o Osteoid is new bone laid down by osteoblasts and is non-mineralised o Osteoid is laminar, present on <25% of bone surface and covered with osteoblasts (40%) o Bone resorption is minimal (<7%) and osteoclasts are present on <2% of surface • Mineralized bone: blue • Tetracycline is given twice, 10-14 days apart o Label is incorporated into mineralised bone and fluoresces under UV light o Bone biopsy done 3-5 days after the last label