Renal Osteodystrophy

Calcium: Normal Metabolism

Normal Total Serum Calcium Concentration: 8.5-10.5 mg/dl (2.12-2.62 mM)

50% ionized form; 10% complexed (mainly to citrate and phosphate); 40% protein-bound (90% to albumin)

Daily intake: – 600-1000 mg, with net absorption of 20%; Urinary excretion: approximately 175 mg/day, or about 2% of the glomerular filtered calcium; 98% being reabsorbed by the kidney: 65% proximal tubule, 25% loop of Henle, 8% distal tubule. Fecal excretion: 825 mg/day.

Phosphate: Normal Metabolism

Normal Serum (Inorganic) Phosphorus Concentration: 2.5 – 4.5 mg/dl (0.81-1.45 mM)

55% ionized (HPO4-2, H2PO4-, PO4-3); 35% complexed (to Na, Ca, Mg); 10% protein-bound

Daily intake: 1400mg, with net absorption of two thirds. Urinary excretion: approximately 900mg/day, or about 12.5% of the glomerular filtered phosphorus, 87.5% being reabsorbed by the kidney: 85% proximal tubule, 15% distal tubule. Fecal excretion: 500mg/day.

Hormones Regulating Calcium and Phosphate Balance

Parathyroid Hormone (PTH)

Single chain protein of 84 amino acids, secreted by the parathyroid glands.

Normal serum range for the intact PTH 10-60 pg/ml.

Factors affecting synthesis and secretion: serum calcium, serum 1,25(OH)₂D, serum phosphorus: indirectly or directly.

Actions: Ý resorption of calcium and phosphorus from the bone; Ý reabsorption of calcium Þ ß reabsorption of phosphorus; Ý renal synthesis of 1,25 dihydroxyvitamin D Þ Ý intestinal absorption of calcium and phosphorus

Net effect: Ý extracellular fluid calcium and ß extracellular fluid phosphorus

Calcitriol (1,25 dihydroxyvitamin D₃)

Steroid with MW 416.3, short half-life of 10h, produced in normal circumstances in the proximal tubules of the kidney.

Normal serum range for calcitriol is 25-45 pg/ml.

Main factors increasing the synthesis of calcitriol: Ý PTH , ß Calcitriol, ß phosphorus. Other: Ca²⁺, metabolic acidosis.

Actions: Ý intestinal calcium and phosphorus absorption; enhance mobilization of calcium and phosphorus from the bone; Ý calcium and phosphate reabsorption in the kidney; (ß PTH synthesis and secretion)

Net effect: increases the serum concentration of calcium and phosphorus

Calcitonin

32 amino-acid peptide secreted by the thyroidal C-cells.
Normal serum concentration is 2-10 pg/ml.
Main biologic action – inhibit osteoclastic bone resorption (transient effect ).
Not an important regulator role in adult calcium homeostasis; more important during growth. Day-Day role: questioned

Bone: Normal Metabolism

Macroscopic organization: Cortical (compact) bone - 80-90% calcified, serves mechanical function; Cancellous (trabecular) bone - 15-25% calcified, metabolic function

Microscopic organization:

Inorganic phase – Mineralized bone; 2/3 of the mature bone weight - 99% of the body Ca (Ca₁₀(PO₄)₆(OH)₂ )
Organic phase - Unmineralized bone – cells: Osteoblasts synthesize matrix; Osteoclast resorb bone mineral; Osteocytes; Lining cells. Composed of matrix (osteoid) 85-90% collagen (type I) and non-collagen proteins.

Mechanisms of Ca mobilization:

Mineral exchanges between bone and extracellular fluid: biophysical mechanism "rapidly exchangeable Ca pool"
Operant on all free bone surfaces: cell mediated mechanism major component of the "remodeling "process requires – hormonal interaction (PTH, 1,25(OH)₂D₃); slower than mineral exchanges. Controlled by local factors (growth factors, cytokines). 10% of the bone is remodeled annually.

Calcium and Phosphate Metabolism in Uremia

ß GFR (30 –50 ml/min) in renal failure Þ Ý serum Pi and ß calcitriol (1,25(OH)₂D₃)

Ý serum Pi

ß calcitriol (suppression of the renal 1a -hydroxylase activity)

ß serum Ca (physicochemically, via the Ca x P solubility product)

Ý PTH, independent of Ca and calcitriol

ß calcitriol (appears at GFR < 50 mL/min) Þ

ß intestinal calcium absorption with secondary hypocalcemia

Ý PTH synthesis and secretion (due to lack of supression)

Hypocalcemia Þ Ý PTH synthesis and secretion.

Causes:

ß 1,25 D Þ ß intestinal absorption

Ý Pi Þ Ý Ca+PiÞ Ca deposition and ß Ca level

renal patients have Ý skeletal resistance to the calcemic action of PTH Þ Ý PTH levels are needed to maintain Ca

Renal Osteodystrophy

Refers to the spectrum of bone diseases that can occur as a complication of renal failure.

Classifications:

High-turnover lesions (due to persistently Ý serum PTH levels): mild uremic bone disease and osteitis fibrosa.

Low-turnover lesions (due either to Ý bone aluminum deposition or to normal or ß PTH serum levels): osteomalacia and adynamic bone disease.

Dialysis related amyloidosis

Osteitis fibrosa (severe hyperparathyroid bone disease)

High turnover bone lesion; most common bone lesion in hemodialysis patients (50-60%).

Represents the response of bone to persistently Ý PTH ( > 250-300 pg/mL) patients.

Pathogenesis: secondary hyperparathyoidism

Clinical presentation: non specific bone pain, proximal myopathy (resolves with vitamin D administration), rarely spontaneous tendon rupture

Radiographic findings: subperiosteal erosions of the phalanges, proximal end of the tibia, neck of the femur or humerus, distal clavicle; patchy osteosclerosis "salt and pepper" skull, "rugger jersey"; vertebrae brown tumors (erosions occurring in concert with the new bone formation) - isolated cysts.

Bone histology: increased number of osteoclasts and osteoblasts, normal osteoid volume (woven osteoid and peritrabecular fibrosis), normal mineralization, increased bone formation rate.

Treatment: Phosphorus control (goal < 5.6 mg/dl)

Diet < 100-1000mg/day; phosphate binders (Ca CO₃, etc) - prevent intestinal Pi absorption; dialysis – hemodialysis (0.6-1g /session), peritoneal dialysis (0.3g /day); calcium control (goal 9.5-10.5mg/ dL); Vitamin D (Calcitriol or analogs); dialysis patients (i.v. or p.o.); parathyroidectomy; calcimimetics – ß PTH by activating Ca receptor on the parathyroid gland.

Osteomalacia

Low turnover bone lesion

Almost always due to aluminum intoxication, rarely vitamin D deficiency, phosphate depletion.

Normal Aluminum Metabolism: Diet 1-4 mg (elemental Al); 10-90 m g/ day intestinal absorption; 10-90 m g/ day renal excretion

Risk factors for Al toxicity: diabetes mellitus, increased consumption of aluminum-based phosphate binders, especially in association with citrate, prior to parathyroidectomy.

Pathogenesis: aluminum inhibits PTH secretion, osteoblasts’ function and hydroxyapatite crystal formation.

Bone histology: decreased number of osteoblasts and osteoclasts, increased osteoid volume, decreased mineralization and bone formation. (Deposits of aluminum along trabecular bone surfaces, in aluminum related cases).

Clinical manifestations: bone pain, fractures of the large bones and proximal muscle wasting.

Radiographic findings: pseudofractures (wide radiolucent bands in the cortex oriented perpendicular to the longitudinal axis of the bone)

Treatment: discontinue all aluminum sources. Deferoxamine (chelation) administered in dialysis for symptomatic patients. Correction of hypocalcemia, calcitriol deficiency in non-Al related cases.

Adynamic bone disease

Low turnover bone lesion, associated with PTH level below 100 pg/ml

Most common bone lesion in peritoneal dialysis patients

Pathogenesis: not known, suspected oversupressed PTH

Predisposing conditions: hypoparathyroidism, corticosteroids, diabetes, Al toxicity.

Bone histology: decreased number of osteoblasts and osteoclasts, low osteoid volume, decreased bone mineralization, with low or no bone formation rate; increased Al staining in about 1/3 of cases.

Clinical signs: bone pain, increased incidence of fractures, hypercalcemia, soft tissue calcifications.

Treatment: avoid PTH oversuppresion.. Stimulate PTH (to the 200’s) by inducing mild hypocalcemia during dialysis with low calcium dialysate. Avoid calcitriol therapy, ß all Al sources (if present).

Dialysis-related amyloidosis

Long term complication in patients > 7-10 years on dialysis; don’t even suspect if not 7 years on dialysis.

Pathogenesis: deposition of a unique, amyloid fibril derived from b 2-microglobulin in bony structures and synovial tissue of dialysis patients. (b 2 microglobulin almost entirely metabolized by the normal kidney).

Clinical manifestations: carpal tunnel syndrome, arthralgias, bone pain, pathologic fractures.

Radiographic findings: Subchondral bone erosions, destructive arthropathy and spondiloarthropathy, multiple cystic bone lesions at the end of long bones.

Treatment: None available right now. Renal transplant stops progression, but does not cause dissolution of the existing amyloid deposits.