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Hanan Ahmed Kotb, M.D.Professor of Rheumatology & Rehabilitation
Faculty of Medicine - Cairo University
Bone disease is one of the possible long-term complications after renal transplantation that can significantly influence quality of life.
The fracture rate in renal transplant patients is four times higher (normal population).
In addition, there is a risk for avascular bone necrosis after transplantation, which mainly affects weight-bearing joints, such as femoral heads.
Kunzendorf et al., Bone disease after renal transplantation. Nephrol Dial Transplant, 2008. 23 (2): 450-458
Retrospectively, 101 039 patients on the waiting list for renal transplantation were evaluatedRetrospectively, 101 039 patients on the waiting list for renal transplantation were evaluated
41 095 (40.7%) had never received a transplant were compared with 59 944 (59.3%) transplant recipients
41 095 (40.7%) had never received a transplant were compared with 59 944 (59.3%) transplant recipients
Mean follow-up duration was 2.98 yearsMean follow-up duration was 2.98 years
Transplant recipients’ risk of fracture was 34% higher than dialyzed patients on the waiting list.
Ball AM et al., Risk of hip fracture among dialysis and renal transplant recipients. JAMA. 288:3014-3018, 2002
Renal Bone Disease before
Transplantation
Renal Bone Disease after Transplantation
Kunzendorf U et al. Nephrol. Dial. Transplant. 2008;23:450-458
Factors causing Bone Disease after Transplantation
Renal Osteodystrophy
Abnormality of Bone Morphology;Turnover, Volume, Mineralization
Extra-skeletal Calcification
When 50% Of Kidney function is lost
Abnormalities of Calcium, Phosphorus, PTH, or vitamin D metabolism
Abnormalities in bone turnover, mineralization, volume, linear growth, or strength
Vascular or other soft tissue calcification
Moe S et al. Definition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 69: 1945-1953, 2006.
Renal OsteodystrophyRenal Osteodystrophy
Reduced GFR<60 ml/min
Reduced GFR<60 ml/min
Secondary Hyperparathyroidism
Secondary Hyperparathyroidism
Hypocalcemia
Hypocalcemia
Phosphorous
Retention
Interference of 1,25 (OH)2
Vit D synthesisby kidneys
Low or Normal
1,25 (OH)2Vit D
Vit. D Binding Protein
DeficiencyVit. D resistance
Decreased expression
of Vit D receptors
on Parathyroid
Relative/Absolute
Vit D Deficiency
1-α-hydroxylase inhibition
High Bone TurnoverResorption > Formation
Decreased Bone Strength
Disrupts Trabecular Architecture
Decreases Bone Mass
Increases Cortical PorosityDecreases Cortical Thickness
Alters Bone Matrix Composition L. MosekildeTech and Health Care, 1998
Bouxsein. Best Practice in Clin Rheum. 2005; 19:897-911Seeman & Delmas, New England J Med, 2006; 354:2250-61
Secondary Hyperparathyroidism
Disorder Description Pathogenesis
Osteitis fibrosa Increased remodeling frequency, increased osteoclast activity and resorption depth, marrow fibrosis
Secondary hyperparathyroidism
OsteomalaciaDefective mineralization, increased osteoid
Vitamin D deficiency, aluminum deposition, other unknown factors
Adynamic renal bone disease
Decreased remodeling, hypocellular bone surface
PTH over suppression, other unknown factors
Mixed renal osteodystrophy
Increased remodelingDefective mineralization
Elements of the effects of hyperparathyroidism on bone together with mineralization defects
High- Turnover Metabolic Bone
disease
AD: Adynamic Bone OM: Osteomalacia OF: Osteitis Fibrosa
Prevalence of types of bone disease as determined by bone biopsy in patients with CKD-MBD.
Prevalence of types of bone disease as determined by bone biopsy in patients with CKD-MBD.
TransplantationTransplantation
2 ry Hyperthyroidism
Hyperphosphatemia
Hypocalcaemia
Vitamin D deficiency
Hypogonadism
2 ry Hyperthyroidism
Hypophosphatemia
Hypercalcaemia
Vitamin D Status
Immunosuppressive ttt
Loss of BMD (1st year)
Transplant Function
CKD-MBDCKD-MBD
Post- TransplantationPost- Transplantation
Factors Independent of the
Renal DiseaseDiabetes
Metabolic Acidosis
Hypogonadism, dysregulation of sex
hormones
Medications: Anticonvulsants, loop
diuretics, heparin
Advancing age, Physical inactivity, smoking
Kunzendorf U et al., Bone disease after renal transplantation. Nephrol. Dial. Transplant. 23 (2): 450-458, 2008.
Bone Disease after Transplantation
Bone Disease after Transplantation
Often AsymptomaticOften AsymptomaticFracturesFractures
Bone painBone pain
Loss of height
Vertebral fractures
Reduced pulmonary function
Chronic disability
Spontaneous tendon ruptureSpontaneous tendon rupture
Proximal muscle weakness
Proximal muscle weakness
Deformities in growing children, reduced growth velocity, and abnormal height
Deformities in growing children, reduced growth velocity, and abnormal height
Hip fractures
Nonspecific
Serum Ca, PhosphorusSerum (OH) Vitamin DSerum PTHSerum Alkaline PhosphataseMeasurement of markers of:Bone formation (serum osteocalcin)
and Bone resorption (urinary
deoxypyridinoline/creatinine)
Plain radiography May reveal only
osteopenia. Complications such as
Looser zones and complete fractures.
The findings of renal osteodystrophy
Looser zones
Bone scans may reveal diffuse skeletal uptake
In addition, bone scans may reveal pseudofractures or sites of extraskeletal calcification, which also may be distinctive for secondary hyperparathyroidism.
Bone scan findings usually are supportive of, but are of limited primary diagnostic value to, renal osteodystrophy.
BMD after transplantation can be measured by means of bone density (DEXA or quantitative CT) with X-rays of thoracic & lumbar spine to identify fractures.
DXA does not distinguish between CKD-MBD effects on cortical and trabecular bone.Bone turnover: (through bone
histomorpho-metric examination) of trans-iliac crest bone biopsies after tetracycline labeling.
Bone turnover: (through bone histomorpho-metric examination) of trans-iliac crest bone biopsies after tetracycline labeling.
What is the Management?Hypophosphatemia
2ry HyperparathyroidismHypercalcemia
Vitamin D deficiencyImmunosuppressives
Bone Formation and mineralization
Bone Resorption
Effect
The bone disease that develops with renal insufficiency is aggravated after renal transplantation by other factors:
Optimal treatment of Renal Osteodystrophy pre- transplantation
Prevention of Bone disease during the 1st year
Treatment of post-
transplantation bone disease
To correct Vitamin D deficiency by ergocalciferol in sufficient dosage to raise 25-hydroxyvitamin D levels above 30 ng/ml.
In advanced kidney disease, the use of active vitamin D; calcitriol
Dietary restriction of phosphorus Calcium supplementation Treatment of established secondary
hyperparathyroidism
Normal 2ry HyperparathyroidismDiffuse Hyperplasia
Point of No Return3ry Hyperparathyroidism
Nodular Hyperplasia
Control of Serum CalciumCalcitriol/Ergocholecalciferol Parathyroidectomy
Direct Injection Therapy
Calcimimetic Agents - Cinacalcet(Mimpara 30,60,90mg)
Management of Secondary Hyperparathyroidism in CKD-MBD
Komaba et al. Treatment of chronic kidney disease-mineral and bone disorder. Inter Med 47: 989-994, 2008
Treatment for secondary hyperparathyroidismCalcitriol has been shown to suppress PTH secretion
effectively and inhibit cell proliferation in parathyroid hyperplasia (400-800 IU/d)
Calcitriol has been shown to suppress PTH secretion effectively and inhibit cell proliferation in parathyroid
hyperplasia (400-800 IU/d)This treatment may increase the risk for hypercalce- mia and hyperphosphatemia, resulting in withdrawal or a reduction in the dose of calcitriol. Parathyroid intervention, i.e., surgical parathyroidectomy and direct injection therapy, should be indicated for refractory hyperparathyroidism associated with nodular hyperplasia.
Vitamin D Calcitriol 0.25–0.5 μg/day or cholecalciferol 600 units/day
Calcium 1000 mg/day, or 1500 mg/day in post-menopausal women
Bisphosphonates In patients with an increased fracture riskb and good transplant function GFR > 60 ml/min and a T-score <-2SDAvoidance of loop diureticsSex hormone replacement therapyTreatment of:
Thyroid dysfunctionHyperparathyroidismHypophosphataemiaHypomagnesaemiaPhysical activityNo smokingUse of calcitonin
Treatment and Prevention of Bone Disease after Renal Transplantation According to the European Best Practice Guidelines
Hypercalcaemia is a contraindication. Consider, calcitriol may further impair a deteriorated kidney function
European best practice guidelines for renal transplantation. Nephrol Dial Transplant 2002
Factors associated with increased fracture risk include: # Severe osteoporosis, # Previous fractures, # Diabetes mellitus, # Postural Instability# Prolonged Oral GCs# Post-menopausal women.
Factors associated with increased fracture risk include: # Severe osteoporosis, # Previous fractures, # Diabetes mellitus, # Postural Instability# Prolonged Oral GCs# Post-menopausal women.
Bisphosphonates have proven effective in preventing bone loss after transplantation.
Has no significant effect on fracture reduction.
Oral administration does not appear to alter renal function.
Before starting treatment with bisphosphonates, teeth with poor prognosis should be extracted and surgical dental procedures performed.
Bisphosphonates pose potential risks for adynamic boneBisphosphonates pose potential risks for adynamic bone
Most patients who undergo kidney Tx have renal osteodystrophy, and immediately after transplantation bone mineral density (BMD) commonly falls.
Together, these abnormalities predispose to an increased fracture incidence.
The administration of vitamin D and calcium is effective in preventing post-transplant bone density loss.
This also applies to therapies with bisphosphonates, which are indicated in patients with a high fracture risk.
The use of vitamin D and calcium is limited by hypercalcaemic episodes and hyperparathyroidism in many cases.
Bisphosphonates pose potential risks for adynamic boneBisphosphonates pose potential risks for adynamic bone
The gold standard in the diagnosis and classification of skeletal lesions in renal osteodystrophy remains quantitative histomorphometry of transiliac crest bone biopsies after tetracycline labeling.
Unfortunately it is an invasive procedure that is of limited availability.
BMD after transplantation can be measured by means of bone density (DEXA or quantitative CT) with X-rays of thoracic & lumbar spine to identify fractures.
DXA does not distinguish between CKD-MBD effects on cortical and trabecular bone.
Bone turnover (through bone histomorpho-metric examination). DXA may be of limited value in CKD
The radius: preferred site of measurement in CKD pat.
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