Hanan Ahmed Kotb, M.D.

Professor of Rheumatology & Rehabilitation Faculty of Medicine - Cairo University

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 dorf et al., Bone disease after renal transplantation. Nephrol Dial Transplant, 2008. 23 (2): 45

Bone

Retrospectively, 101 039 patients on the waiting list for renal transplantation were evaluated Mean follow-up duration was 2.98 years 41 095 (40.7%) had never received a transplant were compared with 59 944 (59.3%) transplant recipients 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.

Factors causing Bone Disease after Transplantation

Renal Bone Disease before Transplantation
When 50% Of Kidney function is lost

Renal Osteodystrophy Abnormality of Bone Morphology; Turnover, Volume, Mineralization Extra-skeletal Calcification

Kunzendorf U et al. Nephrol. Dial. Transplant. 2008;23:450458

Renal Bone Disease after Transplantation

Renal Osteodystrophy

Abnormaliti es of Calcium, Phosphorus, PTH, or vitamin D metabolism

Abnormalitie s in bone turnover, mineralizatio n, volume, linear growth, or strength

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.

Vascular or other soft tissue calcification

Reduced GFR <60 ml/min

Phosphoro us Retention
1--hydroxylase inhibition

Vit. D Binding Relative/Absolut Protein Deficiency e Vit. D resistance

Vit D Deficiency

Decreased expression of Vit D receptors on Parathyroid

Low or Normal 1,25 (OH)2 Vit D

Interference of 1,25 (OH)2 Vit D synthesis by kidneys

Hypocalce mia Secondary Hyperparathyroidism

econdary Hyperparathyroidism High Bone Turnover Resorption > Formation

Decreases Bone Mass Disrupts Trabecular Architecture Increases Cortical Porosity Decreases Cortical Thickness Alters Bone Matrix Composition
L. Mosekilde Tech and Health Care, 1998

Decreased Bone Strength

Bouxsein. Best Practice in Clin Rheum. 2005; 19:897-911 Seeman & Delmas, New England J Med, 2006; 354:2250-61

Disorder Osteitis fibrosa

High- Turnover Metabolic Bone disease

Description

Pathogenesis

Increased remodeling Secondary frequency, increased hyperparathyroidism osteoclast activity and resorption depth, marrow fibrosis Defective mineralization, increased osteoid Vitamin D deficiency, aluminum deposition, other unknown factors

Osteomalacia Adynamic renal bone disease Mixed renal osteodystrophy

Decreased remodeling, PTH over suppression, hypocellular bone other unknown factors surface Increased remodeling Defective mineralization
Elements of the effects of hyperparathyroidism on bone together with mineralization defects

Prevalence of types of bone disease as determined by bone biopsy in patients with CKD-MBD.

AD: Adynamic Bone OM: Osteomalacia OF: Osteitis Fibrosa

Bone Disease after Transplantation

Transplantation Post- Transplantation 2 ry Hyperthyroidism Hypophosphatemia Hypercalcaemia Vitamin D Status Immunosuppressive ttt Loss of BMD (1st year) Transplant Function

CKD-MBD Factors Independent 2 ry Hyperthyroidism of the Renal Disease Hyperphosphatemia

Diabetes Metabolic Acidosis Hypogonadism, dysregulation of sex Vitamin D deficiency hormones Medications: Anticonvulsants, Hypogonadism 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.

Hypocalcaemia

Often Asymptomatic Bone pain

Non specific

Hip fractures

Fractures Vertebral fractures Loss of height Reduced pulmonary function Chronic disability

Proximal muscle weakness Spontaneous tendon rupture

Deformities in growing children, reduced growth velocity, and abnormal

 Serum Serum Serum Serum

Ca, Phosphorus (OH) Vitamin D PTH Alkaline Phosphatase Measurement 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

 BMD

after transplantation can be measured by means of bone density (DEXA or quantitative CT) with Xrays of thoracic & lumbar spine to identify fractures. DXA does not distinguish between CKD-MBD effects on cortical and Bone turnover: (through bone trabecular bone. histomorpho-metric examination) of trans-iliac crest bone biopsies after

The bone disease that develops with renal insufficiency is aggravated after renal transplantation by other factors:

Hypophosphatemia 2ry Hyperparathyroidism Hypercalcemia Vitamin D deficiency Immunosuppressives Effect Bone Formation and mineralization Bone Resorption

What is the Management?

Optimal treatment of Renal Osteodystrophy pre- transplantation Prevention of Bone disease during the 1st year Treatment of posttransplantation 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

Management of Secondary Hyperparathyroidism in CKD-MBD

Point of No Return 3ry Hyperparathyroidism Nodular Hyperplasia 2ry Hyperparathyroidism Diffuse Hyperplasia

Normal

Control of Serum Calcium Calcitriol/Ergocholecalciferol

Parathyroidectomy Direct Injection Therapy

Calcimimetic Agents - Cinacalcet (Mimpara 30,60,90mg)

et al. Treatment of chronic kidney disease-mineral and bone disorder. Inter Med 47: 989-994, 2008

 Treatment

for secondary hyperparathyroidism Calcitriol has been shown to suppress PTH secretion

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

effectively and inhibit cell proliferation in parathyroid hyperplasia (400-800 IU/d)

Treatment and Prevention of Bone Disease after Renal Transplantation According to the European Best Practice g/day or Guidelines Vitamin D Calcitriol 0.250.5
cholecalciferol 600 units/day

Hypercalcaemia is a contraindication. Calcium 1000 mg/day, or 1500 mg/day in postConsider, calcitriol may further impair a deteriorated menopausal women kidney function
Bisphosphonates In patients with an increased fracture Factors associated riskb and good transplant function with GFR > 60 ml/min and a T-score <-2SD increased fracture risk include: Avoidance of loop diuretics Sex hormone replacement therapy # Severe osteoporosis, Treatment of: # Previous fractures, Thyroid dysfunction # Diabetes mellitus, Hyperparathyroidism # Postural Instability Hypophosphataemia # Prolonged Oral GCs Hypomagnesaemia Physical activity # Post-menopausal No smoking women. European best practice guidelines for renal transplantation. Nephrol Dial Use of calcitonin

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 sphosphonates pose potentialextracted and prognosis should be risks for adynamic bo

Bisphosphonates

 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.

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 adynamic bo sphosphonates pose potential risks for many

The

 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.

Lifestyle Modificati on

Exercise

Weight bearing exercises Back strengthening exercises Balance training exercises

Often asymptomatic. It may result in fractures (including asymptomatic fractures seen on vertebral radiographs), bone pain, deformities in growing children, reduced growth velocity, and abnormal height. Spontaneous tendon rupture & proximal muscle weakness. Vertebral fractures lead to height loss, reduced pulmonary function and chronic disability. Complications of hip fractures include

Stimulates renal reabsorption Stimulates bone resorption of Ca Serum Ca Inhibits bone formation and Inhibits renal reabsorption of mineralization phosphorus Serum P Serum Ca Serum Calcium Net effect of PTH Serum phosphate Stimulates synthesis of Calcitriol.

Stimulates renal reabsorption of Ca and phosphorus

Stimulates bone resorption

Stimulates absorption of both Ca and Phosphate

Net effect of Calcitriol

Serum Calcium Serum

 Treatment

for secondary hyperparathyroidism Treatment for Osteomalacia Bisphosphonates:

Pamidronate Zoledronic acid

Replacement Therapy and Estrogen Receptor Modulators after Renal pamidronate treatment was In 2 studies,Transplantation
associated with development of adynamic bone

Hormone

Frequency of Measurement of Ca, P, and PTH after Kideny Transplantation Parameter Calcium Phosphate PTH First 3 months Every 2 weeks Every 2 weeks Monthly 3-12 months Monthly Monthly Every 3 months

One year after transplantation, the frequency measuring should depend on the level of kidney function

Baker R. Post-operative Care of the Kidney Transplant Recipient. UK Renal Association Final Version (2011)

Baker R. Post-operative Care of the Kidney Transplant Recipient. UK Renal Association Final Version (2011)

Osteoporosis KTRs suffering from osteoporosis or at high potential risk should be considered for steroid-avoiding immunosuppression. (2D) KTRs on longterm steroids or at high risk for osteoporosis should undergo DEXA scanning if eGFR>30 ml/min/1.73m2. (2D) Treatment should be according the RCP guidelines for steroid-induced osteoporosis. (2D) Tertiary hyperparathyroidism Severe hyperparathyroidism should be treated prior to transplantation. (2D) Cinacalcet can be used in KTRs. (2C) Treatment should be the same as for other patients with CKD (2D)

 The

use of bisphosphonates is limited to the high-risk group with a T-score <-2SD.

Patients with preexisting fractures and

severe osteoporosis, Type II diabetes, Recipients of kidney and pancreas transplants, Postmenopausal women.

Factors causing Bone Disease after Transplantation

Renal Bone Disease before Transplantation Factors Associated Factors Independent with Transplantation of the Renal Disease
2ry Hyperparathyroidism Hypophosphatemia Vitamin D status Immunosuppressive therapy Hypomagnesemia Transplant function
Diabetes Metabolic Acidosis Hypogonadism, dysregulation of sex horrmones Medications: Anticonvulsants, loop duiretics, heparin Advancing age, inactivity, Kunzendorf U et al. Nephrol. Dial. Transplant. 2008;23:450smoking
458

Renal Bone Disease after Transplantation

after transplantation can be measured by means of bone density (DEXA or quantitative CT) with Xrays of thoracic & lumbar spine to identify fractures. DXA does not distinguish between CKD-MBD effects on cortical and trabecular bone. DXA may be of (through bonein CKD Bone turnover limited value histomorpho-metric examination). radius: preferred site of measurement in CKD

BMD

Control serum phosphorus levels in patients with CKD

Reduced GFR <60 ml/min

Phosphoro us Retention Low or Normal 1,25 (OH)2 Vit D Interference of 1,25 (OH)2 Vit D by kidneys

ve Dietary phosphorus irestriction and ect

conventional dialysis

f Inef

Most dialysis patients require phosphorus binders.

ed on Aluminum-basednd binders were ba A
once used extensively

Aluminum was binders alcium-basedfound to contribute to:

linked to arterial anemia, myopathies, calcification dementia, and observed inlowturnover bone disease. hemodialysis Non-calcium and nonpatients

Phosphorus is the most significant Hypocalce and probably the most studied mia aluminum-based binders vascular Secondary calcification promoter Hyperparathyroidism

 The

management of bone disease after renal transplantation should take into account at least three different issues:
The optimal treatment of renal

osteodystrophy before renal transplantation and the Prevention of bone disease during the first year, when the bone loss has been demonstrated to be most important Treatment of decreased bone mass in

Osteoblasts Osteoclasts Growth factors and Cytokines Mechanical Stress Systemic hormones

The skeleton is a highly specialized and dynamic organ Modeling

Remodelin The skeleton is sculpted g to achieve its shape and Growth Mineral size Regeneration Homeostasis

The main recognized for the body bone Provide support functions of remodeling include preservation of bone Provide leverage and movement mechanicalProtect body organs strength by replacing older, Hematopoiesis within marrow spaces microdamaged bone with newer, healthier Maintenance of mineral phosphate bone and calcium andhomeostasis

enal Osteodystrophy

Chronic Kidney Disease

CKD-MBD
Calcium and Phosphorous Abnormalities Secondary Hyperparathyroidism Vitamin deficiency Vascular Calcification Bone Abnormalities

Cardiovascular Disease

Decrease d QOL CHRONIC KIDNEY DISEASEBone Disease

Mortalit y

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.

MINERAL AND BONE DISORDER

 The

main alterations in bone remodeling after renal transplantation consist of:

A decrease in bone formation and

mineralization Producing an imbalance in remodeling and Persistent bone resorption, favoring resorption over bone formation.

Likewise,

the defective bone formation may be a consequence of