Final 2 Bone Disease After Kidney Transplantation

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.