Case 3: A 61-year-old male with a kidney transplant 24 years ago presented with generalized bone pain

1. CKD-MBD By
Mohsen El Kossi
Consultant Renal
Physician

2. CKD-MBD and
Increase
Morbidity and
Mortality
Cardiovascular
novel risk factors:
• Hyperphosphataemia
• Vascular calcification
(intimal and medial)
• Increased FGF23
General
population and
CKD

6. Recognized Players of CKD-MBD
Phosphate
Osteoblast transition
in extraskeletal
tissues
Increase PTH
secretion
Inhibits 1 alfa
hydroxylase
Stimulates FGF23
Calcium PTH
Bone resorption with
more Ca and P in the
circulation
Vitamin D
Deficient in CKD due
to elevated FGF23
FGF23
Cardiac hypertrophy
directly and indirectly
Associated with
kidney transplant loss
Increased risk of
mortality
Klotho
Decreased in CKD
Main player of
phosphate regulation
will be PTH rather
than FGF23

7. Pathophysiology
of CKD-MBD
GFR reduction
(stage 2):
Phosphate
retention
FGF23 and PTH
reduce tubular
reabsorption
Serum
phosphate
elevation (stage
4-5)

8. New Players in CKD-MBD
DKK1
Wnt inhibitor
Sclerostin
Wnt inhibitor
Regulator of bone
mass
Bone
morphogenetic
protein (BMP)
Instrumental in
vascular calcification
and tissue fibrosis
Activin
Mediates CKD
endothelial
mesenchymal
transition and vascular
calcification

9. Mal-adaptive
Physiology
Increased PTH
increase bone
resorption
High Ca
dialysate
Excess
Circulating
Ca and P

10. HighTurnover
(OF)
Abnormal
Mineralisation(OM)
Low
Turnover
(AD)
Mixed
Skeletal Changes (TMV)
(1) Turnover (2) Mineralisation (3) Volume

11. Soft Tissue Calcification
(Vascular and Valvular)

12. CKD-MBD Bone Disorders
1- Osteitis fibrosa cystica
Secondary or tertiary HPTH.
High turnover bone disease.
Cortical bone loss, increased osteoclast activity, endo-osteal fibrosis.
Biochemically: high Ca, PTH, Pi, AP and osteocalcin.
• (Malluche et al; 2010)

13. CKD-MBD
Bone
Disorders
2-Adynaemic
bone disease
Over suppression of PTH.
Patients at risk, elderly, peritoneal dialysis, ca
based binders, over-suppressed PTH.
Low cellular activity (few osteoblasts and
osteoclasts) with thin osteoid.
Loss of cancellous bone.
High cardiovascular and soft tissue
calcification and high mortality.
Biochemically: High Ca, low PTH and AP.

14. CKD-MBD
Bone
Disorders
3-Osteomalcia
• Defective mineralization.
• Risk factors: hypophosphataemia, low vitamin
D, and aluminum intoxication (lack of water
purification in the past).
• Wide un-menarlized osteoid, absent/few
osteoblast and osteoclasts.
• Biochemically: low phosphate, Ca, and normal
to high PTH and AP.

15. CKD-MBD
Bone
Disorders
4- Osteopenia
• Diagnosed by low BMD on DEXA scan.
• Risk factors, females, elderly, malnutrition,
immobility, Caucasians, hypogonadism,
metabolic acidosis, long term use of steroids.
• No specific biochemical abnormality.

16. Radiography of Osteoporosis

18. CKD-MBD Bone Disorders
5-Dialysis Related Amyloidosis
B2-microglobulin with lytic
bone lesions and destructive
arthropathy
01
Arthritic symptoms improve
post Transplantation but lytic
lesions persist
• (Zhang et al; 2008.)
02

19. Evidence Base and CKD-MBD
Current practice is based on understanding of
pathophysiology rather than good quality trails
with hard end point
(Fracture, CV events, CKD progression and
mortality)

20. KDIGO CKD-
MBD 2017
Guidelines
Chen and Bushinsky 2017

21. CKD-MBD Post Kidney
Transplantation

22. Post Kidney Transplantation Bone Mineral Changes
Any of pre
transplant forms
could persist.
Mixture of any of
these forms.
Evolution into
different forms.
Fractures
Biochemical
changes.
Unique forms.
Bone pain
syndrome
Osteonecrosis.

23. Corticosteroids
• Increasedriskofvertebralfracturewithanoraldoseof
prednisoloneofas lowas2.5mg/d.
• Inhibitboneformationthroughreducingosteoblast
proliferationandfunction.
• Stimulate osteoblastapoptosis.
• Promoteboneresorptionbystimulatingosteoclastogenesis.
• Createnegativecalciumbalancethroughreducingintestinal
absorptionandincreasing urinaryexcretionstimulatingPTH
secretion.
• Lessmobilitywithmuscleweakness.
• Inducehypogonadotrophichypogonadism.
• Disproportionatelossofcancelloustotrabecularbone.
• Maximumreductioninbonevolumeoccursinthefirst6
monthpost-transplantation

24. Recommendations
1
There is no threshold for
daily maintenance dose or
cumulative dose.
2
The least possible or steroid
avoidance due to multiple
negative effects on bone
metabolism.
3
It’s recommended to
reduce steroid to minimize
risk of fracture for those
with pre-transplant
osteoporosis.
4
Reduced risk of fracture
and fracture related
hospitalization in steroid
free kidney transplant pts
(USRDS data).
5
Be cautious in
immunologically high risk
recipients to avoid rejection
and increasing steroid
pulses.

25. Post Kidney
Transplant
Bone Mineral
Changes
2-
Osteonecrosis
6-24 month post transplantation affect around
15% of pts.
Common in the femoral heads but can occur in
knees, shoulders or elbow.
Joint pain is the presenting symptom.
MRI is the investigation of choice.
Main risk factor is cumulative steroid dose, DM
and lupus.
Management: rest, decompression,
vascularised bone graft and joint replacement.

26. Avascular Necrosis

27. Post Kidney
Transplantation
Bone Mineral
Changes
3- Fractures
Kidney transplant recipients are at increased risk of
fracture compared to general population or dialysis
patients (20% experience fracture).
Fracture risk is similar to post menopausal women.
Fracture reduces recipient survival (60% mortality).
Classic patients at increased risk: women, with low
body weight (<70 kilo), White and Asian, prolonged
period of amenorrhea, or early menopause.

28. Fracture Post Kidney
Transplantation
FRAX (Fracture Risk Assessment
Tool)
• Predictriskofmajorfractureover10yearsinthegeneral
population.
• Majorfracturesareproximalhumorous,forearm,hipand
vertebral.
• Variablesareage,sex,alcoholusemorethan3units/day,
smoking, glucocorticoiduse,rheumatoidarthritis, BMI,hip
BMDandparentalhipfracture.
• Thistoolneedsadjustment toincludetransplantationspecific
factorsandvalidationtoworkinkidneytransplantpatients.
• AstudyexploredFRAXintransplantationpatientsandarea
underROC0.62butthestudypowerwaslow(21 fractures
only)(Nayloretal2014).

29. Post Kidney Transplantation Bone Mineral Changes
4-Biochemical Changes
Dramatic drop of serum
Pi, Mg, and PTH early
post transplant.
01
Improvement of 25(OH)
and 1,25(OH)2vitamin D.
02
These changes are
followed by persistent
low levels of vitamin D
due to high FGF23 .
03
Subset of patients have
persistent
hyperparathyroidism
either due to autonomus
gland and/or low vitamin
D levels.
04
Persistent high PTH can
induce hypercalcaemia.
05

30. Post Kidney Transplantation Bone Mineral
Changes
• Serial analysis of bone parameters in 129 CyA and steroid treated
kidney transplants:
• Serum phosphorus remained at low normal (0.98 mmol/l) 12 month after
transplant.
• AP and bone specific AP peaked at 5 month.
• Serum PTH correlated with graft function.
• 1,25 Vitamin D was low normal from month 2 although was gradually
improving. (Reinhardt et al 1998)

31. PTH Serum
Levels After
Kidney
Transplantation
 Sharpdropinthefirst3-6monthfollowedbygradualreduction.
 25%ofpatients withnormalrenaltransplantfunctionhavepersistent elevation
ofPTHafter1year.(variesbetween 17-50%)
 Riskfactorsforpersistent PTHelevationaredurationofCKD,elevatedalkaline
phosphatase, highPTHandphosphatelevelspretransplant.
 Nocorrelationbetween serumPTHlevelsandboneturnover.
 LowvitaminDserumlevelsandreceptorsandreducedCasensing receptors
inducepersistent PTHelevation.

32. Hypophosphataemia
• Described beforeCNIera‘Hypophosphataemicosteomalacia’
followingkidneytransplant.(Moorehead etal1974)
• Oneofthe commonbonemineraldisordersintheearlypost
transplantperiod(2weeks-3month). (Massarietal1997)
• Commonlytransient butcanpersistforyears.
• Possiblemechanisms:
• Hyperparathyroidism (Levi2001),(canoccurwith
normalPTH).
• Persistently elevatedFGF23(Bhanetal2006).
• Renaldenervation (Mannetal1992).
• CNI (LeeandKim2007).

33. 1-Hypercalcaemia
Usually highest in the first 3
month post
transplantation.
30% and 12% renal
transplant recipients
experience hypercalcaemic
episodes 1 and 5 years post
transplantation.
5-10% has hypercalcaemia
following first year of
transplantation.
No relation between
hypercalcaemia and bone
turnover.
Persistent elevation of PTH
and hypercalcaemia can
cause microcalcification in
the renal graft with
impaired function.

34. 2-
Hypercalcaemia
• Riskfactors,highserumPTHpre-transplantparticularlywithcinacalcet
withdrawal.
• Pre-transplantcinacalcetdoseisapredictorofposttransplant
hypercalcaemia.
• HigherproportionofpatientswithsimilarPTHandcalciumlevelsbutwas
oncinacalcetdevelophypercalcaemia3monthpostTxpcomparedtothose
whowerenot.
• PTHincreasesrenaltubularCaabsorption,stimulatessynthesisof
calcitriolwithincreasedintestinalcaabsorptionandincreasedbone
resorption.

35. 3-
Hypercalcaemia
 Impactongraftfunction:
 Vasoconstrictionwithacuteandchronicgraftdysfunction.
 Tubulointerstitialmicrocalcification.
 Reportedcasesofpancreatitis.
 Softtissueandvascularcalcification.
 Persistenthypercalcaemiareflectsdeterioratingbonedisorders.

36. 4-
Hypercalcaemia
• Managementdependson:
• Calevel<(11mg/lor2.75mmol/l)
• Duration<(3-6month).
• Symptoms.
• PTH>120pg/lor42pmol/l.
• Watchfulwaitingotherwise options:
• PTHectomy(hungrybone,complications,graftdysfunction?).
• Calaemimetics(graftdysfunction??,cost,recurrence)
• Bisphosphonates.

37. Serum Phosphate &
Dietary Restrictions
• Guidelines recommend dietary
phosphate restriction with higher than
normal serum P (usually eGFR<30
ml/min)
• Bioavailability of phosphate sources:
• Plant sources: 40-50% absorbed.
• Animal source: 60-70% absorbed.
• Inorganic phosphate (food
additives): 100%.
• Patient Education is Crucial:
• Patients educated on phosphate
restrictions through food additives
has reduced serum phosphate
versus standard care

38. Phosphate Binders

39. All Cause Mortality in Ca versus Non Ca Based Binders
Jamal et al 2013

40. Iron Based
Phosphate
Binders

41. Case Scenarios
Case 1
• 35 years male.
• Rapidly progressive IgA nephropathy
• Failed to respond to steroid treatment.
• End stage renal disease requiring HD.
• He was not compliant with dialysis treatment and missed his
treatment on frequent occasions.
• Anuric.
• Medications: Calcium carbonate phosphate binder, alfa calcidol 2
ug/day, cinacalcet 180 mg/day and colecalciferol 800 units every day.

42. Investigations Results
Bone parameters
CorrCa PO4 PTH VitD
2.72 2.5
2.62 2.5
2.8 2.8 264.3 44.2
2.49 3.6
2.58 1.6
2.66 2.7 178
2.45 1.9 98

43. Imaging
Whilst he was worked up for kidney transplant started to complain of
dull aches in the right groin. Simple analgesics were tried without
effect. On examination, he did have a palpable mass with CT images as
below.

44. Case 2
• 71 years female
• Regular HD for the last 3 years.
• She is doing well on dialysis without reporting any symptoms in the
past.
• Dialysis adequacy is within recommended targets.
• She started to complain of backaches over the last 8 month.
• Serial bone parameters over this interval as shown below.
• Medications: phosphate binder calcium acetate and alfa calcidol 250
ng alt days. She tried most of the well known analgesia without a
noticeable effect.

45. Investigations
CorrCa PO4 CaxPO4 PTH VitD
2.42 1.5 3.63
2.42 1.5 3.63
2.4 1.8 4.32 64.3 44.2
2.49 1.6 3.984
2.48 1.6 3.968
2.46 1.7 4.182 64.9
2.45 1.9 4.655
• Bone parameters

46. Imaging

47. Case 3
• 61 years male.
• Two previous Txps & second one 24 years ago. First transplant lasted 7
years.
• Maintained on cyclosporine, myfortic and prednisolone, alfacalcidol of 750
ng/day and colecalciferol 800 unit/day.
• PMHx: rheumatoid arthritis which is in remission, right knee and left hip
replacements.
• Graft function is stable with serum creatinine of 170 μmol/l.
• Presenting C/O: generalised bone aches over the last few months
• Bone profile: PTH of 56 pmol/l, corrected calcium level of 2.33 mmol/l,
serum phosphate of 1.1 mmol/l and 25 hydroxy vitamin D was 53.6 ng/ml.

48. Imaging