A review on CKD MBD dating from 2017

1. CKD-MBD 2017
Professor Meguid El Nahas
Global Kidney Academy
Sheffield, UK

2. CKD-MBD or CKD-M?D

3. CKD-MBD or CKD-MVD

4. The QUIZ
Which of the following is not associated with
higher mortality in CKD:
a. Low serum Phosphorus
b. Low PTH
c. Low Vitamin D
d. Low FGF23
e. Low Magnesium

5. Clinical
Pathology
Mediators
Treatment
CKD-MBD

6. HT/Osteitis Fibrosa LT: ABD
MIXED ………????
CKD-MBD

7. HT/Osteitis Fibrosa LT: ABD
MIXED Osteoporosis
CKD-MBD

8. Ca,Pi, ALP ALP, PTH
VitaminD ……..?????
CKD-MBD

9. Ca,Pi, ALP ALP, PTH
VitaminD FGF23
CKD-MBD

10. Ca,Pi, ALP
ALP, PTH
VitaminD FGF23
CKD-MBD
……..?????

11. CASE 1
• 74 year old with CKD 4, also suffers from Crohn’s Disease with frequent diarrhea
• Severe weakness, tremor and depressive mood
• eGFR = 20 ml/min
• sCa: 2.1mmol/, sPi: 2.5 mmol/l, ALP: 600iU/L, PTH: 335pg/ml
HOW WOULD YOU MANAGE?

12. CASE 1
• 74 year old with CKD 4, also suffers from Crohn’s Disease with frequent diarrhea
• Severe weakness, tremor and depressive mood
• eGFR = 20 ml/min
• sCa: 1.9 mmol/, sPi: 2.5 mmol/l, ALP: 600iU/L, PTH: 335pg/ml
• TTT: Alfacalcidol: 250ng/qd, Calcium Carbonate supplementation:1g/qid

13. CASE 1
• 74 year old with CKD 4, also suffers from Crohn’s Disease with frequent diarrhea
• Severe weakness, tremor and depressive mood
• eGFR = 20 ml/min
• 3 months later:
• sCa: 1.9 mmol/, sPi: 1.8 mmol/l, ALP: 600iU/L, PTH: 335pg/ml
WHAT WOULD YOU DO NEXT?

14. Ca,Pi, ALP
ALP, PTH
VitaminD FGF23
CKD-MBD
……..?????

15. Ca,Pi, ALP
ALP, PTH
VitaminD FGF23
CKD-MBD
……..?????

16. CASE 1
• 74 year old with CKD 4, also suffers from Crohn’s Disease with frequent diarrhea
• Severe weakness, tremor and depressive mood
• eGFR = 20 ml/min
• 3 months later:
• sCa: 1.9 mmol/, sPi: 1.8 mmol/l, ALP: 600iU/L, PTH: 335pg/ml,
• Vitamin D: 67ng/ml (NR >30ng/ml)
WHAT WOULD YOU DO NEXT?

17. Ca,Pi, ALP
ALP, PTH
VitaminD FGF23
CKD-MBD
……..?????

18. CASE 1
• 74 year old with CKD 4, also suffers from Crohn’s Disease with frequent
diarrhea
• Severe weakness, tremor, and depressive mood
• eGFR = 20 ml/min
• 3 months later:
• sCa: 2.1mmol/, sPi: 1.8 mmol/l, ALP: 600iU/L, PTH: 335pmol/l, Vitamin D: 67ng/ml
• sMg: 0.35mmol/l (NR: 0.7-1mmol/l)

19. Hypomagnesemia
Which is NOT caused by hypomagnesemia?
a. Hypercalcemia
b. Hypertension
c. Arrhythmias
d. Diabetes Mellitus

20. (ARIC) cohort, which included >14,000 participants,
reported an independent association between low mag-
nesium levelsand incident heart failure.11
Patientswith
than on changesin magnesium metabo
CKD.Asaresult of thepaucity of availa
Kidney Disease: ImprovingGlobal Out
on CKD–mineral and bonedisorder (C
not elaboratespecificdiagnosticand the
mendationswith respect to magnesium
thoseprovided for calcium and phosph
Theattention paid to thisneglected c
with CKD is, however, increasing. Sev
thisincreased interest exist, including
studiesthat suggest linksbetween low
sium levels, theincidenceand progress
and adverse outcomes in patients wit
or acutekidney injury;18
intervention
possiblebenefitsof oral magnesium sup
patientswith CKD;19,20
and experimenta
inginhibitoryeffectsof magnesium on v
tion in normal and/or uraemicanimals21
models.24,25
Theintroduction of anew
binder formulation for patientsreceiv
combinesamagnesium salt with acalci
led to increased interest in theeffectsof
In thisReview, weexamineevidencefr
tal studiesand clinical investigationsth
of magnesium in thehigh frequency o
diseasein patientswith CKD.
In vitro experimental data
Magnesium exertsdirect and indirect a
and vascular tissues. Although thebes
relateto vascular calcification, direct ac
sium on arterial function viaeffectson
musclecells(VSMCs) and theendothe
likely (Figure 1).
Vascular calcification
In micewithCKD,themagnesium conte
isreportedlyelevatedsimilar tothat of ca
phate.28
Magnesium can theoretically in
diovascular calcification byindirect actio
binding in theintestinal lumen, by sys
CKD–MBD-associatedfactors,andbydir
level of vascular tissues. Consistent with
Table 1 | Manifestations of hypomagnesaemia70,96
and hypermagnesaemia97
Disorder Serum
magnesium
level (mmol/ l)
Manifestation(s)
Severe
hypomagnesemia
<0.35 Ataxia, tremors, tetany, depression
Muscle brillation
Psychotic behaviour
Irritability
Mild to moderate
hypomagnesemia
0.35–0.70 Anorexia, nausea
Hyper-re exia, irritability, weakness; vertigo
Electrocardiographic changes (QT prolongation,
ST segment shortening)
Increase in myocardial irritability, reduced
myocardial contractility
Positive Trousseau and Chvostek signs
Abnormal skeletal muscle function
Hypertension
Hypokalaemia, hypocalcaemia
Reduced PTH level, resistance to PTH action
Increased renin and aldosterone secretion
Increased incidence of osteoporosis
None (normal
magnesium balance)
0.10–1.00 None
Hypermagnesaemia
≤2 mmol/ l
1.00–2.00 Usually asymptomatic
Mild
hypermagnesaemia
2.00–3.00 Drowsiness
Lethargy
Hypore exia
Moderate
hypermagnesaemia
3.00–5.00 Somnolence
Are exia
Hypocalcaemia
Hypotension
Bradycardia
Electrocardiographic changes (prolongation of
PR and QT intervals, increase in QRS duration)
Severe
hypermagnesaemia
>5.00 Muscle paralysis
Quadriplegia
Apnoea
Complete heart block
Cardiac arrest
Abbreviation: PTH, parathyroid hormone. Modified with permission from Wiley © Navarro-Gonzalez, J. F.
et al. Clinical implications of disordered magnesium homeostasis in chronic renal failure and dialysis.
Semin. Dial. 22, 37–44 (2009).
0.7-1
Massy and Drueke, 2015

21. Magnesium in CKD
washighly significant. Similarly, astudy of 515patients
on long-term haemodialysiswith 51 month follow-up
reportedsignificantlyhigher mortalityamongthosewith
baselinemagnesium levels<1.14mmol/l (2.77mg/dl)
than in thosewith higher magnesium levels.86
A multi-
variateCox proportional hazard analysisof thesedata
showed that serum magnesium wasasignificant, inde-
pendent predictor of all-causemortalityafter adjustment
for potential confounders,includingpatient age,gender,
haemodialysisvintageanddiabetesstatus.Notably,lower
serum magnesium levelswereassociated with increased
mortality from non-cardiovascular causesbut not from
cardiovascular causes. Theresearchersstated that the
reason for theassociation between lowmagnesium levels
and noncardiovascular death isunknown,but suggested
that associationsof low magnesium levelswith inflam-
mation, immune deficiency and neoplasia might be
amongseveral possibleexplanations.
Thepotential association between hypomagnesaemia
and mortality wasalso investigated in alargeregistry-
based cohort study that included 142,555 patients
receiving haemodialysis in Japan.87
The researchers
reported 11,454 deaths, of which 4,774 weresecondary
to cardiovascular disease, during the1-year follow-up
period. Followingappropriateadjustmentsfor relevant
clinical factors(such asdemographics, CKD-associated
mineral and bone abnormalities and malnutrition–
inflammation–atherosclerosiscomplex-related factors)
they observed a J-shaped association between serum
magnesium levelsand theoddsratioof all-causemortal-
Nature Reviews | NephrologyAdjustedORforall-causemortallity
Serum magnesium (mmol/ l)
0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4
0.04
0.09
0.08
0.10
0.07
0.06
0.05
Figure 4 | Fully adjusted association between serum
magnesium level and all-cause mortality in patients on
long-term haemodialysis. Data obtained from a Japanese
registry-based cohort study of 142,555 patients. The
dashed lines represent the 95%confidence interval.
Permission obtained from Nature Publishing Group ©
Sakaguchi, Y. et al. Kidney Int. 85, 174–181 (2014).
REVIEWSJapanese HD Population

22. Mg & CKD-MVD

23. Types of Vascular Calcifications in CKD
Uremic arteriopathy Atherosclerosis

24. Control of Vascular Calcifications
SMC Osteoblast
Inhibitors
Fetuin A
MGlaP
Osteoprotegerin
Osteopontin
Activators
Phosphorus
Uremic toxins
PTH
VitaminD
OxLDL
- +
UREMIA

25. Vascular Calcifications

26. Control of Vascular Calcifications
SMC Osteochondroblast
Inhibitors
Fetuin A
MGlaP
Osteoprotegerin
Osteopontin
Activators
Phosphorus
Uremic toxins
PTH
VitaminD
OxLDL
- +
UREMIA
Mg

27. Ca,Pi, Mg, ALP
ALP, PTH
VitaminD FGF23
Mg

28. CASE 2
• 54 year old woman with CKD 3b
• eGFR = 38 ml/min
• sCa: 2.1mmol/, sPi: 1.8 mmol/l, Mg:1.5mmol/l, ALP: 600iU/L, PTH: 335pg/ml
• In spite of treatment with alfacalcidol: 1ug/day and CaCO3: 1g/qid (between meals)
WHAT WOULD YOU DO NEXT?

29. CASE 2
• 54 year old woman with CKD 3b
• eGFR = 38 ml/min
• sCa: 2.1mmol/, sPi: 1.8 mmol/l, Mg: 1.5mmol/l, ALP: 600iU/L, PTH: 335pg/ml,
25Vit D: 15ng/ml
• In spite of treatment with alfacalcidol: 1ug/day and CaCo3: 1g/qid (between meals)
WHAT WOULD YOU DO NEXT?

30. CASE 2
How would you Manage?
• Vitamin 25D supplementation
• 1-25D Supplementation
• Increase calcium Supplementation
• PTH (Terapatide) injections

31. CASE 2
How would you Manage?
• Vitamin 25D supplementation:
• Loading: 20,000iU/week x12 w = ~ 300,000iU
• 800iU/day maintenance
• 1-25D Supplementation
• Increase calcium Supplementation
• PTH (Teriparatide) injections

32. What does KDIGO say?

33. Few significant
dietary sources
UVB (290-315 nm)
7-dehydrocholesterol
Pre-vitamin D3
Vitamin D3 (cholecalciferol)
intestine
skin
Vitamin D2 (ergocalciferol)
(extremely) few
significant
dietary sources
25OHD
1,25OH2D
PTH +
parathyroids
intestine
bone
Classical
Endocrine
effects
1 alpha
hydroxylase
24,25OH2D
calcitroic
acid
24-
hydroxylase
liver P et Ca
-
Souberbielle, Cavalier, 2013

34. Native Vitamin D Epidemiology
Definition
• Insufficiency: [25(OH)D] < 30 ng/mL
• Deficiency: [25(OH)D] < 10-15 ng/mL
Causes
• CKD is associated with 25OH VitaminD deficiencies
Prevalence
• Differences with age, ethnicity, latitude, culture and seasons
• In US HD Patients:
• Insufficiency: 78%, Deficiency: 18%

35. VITAMIN D is a Pleotropic Hormone
Vitamin D Depletion:
• Progression of CKD: No effect
• Hospitalisations: Increase
• Mortality: Increase
Vitamin D Treatment:
• Bood Pressure: Reduce
• LVH (PRIMO, OPERA): Reduce
• Proteinuria (VITAL): Reduce

36. Vit D & CKD-MVD

37. Vitamin D and Vascular Pathology
Massy and Drueke, 2012
LOW HIGH

38. Vitamin D and Vascular Pathology
Massy and Drueke, 2012

39. Ca,Pi, Mg
ALP ALP, PTH
VitaminD
25D
1,25D
FGF23

40. CASE 3
• 72 year old female with IgA nephropathy
• Started haemodialysis in 2010. Good access dialyses 4x week
• On alfacalcidol 0.5ug od, calcium acetate, amlodipine, lisinopril, EPO
• Between 2010 and 2012 gradual rise in PTH to >600 pg/ml
• LFTs normal but alkaline phosphatase persistently elevated
• Vitamin D level >50ng/ml
• Calcium 2.48 mmol/l (normal range 2.2-2.6mmol/l). Phosphorus 1.7 mmol/l (0.8 to
1.5 mmol/l)
What would you do?

41. What does KDIGO say?

42. Vitamin(s) D and PTH
VitD v Placebo
Old v New
Oral v IV

43. CASE 3
• 72 year old female with IgA nephropathy
• Started haemodialysis in 2010. Good access dialyses 4x week
• On alfacalcidol 2ug iv x3 /week
• Between 2012 and 2014 gradual rise in PTH to >1000 pg/ml
• LFTs normal but alkaline phosphatase persistently elevated
• Vitamin D level >50ng/ml
• Calcium 2.68 mmol/l (normal range 2.2-2.6mmol/l). Phosphorus 2.1 mmol/l (0.8 to
1.5 mmol/l)
What would you do next?

44. How would you Manage SHPT?
• Increase alfacalcidol dose
• Switch alfacalcidol to paracalcitol
• Add cinacalcet to alfacalcidol
• Parathyroidectomy
• Do nothing – leave alone

45. How would you Manage SHPT?
• Increase alfacalcidol dose
• Switch alfacalcidol to paracalcitol
• Add cinacalcet to alfacalcidol
• Parathyroidectomy
• Do nothing – leave alone

46. Calcimimetics

47. EVOLVE Study – Cinacalcet in chronic haemodialysis patients
EVOLVE INVESTIGATORS NEJM.2012.367;2482-97
•3883 patients on HD
•Placebo or Cinacalcet
•Death +CV events
No benefit in cinacalcet on death
Higher risk of GI side effects but lower risk parathyroid surgery
Difficult study – high crossover and drop out

48. Calcimimetics – overview of effects
No effect on mortality
Less Parathyroid surgery
More hypocalcaemia
More Nausea

49. EVOLVE Study – Cinacalcet impact on fractures
EVOLVE INVESTIGATORS NEJM.2012.367;2482-97
•3883 patients on HD
•Placebo or Cinacalcet
•Death +CV events
•No impact on fracture

51. Etelcalcitide

52. How would you manage?
• Increase alfacalcidol dose
• Switch alfacalcidol to paracalcitol
• Add cinacalcet to alfacalcidol
• Parathyroidectomy
• Do nothing – leave alone

53. Less Parathyroid surgery
Parathyroidectomy – risks exchanging high turnover bone
disease for adynamic bone disease

54. HT/Osteitis Fibrosa LT: ABD
MIXED Osteoporosis
VLPL

55. VLPL & CKD-MVD

56. DOPPS PTH and Outcomes
Tentori et al, 2015

57. How would you Manage VLPL?
• Stop calcium Supplementation
• Stop Vitamin D supplementation
• Reduce Dialysate calcium Supplementation
• None of the Above
• All of the above

58. How would you Manage VLPL?
• Stop calcium Supplementation
• Stop Vitamin D supplementation
• Reduce Dialysate calcium Supplementation
• None of the Above
• All of the above

59. CKD-MBD: General management tips
• Adynamic Bone Disease with low PTH:
• stop calcium binders and vitamin D supplements.
• High turnover Bone Disease (with PTH >9 times normal):
• ensure native vitamin D levels normal. Control phosphate. Increase
calcitriol/alfacalcidol as much as calcium/phosphate allow.
• High turnover Bone Disease (with PTH >9 times normal) with hypercalcaemia:
low calcium dialysate, non-calcium binders, switch to cinacalcet, consider
parathyroidectomy
• Always ensure magnesium levels and vitamin D3 levels maintained

60. What KDIGO says about PTH in dialysis
• In patients with CKD5D we suggest maintaining iPTH levels between 2 –9 times
upper limit of normal(2C).
• In patients with CKD5D and elevated or rising iPTH, we suggest calcitriol, vitamin
D analogues, calcimimetics or a combination to lower PTH (2B).
• In patients with hypercalcaemia recommend stopping or reducing calcitriol or
vitamin D sterols (1B).
• In patients with hyperphosphataemia, recommend stopping or reducing calcitriol or
vitamin D sterols (2D).

61. Ca,Pi, Mg, ALP
ALP, PTH
VitaminD
25D
1,25D ……..?????
CKD-MBD

62. Ca,Pi, Mg, ALP
ALP, PTH
VitaminD
25D
1,25D FGF23
CKD-MBD

63. FGF23 and CKD
lotho levelsof CKD patients have been
ein thevery early stagesof CKD and to
KD progresses [36]. In a rodent CKD
vels in plasma, urine, and kidney were
se in parallel [36], but the relationship
elsin CKD patientsremainsto bedeter-
ore, almost all modelsof CKD, includ-
avebeen createdbyrenal tissueablation,
tis, nephrotoxin, diabetic nephropathy,
e kidney damage, are characterized by
wnregulation of Klotho mRNA and pro-
ey and by low plasma or urine-soluble
]. Plasma soluble Klotho levels are also
early stagesof CKD [58].Pavik et al.[63]
dingthatsolubleKlothoand1,25(OH)2D
nd FGF23 levels increase in the early
nd that PTH levelsincreasein themore
Akimoto et al. [64] haverecently shown
Klotho levels of CKD patients, rather
Klotholevels,arelinked totheir number
phrons.Sakan et al.[65] recentlyreport-
renal α-Klotho levelsweresignificantly
um FGF23 levels were significantly ele-
d intermediate CKD, serum P levelsre-
he normal range. Despite falling renal
heincreasein FGF23 enhanced urinary
d serum 1,25(OH)2D levelsin early and
D, though not in advanced CKD. In ad-
ubleKlotho levelsfell significantly over
overlapping distinct mechanisms of initiation and pro-
gression [68, 69].Vascular calcification isadynamicpro-
Fig. 5. Timeprofileof changesinplasmaFGF23,Klotho,activevi-
taminD,andphosphatelevelsasCKDprogresses. Thedecreasein
Klothoproteininthebloodisanearlyevent inCKDandisprogres-
sivelyreducedalongwiththedeclineof renal function.LowKlotho
partiallyinducesFGF23resistance,causinganinitial compensatory
increasein blood FGF23tomaintain Phomeostasis. Theincrease
inFGF23decreasesactivevitaminDlevelsandisfollowedbyeleva-
tion of PTH. Hyperphosphatemia is relatively late event in ad-
vancedCKD[reprintedwithpermissionfrom 60].
Colorversionavailableonline

64. PTH or FGF23

65. FGF23 and CKD
havebeen found to predict mortality not only among di-
alysispatientsbut amongpredialysisCKD patientsaswell
[22].
tial to facilitate thebinding of FG
The potential role of soluble Klo
in vivo remainsunknown at this
Fig. 2. Plasma FGF23 levels in thefour CKD stage groups. Boxes
represent the interquartile range with the upper and lower edges
representing the75th and 25th percentiles, respectively. Thereisa
statistically significant linear increase in plasma FGF23 levels
acrossthefour CKD groupsdivided by eGFR[reprinted with per-
mission from 21].
Fig. 3. Klotho family showing theth
themammalian genome. Homologo
mainsareconserved. Solubleformso
byalternativesplicingof itstranscrip
of thetransmembraneformbyβ-secr
Colorversionavailableonline

66. FGF23 and CKD Mortality
Figure 2. FGF23 is an independent risk factor for mortality in CKD stages 2–4
The cumulative incidence of death of CKD stage 2–4 patients increases significantly with
ascending quartiles of baseline FGF23 levels in unadjusted analyses (plot) and after full
multivariable adjustment (hazard ratios and 95% confidence intervals in the inset). 86
Wolf Page 20
$watermark-text$watermark-tex
Wolf, 2012

67. FGF23 & CKD-MVD

68. FGF23 & CKD-MVD
Jimbo and Shimosawa, 2014

69. Etelcalcitide

70. HT/Osteitis Fibrosa LT: ABD
MIXED ………????
CKD-MBD

71. HT/Osteitis Fibrosa LT: ABD
MIXED Osteoporosis
CKD-MBD

72. Kalwansky S et al. Osteoporosis Int (2003) 14: 570–576
Significant co-prevalence of osteoporosis and CKD in the
elderly
Increasing osteoporosis with declining kidney function
Age eGFR<35mls/min
20-29 0%
30-39 0%
40-49 0%
50-59 0%
60-69 7.3%
70-79 21.3%
80+ 53.9%

73. Healthcare database 679114 adults, Ontario, Canada
Naylor Kl et al. Kidney International (2014) 86, 810–818
Fractures are more common in CKD

74. RANK-RANKL-OPG regulate Osteoclastic activity
Lewiecki, E. M. (2011) Nat. Rev. Rheumatol.
Maturation of preosteoclasts dependent on RANKL and OPG activity

75. Improving bone density
Targeting bone resorption
Salam S, Eastell RE, Khwaja A, AJKD 2014
Bisphosphonate
Denosumab

76. How would you manage osteoporosis and low impact fractures in a
Patient CKD3
• Bisphosphosphonates
• Denosumab
• Bone biopsy
• Do nothing as risk of adynamic bone disease with anti-osteoporosis
medication

77. The problem with bisphosphonates in CKD
• Clearance by kidney
• 50% of dose deposits in skeleton and may be there for 10 years!
• Exacerbate adynamic bone disease (may require bone biopsy)
• Atypical fractures
• FSGS

78. How would you manage osteoporosis and low impact fractures in a
Patient with CKD4-5
• Bisphosphosphonates
• Denosumab
• Bone biopsy
• Do nothing as risk of adynamic bone disease with anti-osteoporosis
medication

79. Approach to fragility fracture in CKD
Salam S, Eastell RE, Khwaja A AJKD 2014
ABD

80. Fractures – its not just about bone
Bone Strength
Falls
Postural hypotension,
autonomic
dysfunction, drugs
FRACTURES
Soft Tissue
padding
Fraility
Lifestyle
Nutrition
Exercise

82. HT/Osteitis Fibrosa LT: ABD
MIXED
Osteoporosis

83. Ca,Pi, Mg, ALP
ALP, PTH
VitaminD
25D
1,25D FGF23

84. CKD-MBD 2017
Professor Meguid El Nahas
Global Kidney Academy
Sheffield, UK