Dr ahmed albeyaly ckd-mb

DR.AHMED MOHAMED ALBEYALY
Nephrology Specialist
Nephrology Moderator In Dakahlia Health directorate

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 Introduction
 Pathogenesis
 Normal Bone Remodeling
 Hyperparathyroidism
 Classifications of bone disease
 Diagnosis of bone disease
 Treatment of bone disease in CKD

Stage Description GFR
(ml/min/1.73 m2)
1 Kidney damage with normal or 
GFR
 90
2 Kidney damage with mild  GFR 60-89
3 Moderate  GFR 30-59
4 Severe  GFR 15-29
5 Kidney failure < 15
(or dialysis)
KDOQI: CKD Staging

KI (2007) 71, 31-38. Levin et. al.
Prevalence of Abnormal Mineral Metabolism in CKD
>4.6

CKD
Stage 3
CKD
Stage 4
CKD
Stage 5
(on dialysis)
P
(mg/dL)
2.7 - 4.6 2.7 - 4.6 3.5 - 5.5*
Ca
(mg/dL)
“Normal” “Normal”
8.4 - 9.5;
Hypercalcemia =
>10.2
Intact
PTH
(pg/mL)
35 - 70 70 - 110
150 - 300*
*Evidence

EU1 KDIGO Japan2
PTH
pg/mL (pmol/L)
85–170
(9–18)
150–300
(16.5–33)
60–180
Ca
mg/dL (mmol/L)
8.8–11
(2.2–2.7)
<10.2 pref: 8.4–9.51
(<2.54 pref: 2.10–2.37)
8.4–10
(2.1–2.5)
Pi
mg/dL (mmol/L)
2.5–5.5
(0.8–1.8)
3.5–5.5
(1.1–1.8)
3.5–6.0
(1.1–2)
Ca x P
mg2/dL2
<55 mg2/dL2 <55 mg2/dL2 (not specified)

0.01
100
10
1
0.1
Annualmortality(%)
25–34 45–54 65–74 8535–44 55–64 75–84
Age (years)
Cardiovascular Mortality in the General
Population and in Dialysis Patients
General population
Male
Female
Black
White
Dialysis population
Male
Female
Black
White

 The term renal osteodystrophy (ROD)
should be used exclusively to define the
bone pathology associated with CKD.
 The clinical, biochemical, and imaging
abnormalities should be defined more
broadly as a clinical entity or syndrome
called Chronic Kidney Disease-Mineral
and Bone Disorder (CKD-MBD).

A systemic disorder of mineral and bone
metabolism due to CKD manifested by either
one or a combination of the following:
◦ 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 et al Kidney International June 2006

A Framework for Classification of CKD-MBD
Type
*
Laboratory
Abnormalities
Bone Disease
Calcification of
Vascular or Other
Soft Tissue
L + - -
LB + + -
LC + - +
LBC + + +
* L = laboratory abnormalities (of calcium, phosphorus, PTH,
alkaline phosphatase or vitamin D metabolism); B = bone disease
(abnormalities in bone turnover, mineralization, volume, linear
growth, or strength); C = calcification of vascular or other soft
tissue.

17
Elevated:
• FGF-23
• PTH
• Phosphorus
Decreased:
• Calcitriol
• Calcium
• Coronary calcification
• Aortic calcification
• Calciphylaxis
• Abnormal bone
– Mineralization
– Turnover
– Volume
KDIGO = Kidney Disease: Improving Global Outcomes.
KDIGO® is a registered trademark of Kidney Disease: Improving Global Outcomes, Inc.
Moe S, et al. Kidney Int. 2006;69:1945-1953.
KDIGO® Overview slide presentation at: http://www.kdigo.org/pdf/KDIGO%20Overview%20Slide%20Set.ppt

 Traditionally classified according to degree
of abnormal bone turnover
High Turnover (osteitis fibrosa)
◦ Hyperparathyroidism
Low turnover
◦ Adynamic - Osteomalacia
Beta 2 MG amyloidosis
Osteoporosis
◦ Post-menopausal - Post-transplant

 Kidney failure disrupts systemic calcium and
phosphate homeostasis and affects the bone, GIT and
parathyroid glands.
 In kidney failure there is decreased renal excretion of
phosphate and diminished production of calcitriol
(1,25-dihydroxyvitamin D)
◦ Calitriol increases serum calcium levels
 The increased phosphate and reduced calcium,
feedback and lead to secondary hyperparathyroidism,
metabolic bone disease, soft tissue calcifications and
other metabolic abnormalities

• 4 or more small glands on
the posterior surface of
the thyroid gland.
• Can function without
neural control so can
transplant to another part
of the body
• 2 types of cells
– Chief cells – produce
parathyroid hormone
– Oxyntic cells – function
unknown

 Responsible for maintaining serum calcium
in a normal range preventing hypocalcemia.
 Does this by;
1. acting directly on the distal tubule of the kidney
to increase calcium reabsorption
– Increases calcitriol production (D3)
– D3 increases GIT absorption of Ca and Phos and
promotes osteoclast formation.
2. Acting on bone to increase calcium and
phosphate efflux

 Can occur once eGFR < 60
 PTH levels increase progressively as renal function declines and
by CKD stage 5(<15) most pt’s expected to have this.
 Usually the 1st sign and occurs before lab tests pick up ⁭
phosphatemia, ↓ Vit D3 and ↓ calcium
 Unless treated, progresses and frequency of parathyroidectomy
proportional to yrs on dialysis

 Primary
Adenoma 80%
Multiple adenomas 4% (10% in elderly women)
Hyperplasia 15%
Carcinoma <1%
 Secondary MEDICAL TTT
CRF, Malabsorption
 Tertiary Surgical TTT
In long standing cases

 In renal failure driven by
◦Hypocalcaemia
◦Decreased vitamin D
◦hyperphosphataemia

 Due to excess PTH
 Increased bone turnover activity (greater
number of osteoclasts and osteoblasts) and
defective mineralization.
 Associated with bone pain and increased risk
of fractures.

 Formally linked to aluminium toxicity
◦ From aluminium based phosphate binders
◦ From contamination of water in dialysate solutions
unmineralised osteoid

 Characterized by low osteoblastic activity and bone
formation rates
 Seen in up to 30% HD
 May be due to excess suppression of the
parathyroid gland with therapies, particularly
calcium-containing phosphate binders and vitamin
D analogues.
 Typically maintain a low serum intact PTH
concentration, which is frequently accompanied by
an elevated serum calcium level.
 Felt to represent a state of relative
hypoparathyroidism
NORMAL diseased

Adapted from Goodman WG. In: Bilezikian JP, et al, eds. Principles of Bone Biology. 3rd Ed. San Diego, CA: Academic Press;
2008:1478-1510; Adapted from Moe SM, et al. In: Brenner BM, ed. The Kidney. 8th ed. Philadelphia, PA: Saunders Elsevier;
2008:1784-1813.
Mixed
Lesion
Osteitis FibrosaNormal Bone
Formation
High
Low
turnov
er
High turnover
Adynamic
Osteomalacia
Low PTH

 Most with CKD and mildly elevated PTH are
asymptomatic
 When present classified as either
1. Musculoskeletal
2. Extra-skeletal

 Fractures, tendon rupture and bone pain
from metabolic bone disease, muscular pain
and weakness.
 Most clinically significant is hip fracture and
fracture neck of femur , seen in CKD 5 (and is
associated with increase risk of death)
◦ NB. In dialysis pts there is already a 4.4 x increase
risk of hip fracture.

 Important to recognise disordered bone and
mineral metabolism is a systemic disorder
affecting soft tissues, particularly vessels,
heart valves and skin.
 CVD accounts for around half of all deaths of
dialysis patients.
 Coronary artery and vascular calcifications
occur frequently in CKD 5 (and increase each
year on dialysis)

• A, Confluent calf plaques
(borders shown with
arrows). Parts of the skin
are erythematous, which is
easily confused with simple
cellulitis. B, Gross
ulceration in the same
patient 3 months later. The
black eschar has been
surgically débrided. C,
Calciphylactic plaques, a
few of which are beginning
to ulcerate. (Photographs
courtesy of Dr. Adrian Fine. Up
To Date)

A. Zerbi S, et al. J Clin Endocrinol Metab. 2008;93:1121-1122; B. London GM, et al. Nephrol Dial Transplant.
2003;18:1731-1740.
B
A

Slide courtesy of D. Sherrard.

Calcification of the Lung
Sanders C, et al. Am J Roentgenol. 1987;149:881-887.
Kuzela DC, et al. Am J Pathol. 1977;86:403-424.
Slide courtesy of E. Slatopolsky.
CalcifiedNoncalcified

1. Ribeiro S, et al. Nephrol Dial Transplant. 1998;13:2037-2040.
Presence of Valvular
Calcification1
0%
10%
20%
30%
40%
50%
60%
PercentageofPatients
Dialysis
Normal
Mitral Annulus Aortic Annulus
45%
10%
52%
4%

 Vascular calcification was present in 63–
69% of incident dialysis patients
1Block GA, et al. Kidney Int. 2005;68:1815-1824.
2Raggi P, et al. J Am Coll Cardiol. 2002 39:695-701.

Adapted from Kalpakian MA, Mehrotra R. Semin Dial. 2007;20:139-143.
92%
83%
70%
53%
82%
92%
72%
0
10
20
30
40
50
60
70
80
90
100
Oh,
2002
Raggi,
2002
Moe,
2003
Stompor,
2003
Matsuoka,
2004
Nitta,
2004
Barreto,
2005
Prevalence(%)
N 37 205 71 43 104 53 101
%
Diabetes
Mellitus
0% 30% 34% 9% 38% 40% 9%

 Pts on dialysis for 7- 10 years can develop
osteoarticular amyloid deposits.
 May present with carpel tunnel syndrome and
arthritis

 Introduction
 Pathogenesis

 Blood
◦ PTH
 Random circulating PTH (1/2 life 2-4 mins)
 Excreted renally so present for longer in RF
◦ Calcium
◦ Phosphate
 Bone biopsy
◦ no longer frequently performed
 Imaging
◦ In general not indicated

CKD Stage KDIGO
3 Every 6–12 months
5 or D Every 1–3 months
Phosphate and Calcium

CKD Stage KDIGO
5 or D Every 3–6 months
PTH

 Pathogenesis
 Treatment of bone disease in CKD

Controlling Ca, Pi, PTH, Vitamin D
To Prevent
MBD
CVD
lower mortality!!!!

 Phosphorus is unevenly distributed in the body
 The major portion of phosphorus removed by HD is from
cell cytoplasm. The rate of phosphorus removal is slowed
by rate of transfer from within cells to plasma
◦ haemodialysis (HD) removes ~800 mg Pi/treatment
◦ peritoneal dialysis (PD) removes 150–200 mg Pi/PAK
 Average phosphorus absorption = 600 mg/day or 4,200
mg/week
 3 x weekly HD (4-hour sessions) removes 2,400 mg
phosphorus leaving 1,800 mg or 257 mg/day1

 Aluminium used historically but now rarely used as concerns re
bone/CNS toxicity. May not be an issue if water quality good for
dialysis
 Calcium based binders but concerns about about exacerbating
hypercalcaemia and thereby promoting vascular calcification.
Also concerns about promoting hypercalcaemia in adynamic low
turnover) bone disease
 Sevelamer Hydrochloride and Lanthanum Carbonate are the
current non-calcium based binders used in clinical practice. May
avoid problems associated with calcium based binders but more
expensive

Brand Compound /form Dose (mg/day) Type Manufacturer
Alu-cap® Aluminium hydroxide capsule 4–20 x 475 mg/day
(2–10 g)
Metal Meda Pharmaceuticals (UK)
Calcichew® Calcium carbonate tablet 2–3 x 1250 mg/day Calcium Shire Pharmaceuticals
Calcium 500® Calcium carbonate tablet 1–2 x 1250 mg/day Calcium Generic (Twinlab, etc)
Phosex® Calcium acetate tablet 3–6 x 250 mg/day Calcium Vitaline Pharma (UK)
Titralac® Calcium carbonate tablet Up to 20 x 420 mg/day Calcium 3M Health Care
PhosLo® Calcium acetate (generic) 9–12 x 667 mg/day Calcium Generic (Fresenius Medical Care)
Fosrenol® Lanthanum carbonate tablet 750–3750 mg/day Metal Shire Pharmaceuticals
RenaGel® Sevelamer hydrochloride
capsule
3–9 x 800 mg/day Non-metal Genzyme
Renvela® Sevelamer carbonate film-
coated tablet
3–6 x 800 mg/day Non-metal Genzyme (USA)
OsvaRen® (EU)
Rephoren (UK)
Calcium acetate/ magnesium
carbonate tablet
3–12 x 435/235 mg/day Metal Fresenius

Class of phosphate binder Advantages Disadvantages
Al-based
(Al hydroxide)
Effective across wide pH range,
inexpensive1
Absorption of Al can lead to long-term toxicity resulting in
neurological damage and possible death1
Ca-based
(Ca acetate, Ca carbonate)
Effective, inexpensive, well tolerated,
well established, widely available
Likely to increase hypercalcaemia, and risk of arterial
calcification, function over a narrow gastric pH range,
high tablet burden
Sevelamer (hydrogel
polymer/resin)
Metal-free, low toxicity, lowers lipids and
arterial calcification – does not affect Ca
Acidosis due to HCl, expensive. Benefits in controlling Pi
levels and reduced calcification not sufficiently evaluated
in comparison with other treatments.2 Not effective over
wide pH range
La-based
(La carbonate)
Effective, well tolerated, low toxicity, low
tablet burden Ca-free, reasonable cost
Efficacy similar to Ca-based binders. Possible tissue
accumulation not ruled out but refuted by some authors

 Rationale: elevated PTH may increase Ca and Pi thereby
promoting vascular calcification
 Vitamin D analogues 1st line therapy as PTH driven by lack of
activated vitamin D
 Calcimimetics avoid adverse effects on Ca and Pi
 Low PTH associated with adynamic bone disease

 Vitamin D
- decreases PTH secretion but increases Ca uptake from intestine
- vitamin D sterols include calcitriol, alfacalcidol, doxercalciferol, paricalcitol
 Calcimimetics
- increase sensitivity of parathyroid Ca receptor thereby reducing PTH – without
increasing Ca2
- also reduce Phosphate
 Surgery
• permanently reduces PTH secretion in patients unresponsive to medication
• BUT may result in adynamic bone disease
 Phosphate binders are also used to manage hyperphosphataemia associated with
SHPT

 Calcitriol directly suppresses PTH secretion
 Vitamin D receptor on PTH gland down regulated
as hyperplasia of the gland is advanced

 Intravenous or oral pulses are equally
effective
 Equal efficacy of daily versus equivalent pulse
doses
 Hypercalcaemia remains a complication
 Hyperphosphatemia also a complication

Therapy Advantages Disadvantages
Cinacalcet Effective in reducing PTH
levels
No hypercalcaemia
Phosphate levels may improve
Lack of good outcome data
showing reductions in CV
events
and bone effects
Expensive
Vitamin D and
analogues
Effective in reducing PTH
levels
Studies show improved
survival
Can cause hypercalcaemia
Can cause
hyperphosphataemia
Surgery Permanent/irreversible Can cause adynamic bone
disease
Can injure local nerve tissue

 Autonomous hypersecretion which
continues despite of correction of the
underlying renal disease by
transplantation

Dr ahmed albeyaly ckd-mb

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