Prof sobh renal osteodystrophy

Urology & Nephrology Center, Mansoura University, Egypt
RENAL OSTEODYSTROPHY:
AN UPDATE
By
Mohamad A. Sobh, MD, FACP
Prof. & Head of Nephrology
Urology & Nephrology Center
Mansoura University
Egypt

Bony problems and extraosseous
calcification may be a major
obstacle to the rehabilitation of
patients treated for ESRF.

Renal Osteodystrophy
Is a heterogeneous disorder leading to diminished
bone strength in patients with impaired kidney
function.
After prolonged HD, patients suffers from:
Hyperparathyroidism.
Low bone turnover disease, often associated with
soft tissue calcifications.
B2 – microglobulin derived amyloidosis.
Aluminium – related bone disease.
Uraemic mineral metabolism (and its treatment)
impact on cardiovascular morbidity and mortality in
CKD patients.

Osteodystrophy is a dysfunction of bone
turnover, density, mineralization and
architecture.

Bone biopsy with histological and
histomorphometric assessment is
required for diagnosis and
classification. Yet, this is invasive, need
high experience.

When renal function is intact,
concentration of Po4, Ca2+ are
maintained through interaction
between PTH, 1.25 (OH)2D (calcitriol)
and their primary targets: bone,
kidney and GIT tract.

Parathyroid Hormon
PTH secretion (and parathyroid gland
proliferation) is stimulated by ↓ Ca2+, ↓ 1.25
(OH)2D and ↑ Po4.
In most circumstances ↓ Ca2+ (acting via the
parathyroid calcium sensing receptor)
overrides the other two.
PTH acts on 3 fronts.
1- Mobilizing skeletal calcium,
2- ↓ urinary Ca2+↑urinary Po4 excretion,
3- ↑renal production of 1.25 (OH)2D (in turn →↑
intestinal Ca2+ and Po4 absorption).

Calcitriol inhibits PTH synthesis at the
pre-pro-PTH messenger RNA level by
acting on calcitriol receptor in the
parathyroid cells.
In uraemia, the calcitriol receptor
density is reduced.
Also there is ↓ sensitivity of the gland to
Ca2+ suppression perhaps due to ↓
expression of Ca2+ receptors .

Hyperphosphataemia directly stimulate PTH
secretion.
SHPT and likely inadequate production of
other substances, such as bone morphogenic
protein (BMP7) result in progressive
osteodystrophy.

In dialysis patients bone resistance to
PTH develops, higher levels are needed
for bone turnover → level double to
four fold normal is ok, low level may
cause ABD, and markedly high level
may cause osteitis fibrosa (HBD).

Is an 84 AA peptide that activates a
signaling cascade via the PTH1 receptor
present on a variety of tissues through its
N- terminal and not C- terminal.
Fragments of PTH are rapidly cleared by
the kidney → accumulate in CKD.
PTH

Only N- terminal containing fragment can
activate PTH1 receptors.
Intact PTH (iPTH) RIA detect the intact
molecule and more recently the more
accurate 2nd generation RIA detect the
biointact PTH (biPTH) which is nearly 55%
of iPTH values.
(iPTH measures 1-84 AA peptide + 7-84 AA
peptide fragments while biPTH measure
only the 1-84 AA peptide only).

Vitamin D
Inactive vitamin D (from dietary source and
UV conversion in the skin) is metabolized in
the liver to 25(OH)D and then converted to
1.25 (OH)2 D by the renal 1α- hydroxylase
enzyme.
Calcitriol alters gen expression by binding to
an intracellular receptor (VDR) and exerts a
number of important effects.

Normal range 8.4-10.2 mg/dL (2.1-2.6 mmol/L).
K DOQI bone guidelines recommend a target
predialysis correct calcium within normal
preferably ≤ 9.5 mg/dL (2.4 mmol /L).
Corrected calcium (mg/dl)
= Total calcium+ (0.8x4-s.alb “in g/dL”).
Hypercalcaemia in dialysis patient is mostly due
to →↑ CCPB , ↑ vit D, tertiary
hyperparathyroidism.
Hypocalcaemia→ is mostly due to↓ vit D, ↑↑
PO4 ,calcimimetics.
Calcium

Normal range is 2.7 -4.6 mg/dl (0.9-1.5
mmol/L) in patients with normal renal
function and CKD 3 and 4.
In dialysis patient KDOQI bone guide lines
recommended a pre dialysis level of 3.5-5.5
mg/dl (1.1-1.8 mmol/L)
Hyperphosphataemia is due to → ↑dietary
intake, poor dialysis, ↓ binders,↑ vit D
analogue, HPT.
Hypophosphataemia is due to →↓ dietary
protein, ↑binders.
Phosphorus

Sources are livers, intestine, kidney, and
bone.
Bone alkaline phosphates ↑ with osteitis
fibrosa and HPT.
Fall with successful treatment of SHPT
and in ABD
AlKaline phosphatase

25 (OH)D
PTHRenalPo4
- +
-
1.25 (OH)2D
Gut Bone Parathyroid Kidney
↑Ca2+ +Po4
absorption
↑ steoclast
activity
↓ PTH
secretion
↑Ca2++Po4
absorption
Overview of vitamin D metabolism

Bone is not static, it continuously adapt to
mechanical and metabolic requirements by a
remodeling process centered around the
coupling of osteoblastic formation and
osteoclastic resorption.
Multiple systemic hormons including PTH
and calcitriol and local growth factors
influence this process.
Bone is the most important body reservoir of
Ca2+ and PO4.
Bone Biology

Effect of Renal failure
Loss of renal mass→
 Phosphate accumulation.
 ↓ 1.25 (OH)2D (→↓ serum Ca2+)
Secondary hyperparathyroidism→
 ↓ Ca2+ + ↓ 1.25 (OH)2D + ↑PO4→ PTH
synthesis and release.
 Prolonged stimulation of parathyroid
tissue→ clonal proliferation of parathyroid
cells (with areas of nodular hyperplasia).
 These clones express less calcium sensing
receptors (CaR) and VDR.
-1-

Effect of Renal failure
 Refractoriness to treatment is inevitable
(tertiary or autonomous HPT).
 In addition there is relative “skeletal
resistance” to the effects of PTH (mechanism
unclear).
 Abnormal bone turnover result.
 ↑ PTH also has non- skeletal effects→ LVH,
cardiac fibrosis, extra- skeletal calcifications,
peripheral neuropathy, impotence.
-2-

The pathogenesis of SHPT
↓ CaR↓ VDR
Parathyroid gland
Calcitriol PO4
PTH
PTH
Ca2+
Skeletal
resistance
GFR
Systemic
toxicity
Bone disease

↑ Formation and resorption of bone due to ↑
number and activity of asteoblasts and
osteoclclasts.
When severe, bone is laid rapidly with
defective mineralization →↑ unmineralized
bone (osteoid), alignment of collagen is
irregular instead of lamellar pattern,
mineralization is amorphous calcium
phosphate rather than hydroxyapatite
→weak bone →bone pains, joint pains, easy
fracture.
Bone is stronger in mild osteitis fibrosa than
ABD.
Osteitis fibrosa

Calcium containing binders, Vit-D,? calcimimetic
PTH
<100 pg/ml 150- 300 pg/ml > 450 pg/ml
A dynamic
Bone
Normal Bone
Turnover
Mild
SHPT
Osteitis
Fibrosa
Spectrum of renal bone disease
Osteomalacia
“Low turnover” “High turnover”

Clinical Features
Secondary hyperparathyroidism
Usually asymptomatic.
Clinical sequelae occur late (with significant
biochemical and histologic disease), including:
 Bone pains and arthraglia.
 Muscle weakness (esp. proximal).
 Pruritus.
 Bone deformity (e.g. resorption of terminal
phalanges)
↑ fracture risk
 Hip fracture risk ~ 5X in dialysis patients.
 Mortality following fracture rises ~ 2.5 X.
Marrow fibrosis, contributes to anaemia and poor
response to EPO therapy.

Is characterized by reduced osteoblast
and osteoclast number and low or
abscent bone formation rate as
measured by tetracycline labeling.
Osteoid thickness is normal or
reduced, distinguishing it from
osteomalacia.
Adynamic bone disease

Adynamic Bone disease
Usually asymptomatic.
Laboratory → iPTH < 100pg/ml, low bone
specific alkaline phosphatase, slightly
elevated Ca2+.
Vertebral and peripheral bone densities tend
to be normal or low.
It carry higher risk of fracture and soft tissue
calcification.
Aluminium related low turnover bone disease
is often painful.

Adynamic bone disease of dialysed patients
Cause Unknown (aluminium? high calcium?
low PTH? diminished response to PTH?)
Clinical findings No symptoms
Post-transplant osteonecrosis?
Tendency to hypercalcaemia
Tendency to extraosseous calcification
Bone histomorphometry Decreased bone formation and
resorption
Predisposing factors Low PTH
Diabetes mellitus
Hypothyroidism
Glucocorticoid treatment

Osteomalacia
Like ABD, osteomalacia represent a
state of low turnover.
If differ, however, because of presence
of a large amounts of unmineralized
osteoid.
Vitamin D deficiency, Aluminium
overload, iron overload, others.

Osteomalacia in uraemic patients
Cause Aluminium overload or vitamin D deficiency
Clinical aspects Bone and joint pain
Skeletal deformities
Proximal myopathy
Plasma chemistry Elevated aluminium (>60 μg/l) or decreased 25(OH)D3
Radiographic Low bone mineral density
Woven spongiosal texture
Looser zones
Bone histomorphometry Decreased bone formation
Increased osteoid seams
Variable bone resorption (positive aluminium stain)

Low PTH.
Overtreatment with vit D.
↑Calcium intake.
Diabetes mellitus.
↑ age.
Alluminium accumulation.
Acidosis.
CAPD.
Corticosteroid therapy.
Factors contributing to a dynamic bone
disease

W. Massoud 31
The So Called “Kidney Medicine!!”
‫دكتور‬
‫المفتح‬ ‫محتاس‬
‫الكلى‬ ‫و‬ ‫الرئة‬ ‫و‬ ‫القلب‬ ‫اخصائى‬
‫الذكورة‬ ‫و‬ ‫الجلدية‬ ‫و‬
Dr.
Mehtass Elmefattah
Betaa kollo
‫االسم‬:‫تعبان‬ ‫غلبان‬ ‫مرضان‬
‫الحمام‬ ‫برج‬ ‫معمل‬
Name of patient: ‫تعبان‬ ‫غلبان‬ ‫مرضان‬
Referred by: prof. Dr. Mehtass Bek
s. creatinine: 3.4mg%
Blood Urea: 97mg%

‫منه‬ ‫وليد‬ ‫الدكتور‬
‫عنى‬ ‫منع‬ ‫هلل‬‫دوا‬
‫الكلى‬
‫من‬ ‫خويا‬ ‫يا‬ ‫انا‬
‫و‬ ‫عييت‬ ‫ما‬ ‫ساعت‬
‫بطلته‬ ‫ما‬ ‫عمرى‬

Osteoporosis
Age and sex hormone related.
Usually defined in terms of bone mineral
density (BMD).
Has little diagnostic meaning in the context
of osteodystrophy where BMD can coexist
with low or high turnover disease.
DEXA scanning does not predict fracture
risk in CKD.

Bisphosphonates→↑ bone density in
osteoporosis. It inhibite osteoclasts
→↓ bone turnover.
In dialysis may lead to ABD, so it is
not to be used.

Teriparatide, a synthetic form of PTH
(1-34) → marked ↑ in bone density
→ useful in osteoporosis and possibly
helpful in ABD.

Osteopenia/osteoporosis in uraemic patients
Causes Same as in general population
Oestrogen deficiency?
Glucocorticoids after renal transplant
Clinical aspects Non-specific
Loss of height
Plasma chemistry Unremarkable (tendency to hypercalcaemia?)
Radiography Diffuse demineralization
Longitudinal striation of vertebral bodies
Wedge deformity of vertebral bodies
Bone histomorphometry Decreased bone mass

Mixed turnover disease
Relatively common, as is evolution
from one form to another.

Features of “high” and “low” turnover bone disease
High Low
Hyperparathyroid
bone disease
A dynamic bone disease Osteomalacia
Bone biopsy
findings
↑osteoblastic and
osteoclastic activity.
Fibrosis
↓osteoblastic and
Thin osteoid seems
↓Osteoblastic and
Widened osteoid
seems.
Aluminum deposition
PTH High Low or normal Usually lower normal
Alkalin
Phosphatase
↑ Normal Normal
Calcium ↑ Often ↑ Normal or ↑
Phosphate ↑ Normal or ↑ Normal or ↑
DFO test Normal Normal Often elevated

Cardiovascular Risk
Poor control of serum PO4 , calcium
phosphate product (Ca x P) and PTH
are all associated with ↑ CV morbidity
and mortality.
↑ Ca X P is associated with soft tissue
and cardiac calcification.

Calcification of the femoral artery intima
Calcification of the femoral
artery intima (a) and media
(b), respectively.
Calcification of the media of
the m-pelvic arteries (c) and
mixed calcifications of the
iliac arteries (d) Assessment
by postero-anterior fine-
detail native, unenhanced
X-ray of the pelvis and the
thigh taken from chronic
haemodialysis patients in
recumbent position.

Extensive soft tissue calcifications in a dialysis patient with primary
hyperoxaluria. Diffuse calcium deposits are present in skin and blood vessels. A
periarticular tumour-like calcium deposit is present in the elbow area

Diagnosis of osteodystrophy
No one marker is perfect, clinical dataset is
used:
Biochemical
Check Ca2+ , PO4, and PTH at least 3 monthly
in CKD stage 4 and 5 and annually in stage 3.
PTH (>450, <100 pg/ml).
Calcium ↓ in SHPT, ↑ in ABD, Ca based
phosphate binders and Vit. D analogue.
Phosphate: raised.
Alkalin phosphatase: ↑ in SHPT (marker of
bone formation- also osteocalcin).

Recommended skeletal X-ray series for
assessment of secondary hyperparathyroidism
Hand, anteroposterior
Shoulder, lateral
Skull, lateral
Spine, lateral
Pelvis, anteroposterior

Radiographic signs of renal osteodystrophy in patients with chronic renal failure
Hyperparathyroidism
Accelerated bone resorption
Subperiosteal resorption, maximal at radial aspect of middle phalanx of index and
midfinger, also at distal ends of clavicles, and in the skull (pepper-pot aspect); acro-
osteoylsis of terminal phalanges; cortical bone thinning; cortical striation, fluffy trabecular
structure, seldom pathological fractures
Enlarged syndesmoses
Resorption of cortex of lateral clavicle, of symphysis, and of sacroiliac joints
Osteosclerosis
Increased density of ground plates of vertebrae (rugger jersey spine), or of radial and
tibial metaphyses, or osteosclerosis of diploe (ground glass)
Accelerated bone apposition
Periosteal neostosis
Soft tissue calcification
Periarticular and vascular radiodense deposits; less frequently deposits in viscera (lungs,
myocardium) and skin
Aluminium-related bone disease
Generally no specific radiological signs; pseudofractures (Looser zones) at predilection
sites; low mineral density
Differential diagnosis
β 2 -Microglobulin-associated osteo-arthropathy Periarticular bone erosions, subchondral
bone cysts, destructive arthropathy

Radiographic signs in hand skeletons of haemodialysis
patients with severe secondary hyperparathyroidism
(a) subperiostal erosion (particularly pronounced in middle
phalanges) and acro-osteolysis of the terminal phalanges;

Radiographic signs in hand skeletons of haemodialysis
patients with severe secondary hyperparathyroidism
(b) periostal new bone formation
(periostal neostosis) (arrow);
(c) subperiostal resorption
zones (arrow).
Both (b) and (c) show cortical thinning, cortical striation, and
fluffy trabecular structure.

Resorptive defects of diploë (pepper-pot aspect) in the skull of a
haemodialysis patient with severe hyperparathyroidism.

Increased density of ground plates of vertebrae contrasting with radiolucency
of the central vertebral slices (rugger jersey spine) in a haemodialysis patient
with severe hyperparathyroidism. Note the severe aortic calcification.

Extraosseous calcifications in terminal renal failure

Schematic presentation of the preferential sites for the occurrence of Looser
zones in aluminium-intoxicated uraemic patients. Less frequent localizations
(e.g. at the scapula) are not shown.

Looser zones (arrows) at both pubic bones in a
haemodialysis patient with severe aluminium intoxication.

MRI scan of the spine of a haemodialysis patient with spondylodiscitis
C5/C6. Note the destruction of vertebral bodies and compression by soft
tissue swelling of the spinal cord.

Unilateral femoral head necrosis in a patient with a kidney
transplant

Treatment
Goals
 Keep serum Ca2+ and PO4 with the normal
range.
 Keep bone turnover and strength as near
normal as possible.
 Keep appropriate serum PTH.
 Prevent the development of parathyroid
hyperplasia.

Standard Treatment Package Comprises
Measures to ↓ serum PO4 :
Dietary PO4 restriction.
Removal through adequate dialysis.
Oral phosphate binders.
-1-

Standard treatment package comprises
Measures to ↑Ca2+ and suppress PTH
synthesis and secretion.
Calcium salts (e.g. Caco3), also act as
phosphate binders.
Vitamin D analogues (e.g. calcitriol,
alfacalcidol).
Measures to suppress PTH synthesis
and secretion directly by calcimimetics.
-2-

Therapeutic targets (K- DOQI)
CKD
stage
GFR
ml/min
PTH
pg/ml
Calcium
mmol/L
Phosphorus
mmol/L
3
4
5
30-59
15-29
<15
35-70
70-110
150-300
N
N
2.1-2.37
0.87-1.48
0.87-1.48
1.13-1.38

Occurs through dialysis water contamination and ↑
phosphate binders.
Al toxicity →↓ PTH secretion, ↓ mineralization, and
↓ osteoblastic activity→ low turnover bone disease.
Serum AL level should be <20 ug/l, levels> 60 ug/L
means overload
In expected toxicity with low level → do DFO test
→ if +ve → DFO chelation treatment.
AL- containing binders are not to be used except <4
weeks and with limited life expectancy.
Coingesion of citrate (Shohl sol., Ca citrat, Fruit
Jauice, Alka- seltzer) greatly enhance AL absorption
up to AL neurotoxicity.
Aluminium toxicity

Hyperphosphataemia
Control of phosphate
Phosphate control is the weak link in the
therapeutic approach to SHPT.
Dietary restriction.
Phosphate is contained in almost all
foods (esp. meats, milk, eggs, and
cereals).
It is difficult to balance dietary
phosphate restriction against adequate
protein intake (recommended level of
daily dietary protein provide 30-40 mml
of phosphate).

Phosphate binders
Taken a few minutes before meal (1-3
tab).
None are particularly potent and large
amounts are needed.
The most effective binder is the one
that the patient will take.
Should not be taken at the same time as
iron supplement.
Combination of phosphate binders.
Dose parallel to PO2 content in meal.
AL(OH) is the most effective.

Calcium containing phosphate binders
(CCPB).
Are the mainstay.
Not only bind PO4 but also correct ↓
Ca2+ (suppress PTH).
Cause +ve calcium balance.
Have been implicated as a cause of
vascular calcification.
Should be restricted to 1500 mg
elemental calcium/ day.
To be avoided if low turnover disease
(PTH < 150 pg/ml).

Non-calcium , non- aluminum containing binders
Sevelamer hydrochloride (Renagel) and
lanthanum carbonate (Fosrenol).
Both extremely expensive.
Not more effctive than CCPBs.
Renagel lowers LDL cholesterol.
Adequate dialysis
Dietary phosphate exceed removal by dialysis.
After dialysis significant PO4 rebound from
intracellular compartment.
CADP is more efficient in PO4 removal.
Daily HD regimens can control phosphate and
more.

Phosphate binders
Binder Advantage
s
Disadvantages Examples
Calcium
based
binders
Inexpensive
Help correct
Ca2+ and
Suppress
PTH
Calcium load
May predispose
To vascular and soft tissue calcification
Calcium carbonate
- Titralac 9168 mg calcium)
- Calciucheew (500 mg calcium)
- Calcium 500 (500 mg calcium)
- Adcal (600 mg calcium)
Calcium acetate phosex (250 mg
calcium).
Aluminiu
m based
Cheap very
effective
Risk of aluminium toxicity
Need to monitor levels
Short term use only
Alucaps
- Al (OH)3 475 mg
Aludrox (liquid)
Sevelamer
HCL
Avoids
calcium and
aluminium
Expensive
GI intolerance
Large doses needed
Long-term outcome data not yet
available
Causes a mild metabolic acidosis
Sevelamer hydrochloride
(Renagel)
- 1-3 800 mg tablets with each
meal
Lanthanu
m
Avoids
calcium and
aluminium
Expensive
Long term consequences of
administration unknown (no toxicity
studies)
Role in clinical practice not yet
established
Lanthanum carbonate
(Forsrenol)
- 750-3000 mg.d in divided
doses

Vitamin D analogues
The other mainstay of SHPT treatment.
Vit D requires 1α hydroxylation by the
kidney.
This is pharmacologically bypassed by
using 1α (OH) vit D analogues calcitriol (1,
25 (OH)2 D) or alfacalcidol (1α calcidol).

Start with low dose (0.25 ug/d, orally) and
increase as necessary over several weeks
(rarely > 0.5- 1.0 ug/d),
CKD stage 3 → target PTH 35-70 pg/ml.
Pulsed oral or I.V. therapy (usually 0.5-2.0 ug
x 3/w) are an alternative to daily regimens
and appear equally effective.
Monitor serum Ca2+, PO4, and PTH.
Side effects →↑ adynamic bone disease, soft
tissue/ vascular calcifications.

Newer vitamin D analogues
Much attention has been given to the
development of vit D analogues with less
propensity to hypercalcaemia
Many have show potential in experimental
settings and a few are available for clinical
use (e.g. Paricalcitol “zemplar”).
Advantages over calcitriol remain unproven,
though there may be marginal benefits.

Calcimimetics
Calcium sensing receptors (CaR) are
expressed across multiple cell types, its
main function is the control of
extracellular Ca2+ concentration and
regulation of steady state PTH secretion.

Calcimimetic agents
Small molecules that bind to the
parathyroid CaR and mimic the effect
of ↑ extracellular calcium.
• ↓ PTH with a simultaneous ↓ in serum
Ca2+.
• ↓ In PO4 and CaXP.
• Extremely expensive.
• Cinacalcet (sensipar) 30, 60, 90 mg,
starting oral dose 30 mg, ↑ gradually
to maximum 180mg/d, guided by PTH
and serum Ca2+

Relative actions of current treatments on
Ca2+, PO4, CaxP and PTH concentration
Calcium
based
binders
Calcium
- free
binder
Vit D
free
sterol
Calcimimetics
PTH ↓↓ ↓ ↓↓↓ ↓↓↓
Calcium ↑↑ ↔ or↑ ↑ ↓
Phosphorus ↓↓ ↓↓ ↑ ↓
CaxP ↓or↑ ↓ ↑ ↓

From the biochemical standpoint,
therapy (vit D sterol or calcimimetic)
can be chosen according to the clinical
phenotype of the patient.

The two clinical phenotypes frequently
encountered in CKD patients
Calcium phosphorus CaxPO4
Vitamin D
phenotype
Low
normal or
low
In target In target
Calcimimetic
type
High
normal or
high
Above
target
High

Parathyroidectomy
Persistent refractory hypercalcaemia and/or hyperphosphataemia associated
with high plasma intact PTH
Severe clinical osteitis fibrosa (e.g. biochemical problems), due to parathyroid
overfunction i.e. not manageable by calcitriol
Marked enlargement of parathyroid glands, associated with high intact PTH
values (8–10 times normal or higher), and unresponsiveness to an 8–12 week
course of calcitriol therapy
Marked soft tissue calcification and high plasma intact PTH, Intractable
pruritus and high plasma intact PTH
Note: It is imperative to exclude other causes of hypercalcaemia, soft tissue
calcification, and, in particular, aluminium intoxication. If present, aluminium
intoxication should be treated by desferrioxamine before parathyroidectomy.
Indications for parathyroidectomy in patients with chronic
renal failure

Imaging
Isotope scans (e.g. MIBI) → allow
localization of the glands perior to surgey
and indetify ectopic tissue (e.g.
retrosternal)
 CT neck scan.
ENT → pre-existing vocal cord problems to be
documented.
Prevention of “hungry bone syndrome” →
high dose vit D (4ug/ daily for 5 days)
Pre-op considerations

CT scan of the neck region of a haemodialysis patient showing an
enlarged parathyroid gland in paratracheal localization.

Bone biopsy is indicated before
parathyroidectomy to diagnose osteitis and to
exclude AL accumulation.
Static and dynamic histologic assessment of
transiliac bone biopsy.
Fluorescent labels, tetracycline, and
demeclocycline are deposited along the line
of mineralization
Drugs are given for 1-3 days → rest for 1-2
weeks→ again → biopsy→ distance between
the two lines→ rate of bone turnover.
For AL deposits biopsy is stained by acid
solochrome azurin.

Histology of normal bone. Two distinct tetracycline labels are found at the
bone–osteoid interface (undecalcified sections, unstained, fluorescence light
microscopy, 200×).

Bone histology in osteitis fibrosa.
(a) The mineralized trabeculas are covered
by broad osteoid seams; osteoblasts are
numerous and cellular fibrosis is seen in the
marrow spaces (magnification 125×).
(b) Active osteoblasts with irregular
polygonal shapes along an osteoid
seam (magnification 800×).

Bone histology in osteitis fibrosa.
(c) Multinucleated osteoclasts resorb the
mineralized matrix; note cytoplasmic
folding (brush border) in contact with
bone tissue (undecalcified section)
(toluidine blue stain; magnification
800×).
(d) The main bone type observed is woven
bone; at some sites (arrows) trabeculas are
covered by thin layers of lamellar bone
(undecalcified sections; polarized light
microscopy; magnification 125×).

Renal osteodystrophy: bone histology in aluminium-related
low-turnover osteomalacia.
Osteoid tissue surrounds the mineralized trabeculas, and the interface between
osteoid and mineral is sharply delineated; note the absence of osteoblasts,
osteoclasts, and marrow fibrosis (undecalcified sections; toluidine blue stain;
magnification 125×).

(b) Aluminium deposits at the osteoid–bone interface (undecalcified
sections; aurintricarboxylic stain for aluminium; magnification 125×).
Renal osteodystrophy: bone histology in aluminium-related
low-turnover osteomalacia.

bone histology in non-aluminium-related osteomalacia. Broad lamellar
osteoid seams cover the calcified tissue. The interface between osteoid
and mineral is blurred. Marrow fibrosis is found along the trabeculas
(undecalcified sections; toluidine blue stain; magnification 125×)..
Renal osteodystrophy

Bone histology in aluminium-related adynamic bone disease
(serial sections).
(a) no osteoid tissue is observed. Osteoblasts, osteoclasts, and
marrow fibrosis are absent (undecalcified sections; toluidine blue
stain; magnification 125×);

(b) aluminium deposits are present along the mineralized trabeculas
(undecalcified sections; aurintricarboxylic stain for aluminium;
magnification 125×).
Bone histology in aluminium-related adynamic bone disease
(serial sections).

Electron microscopy of parathyroid tissue in aluminium intoxication
(a) Ultrastructural aspect of a parathyroid gland
chief cell from an aluminium-intoxicated
haemodialysis patient. Note the numerous
mitochondria, secretion granules, and folding of
plasmalemma indicating active hormone
synthesis (magnification 12,000×).
(b) Dense deposits (arrow) which emit
X-rays characteristic of aluminium
are present within lipoid bodies
(magnification 63,000×).

Monitor drains for haemorrhage.
Hypocalcaemia → give calcitriol oral 0.5-
2.0 ug/d and oral calcium 1-3 gm/d.
PTH measurement.
Post-op considerations

Partial parathyroidectomy.
Total parathyroidectomy with re-
implantation.
Total parathyroidectomy plus
maintenance calcium and calcitriol
supplmentation.
Radiologic localization and ethanol
injection.
Parathyroidectomy technique

Is a small vessel vasculopathy involving
mural calcification with intimal
proliferation, fibrosis and thrombosis.
It occurs predominately in individuals,
with renal failure and results in ischaemia
and necrosis of skin, soft tissue, viseral
organs, and skeletal muscles.
Calciphylaxis
(Calcific uraemic arteriolopathy)

Incidence
 Incidence is 1%, prevelance is 4%, mortality
80% at one year (almost always due to sepsis).
Presentation
 Painful erythematous livedoreticularis like
skin patches which ulcerate, secondary
infection follow.
 Two patterns are recognized
(i) Ulcers on the trunk, buttocks or thighs (over
adipose tissue), and (ii) ulceration on
extremities.
 Other organs.
 Skin biopsy is characteristic.

Several lesions of calciphylaxis that occurred on the lower extremity of a
patient undergoing dialysis. These lesions developed in areas of livedo
reticularis and followed the path of the vasculature

An isolated lesion of calciphylaxis manifesting as an enlarging necrotic
plaque on the lower extremity of a patient undergoing dialysis. The stellate
purpuric morphology can be appreciated surrounding the area of necrosis.

Calciphylaxis may manifest as rapidly progressive, diffuse and extensive,
cutaneous necrosis, as is seen in this patient with chronic renal failure.
Bullae may also be seen as a rare manifestation of calciphylaxis

Histologically, calcification of the blood vessels, as well as the subcutis, can
be seen in calciphylaxis

Demonstrated here is the characteristic circumferential medial calcific
deposit in an arteriole with subintimal edema.

This image shows circumferential medial calcific deposits obliterating the
external elastica of an arteriole.

(b) Multiple intimal calcifications
(red particles) and thrombosis signify
calciphylaxis (hematoxylin and eosin;
original magnification, 400).
(a) Skin pathology showed
longitudinal necrosis of epidermis
(hematoxylin and eosin; original
magnification, 100)

Risk factors
 Uraemia (also post-Tx, 1ry HPTH).
 ↑ calcium phosphate products.
 ↑ PTH.
 Vit D analogue abuse.
 Caucasian.
 ♀>♂.
 Obesity (BMI>30).
 Warfarin use.
 Protein C or S deficiency.
 Diabetes mellitus.
 Malnutrition.

Treatment
 Wound care.
 Lower CaxP, daily HD, lower dialysate Ca.
 Parathyroidectomy may help.
 Control risk factors.

SHPT
 Check Ca2+, PO4, PTH at least 3
monthly in CKD 4 and 5, annually in
stage 3.
 Control serum phosphate with
combination of diet, phosphate binders
and adequate dialysis.
Summary
Renal bone disease management

 Once phosphate controlled, add calcitriol,
titrat to reach target PTH and serum
calcium.
 Uncontrolled SHPT→ review diet, ↑
phosphate binders, consider paricalcitriol
(cinacalcet).
 If ↑ Ca2+ → switch to non- calcium
containing binders and consider low
dialysate Ca2+, and more frequent dialysis.
 Parathyroidectomy is last resort.

Aim to increase PTH.
Reduce or stop calcium containing
binders.
Reduce or stop vit D analogues (small
dose may be needed to ↑ intestinal ca
absorption).
↓ dialysate calcium.
Exclude significant aluminium
deposition.
Adynamic bone disease

M. Sobh MD, FACP
THANK YOU

Prof sobh renal osteodystrophy

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