secondary hyperparathyroidism in CKD patients, pathophysiology, clinical picture, management

1. Hyperparathyroidism

2. Calcium Homeostasis
*normally serum Ca is mentained within very narrow range ess
ential for optimal activity of many intracellular & extracellula
r processes .
*Normal range :
total Ca : (8.5 - 10.5 mg /dl) = (2.12 - 2.62 mmol/l)
ionized Ca : (4.65 – 5.25 mg/dl) = (1.16 – 1.31 mmol/l)
*Ca metabolism involve 3 important components :
( Absorption , Distribution , Renal handling )

3. A- Absorption :
* Unlike Na & K , Ca absorption from intestine is incomplete due to :
-dependence on vit D
-binding to anions to form non absorpable complexes
* Ca absorption occurs via :
- Transcellular in deudenum & jejunum via TRPV6 channel
- Paracellular along whole length of intestine

4. B- Distribution IN ECF:
* When protin concentration (particularly albumin) fla
ctuate total calcium concentration may change whil
e ionized remain relatively stable so in such cases w
e need to correct Ca with serum albumin .
* Even in presence of normal albumin changes in PH c
an affect binding of Ca to albumin & consequently
affect free ionized active CA
*While acidosis reduce this binding & increase the acti
ve Ca
Alkalosis favor this binding & decrease the active ioniz
ed Ca
*So , in such cases ionize Ca will be more accurate than
total Ca even if corrected

5. C-Renal Handling :
*only ionized Ca is filtered by glomeruli
*60-70% reabsorped in PCT passively
*20% reabsorped in TALH passively
*10-15% reabsorped in distal nephron
via TRPV5 by active process under
hormonal regulation

6. Role of Hormones In Regulation of Ca
& PO4 Homeostasis.

7. 1- PTH:
 Main stimulus : hypocalcemia
 Effect:
GIT : increase absorption of Ca & Po4
Via ++ of one alpha hydroxylase >> more active vit D
Kidney : increase Ca reabsorpsion & Po4 excretion
Via ++ of TRPV5 channels
Bone : bone resorption , releasing Ca from bone
 Net result : increase ca & decrease PO4

8.  Feed back :
 Calcium ions bind to CASR & -- PTH
 Active vitamin D bind to VDR & -- PTH
 FGF 23 – PTH
 Decreased Po4 ??--PTH

9. 2- Vitamin D :

11. Vit.D
Main stimulus : Hypocalcemia
Effect :
GIT : increase intestinal absorpsion of Ca & Po4
Via ++ TRPV6 channels
Kidney : increase Ca reabsorpsion in distal nephron
Via ++ TRPV5 channels
Bone : it increase intestinal absorpsion of Ca & Po4 thus promotes for
bone mineralization
However Vit D in toxic doses , especially with Ca & Po4 defisciency ma
y ++ bone resorpsion
NET result : hypercalcemia & hyperphosphatemia
Feedback : vit D bind to VDR in :
parathyroid gland : -- PTH
kidney : -- 1 alpha hydroxylase & ++ 24 alpha hydroxylase

12. FGF 23 :
Secreted from :osteocytes
Act by : forming FGF23 klotho complex important for its action on parathyr
oid
Effect :
kidney : -- Na Po4 co transporter in PT >
Po4 reabsorption
-- one alpha hydroxylase > -- active vit D
Parathyroid gland : -- PTH
NET result : Po4
active vit D
PTH

13. hyperparathyroidism
Primary
Secondary
Tertiary

14. Primary hyperparathyroidism
 Hyperplasia
 Adenoma
 Carcinoma (rar
ely)

15. Secondary hyperparathyroidis
m
 overproduction of parathyroid hormone secondary to a c
hronic abnormal stimulus for its production. Typically, th
is is due to chronic renal failure Another common cause
is vitamin D deficiency.
 In chronic kidney disease, overproduction of parathyroid
hormone occurs in response to hyperphosphatemia, hyp
ocalcemia, and impaired 1,25-dihydroxyvitamin D produ
ction by the diseased kidneys.
 Hyperphosphatemia appears to be particularly importan
t; it can directly stimulate parathyroid hormone synthes
is and parathyroid hyperplasia and indirectly promotes s
econdary hyperparathyroidism by decreasing free calciu
m level.

16. Pathophysiology

17. Decrease no of functioning nephrons
Decrease the ability to excrete ingested Po4 from food
Hyperphosphatemia
++ FGF23
++ Po4 excretion
PO4
Active vit D
functioning renal mas
s
Po4 absorpsion HYPOCALCEMIA

18. Po4Ca Vit D
++ PTH
GIT
++ Ca & Po4 ab
sorpsion
KIDNEY
++ Ca reabsorpsi
on
++ Po4 excretion
BONE Resorp
sion

21. This compensatory mechanisms net effect is maintenance
of serum Ca & PO4 within normal range till stage 5 CKD
where this elegant system breakdown.

23. Osteitis fibrosa : (high turn over bone disease)
*↑PTH →↑activity of osteoblast &osteoclast leading
to accelerated bone formation &resorption so bone is
laid down rapidly in irregular rather than lamellar pat
tern& improperly mineralized so bone is more liable t
o fracture.
*Lab.: Ca low(unteated)&PTH &alk ph. &po4 high
*Radiology: subperiosteal erosions in bone.

24. Clinial picture
Usually asymptomatic. Clinical sequelae occur late (with si
gnifi cant biochemical and histological disease), including:
• Bone pain, arthralgia, and muscle weakness (esp. proxim
al).
• Pruritus (cutaneous calcium phosphate deposition). • Bo
ny deformity (e.g. resorption of terminal phalanges).
• inc fracture risk (hip fracture risk 5 x in dialysis patients)
. Fracture risk is equivalent to a non-dialysis patient 10 – 2
0 years older. Mortality following a fracture rises by 2.5 x
.
• Marrow fi brosis contributes to anaemia and poor ESA res
ponse.
* Poor control of serum PO4, serum Ca 2+ , calcium phosp
hate product (CaxP), and PTH are all associated with i CV
morbidity and mortality.
• i CaxP is associated with soft tissue and cardiac calcifi ca
tion.

25. Complications
 Bone fractures and disability
 Vascular calcifications with cardiovascular morbi
dity and mortality
 Soft tissue calcifications
 Impaired erythropoiesis , ESA resistance
 Neurological disturbances
 Calciphylaxis : ischemic skin necrosis caused by
deposition of califiaction and subsequent throm
bosis of small blood vessels .. Rare but Fatal con
dition.

26. Management
*Prevention is the primary goal in management.
*Therapy for hyperparatyhrodism should be initiated in CKD stage 3
so that parathyroid gland hyperplasia can be prevented.
*Management greatly depends on increasing evidence that reliance
on calcium based phosphate binder& high dose of vit.D may be as
sociated with adverse effects(e.g:vascular calcifications&CVS mor
tality)
*Approach relying more on calcimimetics&non calcium phosphate b
inder provide clinical benefits.

27. Goals of therapy:
KIDOQI:
KDIGO :
In stage 3 , 4 maintain in normal range
In stage 5 or on dialysis :
(1) iPTH: 2-9 times upper limit normal (i.e 150-600)
(2)Lowering elevated phosphorus toward normal .
CKD stage PTH (pg/ml) Ca (md/dl) Ph (mg/dl)
3 35-70 8.5-10.5 2.7-4.6
4 70-110 8.5-10.5 2.7-4.6
5 or Dialysis 150-300 8.4-9.5 3.5-5.5

28. Lines of Management:
(1)Prevention of hypocalcemia.
(2)Control of phosphate.
(3)Suppression of PTH.
(4)Parathyriodectomy.

29. (A)Prevention of hypocalcemia:
*should be corrected as it is apotent stimulus of P
TH secretion.
*in mild to mod. CKD : calcium supplements ()me
als.
*if there is hyperPTH & hypocalcemia & in patient
s with ESRD :active vit.D sterols should be consider
ed.

30. Initial point of management is treating hyperphosphatemia
By:
1-Dietary phosphate restriction.
2-Choice of phosphate binder.
3-Haemodialysis:
average standered 4 hrs session remove 800mg phosphate.
Frequancy is more important than duration as phosphate re
moval itradialytic is more prominent in first hours of sessions.

31. (B)Control of phosphate:
(1)Dietary phosphate restriction(800-1000mg/day):
*avoid processed food,dairy product,cola,some additives,nuts,seeds,beans,
peas.
*but be aware of malnutrition so increase uptake of high biologic sources o
f protein such as meat&eggs(ptn 0.8 gm/kg).

32. (2)Phosphate binders:
1-Calcium containing phosphate binder.
2-Non ca cotaining phosphate binder.

33. Choice of phosphate binder
PTH
Normal or high low or e vas.calc
Calcium
Hypoca. Normoca. Hyperca.
acc to level of ca&cost
Ca cont. Non Ca. cont.

35. Calcium containing phosphate binders:
*took with meals to bind phosphate and its absorption.
*effective phosphate binder in 60% to &70% of ptn on HD.
*Dose varies according to dietary phosphate restriction&CKD stage (max. dose of elemen
tal ca is 1500mg/day)
*Limitations of its use:
-hypercalcemia.
-extensive vascular calcifications.
-calciphylaxis.
in such patients aluminium containing antacids may be used for short period(not more
than 40 to 45 mglkglday).

36. (1)Calcium Carbonate (Calcimate 500 mg):
elemental calcium is 40%(200mg).
1gm binds 40 mg phosphate
(2)Calcium Acetate (Marcal 700mg):
elemental calcium is 25%(180mg).
1gm binds 45 mg phosphate
(3)Calcium Citrate(Cal-mag):potentaites aluminium uptake and should be avoided in CK
D.

37. 800mg every 8 h with meals *S po4 5.5-7.5
1200mg every 8 h with meals *S po4 7.5-9
1600mg every 8 h with meals *S po4 more than 9
Maintainance : evaluation after 2 w
If More Than 5.5 increase dose by 400-800 per meal Max 4000 pe
r meal
3.5-5.5 Same Dose
Less Than 3.5 decrease dose by 400-800 per meal
It is recommended to give other Drugs 1 h before & 3 h after
SE: GIT Symptoms & Hypocalcemia
Sevelamer
d
c

38.  Mg found to decrease vascular and soft tissue calcifica
tion.
 Mortality tend to be reduced in ptn with higher S Mg le
vel
 SucroFerric oxyhydroxel :
 Iron containing po4 binder with minimal oral iron abso
rption

39. Ferric Citrate :
 Iron containing po4 binder improve s Iron
 Decrease need for IV Iron & Epo
 Aluminium Containing: Po4 Binder
 SE : Dementia , Anemia , Constipation & Adynamic Bon
e Disease
 They are Given For Short Periods in
- -Severly elevated po4 with increase in ca.po4 product +
- Hypercalcemia

40. *Level of Pth may be normalized Just by treating huperphosphatemia & Hypocalcemia
*If PTH level more Than 300
N.B:*Cinacalcet shouldnot be initiated if serum calcium <8.4
*Calcitriol shouldnot be given if s.ca >9.5, s.PO4>5.5&Ca.PO4 product >55
Look at s.Ca &PO4
If s.Ca>9.5&PO4<5.5
OR s.Ca>8.4&PO4<5.5
If s.Ca<9.5&s.PO4<5.5
Cinacacet Calcitriol

41. Calcimimetics ( cinacalcet)
 Dose 30 mg po per day
 Dose increase at 2-4 weekly intervals to 60 – 90 – 120 -180
 CI: - hypersensitivity
 -shouldnot be started at s ca less than 8.4
- -Used with caution in ptn with Hx Of seizres

42. Vit D :
 Vit D analogues used therapeutic :
- Calcitriol (1,25-dihydroxyvitamin D 3)
- Alfacalcidol (1-hydroxyvitamin D3)
- Paricalcitol (synthetic analogue of active vit D2)
- Doxercalciferol (synthetic analogue of vit D2)
- Dose 0.25 -1 mcg orally daily
- Less hypercalcemia if dose given at night
- Pulse therapy (1-3) mcg two to three times per week provide better suppretion of PTH wit
h lower risk of hypercalcemia than daily therapy
- Pulsed oral probable is as effective as iv TTT & Cheaper

44. Follow up

45.  Severe hyperparathyroidism with :
 Persistent hyperphosphatemia
 unresponsive to calcitriol and calcium
 Hypercalcemia with intolerance or unresponsiveness to calcimimetics
 Renal transplantation candidate
 Evidence of metastatic calcification
 Calciphylaxis with evidence of hyperparathyroidism
 Severepruritus,only if additional evidence of hyperparathyroidism
Parathyroidectomy:

46. Tertiary hyperparathyroidism
 excessive secretion of parathyroid hormone after longst
anding secondary hyperparathyroidism .
 characterized by the development of autonomous hyper
secretion of parathyroid hormone causing hypercalcemi
a. The etiology is unknown but may be due to monoclon
al expansion of parathyroid cells (nodule formation with
in hyperplastic glands). A change may occur in the set p
oint of the calcium-sensing mechanism to hypercalcemi
c levels.
 Even after renal transplantation. The hypertrophied par
athyroid glands fail to return to normal and continue to
oversecrete parathyroid hormone, despite serum calciu
m levels that are within the reference range or even ele
vated.

47. Clinial presentation
 It is presented by persistent hyperparathyr
oidism after renal transplantation or new h
ypercalcemia in the setting of chronic seco
ndary hyperparathyroidism.

48. Management
 Total parathyroidectomy with autotransplantation or su
btotal parathyroidectomy

49. THANK YOU