Presentation given to our transplant team about management of Hyperparathyroidism in Patients who have received a kidney transplant

1. Hyperparathyroidism
In Kidney
Transplantation
CHRISTOS ARGYROPOULOS

2. Learning Objectives
Natural History of abnormalities of Calcium Phosphorus PTH after kidney transplant
Impact of Hyperpara on Organ Function
Impact of Allograft Function on Hyperpara
Management Strategies

3. NATURAL HISTORY OF CALCIUM, PHOSPHATE AND PTH
POST KIDNEY TRANSPLANTATION

4. Hyperparathyroidism and Bone
Health After Kidney Transplantation
CJASN July 2016, 11 (7) 1282-1296

5. SHPT found in pts with native kidney CKD 3-5 differs from SHPT in allograft
recipients
Copley and Wuthrich Clin Transplant 2011: 25: 24–39
CKD 3-5 Transplant
The major differentiating features are the high↑ PTH & FGF-23, combined with an
functional kidney that can respond to these hormonal regulators by increasing
serum calcium and decreasing serum phosphate, the rapid resolution of
sceletal resistance PTH (↑ Ca,P fluxes from the skeleton ) combined with
parathyroid resistence to the calcium levels (↓VDR, CaSR) which impedes the
ability of the gland to shut down PTH production in response to hypercalcemia.

6. SHPT post transplantation (early period)
•Renal function (GFR)
•PTH/FGF-23
•Calcitriol/VDR activation status
Time
CKD stages 3-5 and ESRD
Time
Early post transplant period

7. SHPT after trasplantation (late period)
•Renal Function (GFR)
•PTH/FGF-23
•Calcitriol/VDR activation status
Time
Late post transplant period
Time
Early post transplant period

8. Calcium Phos and PTH in the early post
transplant period (<3 months)
Single Center Retrospective Study of post
txp pts (n=201)
Inclusion criteria: functional graft 3 mos
post Kidney Transplant (KTxP)
Per surgical team protocol ALL VDRAs
were routinely stopped the before
surgery
Immunosuppression (ISP): CsA(12,9%),
TAC(82,1%), AZA/MMF(87,1%),
Steroids (98%)
Evenepoel et al CJASN 2008;4:665-672.

9. Calcium, Phos and PTH abnormalities
are common after a successful KTxP
Evenepoel et al CJASN 2008;4:665-672.
n.l. <2%
n.l. 15-20%

10. Serum calcium levels exhibit biphasic changes post KTxP
Evenepoel et al CJASN 2008;4:665-672.
During the first week post
surgery serum calcium declines
After the 4η week serum calcium
progressively increases
>15% of pts
developed hyperCa
after the first week
41,2% of pts developed
hypoCa in the first week
20% developed serious
hypoCa (<8 mg/dl)

11. Allograft function and the degree of control of SHPT before transplant affect
serum calcium, phos and calcitriol levels after transplantation
HypoCa 1st week: correlates with ↓ PTH & ↑ Ca (before KTxP)
HyperCa at 3 mos correlates with :
◦ ↑ Ca & ↑ PTH before transplant
◦ ↑ PTH & good allograft function at 3 months
High PTH at 3 mos: ↑ PTH before transplant
Calcitriol levels determinants at 3 mos:
◦ Gender (25% lower in men)
◦ ↑ PTH & ↑ 25(ΟΗ) vitD
◦ Good allograft function
Evenepoel et al CJASN 2008;4:665-672.

12. Gender, Race, PTH and Calcium before transplant are correlated with
persistent SHPT (pSHPT) 1 year after successful KTxP
Evenepoel et al Nephrol Dial Transplant 2004;19: 1281–1287

13. Natural History of Ca, Phos and PTH
post TxP
Evenepoel et al Nephrol Dial Transplant 2004;19: 1281–1287
>16% will develop pSHPT while the need for parathyroidectomy
increases over time

14. Persistent SHPT post KTxP is more common in patients with moderate to
severe SHPT before transplantation
Evenepoel et al Nephrol Dial Transplant 2004;19: 1281–1287
Moderate SHPT : biPTH> 100pg/ml
Severe SHPT: biPTH> 400 pg/ml

15. Determinants of PTH
levels post KTxP

16. SHPT control before transplant determines the levels of PTH post KTxP in patients
with good allograft function
Torres et al NDT 1998;13(suppl 3):94-97.
•22,6% had normal PTH
•27,4% had values of PTH > 2 x u.n.l
•75% had normal calcium levels
•Post KTxP PTH is correlated with ClCr
after transplant and PTH levels before
transplant
•PreTransplantation PTH is an even
stronger predictor in patients with Scr< 1,5
mg/dl (ClCr 80±29ml/min) post transplant
Scr < 1,5 mg/dl

17. Allograft function and pretransplantation PTH levels determine PTH levels
post transplant
Evenepoel et al Nephrol Dial Transplant 2004;19: 1281–1287
Interpretation: Early post transplant hypercalcemia
results from high PTH levels targeting a well
functioning kidney

18. Pretransplantation PTH, age and VDR polymorphisms
determine pSHPT and Calcium, Phos disturbances post KTxP
Observational study in patients with good allograft
function 12 mos post KTxP
Patients classified to 2 groups: PTH<80pg/ml (A) &
>80pg/ml(B: persistent SHPT, pSHPT)
Factors correlating with pSHPT: age (39,9 ± 11,5 vs.
48,7 ± 11,7), dialysis dependency (23,8 ±14,4 vs. 44,6
± 37,2), preTransplant PTH (168,1 ±141 vs. 538,8 ±
375,6) & VDR polymorphisms (BB/Bb/bb : 10/17/13 vs.
3/23/15)
Messa et al KI 1998;54:1704-1713.
↑ Ca in group Β

19. Allograft Function and
Persistent SHPT

20. The Effects of SHPT on allograft
function vary
•SHPT does not appear to be related to1:
◦ Delayed Graft Function
◦ Slow Graft Function
•However, SHPT IS related to
◦ Long term allograft survival 2
◦ Allograft calcifications3
1Kalabia et al Nefrología 2009;29(2):143-149.
2Rodnat et al Transplantation 2006;82(3):362-367.
3Gwinner et al Am J Transplant 2005;5:1934-1941.
18% in protocol biopsies 6 mos
post KTxP

21. SHPT is not related to DGF
Kalabia et al Nefrología 2009;29(2):143-149.

22. SHPT is not related to SGF
Kalabia et al Nefrología 2009;29(2):143-149.

23. Inconsistent data about the effects of Calcium and Phosphate in early allograft function
Kalabia et al Nefrología 2009;29(2):143-149.
•Few studies have shown a relation between SHPT biochemical abnormalities &
DGF
•PTH has only been shown to be related with DGF in old, small studies with high
prevalence of DGF that are not representative of modern transplant experience

24. Relation of long term allograft function and SHPT
Rodnat et al Transplantation 2006;82(3):362-367.
22,1%
Distribution of Pretransplantation
PTH
407 pts, 54 lost allograft & 38 deaths

25. Pretransplantion SHPT negatively affects
long term allograft function
Rodnat et al Transplantation 2006;82(3):362-367.
90 pg/ml 540 pg/ml
•PTH not related to DGF
•Acute rejection episodes correlated with
donor age, mismatches in DR/B & PTH
•PreTransplantion PTH ~540 pg/ml
associated with 50% relative risk of
allograft loss

26. SHPT and allograft calcifications post
transplant
•213 kidney transplant recipients with ascertained transplant outcomes 1
year post surgery
•Protocol biopsies were undertaken at 6 wks, 3 mos & 6 mos
•Standardized allograft interpretation according to the Banff 2003 schema
•Allograft calcifications detected and quantified by van Kossa staining
•Examined associations between allograft function, patient demographics
and SHPT control in patients with and without allograft calcifications
Gwinner et al Am J Transplant 2005;5:1934-1941.

27. Luminal and
mixed allograft
calcifications
increase in
frequency over
time after surgery
Gwinner et al Am J Transplant 2005;5:1934-1941.

28. Allograft calcifications are related to better initial allograft function but not
acute rejection episodes
Gwinner et al Am J Transplant 2005;5:1934-1941.
∗p = 0.03, ∗∗p = 0.017;
$p = 0.003 Μ3, #p = 0.027 W6

29. Poorly controlled SHPT post transplant is associated with renal vascular
calcifications
Gwinner et al Am J Transplant 2005;5:1934-1941.
Serum calcium levels on the day of biopsy are related to PTH levels (r=0.62
p<0.02), hence hypercalcemia is caused by the elevated PTH

30. Allograft calcifications & elevated PTH are
associated with renal allograft functional impairment
6W 3M 6M
C(+) 31% 37% 32%
VDRAs
C(-) 26% 42% 52%
C(+) 46% 60% 62%
Phos
C(-) 6% 13% 17%
Gwinner et al Am J Transplant 2005;5:1934-1941.
3 mos
6 mos
Therapy

31. Is persistent SHPT a cardiovascular risk factor in kidney transplant recipients
?
.
1Barenbrock et al Kidney International 1998;54:210-215.
2Suwelack et al Am.J.Hypert 2001;14:1012-1018
SHPT is associated with reduced
carotid distensibility in KTxP
recipients1
SHPT is associated with smaller
reductions in CIMT post transplant2

32. Post Transplant SHPT is associated with
reduced carotid vascular distensibility
Barenbrock et al Kidney International 1998;54:210-215.
In multivariate analyses Age >
PTH>MAP> Hypertension duration

33. Higher Postransplant PTH is associated with higher CIMT post transplant
Suwelack et al Am.J.Hypert 2001;14:1012-1018.

34. Treating Post
Transplant Hypepara

35. Overview of Available Strategies
Vitamin D receptor activators:
Non-selective (calcitriol, high dose of vitamin D3/D2)
Selective (paricalcitol/doxecalciferol
Calcimimetics
Surgery (parathyroidectomy)

36. Non selective VDRA to prevent
SHPT post transplant
Prospective RCT calcitriol (0,5μg/48h + 500mg Ca, C+Ca) v.s. 500mg Ca starting on the third day post
TxP
Discontinue VDRA after the 3rd month
Interrupt therapies for hyperCa(>11.3 mg/dl) x 1 wk
Frequency of laboratory monitoring Ca,P:
◦ 2/wk x 2 wk
◦ 1/wk x 4 wk
◦ 1/15days x 1 ½ mo
PTH,BMD, 24 hr urine collections 0,3,12 months
VDR polymorphisms were analyzed
ISP:
◦ Induction with ATG
◦ maintenance with CSA+MMF/AZA+P (0,3mg/kg x 3mos →10mg 12 mo)
◦ Acute Rejection: 500mg SM x 3 IV
Torres et al KI 2004;65:705-712

37. VDRA therapy prevents post transplant SHPT
Torres et al KI 2004;65:705-712
•HyperCa (3/12 mo):
•4,5% / 5,5% (C+Ca)
•9,8 % / 8,6% (Ca)
• Transient hypercalciuria(C+Ca)
•BMD better preserved with C+Ca in
pts with ΒΒ/Βb VDR polymorphisms

38. De novo nutritional vitamin D & large doses of elemental calcium may
prevent post transplant SHPT
Wissing et al Transplantation 2005;79:108-115
Prospective RCT D3 (25000IU/mo + 1600mg Ca) v.s. 1600mg Ca from the 1st wk post
surgery x 3 months
After the 3rd month all patients converted to 1000 mg Ca po
Excluded patients on VDRA therapy before transplant and patients who developed
hyperCa in the first week after surgery
Therapy was interrupted when Ca>11 mg/dl x 2 wk & supplements restarted when Ca<
10.5 mg/dl
PTH,BMD, 24 hr urine collections 0,3,6,9, 12 months
ISP:
◦ Induction with ATG (high risk pts), Simulect (low immunologic risk)
◦ Maintenance with CSA/ΤΑC+MMF+P (taper over 6 mos)
◦ Acute rejection episodes: 3 mg/kgr SM x 5 IV

39. Nutritional vit D + Ca resulted in better PTH control without inducing
hypercalcemia
Wissing et al Transplantation 2005;79:108-115

40. VDRA administration attenuates rates of GFR loss and improves long term allograft
outcomes
Retrospective study of pts with impaired
allograft fx and biopsy proven Chronic Allograft
Nephropathy
Control group: matched patients on the basis
of age, gender, year of trasplantation and level
or renal function
All patients on 3 drug ISP regimnes
Rate of loss of renal function reversed after
the first year of Tx
Allograft survival curves separate after the
first year
O’Herrin et al Am J Nephrol, 2002;42, 2924–2927

41. Paricalcitol reduces PTH without elevating serum or urine calcium in kidney
transplant recipients
Perez et al Transplantation Proceedings, 42, 2924–2927 (2010)

42. “Oral paricalcitol in Kidney Transplant
Recipients”
Randomized placebo controlled trial evaluating paricalcitol in
transplant recipients (sponsor: Mayo Clinic)
End Points: PTH and changes in BMD at the spine and hip one
year post transplant
Pari Dose regime: 1 μg/d adjusted after 2 wks to 2μg/d based on
urine calcium
This was used as preventive therapy upon kidney transplant
http://clinicaltrials.gov/ct2/show/NCT00587158

43. 0M
p=0.18
3M
P<0.0001
12M
P<0.0001
Paricalcitol
Ν=51
197
(134,291)
43
(29,62)
42
(33,65)
Control Group
Ν=49
236
(155,341)
70
(54,108)
85
(116,49)
Paricalcitol safely reduced PTH
Amer et al Joint Annual Meeting of the American Society of Transplant Surgeons (ASTS) and the American
Society of Transplantation (AST); June 2-6, 2012; Boston, MA, USA. Abstract LB33
Am J Transplant. 2013 Jun;13(6):1576-85. doi: 10.1111/ajt.12227
•During the study 2 patients had to reduce the dose of paricalcitol
•4 patients went off therapy due to hypercalcemia
•There no changes in (iothalamate measured) GFR 12 months post transplantation: 55
± 16 vs. 57±18 ml/min p=0.5

44. Paricalcitol for Secondary Hyperparathyroidism in Renal
Transplantation
J Am Soc Nephrol 26: 1205–1214, 2015

45. Paricalcitol Reduced PTH and Proteinuria After Kidney
Transplantation
J Am Soc Nephrol 26: 1205–1214, 2015

46. Nutritional VitD OR
active analogs?
Started therapy if PTH the day before the transplant was 250-600
Kidney Int Rep (2018) 3, 122–132

47. Meta-analysis of allograft function
post administration of cinacalcet
Henschkowski et al Kidney Blood Press Res 2011;34:97–103
115 pts administered cinacalcet 37.8 mos (range 6-74) post KTxP

48. ↓PTH and calcium in response to cinacalcet is associated with worse allograft
function
Renal function was related to
changes in serum calcium by
meta-regression methods.
Analyses demonstrate a
small but monotonic dose
response curve between
serum calcium reductions
after cinacalcet and allograft
function
Henschkowski et al Kidney Blood Press Res 2011;34:97–103

49. Safety profile of calcimimetics in KTxP
Prospective observational studies of patients enrolled according to:
◦ ↓eGFR (43±19 ml/min/1.73m2),
◦ hyperCa (2.73±0,22 mmol/l)
Patient characteristics:
◦ Nephrocalcinosis (58% patients)
◦ Age: 55.1 ± 9.1 years
◦ HD duration: 6.9±3.5 έτη
◦ Time since transplant 3.8 ± 4.4 yrs
◦ Dose of cinacalcet: 30mg (> 30mg in 4/58)
Schwarz et al Transplantation 2011;91(5):2011

50. Low dose cinacalcet is not effective in reducing PTH and is associated with
declines in renal fx
Schwarz et al Transplantation 2011;91(5):2011
One pt stopped tx due to GI SE, one developed AKI (considered to be drug
related by the investigator), one pt required dialysis after 3 months of therapy,
while 7 pts had progressed to dialysis dependency 12 months after the study

51. ↓PTH and Ca post parathyroidectomy affects immediate graft function but not (?)
long term transplant outcomes
Schwarz et al NDT 2007;22:584-591
> 80 % PTH decline was
associated with ↓ GFR
78%
50%
Inulin Clearance ↓from 67 to 55 ml/min/1.73m2, P<0.001
PAH Clearance ↓ from 360 to 289 ml/min/1.73 m2, P<0.001

52. Cinacalcet in hypercalcemic
hyperpara: a PBO RCT
INCLUSION CRITERIA
Kidney transplant > 9 wks <24
randomization
eGFR > 30
PTH > 100
Ca > 10.5
Cinacalcet (N = 57)
Placebo (N = 57) Total (N = 114)
Age, mean (SD) 53.0 (10.7) 51.7 (9.9) 52.3 (10.3)
Sex, n (%)
Male 31 (54.4) 32 (56.1) 63 (55.3)
Female 26 (45.6) 25 (43.9) 51 (44.7)
Race, n (%)
White 47 (82.5) 46 (80.7) 93 (81.6)
Black 5 (8.8) 4 (7.0) 9 (7.9)
Other 5 (8.7) 7 (12.3) 12 (10.5)
Blood pressure,
mean (SD)
Systolic (mmHg) 133.9 (18.4) 129.9 (14.0) 131.9 (16.4)
Diastolic (mmHg) 77.4 (10.4) 77.7 (9.3) 77.5 (9.8)
Dialysis vintage,
mean (SD), months
62.0 (44.2) 62.7 (35.8) 62.4 (40.1)
Age of most recent
kidney transplant,
mean (SD), months
7.8 (5.6) 6.5 (3.0) 7.2 (4.5)
Number of subjects
exposed to
cinacalcet, n (%)
36 (63.2) 35 (61.4) 71 (62.3)
American Journal of Transplantation 2014; 14: 2545–2555

53. Cinacalcet reduces calcium yet…
CINACALCET DOSING
Dose level
(mg/day)
Cinacalcet (N = 57)
End of
titration
(N1 = 57)
End of EAP
(N1 = 52)
End of
maintenanc
e (N1 = 53)
End of
study
(N1 = 57)
n (%) n (%) n (%) n (%)
30 17 (29.8) 15 (28.8) 17 (32.1) 19 (33.3)
60 21 (36.8) 19 (36.5) 17 (32.1) 18 (31.6)
90 11 (19.3) 10 (19.2) 11 (20.8) 12 (21.1)
120 5 (8.8) 3 (5.8) 3 (5.7) 3 (5.3)
180 3 (5.3) 5 (9.6) 5 (9.4) 5 (8.8)
RESULTS
Primary endpoint (calcium < 10.2) : 78.9%
(cinacalcet) vs 3.5% (PBO)
Slightly higher phosphorus (by 0.45
mg/dl)
No change in the BMD at femoral neck
(p=0.266)
American Journal of Transplantation 2014; 14: 2545–2555

54. J Am Soc Nephrol 27: 2487–2494, 2016

55. J Am Soc Nephrol 27: 2487–2494, 2016

56. Parathyroidectomy was associated with greater reduction in PTH, calcium,
improved bone density mass and less eGFR loss compared to cinacalcet
J Am Soc Nephrol 27: 2487–2494, 2016

57. Is parathyroidectomy before
transplant a better option?
odds ratio for graft failure: 0.547; 95% CI0.327–0.913
Surgery. 2017 Jan;161(1):44-50.

58. Pre-transplant PTH and the odds of
graft failure
Surgery. 2017 Jan;161(1):44-50.

59. Overview of management strategies
CJASN July 2016, 11 (7) 1282-1296

60. Conclusions:
SHPT post
transplant
Persistent SHPT is common after transplantation
The severity of post transplant SHPT depends on the degree of control of
SHPT before transplantations
SHPT post transplant is associated with structural and functional
alterations in the allograft and possibly with worse long term outcomes
KDIGO guidelines do not adequately address the pathophysiology of post
transplant SHPT
Prevention with VDRA may be reasonable
Cinacalcet only fixes calcium and nothing else
Consider surgery for refractory cases post transplant (and possibly pre
transplant)