1. pierre.cochat@chu-lyon.fr
Centre de référence des
maladies rénales rares
Université de Lyon
Kidney transplantation in children

2. The very first kidney transplantation in humans
has been performed in
A.
B.
C.
D.
E.
Mumbai, India, 1915
Chicago, USA, 1912
Moskow, Russia, 1909
Lyon, France, 1906
London, UK, 1903

3. Pig-to-man kidney transplantation…
Vascular anastomosis to the humeral vessels!
Jaboulay Lyon Medical 1906

5. The first kidney transplantation in humans has
been performed in
A.
B.
C.
D.
E.
Mumbai, India, 1915
Chicago, USA, 1912
Moskow, Russia, 1909
Lyon, France, 1906
London, UK, 1903

6. What is the lower age limit for kidney Tx?
A.
B.
C.
D.
E.
Birth
6 months
1 year
2 years
3 years

7. Indication for kidney transplantation
 Children with irreversible renal failure
 Minimal age: 6 to 12 mos
 Minimal BW: 5 to 10 kg
According to local
experience & guidelines
 Relative contraindications





ABO incompatibility
Malignancy within the previous 12 months
Active viral infection: HIV, VHB, VHC
Active systemic disease: HUS, SLE, RPGN, vasculites, etc.
Multiorgan failure, severe brain damage, etc.

8. Options according to age at start of RRT
Age
PD
HD
Tx
Premature baby – Birth – 6 mos – 12 mos – 18 mos – 2 yrs

9. Transplantation
6 mos – 5.4 kg
RRT options
1st yr of life
Hemodialysis
5 mos – 4.8 kg
Peritoneal dialysis
1000 g

10. NAPRTCS 2010

11. What is the lower age limit for kidney Tx?
A.
B.
C.
D.
E.
Birth
6 months
1 year
2 years
3 years

12. What is the part of pediatrics among all kidney Tx?
A.
B.
C.
D.
E.
1%
2.5%
5%
7.5%
10%

13. Kidney transplantation activity in Europe
Cochat Comprehensive Pediatric Nephrology 2008
Country
Total Nb of Tx
Tx in children (%)
Croatia
109
4 (3.66%)
Czech Republic
427
15 (3.51%)
France
2423
81 (3.34%)
Germany
2478
117 (4.72%)
Israel
94
21 (22.3%)
Italy
1746
58 (3.32%)
Lithuania
63
2 (3.17%)
Netherlands
420
14 (3.33%)
Norway
256
9 (3.51%)
Poland
1067
38 (3.56%)
Spain
2057
68 (3.31%)
Sweden
372
13 (3.49%)
Turkey
665
59 (8.87%)
UK
1516
128 (8.44%)
67
3 (4.47%)
Serbia
Average
% Tx in
children
4.5 %

14. What is the part of pediatrics among all kidney Tx?
A.
B.
C.
D.
E.
1%
2.5%
5%
7.5%
10%

15. What is the main cause of ESRD in children < 5 yrs?
A.
B.
C.
D.
E.
CAKUT
Steroid resistant nephrotic syndrome
Inherited renal diseases
Hemolytic uremic syndrome
Chronic pyelonephritis

16. Wühl Clin J Am Soc Nephrol 2013

17. What is the main cause of ESRD in children < 5 yrs?
A.
B.
C.
D.
E.
CAKUT
Steroid resistant nephrotic syndrome
Inherited renal diseases
Hemolytic uremic syndrome
Chronic pyelonephritis

18. What are the 2 critically important outcomes in
kidney Tx?
A.
B.
C.
D.
E.
Patient survival
Blood pressure
Graft survival
Acute rejection
Graft function

19. Hospices Civils de Lyon & Université Claude-Bernard Lyon 1
ERA-EDTA ERBP in press

20. What are the 2 critically important outcomes in
kidney Tx?
A.
B.
C.
D.
E.
Patient survival
Blood pressure
Graft survival
Acute rejection
Graft function

21. Preemptive kidney Tx
A.
B.
C.
D.
E.
Is used for an average 25% of the pediatric population
Is associated with a greater risk of nonadherence
Can be proposed irrespective of the primary disease
Provides the same survival than in dialysis children
Relies on local facilities

22. % Preemptive Tx in Europe
Cochat Comprehensive Pediatric Nephrology 2008
Sweden
Norway
Netherlands
USA
UK
Spain
Croatia
France
Germany
Turkey
Czech Rep
Israel
Serbia
0
10
20
30
40
50

23. Transplant characteristics in USA NAPRTCS 2007

24. The best option for RRT in children is preemptive Tx
Dialysis should be limited to those children who cannot benefit from preemptive Tx
Advantages
 Avoids dialysis (school attendance, social and family life)
 Avoids vascular/peritoneal access
 Better results than non-preemptive Tx
 Cost effectiveness
Drawbacks
 Timing for putting the patient on the waiting list?
 Increased risk of non-adherence?

26. Preemptive kidney Tx
A.
B.
C.
D.
E.
Involves an average 25% of the pediatric population
Is associated with a greater risk of nonadherence
Can be proposed irrespective of the primary disease
Provides the same survival than in dialysis children
Relies on local facilities

27. In Europe, the average rate of living donation for
children is
A.
B.
C.
D.
E.
15%
20%
25%
30%
40%

28. % Living (related) donors in pediatric kidney Tx
Cochat Comprehensive Pediatric Nephrology 2008
100
80
60
40
20
Sw USA
itz
er
la n
d
Tu
rk
ey
S
Sc erb
ia
an
di
na
via
lan
ds
he
r
UK
Ne
t
ae
l
Isr
Sp
ain
Po
lan
d
Fr
an
c
Ge e
rm
an
y
Cr
oa
t ia
Cz
e
ch
Re
p
0

29. In Europe, the rate of living donation for children is
A.
B.
C.
D.
E.
15%
20%
25%
30%
40%

30. In the post-operative period after cadaver Tx,
A.
B.
C.
D.
E.
The use of 20% mannitol is recommended
The use of dopamine at ‘renal’ dose enhances diuresis
Urinary bladder catheter can be removed after 3 days
IV wide-spectrum antibiotics should be given for 1 week
A 2-week strict isolation period is mandatory

31. Hospices Civils de Lyon & Université Claude-Bernard Lyon 1
ERA-EDTA ERBP in press

32. In the post-operative period after cadaver Tx,
A.
B.
C.
D.
E.
The use of 20% mannitol is recommended
The use of dopamine at ‘renal’ dose enhances diuresis
Urinary bladder catheter can be removed after 3 days
Antibiotic prophylaxis should be given for 1 week
A 2-week strict isolation period is mandatory

33. The current rate of acute rejection in kidney Tx is:
A.
B.
C.
D.
E.
3%
13%
23%
33%
43%

34. Hospices Civils de Lyon & Université Claude-Bernard Lyon 1
N
Transplants with
TheatissueRejection
of ARE
Least 1
N
%
N
%
11519
All Transplants
%
100.0
5846
100.0
5673
100.0
5256
45.6
2388
40.9
EXHIBIT 4.1A
FREQUENCY OF ACUTE REJECTIONS
6263
54.4
3458
59.2
1987-2010
NAPRTCS 2010
2868
50.6
Transplantation
Number of Acute Rejections
0
1
2
3
>4
Transplants with
All Transplants
at Least 1 Rejection
Transplants withEra
by Transplant
at Least 1 Rejection
1987-1990
Number of Acute Rejections
1991-1994
0
1995-1998
1
1999-2002
2
2003-2006
3
2007-2010
>4
2805
49.4
2715
23.6
1289
22.1
1426
25.1
1253
10.9
597
10.2
656
11.6
Total
653
*
5.7
263
4.5
Living Donor
390
6.9
Deceased Donor
635
N
5.5
%
239
N
4.1
%
396
N
7.0
%
11519
100.0
5846
100.0
5673
100.0
5256
1509/2127
45.6
70.9
2388
593/908
40.9
65.3
2868
916/1219
50.6
75.1
1463/2413
6263
1126/2473
2715
653/2046
1253
394/1621
653
111/839
635
60.6
54.4
45.5
23.6
31.9
10.9
24.3
5.7
13.2
5.5
668/1198
3458
571/1362
1289
359/1239
597
163/808
263
34/331
239
55.8
59.2
41.9
22.1
29.0
10.2
20.2
4.5
10.3
4.1
795/1215
2805
555/1111
1426
294/807
656
231/813
390
77/508
396
65.4
49.4
50.0
25.1
36.4
11.6
28.4
6.9
15.2
7.0
Transplants with
at Least 1 Rejection
Total with known Era source (84 additional transplants have unknown donor source).
by Transplant donor
*
1987-1990
1509/2127
70.9
593/908
65.3
916/1219
75.1
1991-1994
NAPRTCS 2010
1463/2413
60.6
668/1198
55.8
795/1215
65.4
1995-1998
1126/2473
45.5
571/1362
41.9
555/1111
50.0

35. The current rate of acute rejection in kidney Tx is:
A.
B.
C.
D.
E.
3%
13%
23%
33%
43%

36. In children, the main cause of graft failure is:
A.
B.
C.
D.
E.
Vascular thrombosis
Recurrence of the primary disease
Acute rejection
Chronic rejection
PTLD

37. NAPRTCS 2007

38. In children, the main cause of graft failure is:
A.
B.
C.
D.
E.
Vascular thrombosis
Recurrence of the primary disease
Acute rejection
Chronic rejection (high rate of non-adherence)
PTLD

39. In children, the risk of metabolic syndrome at 1 yr
post-Tx is:
A.
B.
C.
D.
E.
5 to 10%
15 to 20%
25 to 30%
35 to 40%
45 to 50%

40. Hospices Civils de Lyon & Université Claude-Bernard Lyon 1
Metabolic syndrome in children after renal Tx
 Reversal of metabolic abnormalities depends on post-Tx GFR
 But immunosuppressive drugs cause metabolic abnormalities
 Atherosclerotic dyslipidemia
 Insulin resistance
 Risk of new-onset diabetes after Tx
 Prevalence in children 1 year post-Tx: 35 to 40% (mostly de novo)
 Major role of glucocorticoids
 Falls to 5% in the absence of steroids
 Greater risk of
 Lower graft survival
 Lower GFR
 Left ventricular hypertrophy
Litwin Pediatr Nephrol 2013

41. In children, the risk of metabolic syndrome at 1 yr
post-Tx is:
A.
B.
C.
D.
E.
5 to 10%
15 to 20%
25 to 30%
35 to 40% with steroid-based immunsuppression
45 to 50%

42. In children, the risk of metabolic syndrome at 1 yr
post-Tx is:
A.
B.
C.
D.
E.
5 to 10% without corticosteroids
15 to 20%
25 to 30%
35 to 40%
45 to 50%

43. Antibody-mediated rejection
A.
B.
C.
D.
E.
Is associated with serum donor-specific antibodies
Can be treated by high-dose methylprednisolone
Involves complement activation and endothelial injury
Is characterized by peritubular capillary C4d staining
Has better outcomes than cellular acute rejection

44. Humoral [antibody-mediated] rejection
Diagnosis

Circulating anti-HLA Ab

Protocol biopsy (C4d)

Graft dysfunction
Post Tx anti-HLA antibodies

DSA, donor specific antibodies




Blood transfusion
Pregnancy
Retransplantation
DR matching

45. Pathology
Pericapillary inflammation
Courtesy Dr F Dijoud Lyon 2011
C4d+ on peritubular capillaries

46. Hospices Civils de Lyon & Université Claude-Bernard Lyon 1
Impact of donor-specific anti-HLA antibodies
FO
CUS O RENAL TRANSPLANTATIO
N
N
2005 Banff clasCAN as an entity
se definition of
ocesses that lead
hy.25
Complement activation
FO US O RENAL TRANSPLANTATIO
C
N
N
for this point of view grew and in the 2005 Banff clas-
Circulating sification of renal allograft pathology, CAN as an entity
Antibody-targeting
DSAs
therapies and
was eliminated in favor of a more precise definition of
the cellular and/or humoral rejection processes thathigh-dose IVIG
lead
Circulating
DSAs
to interstitial fibrosis and tubular atrophy.25
or ABMR
Complement activation
Acceleration
of arteriosclerosis
Antibody-targeting
therapies and
high-dose IVIG
Current therapeutic approaches for ABMR
Acceleration
of arteriosclerosis
MR are aimed at
Endothelial injur y
Current therapeutic approaches for ABMR are aimed at
Endothelial injur y
antibody reduction and the inhibition of complement
of complement
activation and injury. The available therapies include
erapies include
plasma exchange with low-dose IVIG, high-dose IVIG
and rituximab for antibody reduction, and high-dose
high-dose IVIG
IVIG for complement inhibition.
The activity of
2
and high-dose
high-dose IVIG includes the inhibition of C3 convertase and the ability to absorb complement activation
Figure 4 | DSA-mediated acceleration of arteriosclerosis. The presence of DSAs is
The activity of
fragments (such as C3a, C5a and C4b). Other, more
associated with acceleration of arteriosclerosis after transplantation. This
n of C3 converspecific, inhibitors of complement (such as eculizumab,
phenomenon is observed in patients with either preformed/ persisting or de novo
DSAs. The use of prophylactic anti-CD20 antibodies combined with high-dose IVIG
an anti-C5 antibody) and inhibitors of C1 are likely to
ment activation
is associated presence of DSAs is
Figure 4 | DSA-mediated acceleration of arteriosclerosis. Thewith lower grade arteriosclerosis 1 year after transplantation.
show benefit in the prevention and treatment of ABMR.
33
Abbreviations: DSAs, donor-specific
Human acceleration of kidney transplantation are
trials of these drugs in arteriosclerosis after transplantation. This anti-HLA antibodies; IVIG, intravenous
). Other, more
associated with
immunoglobulin.
now underway.
h as eculizumab,
phenomenonAis observedABO-incompatible transplantation
in patients with either preformed/ persisting or de novo
study of human
published in 2012 showed anti-CD20 antibodies combined
DSAs. The2012;of prophylactic that patients who received Conclusions with high-dose IVIG
use Everly Transplantation 2013
Loupy Nat
C1 are likely to Rev Nephrol
12
32,34
33
75
76–78
75
B-cell depletion with rituximab as an induction agent
The increasing recognition of the frequency and diversity
is associated with lower grade arteriosclerosis 1 year after transplantation.

47. Antibody-mediated rejection
A.
B.
C.
D.
E.
Is associated with serum donor-specific antibodies
Can be treated by high-dose methylprednisolone
Involves complement activation and endothelial injury
Is characterized by peritubular capillary C4d staining
Has better outcomes than cellular acute rejection

48. In children, these diseases have a 80 to 100% risk
of recurrence in the renal graft
A.
B.
C.
D.
E.
Focal segmental glomerulosclerosis
Atypical HUS with factor H mutation
Primary hyperoxaluria type 1
Lupus nephritis
MPGN type 2

49. Recurrent renal diseases: an overview
Recurrence of the full primary renal disease
High risk of graft loss
Low risk of graft loss
Late risk of graft loss
Primary hyperoxaluria type 1
IgA nephropathy
Type 1 diabetes
Steroid resistant NS / FSGS
Lupus nephritis
Sickle cell disease
Atypical HUS
ANCA-associated GN
Membranoproliferative GN
Membranous nephropathy
Recurrence of specific features
Alloimmunization
Urinary tract malformations
Nephrin, Podocin
Alport syndrome
Posterior urethral valves
Different from recurrence
De novo renal diseases
Specific deposits
Membranous GN, TMA
Cystinosis, Fabry

50. Recurrence rate after the 1st renal Tx
Primary disease
Recurrence rate (%)
Graft loss to recurrence (%)
14-50 (average 30)
40-60
Atypical HUS
17 (MCP) – 90 (CFH-CFI)
10 (MCP) – 85 (CFH-CFI)
Typical HUS
0-1
0-1
MPGN type 1
30-77
17-50
MPGN type 2
66-100
25-61
Lupus nephritis
0-30
0-5
IgAN (Berger disease)
32-60
3-7
Henoch Shönlein nephritis
31-100
8-10
Primary hyperoxaluria type 1
90-100
80-100
SRNS/FSGS
Cochat Current Pediatr Rep 2013

51. Hospices Civils de Lyon & Université Claude-Bernard Lyon 1
Graft survival according to primary disease
van Stralen Nephrol Dial Transplant 2013

52. Among 100 patients with SRNS…

53. ~10% will be steroid resistant

54. One third are genetic Another third will recur post-Tx

55. Treatment options for recurrent FSGS
 High-dose iv CsA
 Plasmapheresis/immunoadsorption
 With or without iv CsA
 With or without cyclophosphamide instead of MMF/Aza
 Rituximab?

56. Rituximab
375 mg/m² x 1-6
Sethna J Transplantation 2011

57. aHUS - Transplantation
aHUS is responsible for 2 to 5 % of children with ESRD
Overall recurrence rate: 50-60%
Median time to recurrence: 30 days [0 day – 16 yrs]
Biological defect
% of aHUS
% disease recurrence
% graft loss
Factor H mutation
20-30
50-100
75-95
Anti-factor H antibodies
5-10
MCP/CD46 mutation
10-15
20
Factor I mutation
10-15
80-100
Factor B mutation
<5
100
5-10
50
<5
5
30-40
60
ADAMTS-13 deficiency
C3 mutation
THBD (thrombomodulin) mutation
No gene mutation
100
85
Kavanagh Semin Thromb Hemostasis 2010 - Loirat Pediatr Nephrol 2008 – Noris Am J Transplant 2010 – Sánchez-Corral Br J Haematol 2010

58. Tx options in aHUS
Noris Am J Transplant 2010

59. Eculizumab blocks terminal complement pathway
Ag-Ab complexes
Constitutive
Microorganisms
Lectin
Classical
Alternative
Terminal
Proximal
Microorganisms
C3
C5a

Eculizumab binds with high affinity to
C5

C3a
C3b
C5
Eculizumab
Terminal complement activity is
blocked

Proximal functions of complement
remain intact

C5b
C5b-9
Weak anaphylatoxin

Immune complex and apoptotic
body clearance

Microbial opsonization
Figueroa Clin Microbiol Rev 1991 - Walport N Engl J Med 2001

60. In children, these diseases have a 80 to 100% risk
of recurrence in the renal graft
A.
B.
C.
D.
E.
Focal segmental glomerulosclerosis
Atypical HUS with factor H mutation
Primary hyperoxaluria type 1
Lupus nephritis
MPGN type 2

61. In pediatric kidney Tx, the risk of malignancy is:
A.
B.
C.
D.
E.
Quite null
1 to 3% at 3 yrs
4 to 5% at 3 yrs
5 to 7% at 3 yrs
7 to 9% at 3 yrs

62. Hospices Civils de Lyon & Université Claude-Bernard Lyon 1
The issue of malignancies
NAPRTCS 2010
Transplantation
POST TRANSPLANT MALIGNANCY RATE
By Transplant Era
1 Year
3 Year
%
SE
%
SE
1987 – 1990
0.68
0.20
1.05
0.25
1991 – 1994
1.03
0.22
1.41
0.26
1995 – 1998
1.73
0.28
2.88
0.37
1999 – 2002
1.85
0.32
2.96
0.43
2003 - 2010
0.74
0.20
1.13
0.28
While substantial temporal improvements have been observed in graft failure, rejection and
other endpoints, similar trends for malignancy rates were not observed, although the most
recent cohort suggests that there has been some improvement.
NAPRTCS 2010

63. In pediatric kidney Tx, the risk of malignancy is:
A.
B.
C.
D.
E.
Quite null
1 to 3% at 3 yrs
4 to 5% at 3 yrs
5 to 7% at 3 yrs
7 to 9% at 3 yrs

64. In children with a functioning renal graft, growth
A.
B.
C.
D.
E.
Returns to normal velocity
Is retarded in 10 to 20% of patients
Depends on steroid exposure
Depends on GFR
Can be improved by the use of rhGH

65. Fine Pediatr Nephrol 2009

66. Harambat Pediatr Nephrol 2009

67. In children with a functioning renal graft, growth
A.
B.
C.
D.
E.
Returns to normal velocity
Is retarded in 10 to 20% of patients
Depends on steroid exposure
Depends on GFR
Can be improved by the use of rhGH, if licenced

68. Thank you for your attention!