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Kidney transplantation in children
[email protected] de référence des maladies rénales raresUniversité de Lyon
The very first kidney transplantation in humans has been performed in
A. Mumbai, India, 1915B. Chicago, USA, 1912C. Moskow, Russia, 1909D. Lyon, France, 1906E. London, UK, 1903
Pig-to-man kidney transplantation…Vascular anastomosis to the humeral vessels!
Jaboulay Lyon Medical 1906
The first kidney transplantation in humans has been performed in
A. Mumbai, India, 1915B. Chicago, USA, 1912C. Moskow, Russia, 1909D. Lyon, France, 1906E. London, UK, 1903
What is the lower age limit for kidney Tx?
A. BirthB. 6 monthsC. 1 yearD. 2 yearsE. 3 years
Indication for kidney transplantation
Children with irreversible renal failure
Minimal age: 6 to 12 mos Minimal BW: 5 to 10 kg
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.
According to localexperience & guidelines
Age Premature baby – Birth – 6 mos – 12 mos – 18 mos – 2 yrs
PD
HD
Tx
Options according to age at start of RRT
Peritoneal dialysis1000 g
Transplantation6 mos – 5.4 kg
Hemodialysis5 mos – 4.8 kg
RRT options1st yr of life
NAPRTCS 2010
What is the lower age limit for kidney Tx?
A. BirthB. 6 monthsC. 1 yearD. 2 yearsE. 3 years
What is the part of pediatrics among all kidney Tx?
A. 1%B. 2.5%C. 5%D. 7.5%E. 10%
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%)
Serbia 67 3 (4.47%)
Average % Tx in
children
4.5 %
What is the part of pediatrics among all kidney Tx?
A. 1%B. 2.5%C. 5%D. 7.5%E. 10%
What is the main cause of ESRD in children < 5 yrs?
A. CAKUTB. Steroid resistant nephrotic syndromeC. Inherited renal diseasesD. Hemolytic uremic syndromeE. Chronic pyelonephritis
Wühl Clin J Am Soc Nephrol 2013
What is the main cause of ESRD in children < 5 yrs?
A. CAKUTB. Steroid resistant nephrotic syndromeC. Inherited renal diseasesD. Hemolytic uremic syndromeE. Chronic pyelonephritis
What are the 2 critically important outcomes in kidney Tx?
A. Patient survivalB. Blood pressureC. Graft survivalD. Acute rejectionE. Graft function
ERA-EDTA ERBP in press H
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What are the 2 critically important outcomes in kidney Tx?
A. Patient survivalB. Blood pressureC. Graft survivalD. Acute rejectionE. Graft function
Preemptive kidney Tx
A. Is used for an average 25% of the pediatric populationB. Is associated with a greater risk of nonadherenceC. Can be proposed irrespective of the primary diseaseD. Provides the same survival than in dialysis childrenE. Relies on local facilities
% Preemptive Tx in EuropeCochat Comprehensive Pediatric Nephrology 2008
0 10 20 30 40 50
SerbiaIsrael
Czech RepTurkey
Germany FranceCroatia
SpainUK
USANetherlands
NorwaySweden
Transplant characteristics in USA NAPRTCS 2007
The best option for RRT in children is preemptive TxDialysis 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?
Preemptive kidney Tx
A. Involves an average 25% of the pediatric populationB. Is associated with a greater risk of nonadherenceC. Can be proposed irrespective of the primary diseaseD. Provides the same survival than in dialysis childrenE. Relies on local facilities
In Europe, the average rate of living donation for children is
A. 15%B. 20%C. 25%D. 30%E. 40%
% Living (related) donors in pediatric kidney TxCochat Comprehensive Pediatric Nephrology 2008
0
20
40
60
80
100
Czech
Rep
Spain
Poland
Israe
l
France
German
y
Croati
a UK
Nether
lands
USA
Switzerl
and
Turke
ySerb
ia
Scand
inavia
In Europe, the rate of living donation for children is
A. 15%B. 20%C. 25%D. 30%E. 40%
In the post-operative period after cadaver Tx,
A. The use of 20% mannitol is recommendedB. The use of dopamine at ‘renal’ dose enhances diuresisC. Urinary bladder catheter can be removed after 3 daysD. IV wide-spectrum antibiotics should be given for 1 weekE. A 2-week strict isolation period is mandatory
ERA-EDTA ERBP in press H
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In the post-operative period after cadaver Tx,
A. The use of 20% mannitol is recommendedB. The use of dopamine at ‘renal’ dose enhances diuresisC. Urinary bladder catheter can be removed after 3 daysD. Antibiotic prophylaxis should be given for 1 weekE. A 2-week strict isolation period is mandatory
The current rate of acute rejection in kidney Tx is:
A. 3%B. 13%C. 23%D. 33%E. 43%
The issue of AREH
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NAPRTCS 2010
The current rate of acute rejection in kidney Tx is:
A. 3%B. 13%C. 23%D. 33%E. 43%
In children, the main cause of graft failure is:
A. Vascular thrombosisB. Recurrence of the primary diseaseC. Acute rejectionD. Chronic rejectionE. PTLD
NAPRTCS 2007
In children, the main cause of graft failure is:
A. Vascular thrombosisB. Recurrence of the primary diseaseC. Acute rejectionD. Chronic rejection (high rate of non-adherence)E. PTLD
In children, the risk of metabolic syndrome at 1 yr post-Tx is:
A. 5 to 10%B. 15 to 20%C. 25 to 30%D. 35 to 40%E. 45 to 50%
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
Hos
pice
s Ci
vils
de
Lyon
& U
nive
rsité
Cla
ude-
Bern
ard
Lyon
1
In children, the risk of metabolic syndrome at 1 yr post-Tx is:
A. 5 to 10%B. 15 to 20%C. 25 to 30%D. 35 to 40% with steroid-based immunsuppressionE. 45 to 50%
In children, the risk of metabolic syndrome at 1 yr post-Tx is:
A. 5 to 10% without corticosteroidsB. 15 to 20%C. 25 to 30%D. 35 to 40%E. 45 to 50%
Antibody-mediated rejection
A. Is associated with serum donor-specific antibodiesB. Can be treated by high-dose methylprednisoloneC. Involves complement activation and endothelial injuryD. Is characterized by peritubular capillary C4d staining E. Has better outcomes than cellular acute rejection
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
Pathology
Pericapillary inflammation C4d+ on peritubular capillaries
Courtesy Dr F Dijoud Lyon 2011
Impact of donor-specific anti-HLA antibodiesH
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Loupy Nat Rev Nephrol 2012; Everly Transplantation 2013
Antibody-mediated rejection
A. Is associated with serum donor-specific antibodiesB. Can be treated by high-dose methylprednisoloneC. Involves complement activation and endothelial injuryD. Is characterized by peritubular capillary C4d staining E. Has better outcomes than cellular acute rejection
In children, these diseases have a 80 to 100% risk of recurrence in the renal graft
A. Focal segmental glomerulosclerosisB. Atypical HUS with factor H mutationC. Primary hyperoxaluria type 1D. Lupus nephritisE. MPGN type 2
Recurrent renal diseases: an overview
Recurrence of the full primary renal diseaseHigh 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
Nephrin, PodocinAlport syndrome
Urinary tract malformationsPosterior urethral valves
Different from recurrenceDe novo renal diseases
Membranous GN, TMASpecific deposits
Cystinosis, Fabry
Recurrence rate after the 1st renal Tx
Cochat Current Pediatr Rep 2013
Primary disease Recurrence rate (%) Graft loss to recurrence (%)
SRNS/FSGS 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
Graft survival according to primary diseaseH
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van Stralen Nephrol Dial Transplant 2013
Among 100 patients with SRNS…
~10% will be steroid resistant
One third are genetic Another third will recur post-Tx
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?
Rituximab375 mg/m² x 1-6
Sethna J Transplantation 2011
aHUS - Transplantation
Biological defect % of aHUS % disease recurrence % graft lossADAMTS-13 deficiencyFactor H mutation 20-30 50-100 75-95Anti-factor H antibodies 5-10MCP/CD46 mutation 10-15 20Factor I mutation 10-15 80-100 100Factor B mutation <5 100C3 mutation 5-10 50THBD (thrombomodulin) mutation <5 5No gene mutation 30-40 60 85
aHUS is responsible for 2 to 5 % of children with ESRDOverall recurrence rate: 50-60%
Median time to recurrence: 30 days [0 day – 16 yrs]
Kavanagh Semin Thromb Hemostasis 2010 - Loirat Pediatr Nephrol 2008 – Noris Am J Transplant 2010 – Sánchez-Corral Br J Haematol 2010
Tx options in aHUS
Noris Am J Transplant 2010
Eculizumab blocks terminal complement pathway
Lectin Alternative
C3 C3a
C3b
C5
Proximal
Terminal
Microorganisms Ag-Ab complexesConstitutive
Microorganisms
Figueroa Clin Microbiol Rev 1991 - Walport N Engl J Med 2001
C5b-9
C5a
C5b
Eculizumab
Proximal functions of complement remain intact Weak anaphylatoxin Immune complex and apoptotic
body clearance Microbial opsonization
Terminal complement activity is blocked
Eculizumab binds with high affinity to C5
Classical
In children, these diseases have a 80 to 100% risk of recurrence in the renal graft
A. Focal segmental glomerulosclerosisB. Atypical HUS with factor H mutationC. Primary hyperoxaluria type 1D. Lupus nephritisE. MPGN type 2
In pediatric kidney Tx, the risk of malignancy is:
A. Quite nullB. 1 to 3% at 3 yrsC. 4 to 5% at 3 yrsD. 5 to 7% at 3 yrsE. 7 to 9% at 3 yrs
The issue of malignanciesH
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NAPRTCS 2010
In pediatric kidney Tx, the risk of malignancy is:
A. Quite nullB. 1 to 3% at 3 yrsC. 4 to 5% at 3 yrsD. 5 to 7% at 3 yrsE. 7 to 9% at 3 yrs
In children with a functioning renal graft, growth
A. Returns to normal velocityB. Is retarded in 10 to 20% of patientsC. Depends on steroid exposureD. Depends on GFRE. Can be improved by the use of rhGH
Fine Pediatr Nephrol 2009
Harambat Pediatr Nephrol 2009
In children with a functioning renal graft, growth
A. Returns to normal velocityB. Is retarded in 10 to 20% of patientsC. Depends on steroid exposureD. Depends on GFRE. Can be improved by the use of rhGH, if licenced
Thank you for your attention!