9-1. kidney transplantation in children. pierre cochat (eng)

Kidney transplantation in children

pierre.cochat@chu-lyon.frCentre 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

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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

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France

German

y

Croati

a UK

Nether

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USA

Switzerl

and

Turke

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Scand

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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

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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

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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!