focal segmental sclerosis in a youngster. a good candidate ......two types of recurrence a. fogo...

Focal segmental sclerosis in a

youngster. A good candidate for

LRD?

Pediatric nephrology, dialysis and

transplantation

UZA

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Kindernefrologie UZA

Case

• Cedric 30/7/1992

• Pers History: negative

• July 2001: nephrotic syndrome, renal

biopsy FSGS

– Steroid response Mendoza+ cyclosporin

• July 2002: relapse response Mendoza

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Course

• 2003 steroid toxicity

• 2003 relapse response to Endoxan

• 2004 relapse partial response to Mycophenolate

mofetil

• Conservative therapy ACE/ARB until 2007

• 2008 rituximab trial 4* 375 mg/m²

• 2009 esrd biopsy

• 2009 live related TX maternal kidney with

residual GFR and 10 g proteinuria

Good candidate for LD?

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Arguments

• Pro

• Contra

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Arguments LD

• Pro

– Young

– Pre-emptive

– Good renal function

– Good survival

• Contra

– Relapse rate of

FSGS?

• Native kidneys:

– prothrombotic risk

– Follow up

• Live related?

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Two types of recurrence A. Fogo Nephrol Dial Transplant 2010 25:1034-1036

early

• Massive proteinuria within

hrs or days

• Biopsy

– LM lesions median10-18

days

– Glomerular hypertrophy

– EM lesion foot proces

effacement > 50% ( typical)

• In 2nd time sclerosis

• All<6 months

late

• 6m to 2 years

• Biopsy

– End stage of multiplicity of

injuries ( calcineurin inh,

rejection obstruction ,viral

infection) with collapsing

glomeruli

– EM foot proces effacement

<50%

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FSGS Risk factors 2009 Cochat et al Ped nephrol 2009 24:2097-2108

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FSGS following TX

• Overall graft loss acute rejection 8-9%

• Graft loss recurrence primary disease 7-8%

– FSGS 14-50 graft loss 40-60%

– HUS 20-80

– MPGN I 30-77

– MPGN II 66-100

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Live related TX

• Baum= NAPRTCS

– LRD TX results are worse than other LRD:

Graftsurvival = cadaveric TX

– Combi more relapse + less rejection

• Abbot: USRDS

– 18.7% recurrence vs 7.8% in cadaveric

– Equal graft loss

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Your decision?

• Pro

• Contra

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Our decision in 2009…

Pro

• Literature

– 50% of FSGS in

Naprtcs = LD

– Graft survival is not

different 30%

• Primary disease

responsive to IS

Contra

• no genetic diagnosis

• Primary idiopathic

• Child

• Residual kidney

function

• Proteinuria

(thrombotic risk?)

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Renal transplant

• Donor: mother W 60kg small kidney

• Postoperative function: immediate

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Native versus Tx kidney output

Day 2 3 4 7 9

Uvolume

Alb/crea

1440

14800/

518

1100

9455/

209

700

7235/

133

1840

11700/

313

2080

11762/

686

UVolume

Alb/crea

1660

795/

1096

5620

798/

1124

5080

889/

1168

1860

879/

930

680

530/

564

S creat 0.9 1.0 1.0 1.3 1.3

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Dilemma day 11

• Volume 2280ml, 15399 g protein/ 912 mg creat

• S creat:1.5 , albumin 2g/dl edema+ hypertension

dd

• V renalis thrombosis TX

• Localised thrombosis renal tx

• Relapse FSGS in Tx

• Rejection

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Biopsy day 12

• Microscopie

• Twee ruime cilinders, de ene niercortex, de andere afkomstig van het merg. In totaal

zijn er een elftal glomeruli. Ze vertonen een nagenoeg normale histologie: het

capillaire kluwen is normaal gelobuleerd en de capillairen hebben een dunne wand en

zijn bekleed met normaal endotheel. Het mesangium is niet verbreed en toont een

normale cellulariteit. De ruimte van Bowman is open. De tubuli zijn rug aan rug

geschikt en bekleed met normaal epitheel. Er is geen tubulitis. Geen interstitiële

fibrose. De arteriële vaten hebben een dunne wand en vertonen geen

ontstekingsinfiltratie. Het merg toont geen bijzonderheden.

• Het bioptje voor standaardimmunofluorescentieonderzoek werd hierna doorgewerkt

na fixatie in NF4. Het toont eveneens normale niercortex.

• Immuunfluorescentieonderzoek:

• Het biopt voor dit onderzoek bevat vijf glomeruli en één obsolete glomerulus (niet

terug te vinden op de aanvullende paraffinecoupes). De intacte glomeruli vertonen

geen neerslagen van IgA, IgM, IgG, van C3 of C1q.

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Dilemma d12

• Us normal kidney

• Biopsy: normal kidney

• Renogram:

– 91% function Tx

– 5% left

– 4% right

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Plasmaferesis

15/5/9

3*/week

U alb/creat

8g /1100

S alb

2.9

Cr

1.3

5/6/9

3*/week

15g/1165 2.9 1.3

14/11/9

1*/week

5g/1152 4 3.3 Banff 1

FK506

14/4/10

1*/14d

14g/1162 3.7 1.8 Galactose

2nd biopsy

• Nierbiopsie met bewaarde architectuur. Er zijn 5 glomeruli. Er zijn 2 obsolete

glomeruli. De cellulariteit van de glomeruli is bewaard. Er is geen diffuse, focale of

segmentaire glomerulopathie. Er is geen necrose. Er is geen fibrine. De basale

membraan is niet verbreed. Er zijn geen crescents. Het kapsel van Bowman is niet

verbreed. In het interstitium is er een vrij uitgebreid monocytair ontstekingsinfiltraat

met oedeemvorming. Op meerdere plaatsen is er tubulitis met infiltratie door

mononucleaire cellen in de tubuli (plaatselijk tussen 5 en 10 mononucleaire cellen per

tubulaire cross sectie, t2). Er is geen arteritis. (t0).

• Immunohistochemisch onderzoek : de kleuringen voor C4d en SV 40 zijn negatief.

• 2.1. Immuunfluorescentieonderzoek:

• Het biopt voor dit onderzoek bevat 6 glomeruli. Ze zijn negatief voor IgA, IgM, IgG,

voor C3 en C1q.

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status 2010

• Full time scolar

• Saturday plasmaferesis exchange with SOPP 3 liter

• Prednisone 10 mg

• MMF 2*750

• Tacrolimus level 8-12

• Galactose 2*10g

• GFR 40

• Proteinuria 14 g

• S albumin 3.2

Graft loss 2012

• Policy?

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Your decision?

• Pro

• Contra

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Lessons from the past?

• LD?

• Bilateral nefrectomy?

• Cool down on dialysis?

• Pre transplant plasma exchange?

• Medication

• Markers?

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Anno 2014 relapse FSGS

• Rate: 20%

• Graft loss:

– 12 % at 10 years in adults

– 33% at 5 years in children

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Anno 2014 relapse FSGS

• Risk factors: White,Young age, not LD Focal segmental glomerulosclerosis in children: multivariate analysis indicates that donor

type does not alter recurrence risk. Nehus EJ, Goebel JW, Succop PS, Abraham EC

Transplantation. 2013 Sep;96(6):550-4.

Trend analysis of kidney transplantations for FSGS in children (n=2157) showed an

increase in cases of 5.8% per year or 209% over 20 years (P<0.0001).

Recurrence was reported in 327 (15%) cases overall, with a preponderance for

white recipients (P<0.001) in younger age subgroups (P<0.01). Donor type was

significant (P=0.02), with recurrence reported in 17% versus 14% of recipients of

kidneys from LDs versus deceased donors. Using multivariate analysis,

recipients' young age (P=0.02) and white race (P<0.001) were identified as

significant risk factors for recurrence, whereas receiving a LD kidney became

insignificant.

• Cave genetics: podocin mutations

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Current opinion

• Data from the Recurrent Allograft Disease Registry (RADR) found a similar rate of recurrence

among adult recipients of living or deceased donor kidneys [19]. Based upon a Cox proportional

hazards model, a deceased donor kidney was more likely than a living-related kidney to be lost in

patients with recurrent disease.

• ●Analysis of data from the United States Renal Data System (USRDS) study of adult recipients

demonstrated a similar risk for graft loss from recurrent FSGS between living and deceased

donors [8]. This analysis identified a graft survival advantage for living donor kidneys over

deceased donor kidneys [8].

• ●A report based on the North American Pediatric Renal Transplant Cooperative Study database

(NAPRTCS) compared transplant outcomes of 752 pediatric patients with FSGS with 5732 control

patients [14]. Graft survival at five years was not statistically different between living donors and

deceased donors (69 versus 60 percent), suggesting that, among FSGS patients, the survival

advantage that is usually observed with a living donor kidney was lost [14]. Similar results were

seen in the subgroup of adolescents up to age 17, with graft losses of 56 versus 51 percent with

living and deceased donors, respectively [61]. In both analyses, graft loss was similar in living and

deceased donated kidneys. Notably, graft survival was markedly worse in pediatric patients with

FSGS compared with those with other kidney diseases, a difference that was not accounted for by

recurrence alone.

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• LD?


• Cool down on dialysis?


• Medication rituximab

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Anno 2014 bilateral

nefrectomy? • Children: kidneys as antigenic stimulus

• Adults: worse outcome after nephrectomy Five patients (Group I, 23%) developed FSGS post-transplantation. Of these patients, 60% had undergone bilateral nephrectomy (BN) for

progressive disease compared with none of the patients that were free of recurrence (Group II) (p = 0.0006).

Three hundred sixty-four consecutive cadaveric (n = 214), living-related (n = 137), and living-unrelated (n = 13) renal transplants were

performed in 319 patients with a diagnosis of primary glomerulonephritis. Specific diagnoses included were focal segmental

glomerulosclerosis (FSGS), rapidly progressive glomerulonephritis/idiopathic crescentic glomerulonephritis (RPGN/ICG), IgA nephropathy

(IgA), mesangioproliferative glomerulonephritis, type I and II (MPG), anti-glomerular basement membrane nephritis (anti-GBM), and

membranous glomerulonephritis (MGN). Rates of recurrence and graft loss were compared between patients treated with bilateral native

nephrectomy (n = 61) and those who were not (n = 303). Bilateral nephrectomy did not prevent or delay the onset of recurrent

glomerulonephritis in the renal allograft. In fact, there was a significantly increased five- and ten-year risk of recurrence in patients

undergoing pretransplant nephrectomy vs. no nephrectomy (25.2% and 42% vs. 13.9% and 19.4%, P < 0.02, respectively).

Transplantation. 1996 Jan 27;61(2):228-34.The influence of native nephrectomy on the incidence of recurrent disease following renal

transplantation for primary glomerulonephritis. Odorico JS, Knechtle SJ, Rayhill SC, Pirsch JD, D'Alessandro AM, Belzer FO,

Sollinger HW.

• Presence of proteinuria

– Delays diagnosis

– Prothrombotic action

– High level of LDL interfere with cyclosporin action

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http://www.ncbi.nlm.nih.gov/pubmed?term=Rayhill%20SC%5BAuthor%5D&cauthor=true&cauthor_uid=8600629

http://www.ncbi.nlm.nih.gov/pubmed?term=Odorico%20JS%5BAuthor%5D&cauthor=true&cauthor_uid=8600629

http://www.ncbi.nlm.nih.gov/pubmed?term=Knechtle%20SJ%5BAuthor%5D&cauthor=true&cauthor_uid=8600629

http://www.ncbi.nlm.nih.gov/pubmed?term=Rayhill%20SC%5BAuthor%5D&cauthor=true&cauthor_uid=8600629

http://www.ncbi.nlm.nih.gov/pubmed?term=Pirsch%20JD%5BAuthor%5D&cauthor=true&cauthor_uid=8600629

http://www.ncbi.nlm.nih.gov/pubmed?term=D'Alessandro%20AM%5BAuthor%5D&cauthor=true&cauthor_uid=8600629

http://www.ncbi.nlm.nih.gov/pubmed?term=Belzer%20FO%5BAuthor%5D&cauthor=true&cauthor_uid=8600629

http://www.ncbi.nlm.nih.gov/pubmed?term=Sollinger%20HW%5BAuthor%5D&cauthor=true&cauthor_uid=8600629


• LD?


• Cool down on dialysis? NO data



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Anno 2014 preventive PEX?

• One single study

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• LD?


• Cool down on dialysis? NO data



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FSGS and rituximab Prytula et al Ped Nephrol 2010: 25(3) 461

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Anno 2014 other markers?

• Increased urinary ApoA-1 was initially

detected by proteomic analysis in eight

transplant recipients with recurrent FSGS,

but not in 27 transplant recipients who had

nonrecurrent FSGS in the native kidney.

• In an independent validation study, ApoA-

1 was detected in five of six transplant

recipients with recurrent FSGS, but in only

1 of 34 transplant recipients with

nonrecurrent FSGS in the native kidney.

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Anno 2014 other markers?

• SuPAR Soluble urokinase receptor — Increased circulating levels of soluble urokinase receptor

(suPAR) may be a common causative factor of primary FSGS [35,36].

In a detailed analysis of 148 patients (78 with primary FSGS, 25 with minimal change

disease, 7 with preeclampsia, 16 with membranous nephropathy, and 22 normal

controls), suPAR was significantly elevated in sera from patients with FSGS

compared with normal controls and patients with other proteinuric glomerular

diseases [35]. The highest serum suPAR levels were in pretransplant sera of patients

who developed recurrent FSGS after transplantation, suggesting an association of

suPAR with recurrent FSGS.

But: only in 30% patients , in children the relationship is poor, but so are the data

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Your final Vote? Should we

have performed a LD TX? • Pro

• Contra

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focal segmental sclerosis in a youngster. a good candidate ......two types of recurrence a. fogo...

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