Role of recurrent disease for Role of recurrent disease for late allograft loss late allograft loss Fernando G. Cosio Fernando G. Cosio Mayo Clinic, Rochester MN Mayo Clinic, Rochester MN 10 10 th th Banff conference on Banff conference on allograft pathology allograft pathology
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Role of recurrent disease for late allograft loss Fernando G. Cosio Mayo Clinic, Rochester MN 10 th Banff conference on allograft pathology.
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Role of recurrent disease for late Role of recurrent disease for late allograft lossallograft loss
Fernando G. CosioFernando G. Cosio
Mayo Clinic, Rochester MNMayo Clinic, Rochester MN
1010thth Banff conference on Banff conference on allograft pathologyallograft pathology
Issues to be addressedIssues to be addressed
• Relevance of recurrent disease to the Relevance of recurrent disease to the overall outcomes of kidney overall outcomes of kidney transplantation.transplantation.
• Role of protocol biopsies in Role of protocol biopsies in improving our understanding of improving our understanding of recurrent glomerular diseases.recurrent glomerular diseases.
• Role of protocol biopsies in Role of protocol biopsies in improving our understanding of improving our understanding of glomerulonephritisglomerulonephritis
Causes of Graft Loss in 1317 conventional Causes of Graft Loss in 1317 conventional recipients transplanted between 1996-2006recipients transplanted between 1996-2006
Mayo Clinic experience with recurrent Mayo Clinic experience with recurrent GN: Preliminary analysesGN: Preliminary analyses
• 1317 kidney recipients transplanted from 1317 kidney recipients transplanted from 1996-2006. 1996-2006.
• Subpopulations:Subpopulations:• Controls: 172 patients with ADPKDControls: 172 patients with ADPKD• Patients with GN (FSGS, MN, MPGN)Patients with GN (FSGS, MN, MPGN)
• General observations (vignettes)General observations (vignettes)
Kidney transplantation in Kidney transplantation in focal focal segmental glomerulosclerosis (FSGS)segmental glomerulosclerosis (FSGS)
Death-censored graft survival
Months post-transplant
120967248240
1.0
.9
.8
.7
.6
.5
PKD, N=172
FSGS, N=103
p=0.0048
• Compared to PKD, Compared to PKD, recipients with recipients with FSGS have reduced FSGS have reduced death-censored death-censored graft survival.graft survival.
• Only patients with Only patients with FSGS FSGS andand recurrence have recurrence have reduced graft reduced graft survival.survival.
Death-censored graft survival
Months post-transplant
7260483624120
1.0
.8
.6
.4
.2
0.0
PKD
FSGS + recurrence
FSGS - recurrence
p<0.0001
71%
58%
Kidney transplantation in Kidney transplantation in FSGSFSGS
• 103 patients with 103 patients with FSGS (unselected) FSGS (unselected) (8% of recipients)(8% of recipients)
• 17% of grafts lost 17% of grafts lost due to recurrencedue to recurrence
Kidney transplantation in Kidney transplantation in MPGNMPGN
Month of recurrence
3624120
Pro
po
rtio
n o
f p
atie
nts
with
re
curr
en
t M
PG
N
.5
.4
.3
.2
.1
0.0
• 41% recurrence at 41% recurrence at 3.7 months (0.36-3.7 months (0.36-17.9) post-Tx.17.9) post-Tx.
• Higher likelihood Higher likelihood of recurrence:of recurrence:
• Low C3 or C4Low C3 or C4
• Living donorsLiving donors
• Monoclonal Monoclonal proteinsproteins
Complement levels and rMPGN
Months post-transplant
24120
Pro
po
rtio
n o
f p
atie
nts
with
rM
PG
N
.8
.7
.6
.5
.4
.3
.2
.1
0.0p=0.020
Low C3 and /or C4Low C3 and /or C4
Nl C3 and C4Nl C3 and C4
Kidney transplantation in Kidney transplantation in membranous membranous nephropathy (MN)nephropathy (MN)
Death-censored graft survival
Months post-transplant
120967248240
1.0
.9
.8
.7
.6
.5
PKD (N=172)
MN (N=31)
• 31 patients with 31 patients with MN.MN.
• 2% of recipients.2% of recipients.
• 42% recurrence at 42% recurrence at 2.5 months (4-64)2.5 months (4-64)
• Histologic Histologic recurrence is often recurrence is often subclinical for subclinical for several monthsseveral months
• 11% of grafts lost 11% of grafts lost due to recurrent MNdue to recurrent MN
p=0.284
Protocol biopsies and recurrent disease: Protocol biopsies and recurrent disease: PostulatesPostulates
1.1. Protocol biopsies may allow early Protocol biopsies may allow early diagnosis of recurrent GN diagnosis of recurrent GN beforebefore it it is clinically apparent.is clinically apparent.
2.2. The earliest histologic changes of The earliest histologic changes of GN may give us clues about the GN may give us clues about the pathogenesis of these diseases.pathogenesis of these diseases.
3.3. Early histologic diagnosis may Early histologic diagnosis may allow more effective treatment.allow more effective treatment.
Course and management of GNs in Course and management of GNs in native kidneys: current statusnative kidneys: current status
How do these How do these diseases look diseases look like when they like when they start?start?
• Does the Does the histologic Dx histologic Dx precede clinical precede clinical manifestations? manifestations?
• Are there Are there variables that variables that relate to this relate to this transition?transition?
Should we treat based Should we treat based on histology? Can we on histology? Can we thus achieve better thus achieve better results? Improve results? Improve kidney prognosis?kidney prognosis?
A familiar challenge: diagnosis of A familiar challenge: diagnosis of recurrent FSGS without FSGSrecurrent FSGS without FSGS
4 month 4 month protocolprotocol Bx. Urine protein Bx. Urine protein 420420 mg/day. EM: focal FPF mg/day. EM: focal FPF
Diagnostic challenges are also Diagnostic challenges are also pathogenic lessonspathogenic lessons
• 51 yo recipient of a kidney transplant 51 yo recipient of a kidney transplant in 1/2008. Original disease MN.in 1/2008. Original disease MN.
• One monthOne month post-Tx surgery is done post-Tx surgery is done for lymphocele (for lymphocele (creatinine). A biopsy creatinine). A biopsy done during Sx. Urine protein done during Sx. Urine protein 179179 mg/day.mg/day.
• Light microscopy: Light microscopy: NormalNormal, no , no “spikes” no deposits. C4d done…“spikes” no deposits. C4d done…
C4dC4d
C3C3
IgGIgG
Electron microscopyElectron microscopy
Protocol biopsies and diagnosis of Protocol biopsies and diagnosis of recurrent GNrecurrent GN
• Protocol biopsies can make pre-Protocol biopsies can make pre-clinical diagnoses of some GN.clinical diagnoses of some GN.
• Current diagnostic criteria for GN are Current diagnostic criteria for GN are invalid:invalid:• FSGS without F, S, G or SFSGS without F, S, G or S• MN without C3 or EM depositsMN without C3 or EM deposits• MPGN without MPMPGN without MP
Next question: Does a pre-clinical Next question: Does a pre-clinical diagnosis lead to clinical disease?diagnosis lead to clinical disease?
• 19 patients with MN diagnosed by 19 patients with MN diagnosed by protocol biopsy and followed, untreated protocol biopsy and followed, untreated for at least one year:for at least one year:
• 2 (10.5%) have maintained low levels 2 (10.5%) have maintained low levels of proteinuria.of proteinuria.
• 17 (89.5%) have had progressive 17 (89.5%) have had progressive proteinuriaproteinuria
• Repeat biopsies: MN in all (no Repeat biopsies: MN in all (no spontaneous histologic remissions)spontaneous histologic remissions)
Protocol biopsies Protocol biopsies early diagnosis early diagnosis oror over-diagnosis?over-diagnosis?
Proportion of patients with recurrent MN
Months post-transplant
144120967248240
.8
.6
.4
.2
0.0
Tx year: ‘00-’07 Dx: protocol Bx (N=30) Recurrence: 42% Median months to recurrence: 4 (2-61)
Tx year: ‘90-’99 Dx: clinical with Bx confirmation (N=20) Recurrrence: 55% Median months to recurrence: 83 (6-149)
Postulated benefits of protocol Postulated benefits of protocol biopsies in recurrent GNbiopsies in recurrent GN
3.3. Early histologic diagnosis Early histologic diagnosis maymay allow more effective treatment allow more effective treatment (preliminary studies suggest that (preliminary studies suggest that we can/should start to explore this we can/should start to explore this question)question)
U. Protein (mg/day)U. Protein (mg/day) 132132 9090 165165
Histology:Histology:
Mesangial proliferation Mesangial proliferation
C1q (IF)C1q (IF)
IGG (IF)IGG (IF)
Deposits (EM)Deposits (EM)
NoneNone
TraceTrace
NegativeNegative
NoNo
MildMild
2+2+
3+3+
Not doneNot done
ModerateModerate
3+3+
3+3+
Mesangial Mesangial paramesangiparamesangi
alal
What do we do now?What do we do now?
- Current approach: do not treat unless Current approach: do not treat unless the disease is clinically apparent…the disease is clinically apparent…
- Should we explore alternative Should we explore alternative approaches? approaches?
What do we do now?What do we do now?
- Current approach: do not treat unless Current approach: do not treat unless the disease is clinically apparent…the disease is clinically apparent…
- Should we explore alternative Should we explore alternative approaches? approaches?
Recurrent diseaseRecurrent disease
• 20% of death-censored graft losses are 20% of death-censored graft losses are due to recurrent disease (15% rGN).due to recurrent disease (15% rGN).
• Studies using protocol biopsies suggest:Studies using protocol biopsies suggest:• Need diagnostic criteria for early dis.Need diagnostic criteria for early dis.• Need multicenter studies based on Need multicenter studies based on
protocol biopsies to determine:protocol biopsies to determine:• Histologic diagnosis Histologic diagnosis clinical? clinical?• Effectiveness early Rx?Effectiveness early Rx?
• We finally have good questions and We finally have good questions and reasonable tools to try to answer them!reasonable tools to try to answer them!
If we knew what we were doing it If we knew what we were doing it would not be called researchwould not be called research
A. Einstein A. Einstein
Recurrent disease after kidney Recurrent disease after kidney transplantation-- it is time to unite transplantation-- it is time to unite to to address this problem!address this problem! A. Matas A. Matas
If we knew what we were doing it If we knew what we were doing it would not be called researchwould not be called research
A. EinsteinA. Einstein
In addition, In addition,
Graft loss by cause in 1317 transplants recipients Graft loss by cause in 1317 transplants recipients (1996 to 2006)(1996 to 2006)
Death
Graft failure
(Ziad El-Zoghby, Cosio AJT 9:527-535, 2009)
Impact of recurrent glomerular diseases on Impact of recurrent glomerular diseases on death-censored graft survivaldeath-censored graft survival