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

Cause Group Number of cases

Percent of all transplants

TotalTotal 330330 25%25%

Primary non-functionPrimary non-function 3939 2.9%2.9%

Death with functionDeath with function 138138 10.4%10.4%

Graft loss (death Graft loss (death censored)censored)

153153 11.6%11.6%

(Ziad El-Zoghby, Cosio AJT 9:527-535, 2009)

F/u months: 50 ± 33 (0-138)F/u months: 50 ± 33 (0-138)

Mechanisms of Mechanisms of death-censoreddeath-censored kidney kidney graft loss graft loss (1996-2006)(1996-2006)

0 5 10 15 20 25 30 35 40

Immunologic

Recurrent dis.

Infections

Medical

Unknown

Percent of losses

Cell-mediated Antibody-mediated

1317 transplants

153 losses

1317 transplants

153 losses

(Ziad El-Zoghby, Cosio et al AJT 9:527-535, 2009)

Recurrent glomerular diseases (rGD)Recurrent glomerular diseases (rGD)

Recipient’s original kidney disease

N Losses due to rGD

FSGS FSGS 104104 12 (12%)12 (12%)

IGA nephropathyIGA nephropathy 8484 4 (5%) 4 (5%)

Membranous nephropathyMembranous nephropathy 2929 3 (11%)3 (11%)

MPGNMPGN 2424 4 (17%)4 (17%)

Recurrent non-glomerular diseasesRecurrent non-glomerular diseases

• Graft losses due to recurrent non-GN Graft losses due to recurrent non-GN disease:disease:

7/153 (5%)7/153 (5%)• Oxalosis Oxalosis 22• Sickle cell anemia Sickle cell anemia 11• Light chain DD Light chain DD 11• HUS/TTP HUS/TTP 11• Scleroderma Scleroderma 22

Causes of renal failure in transplant Causes of renal failure in transplant recipients: Mayo versus USA recipients: Mayo versus USA

Cause of ESRD Mayo Clinic Rochester

UNOS 2006

Glomerular diseaseGlomerular disease 35.6%35.6% 21.2%21.2%

DiabetesDiabetes 16%16% 27.8%27.8%

PKDPKD 13%13% 6.8%6.8%

HTN/vascularHTN/vascular 11.5%11.5% 25%25%

OtherOther 15.9%15.9% 17.2%17.2%

UnknownUnknown 6%6% 2%2%

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)

• End points:End points:• Death-censored graft survivalDeath-censored graft survival• Disease recurrence (Disease recurrence (protocol Bxprotocol Bx))

• 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)

• 35% recurrence 35% recurrence (clinical and/or (clinical and/or histologic)histologic)

• Median time to Median time to recurrence: 6.9 recurrence: 6.9 months (0.01-116) months (0.01-116)

Proportion of patients with recurrent FSGS

Months post-transplant

96847260483624120

.5

.4

.3

.2

.1

0.044% 16% 41%

Often subclinical with minor proteinuria and FSGS on protocol bx

Often subclinical with minor proteinuria and FSGS on protocol bx

Present with higher grade proteinuria

but no FSGS lesions

Present with higher grade proteinuria

but no FSGS lesions

Kidney transplantation in Kidney transplantation in membranoproliferative GN (MPGN)membranoproliferative GN (MPGN)

Death-censored graft survival

Months post-transplant

120967248240

1.0

.9

.8

.7

.6

.5

PKD (N=172)

p=0.048

MPGN (N=25)

• 25 patients with 25 patients with MPGN (MPGN (excludingexcluding type II, fibrillary and type II, fibrillary and secondary forms).secondary forms).

• 2% of recipients.2% of recipients.

• Reduced graft Reduced graft survival compared survival compared to PKD.to PKD.

• 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

Disease Disease startsstarts

Clinical Clinical diagnosisdiagnosis

Histologic Histologic diagnosisdiagnosis

Progressive Progressive disease justifies disease justifies

treatmenttreatment

?? Waiting period due to the Waiting period due to the following issues:following issues:

• Disease may go away?Disease may go away?

• Treatments are toxic and Treatments are toxic and partially effectivepartially effective

• Deployment of appropriate Deployment of appropriate treatment is difficulttreatment is difficult

Protocol biopsiesProtocol biopsies suggest several interesting suggest several interesting questions / possibilitiesquestions / possibilities

Disease Disease startsstarts

Clinical Clinical diagnosisdiagnosis

Histologic Histologic diagnosisdiagnosis

Progressive Progressive disease justifies disease justifies

treatmenttreatment

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

Original Dx: FSGSOriginal Dx: FSGS

5 month 5 month clinicalclinical Bx. Urine protein Bx. Urine protein 60306030 mg/day. LM: mg/day. LM: normal.normal. EM: diffuse FPF EM: diffuse FPF

12 month protocol Bx. Urine protein 12 month protocol Bx. Urine protein 1030 mg/day. LM: FSGS, finally!1030 mg/day. LM: FSGS, finally!

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

1.1. Early, pre-clinical diagnosisEarly, pre-clinical diagnosis

2.2. Pathogenic cluesPathogenic clues

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)

Interesting initial observations treating Interesting initial observations treating recurrent MNrecurrent MN

Diagnosis(4 mo post-Tx)Diagnosis(4 mo post-Tx)

1y after Rituximab 1y after Rituximab (no proteinuria)(no proteinuria)

2 y after Rituximab 2 y after Rituximab (no proteinuria)(no proteinuria)

Rituximab treatment of recurrent MN:Rituximab treatment of recurrent MN:

• (1y) 75% complete or partial clinical remission(1y) 75% complete or partial clinical remission

• (2y) Evidence of DD resorption in 6/7(2y) Evidence of DD resorption in 6/7

• (2y) Negative IgG (4/7) and negative C3 (3/7)(2y) Negative IgG (4/7) and negative C3 (3/7)

Rituximab treatment of recurrent MN:Rituximab treatment of recurrent MN:

• (1y) 75% complete or partial clinical remission(1y) 75% complete or partial clinical remission

• (2y) Evidence of DD resorption in 6/7(2y) Evidence of DD resorption in 6/7

• (2y) Negative IgG (4/7) and negative C3 (3/7)(2y) Negative IgG (4/7) and negative C3 (3/7)

45 yo female with SLE. LRD kidney 45 yo female with SLE. LRD kidney transplant 2/2007…transplant 2/2007…

Parameters 4 mo. post-Tx

12 mo. 12 mo. post-Txpost-Tx

24 mo. 24 mo. post-Txpost-Tx

Creatinine (GFR)Creatinine (GFR) 1.1 (57)1.1 (57) 1.1 (57)1.1 (57) 1.0 (63)1.0 (63)

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

Unknown, 5%

Fibrosis/atrophy30%

Recurrent GN16%

Medical16%

Acute Rejection11%

Tx Glomerulopathy16%

De Novo GN7%

(Ziad El-Zoghby, Cosio AJT 9:527-535, 2009)