CHRONIC TRANSPLANT

GLOMERULOPATHY

- clinical and histological

characteristics

Agnieszka Perkowska-Ptasinska1, M. Ciszek, A.L. Urbanowicz, L. Paczek,

M. Glyda, A. Debska-Slizien, A. Rydzewski, K. Dziewanowski, M. Myslak

and M. Durlik

1Transplantation Institute, Warsaw Medical University, Poland

CHRONIC TRANSPLANT

GLOMERULOPATHY

CLINICALLY: proteinuria, hypertension, declining graft function and graft loss

MORPHOLOGY:double contours of glomerular capillaries, no IF/EM deposits

Habib 1993;Regele J Am Soc Nephrol 2002; Sijpkens Ki 2004;Gloor AJT 2006;Sis AJT 2007; Gloor AJT 2007; Cosio AJT 2008;

CHRONIC TRANSPLANT GLOMERULOPATHY

• rare before 6 months after Tx,

• the incidence rises from 1.0-4.0% at 1 year to 20% at 5 years

• more common in patients with:- historical or ongoing acute rejection

- DSA (especially against HLA II Ag )

- ABO incompatibility with a donor

- non-HLA reactive Ab (MICA, anti-endothelial cell Ab,

anti-angiotensin type 1 receptor Ab) Dinavahii J AM Soc Nephrol 2011WillicombeTransplantation 2012Dragun Curr Opin Organ Transplant. 2012

Lesions that accompany TG: PTCitis, glomerulitis C4d in PTCs

,

CHRONIC TRANSPLANT GLOMERULOPATHY

what about the morphology of the interstitium, tubules, arteries,

arterioles?

Regele J AM Soc Nephrol 2002; Shimizu KI 2002;Aita Clin Transplant 2005; Gloor AJT 2007; Sis AJT 2007, Perkowska Trans Proc 2009

The retrospective study of:159 patients with TG and 85 recipients without TG, but with other

chronic changes in the graft biopsy (IF/TA and/or chronic vascular

lesions)

median observational time: 118 months (range 39-270 months)

median time from Tx to biopsy: 55 months (range 0.4-243 months)

F:102, M:142

AIM:

to give a detailed morphological characteristics of TG

to search for potential impact of each of studied lesions on graft survival

Methods:

the analysis of clinical and histological (LM) data

including C4d deposition in PTCs and glomeruli (IHC on paraffin sections)

Methods

Light microscopical evaluation based on Banff classification

Compartment

additional parameters (added to Banff criterias)

glomeruli •linear C4d in glomerular capillaries,

•thrombi,

•mesangiolysis,

•globally and segmentally sclerosed glomeruli (%)

arteries arteriosclerosis without the multiplication of elastic lamina

arterioles •subendothelial sclerotization,

•smooth muscle cells hyperplasia,

•thrombi

interstitium• PTCs’ dilatation

TG vs non-TG caseslight microscopical evaluation

Banff criteria + additional parametersTG Non-TG p

C4d in PTCs 42.9% 1,3% <0.0001

C4d in PTCs and glomerular capillaries 6.5% 0 0.03

C4d only in glomerular capillaries 0 0 NS

PTC-itis 40.9% 11.8% <0.0001

PTCs’ dilatation 35.9% 10.6% <0.0001

Acute interstitial inflammation („i”) 30.8% 10.6% <0.0001

Total interstitial inflammation („ti”) 81.8% 68.2% 0.03

The percantage of globally/segmentally sclerosed glomeruli

30.2 ± 21.7 19.6 ± 21.2 <0.0001

Mesangiolysis 39% 11.8% <0.0001

Increase in mesangial celullarity 39% 8.2% <0.0001

Increase in mesangial matrix volume 48.4% 27.1% 0.002

Glomerulitis 61% 7.1% <0.0001

Tubulitis 31.5% 10.6% 0.0002

Endarteritis 9.8% 0 0.003

Arteriosclerosis without the multiplication of elastic lamina

18.9% 3.6% 0.001

Arteriosclerosis with the multiplication of elastic lamina 28.7% 22.9% NS

Arteriolar sclerotization 47.2% 18.8% <0.0001

Arteriolar SMCs hyperplasia/hypertrophy 39.6% 11.8% <0.0001

Arteriolar wall hyalinisation 86.8% 77.7% NS

Correlation between TG and other morphological lesions

TGrs (p)

C4d in PTCs 0.37 (<0.0001)

increase in mesangial matrix 0.32 (<0.0001)

increase in mesangial cellularity 0.4 (<0.0001)

segmentally and globally sclerosed glomeruli (%) 0.31 (<0.0001)

arteriolosclerosis 0.33 (<0,0001)

PTC-itis 0.27 (<0.0001)

PTCs’ dilatation 0.26 (<0.0001)

linear C4d deposition in glomerular capillaries 0.09 (0.2)

arteriolar SMCs hyperplasia/hypertrophy 0.26 (<0.0001)

„ti” lesion 0.2 (0.002)

tubulitis 0.2 (0.002)

arteriosclerosis without the multiplication of elastic lamina

0.21 (0.002)

„t” lesion 0.15 (0.03)

glomerulitis 0.15 (0.02)

graft survival in TG vs non-TG group

Non-TG group

TG group

months

pro

bab

ility

Patients’ survival

non-TG group

TG group

pro

bab

ility

months months

pro

bab

ility

without graft losswith graft loss

TG group - graft survival

PARAMETER

univariate analysis,

Weibull regression model

HR 95% CI p

>1 Tx 1.5 1.1-2.2 0.02

recipient’s age at the time of Tx >30y 5.3 0.4-0.9 0.02

donor’s age at the time of Tx >30y 2.0 1.3-3.3 0.003

TG recognition before 44th month after Tx 6.4 4.6-9.0 <0.001

TG recognition between 44-89th month after Tx 2.6 1.8-3.6 <0.001

PTCs’ dilatation 1.5 1.0-2.2 0.05

Acute interstitial inflammation („i”) 1.7 1.1-2.5 0.02

AS without the multiplication of elastica 1.7 1.1-2.7 0.04

Thrombi in glomerular capillaries 3.7 1.7-8.0 0.001

C4d in PTCs 0.9 0.6-1.3 NS

C4d in glomerular capillaries (linear deposits) 1.4 0.6-3.3 NS

TG group - graft survival

PARAMETERS included in the

BEST multivariate regression model

multivariate analysis,

Weibull regression

model

HR 95% CI p

C4d in PTCs 1.1 0.8-1.4 0.68

AS without multiplication of elastica

1.5 1.1-2.1 0.02

TG recognition before 44th month after Tx vs base level

5.3 3.8-7.4

<0.01

TG recognition between 44-89th month after Tx vs base level

1.9 1.4-2.6

<0.01

At least moderate interstitial inflammation (Banff ti2+3)

1.2 0.8-1.7 0.47

Mild interstitial inflammation (Banff ti1)

0.7 0.5-1.0 0.06

Recipient’s age at the time of Tx >30y 1.7 1.3-

2.3<0.0

1

Thrombi in glomerular capillaries 2.2 1.1-

4.2 0.02

TG C4d (+) vs TG C4d (-)

clinical variables TG C4d (-) TG C4d (+) p

recipient’s sexF: 50%

M: 50%

F: 27.27%

M: 72.73% 0.005

recipient’s age

at the time of Tx40.1 ± 12.0 34.0 ± 10.7 0.002

No significant difference in the:- level of proteinuria,

- number of current transplantation,- number of HLA mismatches,- percentage of highly (>50%) immunized recipients,- level of immunosupression,- time interval between Tx and recognition of TG.- donor’s age and sex,

histological parameters TG C4d (+) TG C4d (-) p

PTC’s dilatation 60.61% 17.05% <0.0001

PTC-itis 60.61% 26.14% <0.0001

PTC-itis

with neutrophils

10% 0 0.01

pathologial recognitions

TG C4d (+) TG C4d (-) p OR (95%CI)

acute T-cell mediated rejection (type I,II) 27.66% 10.77% 0.03 3.17 (1.15-

8.71)

TG C4d (+) vs TG C4d (-)

clinicallyTG exerts a negative impact on both recipients’ and grafts’ survivalThe earlier TG development is associated with worse prognosis as for the graft survival

morphologicallyTG is associated with a spectrum of both acute and chronic inflammatory as well as structural changes in glomeruli, tubules, arteries and arterioles. Among these lesions AS without elastica multiplication and glomerular thrombi are independent risk factors for the graft loss PTC-itis, the presence of neutrophils in PTCs and PTCs’ dilatation are more common in C4d(+) TG cases

CONCLUSIONS: TG vs non-TG group differ

ARTERIOLAR SUBENDOTHELIAL SCLEROTIZATION AND ARTERIOLAR WALL SMCs HYPERTROPHY/HYPERPLASIA

- very few publications, - documented as a feature of thrombotic microangiopathies in native kidneys

(antiphospholipid syndrome,LN,

malignant hypertension, scleroderma,HUS)

Caetano Hypertension 2001Nochy J Am Soc Nephrol 1999Ruggenenti Am J Kidn Dis

1996

CONCLUSIONS:

Chronic VASCULAR lesions associated with

TG

ARTERIOSCLEROSIS WITHOUT THE

MULTIPLICATION OF ELASTIC LAMINA (proliferative arteriopathy)

Characteristic for dynamic fibrotic tissue proliferation in the intima typical of inflammatory and thrombotic vasculopathies

in renal transplants: one study??? Wieczorek AJT 2006

CONCLUSIONS:

Chronic VASCULAR lesions associated with

TG

EXERTS NEGATIVE IMPACT ON GRAFT SURVIVAL

TG is commonly associated with arterial and arteriolar lesions that share the same pathogenesis, evolve on the background of chronic endothelial injury,

most probable Ab-mediated and/or TMA related

CONCLUSIONS