The Value of Zero-Hour Implantation Biopsies Volker Nickeleit Nephropathology Laboratory, Department of Pathology The University of North Carolina, Chapel

The Value of Zero-Hour Implantation Biopsies

Volker Nickeleit

Nephropathology Laboratory, Department of Pathology

The University of North Carolina, Chapel Hill, USA

Baseline Renal Allograft Biopsies

Purpose:

1) Organ adequacy (Harvest biopsy)

2) Pre-existing Disease (Protocol Biopsy)

a) Post transplant biopsy interpretation (“book-keeping”)

b) Prediction of function / management

c) Diagnosis of (living) donor disease

a)Donor harvest biopsies

Harvest biopsies of limited practical value

Purpose: 1) Organ adequacy :+ / - (adjunct tool)

2) Pre-existing Disease : + / -

a) Adequate post transplant biopsy interpretation

b) Implantation protocol biopsies

Harvest biopsies of limited practical value

Purpose: 1) Organ adequacy : + / - (adjunct tool)

2) Pre-existing Disease : + / - a) Adequate post transplant biopsy

interpretation (“book-keeping”)

Improvement: a) standardization of technique, i.e. needle cores,

deep wedges

b) complete tissue evaluation (PAS, trichrome) and material sharing with managing transplant center

c) systematic studies of criteria to discard organs

a) Donor harvest biopsies

b) Implantation protocol biopsies

- Implantation protocol biopsies to assess donor disease

- Strengths:a) full histological evaluation “no time

constraints”b) good assessment of lesions “special stains”

- Problems:a) Risk of complications / bleeding (caveat: living donations)

b) Sampling: 15 gauge needles, only one core, no frozen tissue, subcapsular wedge biopsies

UNC experience with post perfusion biopsies n=175 kidney transplants

n=114 post perfusion zero-hour biopsies (65% of all organs)

n=1 Complication (extended bleeding)0.9% of all biopsies

Biopsy procedure: biopsy gun, 15 gauge needle, 1 or 2 cores

Tissue fixation in formalin and fresh frozen collection


Purpose: a) Diagnosis of (living) donor

disease

b) Identifying “baseline” histological changes

c) Prediction of function / management



disease



N=114 biopsies n=72 cadaveric, n=42 living origin donor age: median 37 yrs (range: 9 – 61

yrs)

N=78 (68%) Banff minimal adequacy (> 6 glomeruli and > 1 artery; caveat: often

medulla)

N=22 (20%) Normal (no arteriosclerosis, no

glomerulosclerosis)

N=42 (37%) Immunofluorescence analysis N=0 Immuncomplex mediated GN N=0 C4d positivity N=0 Tubular HLA-DR expression

N=0 (0%) Active disease

Histological features (total n=114):

Glomeruli median: 14 (range: 0 - 52)

Sclerosed Glomeruli > 3 sclerosed glomeruli n=1

% Interst. fibrosis 0% n=66, <10% n=31, > 10% n=13

% Tub. Atrophy 0% n=84, < 10% n=22, > 10% n=6

Arteriolosclerosis (0-4) (0) n=57, (1) n=33, (2) n=10, (3) n=1

Intimal sclerosis (0-4) (0) n=45, (1) n=24, (2) n=17, (3) n=4

ATN (0-4) (0) n=0, (1) n=78, (2) n=48, (3) n=14, (4) n=1

Moderate Arteriosclerosis ( Scoring: > 2 / 4 )

21 / 114 biopsies (18%)

18% of cadaveric organs

N= 13 cadaveric organs (mean: 37 yrs, range: 18 –

59 yrs)

N= 1 secondary FSGS (cadaveric organ)

19% of organs from living donations

N= 8 organs of living origin (mean: 46 yrs, range: 37-

54 yrs)



disease

Unexpected arteriosclerosis (suggestive of hypertension induced damage) in 19% of donors


Arteriosclerosis and arteriolosclerosis in 40% of organs


Purpose: a) Diagnosis of (living) donor disease



Acute rejection - graft failure( 12 months post transplantation)

Multi-organ recipients 4/ 114 (4%)

Acute rejection 19/ 110 (17%)

Graft failure 5/ 110 (5%)

BK-Virus nephropathy 8/ 110 (8%)

Lost for follow up 4/ 114 (4%)

40 Patients excluded from functional analyses

Statistical analysisHistological features: % globally sclerotic glomeruli

% interstitial fibrosis% tubular atrophyarteriolosclerosis (0-4)arterial intimal sclerosis (0-4)ATN (0-4)

Clinical data (during 12 months post transplantation):S-Creatinine: 2 weeks, 1, 3, 6, 12 months post txDelayed graft function: at least 1 episode of HD post txBlood-Pressure: 3, 6, 12 months post txAcute rejection episodesGraft loss

Demographic data: Recipient age, sex, race, number of tx

Donor age, sex, raceType of donor organ

Statistical analysis

Histological features: - % globally sclerotic glomeruli

- % interstitial fibrosis- % tubular atrophyarteriolosclerosis - arterial intimal sclerosis

Significantly correlated to one another

Leading variable: arterial intimal sclerosis

Statistical analysis: Arterial intimal sclerosis

A) Arterial intimal fibrosis is correlated with the age of the donor

Age in years( mean + SD)

Scoring 0 27,9 + 12.0

Scoring 1 42,7 + 8.3

Scoring 2 44.7 + 11.9

Scoring 3 46,7 + 6.3 p< 0.0001

B) Arterial intimal fibrosis is not correlated with donor organ type, donor sex, donor race

Statistical analysis **: Arterial intimal sclerosis Arterial intimal sclerosis * Delay. S-Creatinine (mean + SD) Blood pressure

( scoring 0-3 ) Funct. 2 1 3 6 12 3 6 12

% Wks m m m m m m mths

0 n=31 13% 1.27 + .32 1.25 + .33

1 n=14 14% 1.28 + .46 1.29 + .39

2 n=7 0% 1.60 + .43 1.62 + .40

3 n=2 0% 1.25 + .07 1.35 + .21

ns ns ns ns p<0.04 ns ns ns ns

mild (0-1) n=45 13% 1.27 + .36 1.26 + .34

moderate (2-3) n=9 0% 1.52 + .40 1.55 + .37

ns ns ns p<0,04 p<0.02 ns ns ns ns * Biopsies fulfilling minimal adequacy criteria only ** Evaluation of functioning renal grafts without rejection during 12 months

Statistical analysis: ATN

A) Acute tubular injury (ATN) is correlated with donor organ type

Cadaveric Living donation

Scoring 0 4 9

Scoring 1 14 18

Scoring 2 38 10

Scoring 3 11 3

Scoring 4 0 1p<0.001

B) Acute tubular injury (ATN) is not correlated with delayed graft function, acute rejection episodes, arterial hypertension

Statistical analysis **: ATN

Acute tub. injury Delay. Function S-Creatinine (mean + SD)

( scoring 0 - 4 ) 2 1 3 6 12

Wks m m m m

0 n=7 1.13 + 0.29

1 n=16 1.66 + .79

2 n=27 1.82 + 1.31

(3 and 4) n=6 2.17 + 1.35

ns p<0.05 ns ns ns ns

** Evaluation of functioning renal grafts without rejection during 12 months (total n=54)


Purpose: c) Prediction of function / management

Arterial intimal sclerosis: - associated with increased S-Cr 3 and 6 months post

tx

- associated with donor age

ATN: - associated with increased S-Cr 2 weeks post tx


Purpose: a) Diagnosis of (living) donor disease


Impact on diagnoses in post transplant allograft

biopsies


Chronic vascular rejection – versus - pre-existing donor disease

Chronic inactive vascular rejection Zero-Hour Biopsy: Intimal sclerosis

Pre-existing donor disease and superimposed vascular rejection:12 days post transplantation

Media

Donor disease: intimal sclerosis

Banff type II rejection: Endothelialitis

Pre-existing donor disease and superimposed rejection5 months post transplantation:

Arterial intimal sclerosis and chronic active vascular rejection

Calcineurin-inhibitor induced arteriolopathy -versus –

pre-existing arteriolosclerosis

Cyclosporine arteriolopathy Zero-Hour Biopsy: arteriolosclerosis

Baseline (Zero-Hour) Biopsies

• Important for adequate classification of transplant pathology

caveat: fibrosis and atrophy may be donor disease! active and scarred rejection may be superimposed on

donor disease!

• Prediction on graft function

• Some help to detect (living) donor disease

• Help for scientific projects (e.g. gene expression analysis post tx, latent viral load measurements etc)

Specific diagnoses

Back to the Basics of the “Banff Idea”….

…..Bean Counting.

Banff “Edition” for reporting Donor Disease

1) Strongly recommend adequate baseline implantation biopsies

2) Separately score and report donor disease (“D”)

Dcv (0-3): arterial intimal fibroelastosis with marked

multilayering of elastic lamellae

Dah (0-3), Dci (0-3), Dct (0-3)

Dcg: percentage of globally sclerotic glomeruli

3) Post transplantation: - score Banff lesions as usual - specifically comment on previous “D” scores

Documents

The Value of Zero-Hour Implantation Biopsies Volker Nickeleit Nephropathology Laboratory, Department of Pathology The University of North Carolina, Chapel