Histological markers of CNI nephrotoxicity:Specific or not specific?

Marion Rabant MD, Renaud Snanoudj MD, Virginie Royal MD, C. Girardin,E.Morelon MD PHD, C. Legendre MD, PHD and Laure Hélène Noël MD

Pathology department, NECKER Hospital, Paris, FranceRenal transplantation department, NECKER Hospital, Paris, France

Cyclosporin and Kidney transplantation

Calcineurin inhibitor introduced in late 1970s

Considerable improvement in graft survival in the short term

Not in the long term

Transplant Proc 1993; 25: 527-529

Acute and chronic nephrotoxicity

Long-term use of CsA in heart transplant recipients associated with irreversible and progressive tubulo-interstitial injury and glomerulosclerosis

Chronic CNI nephrotoxicity

Myers et al. New Engl J Med 311:699-705, 1984

Vascular effectsArteriolar hyalinosisPearl Necklace pattern

Tubulo-interstitial effectsStriped fibrosis

Glomerular effectsFSGSGlomerulosclerosis

N=119Renal Biopsies=959

Chronic CNI nephrotoxicity

100% after 10 years

Nankivell BJ et al. New Engl J Med 2003…BUT NO CONTROL GROUP WITHOUT CNIAnd small number of biopsies at 10 years

Material and methods (1)

• Retrospective analysis 1975-1990

• N=141

• 423 Renal Biopsies M3, M24, 10 years

• Updated Banff 97 classification

Induction therapy 50%SteroidsAzathioprine 2mg/kg/d

N=93

CONTROL GROUP Cyclosporine (CSA) GROUP

N=48

Induction therapy 85%SteroidsAzathioprineCsA

Material and methods (2)

Demographics

Chronic histological parameters IF/TA (0 to III) Arterial fibrous intimal thickening (cv0 to cv3) Arteriolar hyalinosis (ah0 to ah3)

Pearl Necklace-like pattern **Sub-endothelial deposits *

Renal function (MDRD) and graft survival

CSA doses and blood trough levels*

**

Demographics

INTERSTITIAL FIBROSIS/TUBULAR ATROPHY

0%

20%

40%

60%

80%

100%

p=0.23

3 Months

24.1%

34.1%

0%

20%

40%

60%

80%

100%

24 Months

p=0.031

33.3%

53.7%

0%

20%

40%

60%

80%

100%

CTRLN=98

CsAN=43

10 years

p=0.005

49.5%

79.2%

0

1

2

3

0

1

2

3

0

1

2

3

p=0.013

p=0.016

p<0.0005

Mean IF/TA

CTRL CsA

0

1

2

3

FIBROUS INTIMAL THICKENING

3 months

p=0.34

0%

20%

40%

60%

80%

100% 48.7%

58.3%

24 months

p=0.036

0%

20%

40%

60%

80%

100%

60.5% 79.5%

CTRLn=98

CsAn=43

10 years

p=0.030

0%

20%

40%

60%

80%

100%

73.7% 88.6%

0.7 0.9 1.1 1.1

1.0 1.0 1.4 1.0

1.4 1.1

p=0.59

p=0.07

p=0.12

0

1

2

3

1.7 1.0

CTRL CsA

0

1

2

3

0

1

2

3

0

1

2

3

Nodifference

Mean cv

CTRL(n=93)

CsA(n=48)

3 Months

10 years

0%

20%

40%

60%

80%

100% 48.1% 78.0%

24 Months

ARTERIOLAR HYALINOSIS

0.4 0.6 0.4 0.6

p=0.8

0

1

2

3

0.6 0.8 1.0 0.7

p=0.011

0

1

2

3

1.1 2.1 2.1 1.0

p<0.0001

0

1

2

3

CTRL CsA

Mean ah

32.2%

0%

20%

40%

60%

80%

100% 34.1%

012

3

p=0.8

p=0.001

p=0.002

3 Months

10 years

24 Months

0%

20%

40%

60%

80%

100%

65.5% 92%

35%

8%

75.0

25.0

71.8

28.2

56.7

43.3

0%

20%

40%

60%

80%

100%

0%

20%

40%

60%

80%

100%

80.0

20.0

53.1

46.9

25.0

75.0

CTRL

CsA

3 mo. 24 mo. 10 yr.

Sub-endothelial deposits

Muscular deposits

p<0.01ns

Muscular and sub-endothelial deposits

ns

0

20

40

60

80

3 mo. 24 mo. 10 yr.

CTRL CsA

8.0% (7)

6.8% (3)

13.6%(11)

36.6% (15)

28.0%(26)

68.8 % (33)

p<0.005

p<0.001

% o

f p

ati

en

ts

wit

h C

NI

art

eri

olo

pa

thy

(n

)

p=0.8

Muscular deposits

3 mo. 24 mo. 10 yr.

More frequent in hypertension patients

Renal function and graft survival

0

20

40

60

80

100

1Y 2Y 3Y 4Y 5Y 6Y 7Y 8Y 9Y 10Y

eG

FR

(m

l/m

in)

CTRLCSA

3M

Graft loss CsAGraft loss ControlDeath CsADeath Control

120 240 300 360 420180Time post-transplantation in months

Cum

ula

tive

pro

babi

lity

of g

raft

loss

and

de

ath

0.0

0.2

0.4

0.6

0.8

1.0 Factors associated with graft loss:

• CsA• Male sex• CIT>20 hrs

Factors associated with lower eGFRat 10 y:

• Hypertension• Acute rejection• CsA

No correlation between progressionof histological lesion and CsA exposure

In conclusion

First study comparing biopsies from CNI and non CNI treated patients in the long term

Chronic lesions in the CsA group more frequent and severe…but also present in the control group

CNI arteriolopathy (muscular deposits) not specific neither constant after 10y of CsA exposure

Use great caution before concluding « CNI nephrotoxicity »