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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: , 1984 Vascular effects Arteriolar hyalinosis Pearl Necklace pattern Tubulo-interstitial effects Striped fibrosis Glomerular effects FSGS Glomerulosclerosis
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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=48Induction therapy 85%SteroidsAzathioprineCsA
Material and methods (2)
DemographicsChronic 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 survivalCSA 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/TACTRL CsA
012
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%
0123
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 pat
ient
s w
ith C
NI a
rter
iolo
path
y (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
eGFR
(m
l/min
)
CTRLCSA
3M
Graft loss CsAGraft loss ControlDeath CsADeath Control
120 240 300 360 420180Time post-transplantation in months
Cum
ulat
ive
prob
abili
ty o
f gra
ft lo
ss a
nd d
eath
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 »