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Histological markers of CNI nephrotoxicity : Specific or not specific ?

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, France

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Histological markers of CNI nephrotoxicity : Specific or not specific ?

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  1. 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, France Renal transplantation department, NECKER Hospital, Paris, France

  2. Cyclosporin and Kidney transplantation • Calcineurininhibitorintroduced in late 1970s • Considerableimprovement in graftsurvival in the short term • Not in the long term Transplant Proc 1993; 25: 527-529

  3. Chronic CNI nephrotoxicity • Acute and chronicnephrotoxicity • Long-term use of CsA in heart transplant recipientsassociatedwithirreversible and progressive tubulo-interstitialinjury and glomerulosclerosis Myers et al. New Engl J Med 311:699-705, 1984 • Vasculareffects • Arteriolarhyalinosis • Pearl Necklace pattern • Tubulo-interstitialeffects • Stripedfibrosis • Glomerulareffects • FSGS • Glomerulosclerosis

  4. Chronic CNI nephrotoxicity N=119 Renal Biopsies=959 100% after 10 years …BUT NO CONTROL GROUP WITHOUT CNI And small number of biopsies at 10 years Nankivell BJ et al. New Engl J Med 2003

  5. Material and methods (1) • Retrospectiveanalysis 1975-1990 • N=141 • 423 Renal Biopsies M3, M24, 10 years • Updated Banff 97 classification CONTROL GROUP Cyclosporine (CSA) GROUP N=93 N=48 Induction therapy 50% Steroids Azathioprine 2mg/kg/d Induction therapy 85% Steroids Azathioprine CsA

  6. * ** Material and methods (2) • Demographics • Chronichistologicalparameters • IF/TA (0 to III) • Arterialfibrousintimalthickening (cv0 to cv3) • Arteriolarhyalinosis (ah0 to ah3) • Pearl Necklace-likepattern ** • Sub-endothelialdeposits * • Renalfunction (MDRD) and graftsurvival • CSA doses and bloodtroughlevels

  7. Demographics

  8. p<0.0005 p=0.016 p=0.031 p=0.005 p=0.013 p=0.23 3 100% 2 80% 60% 1 40% 0 20% 0% 3 100% 2 80% 60% 1 40% 20% 0 0% 3 2 100% 1 80% 60% 0 40% 20% 0% INTERSTITIAL FIBROSIS/TUBULAR ATROPHY 3 24.1% 34.1% 2 3 Months 1 0 33.3% 53.7% 24 Months 49.5% 79.2% 10 years CTRL CsA CsA N=43 CTRL N=98 Mean IF/TA

  9. p=0.036 p=0.030 p=0.07 p=0.34 p=0.12 p=0.59 100% 80% 60% 40% 20% 0% 100% 80% 60% 40% 20% 0% 100% 80% 60% 40% 20% 0% FIBROUS INTIMAL THICKENING Mean cv 3 3 0.7  0.9 1.1  1.1 48.7% 2 2 58.3% 3 months 1 1 0 0 3 1.0  1.0 1.4  1.0 No difference 2 79.5% 60.5% 24 months 1 0 1.7  1.0 1.4  1.1 3 2 73.7% 88.6% 10 years 1 0 CTRL n=98 CsA n=43 CTRL CsA

  10. p<0.0001 p=0.011 p=0.002 p=0.001 p=0.8 p=0.8 3 3 3 0.4  0.6 0.4  0.6 2 2 2 1 1 1 0 0 0 0.6  0.8 1.0  0.7 1.1  2.1 2.1  1.0 100% 80% 60% 40% 20% 0% ARTERIOLAR HYALINOSIS 3 32.2% 34.1% 100% 2 80% 1 3 Months 3 Months 60% 0 40% 20% 0% 24 Months 24 Months 48.1% 78.0% 10 years 10 years 100% 65.5% 92% 80% 60% 40% 20% 0% 35% CTRL CsA 8% Mean ah CTRL (n=93) CsA (n=48)

  11. 100% 25.0 28.2 43.3 80% 60% 75.0 71.8 40% 56.7 20% 0% 100% 80% 60% 40% 20% 0% 20.0 46.9 75.0 80.0 53.1 25.0 Muscular and sub-endothelialdeposits Muscular deposits CTRL p<0.001 80 68.8 % (33) 3 mo. 24 mo. 10 yr. p<0.005 60 ns ns p<0.01 36.6% (15) % of patients with CNI arteriolopathy (n) 28.0% (26) 40 p=0.8 13.6% (11) 8.0% (7) 6.8% (3) 20 CsA 0 3 mo. 24 mo. 10 yr. 3 mo. 24 mo. 10 yr. Muscular deposits CsA CTRL Sub-endothelial deposits More frequent in hypertension patients

  12. Renalfunction and graftsurvival 100 1.0 Graft loss CsA Graft loss Control Death CsA Death Control 80 60 eGFR (ml/min) 0.8 CTRL CSA 40 Cumulative probability of graft loss and death 0.6 20 0 3M 1Y 2Y 3Y 4Y 5Y 6Y 7Y 8Y 9Y 10Y 0.4 0.2 0.0 120 180 240 300 360 420 Time post-transplantation in months Factors associated with lower eGFR at 10 y: • Hypertension • Acute rejection • CsA Factors associated with graft loss: • CsA • Male sex • CIT>20 hrs No correlation between progression of histological lesion and CsA exposure

  13. 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 »

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