calcineurin inhibitor toxicity in kidney allograft protocol biopsies l.
Download
Skip this Video
Loading SlideShow in 5 Seconds..
Calcineurin Inhibitor Toxicity In Kidney Allograft Protocol Biopsies PowerPoint Presentation
Download Presentation
Calcineurin Inhibitor Toxicity In Kidney Allograft Protocol Biopsies

Loading in 2 Seconds...

play fullscreen
1 / 33

Calcineurin Inhibitor Toxicity In Kidney Allograft Protocol Biopsies - PowerPoint PPT Presentation


  • 840 Views
  • Uploaded on

Calcineurin Inhibitor Toxicity In Kidney Allograft Protocol Biopsies. Neeraja Kambham M.D. Stanford University. Calcineurin Inhibitor Toxicity (CNIT). CNI toxicity is a very important cause of chronic allograft nephropathy (CAN)

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'Calcineurin Inhibitor Toxicity In Kidney Allograft Protocol Biopsies' - Sophia


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
calcineurin inhibitor toxicity in kidney allograft protocol biopsies

Calcineurin Inhibitor Toxicity In Kidney Allograft Protocol Biopsies

Neeraja Kambham M.D.

Stanford University

calcineurin inhibitor toxicity cnit
Calcineurin Inhibitor Toxicity (CNIT)
  • CNI toxicity is a very important cause of chronic allograft nephropathy (CAN)
  • Later phase of CAN (i.e. > 1 year post txp) is likely due to CNIT, and it’s contribution progressively increases (Nankivell et al.)
  • Acute phase of CNI toxicity is reversible, but chronic phase is probably irreversible
cni toxicity
CNI Toxicity
  • Functional
  • Structural:
    • Acute: tubulopathy (proximal tubules), endothelial injury (thrombotic microangiopathy)
    • Chronic: arteriolopathy, tubular atrophy, striped fibrosis, glomerulosclerosis
calcineurin inhibitor cni toxicity
Calcineurin Inhibitor (CNI) Toxicity
  • Can it it be scored objectively?
  • Is it clinically useful?
  • Does it correlate with subsequent graft function?
  • Is it better than Banff Chronicity score?
study design
Study Design
  • 50 consecutive pediatric renal transplant patients (November 1999- December 2004)
  • Patients on Steroid free immunosuppression protocol*
  • Immunosuppression: Extended Daclizumab induction; Tacrolimus and Mycophenolate mofetil maintenance
  • Biopsies: Protocol 3, 6, 12 and 24 months (P); also as indicated clinically (NP)

(Sarwal MM et al: Transplantation. 76 (9): 2003)

study design7
Study Design…
  • 231 biopsies (P+NP) scored in a blinded fashion
    • 27 were inadequate (diagnosis rendered on 5)
  • CNI toxicity (CNIT) score in biopsies with histological evidence of CNI toxicity
  • Banff chronicity score (BChS): cg, ct, ci, cv
  • Modified Banff chronicity score (MBChS): gs, ct, ci, cv
  • Chronic Allograft Damage Index (CADI)
  • C4d Stains on paraffin embedded tissue
diagnostic categories
Diagnostic Categories
  • CNI Toxicity
  • Acute Rejection
    • graded by Banff criteria
  • Chronic Allograft Nephropathy
    • Unclear etiology of chronic damage
    • Any tubular atrophy or interstitial fibrosis > 5%
  • No Significant Abnormality
    • No tubular atrophy; interstitial fibrosis < 5%
  • Other: ATN, glomerulonephritis, reflux
acute rejection n 29
Acute Rejection (n=29)
  • Non-protocol Biopsies: 21 (9 %)
    • Borderline: 13
    • IA: 6
    • IB: 2
  • Protocol Biopsies: 8 (4.8 %)*
    • Borderline: 4
    • IA: 3
    • IB: 1

* Includes clinical & subclinical acute rejections

features of cni toxicity
Features of CNI Toxicity
  • Tubular isometric vacuolization
  • Arteriolar medial/peripheral hyaline
  • Striped pattern of tubular atrophy and interstitial fibrosis

* Ischemic collapse of glomeruli, Tubular dystrophic calcifications, juxtaglomerular apparatus hyperplasia

results p np biopsies
Results (P+NP Biopsies)

*C4d +ve in 1 of 189 biopsies (NP, AR IB)

diagnostic features of cnit n 70
Diagnostic features of CNIT (n=70)

TV: tubular vacuoles; AH: arteriolar hyaline; SF: striped fibrosis

end points for graft function
End points for graft function
  • CNIT, BChS, MBChS and CADI correlated with
    • Creatinine Clearance (by Schwartz method)
    • Hypertension: # of anti-HTN agents to normalize blood pressure
    • Proteinuria
  • CNIT score also correlated with Tacrolimus trough levels (ng/ml) and dosage (mg/kg)
follow up
Follow up
  • Mean follow up period: 25.7 months (range 24-44 months)
  • 2 patients died with functioning grafts
  • None had urine protein/creatinine ratio > 1
  • Mean Creatinine Clearance at 24 months: 88.2 ml/min (range: 46-135)
  • Mean # anti-HTN agents: 0.27 (range 0-2)
results
Results
  • By Pearson parametric correlation (one side test)
    • CNI Toxicity Score at 3 months significantly correlates with 12 mo CrCl (p=0.021, r2=-0.54) and 24 mo CrCl (p=0.03, r2 =-0.58)
results23
Results…
  • No correlation with hypertension, Tacrolimus dose or levels
  • CADI, BChS and MBChS did not correlate with outcome
  • CNIT and MBChS seem to correlate with each other*

* gs, ct and ci are common parameters in both

parameters of cnit score
Parameters of CNIT Score

Gs:glomerulosclerosis; ct:tubular atrophy; ci:interstitial fibrosis; ah:arteriolar hyaline; tv:tubular vacuolization

can we create a cnit scoring model
Can we create a CNIT scoring model ?
  • We reduced the # of parameters to create the model for CNIT score:

= -0.16+1.05 gs+ 2.05 ct + 0.94 ah +1.03 tv

(P<0.001; r2=-0.95)

Gs: glomerulosclerosis; ct: tubular atrophy; ah: arteriolar hyaline; tv: tubular vacuolization

testing the validity of the model
Testing the validity of the model
  • Identified 14 patients with CNI toxicity on 3 month protocol biopsy with at least 12 months follow up
  • Patients on steroid based (3) and steroid free (11) immunosuppression
  • 11 patients had 24 mo post- txp follow up
validity
Validity..
  • Mean CNIT score (calculated using model): 4.08 (range 1.97-9.28)
  • 3 month CNIT score correlated significantly
    • 12 mo CrCl (p= 0.02; r2 =-0.54)
    • 24 mo CrCl (p= 0.004; r2 =-0.75)
scoring system
Scoring System
  • Is linear scoring of parameters better?
  • Image analysis may be helpful
  • Need to validate the data with more protocol biopsies (steroid free and steroid based regimens)
  • We are probably underestimating the incidence of CNI toxicity
conclusions
Conclusions
  • CNIT score: helpful in objective grading
  • A diagnosis of CNIT requires aggressive monitoring of CNI therapy
  • Need to modify maintenance immunosuppression
  • Arteriolar hyaline: most important factor and likely irreversible cause of progressive loss of graft function
slide33

Acknowledgements

  • Minnie Sarwal M.D., Ph.D.
    • Suja Nagarajan, M.D.
    • Sheryl Shah
    • Li Li