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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)

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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)
  • 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)
  • 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
  • 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
  • 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


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