Calcineurin Inhibitor Toxicity In Kidney Allograft Protocol Biopsies

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Calcineurin Inhibitor Toxicity In Kidney
Allograft Protocol Biopsies

• Neeraja Kambham M.D.
• Stanford University

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Calcineurin Inhibitor Toxicity (CNIT)

• CNI toxicity is a very important cause of chronic
  allograft nephropathy (CAN)
• Later phase of CAN (i.e. gt 1 year post txp) is
  likely due to CNIT, and its contribution
  progressively increases (Nankivell et al.)
• Acute phase of CNI toxicity is reversible, but
  chronic phase is probably irreversible

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CNI Toxicity

• Functional
• Structural
• Acute tubulopathy (proximal tubules),
  endothelial injury (thrombotic microangiopathy)
• Chronic arteriolopathy, tubular atrophy, striped
  fibrosis, glomerulosclerosis

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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?

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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)
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(Sarwal MM et al Transplantation. 76 (9) 2003)
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Study Design

• 231 biopsies (PNP) 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

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Diagnostic Categories

• CNI Toxicity
• Acute Rejection
• graded by Banff criteria
• Chronic Allograft Nephropathy
• Unclear etiology of chronic damage
• Any tubular atrophy or interstitial fibrosis gt 5
• No Significant Abnormality
• No tubular atrophy interstitial fibrosis lt 5
• Other ATN, glomerulonephritis, reflux

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Acute Rejection (n29)

• 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
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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
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CNI Toxicity Scoring
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Results (PNP Biopsies)
C4d ve in 1 of 189 biopsies (NP, AR IB)
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Protocol Biopsies
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Diagnostic features of CNIT (n70)
TV tubular vacuoles AH arteriolar hyaline SF
striped fibrosis
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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)

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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 gt 1
• Mean Creatinine Clearance at 24 months 88.2
  ml/min (range 46-135)
• Mean anti-HTN agents 0.27 (range 0-2)

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Results

• By Pearson parametric correlation (one side test)
• CNI Toxicity Score at 3 months significantly
  correlates with 12 mo CrCl (p0.021, r2-0.54)
  and 24 mo CrCl (p0.03, r2 -0.58)

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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
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Scoring of Protocol Biopsies
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Parameters of CNIT Score
Gsglomerulosclerosis cttubular atrophy
ciinterstitial fibrosis aharteriolar hyaline
tvtubular vacuolization
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Can we create a CNIT scoring model ?

• We reduced the of parameters to create the
  model for CNIT score
• -0.161.05 gs 2.05 ct 0.94 ah 1.03 tv

(Plt0.001 r2-0.95)
Gs glomerulosclerosis ct tubular atrophy ah
arteriolar hyaline tv tubular vacuolization
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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

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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)

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CNIT Score Correlation with 12 mo CrCl (p0.02)
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CNIT Score Correlation with 24 mo CrCl (p0.004)
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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

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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

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Acknowledgements

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