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Parmjeet Randhawa Professor, Division of Transplantation Department of Pathology

ROLE OF ALLOGRAFT BIOPSY IN THE MANAGEMENT OF TRANSPLANTED PATIENT. Parmjeet Randhawa Professor, Division of Transplantation Department of Pathology University of Pittsburgh. OPTIMAL RENAL ALLOGRAFT BIOPSY TECHNIQUES. US guidance: serious AEs including death

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Parmjeet Randhawa Professor, Division of Transplantation Department of Pathology

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  1. ROLE OF ALLOGRAFT BIOPSY IN THE MANAGEMENT OF TRANSPLANTED PATIENT Parmjeet Randhawa Professor, Division of Transplantation Department of Pathology University of Pittsburgh

  2. OPTIMAL RENAL ALLOGRAFT BIOPSY TECHNIQUES • US guidance: serious AEs including death • 2 cores obtained with 18 gauge needle ideal • Evaluate adequacy of sample in biopsy suite • Saving frozen tissue desirable for AMR, necessary for diagnosis ICGN • EM is needed to characterize glomerular disease & demonstrate PTC-BMD

  3. ADEQUACY CRITERIA FOR RENAL ALLOGRAFT BIOPSY • 10 gloms, 2 arteries, examined in 7 slides • Suboptimal biopsies can be diagnostic Cortex -severe tubulitis with no glomeruli -single artery with intimal arteritis Medulla -BKVN -diffuse C4d

  4. GENERAL APPROACH • Determine if it is adequate • Low power grade i, ci, ct, cv • Medium to high power evaluation needed to score g, t, v, cg, ah • Synthesize findings & correlate clinical data

  5. THE BANFF SCHEMA FOR RENAL ALLOGRAFT PATHOLOGY • REJECTION RELATED CATEGORIES -Acute or chronic antibody mediated rejection -Acute or chronic T-cell mediated rejection • NON-REJECTION RELATED -Acute tubular necrosis -Drug toxicity, Donor derived pathology, -Infections, Recurrent disease -Technical & vascular complications

  6. ACUTE REJECTION • Acute T-cell mediated rejection • Acute cellular rejection

  7. Fas Ligand CD95 CTL • Allorecognition • Direct • Indirect Granzyme B Perforin GMP-17 (TIA-1) IL-2 Th IL-15 APC Th Th Th ACUTE T-CELL MEDIATED REJECTION IL-2 Th M IFNg TNFa IL-4 IL-10 anti-HLA Ab B Dr. David Rush

  8. ACUTE T-CELL MEDIATED REJECTION • An alloimmune reaction mediated by cell mediated immunity • Subclinical with normal creatinine • Laboratory evidence of graft dysfunction • Severe cases may show fever, graft tenderness, leukocytosis and eosinophilia

  9. HISTOLOGIC CRITERIA FOR DIAGNOSIS OF ACUTE T-CELL MEDIATED REJECTION • Predominantly mononuclear infiltrate • Presence of parenchymal damage • Occurrence of subendothelial inflammation in venules, arteries

  10. GRADING OF ACUTE TCMR-1 • Severity of inflammation • Intensity of tubulitis • Disruption of tubular architecture • Presence of arteritis

  11. GRADING OF INTERSTITIAL INFLAMMATION • Limit assessment to cortex unless medulla alone sampled • Ignore areas in continuity with capsule • <10% area is assigned grade 0 • Grades 1, 2, 3 are 10-25, 26-50, >50% • Area is evaluated not the intensity

  12. INFLAMMATION IN AREAS OF SCARRING

  13. IMPLICATIONS OF LESION SCORING IN AREAS WITH FIBROSIS • DeKAF study 265 bx from 7 centers (7.5+/-6.1 y) • 72% biopsies had tatr scores>0(conventional t = 0) • 50% had iatr scores >0 (conventional i = 0) • Inclusion of modified scores in data analyses yielded prognostic information Matas et al. Am J Transplant 2010: 10: 315

  14. GRADING OF TUBULITIS • Define area of maximal involvement • Avoid tubules cut tangentially • Grades 0-3 (0, 1-4, 5-10, >10) • Look for disrupted tubules (2 foci, i2, i3) • Atrophic tubules historically ignored • Do not overlook non-atrophic areas or lymphocytes with blast transformation

  15. GRADING OF INTIMAL ARTERITIS • Look closely if interstitial hemorrhage, glomerulitis, or PTC inflammation • Caveat added to report if < 4 arteries • Grade v1 (<25%) (mild to moderate) • Grade v2 (>25%) (severe) • Grade v3 fibrinoid change, necrosis, transmural i (transmural intimal arteritis)

  16. GRADING OF TCMR IN BANFF SCHEMA • Borderline: criteria higher grade not met • Type IA: t2 (i2 or i3) • Type 1B: t3 (i2 or i3) • Type IIA: v1 (any i or t score) • Type II B: v2 • Type III: transmural inflam/fibrinoid • PTC C4d indicates concurrent AMR

  17. BORDERLINE CHANGES SUSPICIOUS FOR ACUTE REJECTION • Looks like rejection but criteria I, II not met • i1 with any t grade OR t1 with any i • Most often t1 tubulitis and i1 inflammation • For biopsies with i2,3 look for t2,t3,v1 • Theoretically i1,t2,t3 & i2,i3,t1 allowed • Some cases evolving or treated higher AR

  18. SHOULD BIOPSIES WITH BORDERLINE CHANGES BE TREATED AS REJECTION? • Scheweitzer et al. 58% CR, 30% PR • Saad et al. 63% CR, 13% PR • Dooper et al. 24% definite rejection • Gaber et al. 8/8 (100%) CR

  19. REASONS FOR HETEROGENEITY IN RESPONSE TO TREATMENT • Borderline changes SUSPICIOUS for AR • Non responsive cases may be non-immune (dehydration, ATN, CNI, infection) • AMR, underlying CR • Responsive cases may be early stage TCMR • Examples of sampling error where biopsy did not sample more significant i or t lesions

  20. TYPE 1A

  21. Type 1B

  22. INTIMAL ARTERITIS NOT ALWAYS TCMR • 56% had donor specific antibodies • 33% had PTC C4d diffuse or focal Can be pure AMR, pure TCMR, or mixed AMR-TCMR Sis et al 2010. Am J Transplantation 10: 421

  23. GRADING OF ACUTE REJECTION IS IMPORTANT FOR PROGNOSIS • Banff 1 = 93% CR, 5 yr GS 67% • Banff 2 = 79% CR, 5 yr GS 56% • Banff 3 = 47% CR, 5 yr GS 32%

  24. HISTOLOGIC GRADING OF INDIVIDUAL LESIONS

  25. IMMUNOHISTOCHEMICAL STUDIES IN ACUTE REJECTION • Not necessary for Dx (except C4d) • May occasionally help d/d PTLD vs AR • Intraglomerular CD68 worse prognosis • CD20 not correlation AMR or response • CD4/CD8/CD68: stage of evolution, patient selection, immunosuppression.

  26. MOLECULAR DIAGNOSIS TCMR • MDx potentially valuable non-invasive tool • Dx TCMR:sensitivity & specificities of 70-90% • Disagreements in an average of 20% • Reflect sampling issues, arbitrary grading thresholds & low frequency diagnoses • Provides information that is complementary

  27. . • ACUTE TUBULAR NECROSIS • ACUTE TUBULAR INJURY • ACUTE KIDNEY INJURY

  28. CALCINEURIN INHIBITOR TOXICITY • Cyclosporine • Tacrolimus

  29. CALCINEURIN INHIBITOR CAN CAUSE FUNCTIONAL TOXICITY • Elevation in serum creatinine • Blood levels Tac/Csa may be elevated • Biopsy shows no specific pathology • Reduction of dosage restores serum creat • Graft dysfunction attributed to vasospasm

  30. CALCINEURIN INHIBITORS CAN CONTRIBUTE TO ATI • CNI induced AKI confirmed in animals • Clinically, prolonged cases of DGF can recover once calcineurin inhibitors switched • Likely mechanism is reversal of drug induced vasoconstriction

  31. TUBULAR VACUOLIZATION IS NOT SPECIFIC FOR CNI • Use of plasma expanders (dextran, mannitol), radiocontrast media, IVIG preps containing sucrose as a stabilizer, hyperosmolar sucrose infusions • Frequently seen in context of ACR • Occurs in donor biopsies • Patients maintained on Azathioprine • Attributed to CNI by exclusion

  32. OTHER CAUSES OF MYOCYTE VACUOLIZATION • Amphotericin B therapy • Use of vasopressors • Injury secondary to cholesterol emboli • Acute cellular rejection with intimal arteritis

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