Parmjeet Randhawa Professor, Division of Transplantation Department of Pathology - PowerPoint PPT Presentation

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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