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Utility of morphometry in the study of donor and protocol biopsies

This study explores the utility of morphometry in donor and protocol biopsies, discussing its advantages, disadvantages, and when it is redundant, useful, or necessary. Topics covered include glomerular adaptation after renal transplantation and potential applications in clinical trials.

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Utility of morphometry in the study of donor and protocol biopsies

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  1. Utility of morphometry in the study of donor and protocol biopsies D. Serón Servicio de Nefrología Hospital Bellvitge Barcelona

  2. Morphometry Disadvantages Advantages

  3. When is morphometry redundant?When may it be useful?When is it necessary?

  4. Topics Redundant Morphometry applied to the study of donor biopsies Potential utility Mophometric evaluation of protocol biopsies in clinical trials Necessary Glomerular adaptation after renal transplantation

  5. Topics Redundant Morphometry applied to the study of donor biopsies Potential utility Mophometric evaluation of protocol biopsies in clinical trials Necessary Glomerular adaptation after renal transplantation

  6. Preexisting donor damage and outcome year parameter ____________________________________________________________ Leunissen Transplantation 1989 sum of scores Serón NDT 1993 Vvint/cortex Wang NDT 1998 ah, GS Gaber L Transplantation 1995 % GS Abdi R Transplantation 1998 glomerular size Karpinski Transplantation 1999 donor vasculopathy Parmjeet R Transplantation 2000 ci, GS Escofet X Transplantation 2003 GS _________________________________

  7. Is there any advantage in the morphometric evaluation of donor biopsies?

  8. Evaluation of donor biopsies(June 2000-Dec 2001, N = 77 (10 glom, 1 art) Banff criteria cg ci ct cv ah mm Quantitative parameters % glomerulosclerosis Vvint/c (%) Vvglom/c (%) Vg x 106m3 Vvintima/artery Lopes JA et al. Kidney Int 2005; 67: 1595

  9. CrCl at 3 m (mL/min) 140 R=0.52 P<0.001 120 100 80 60 40 20 0 -5 0 5 10 15 20 25 30 35 40 45 50 Glomerulosclerosis (%) Results (1)

  10. CrCl at 3 m (mL/min) CrCl at 3 m (mL/min) 140 140 Rho = 0.38 P = 0.0014 Rho = 0.41 P = 0.005 120 120 100 100 80 80 60 60 40 40 20 20 0 0 -,25 0 1 2 0 1 2 ct ci CrCl at 3 m (mL/min) CrCl at 3 m (mL/min) 140 140 Rho = 0.48 P < 0.001 Rho = 0.51 P < 0.001 120 120 100 100 80 80 60 60 40 40 20 20 0 0 0 1 2 0 1 2 3 4 5 6 cv ci+ct+cv Results (2)

  11. CrCl at 3m (mL/min) CrCl at 3m (mL/min) CrCl at 3 m (mL/min) 140 140 140 R=0.26 P=0.021 R=0.57 P<0.001 R=0.30 P=0.010 120 120 120 100 100 100 80 80 80 60 60 60 40 40 40 20 20 20 0 0 0 0 5 10 15 20 25 30 5 10 15 20 25 30 35 0 2 4 6 8 10 12 14 Vvint/cortex (%) Vvintima/art (%) Vg (um3 x 106) Results (3)

  12. All variables _____________________ 1. Vvint/cortex R=0.57 2. Glomerulosclerosis R=0.62 _____________________ Not including morphometric variables ______________________ 1. Glomerulosclerosis R=0.52 2. cv R=0.60 3. ci R=0.64 ______________________ Results (4) Multivariate analysis: histologic lesions and 3m CrCl

  13. Conclusions Morphometric evaluation of donor biopsies does not improve the prediction of outcome

  14. Topics Redundant Morphometry applied to the study of donor biopsies Potential utility Mophometric evaluation of protocol biopsies in clinical trials Necessary Glomerular adaptation after renal transplantation

  15. CAN and sequential protocol biopsies Donor biopsies 15% 4th month protocol bx 42 % 1st year protocol bx 52% % CAN 50 25 0 0 3 6 9 12 m

  16. Prevention trial and protocol biopsies Donor Bx Protocol Bx Fibrosis CAN cv Vvinterstitium/c Vvintima/artery placebo treatment 0 1 2 3 4 5 6 m

  17. Minimum sample size (50% reduction)(=0.05, =0.20) Variable Patients per group ____________________________________ CAN 300 Transplant vasc (cv) 1200 Vvint/cortex63 Vvintima/artery49 ____________________________________ Serón, Transplantation 2000; 69(9): 1849 Moreso et al. Am J Transplantation 2001; 1(1): 82

  18. Conclusions Morphometric evaluation of protocol biopsies in trials aimed to prevent CAN may allow to reduce minimum sample size

  19. Topics Redundant Morphometry applied to the study of donor biopsies Potential utility Mophometric evaluation of protocol biopsies in clinical trials Necessary Glomerular adaptation after renal transplantation

  20. Glomerular number (Ng)Disector /fraccionator (n=56) 0.23-1.82 x 106 Hughson M et al Kidney Int 2003; 63: 2113

  21. Ng and Vg in humans Ng/Vg/BSA Hoy WE et al, Kidney Int Suppl 2003; 83, S31

  22. Renal adaptation after transplantation Ng Vg adaptation

  23. Ng Morfometry Histology Radiology New parameters

  24. Ng in vivo Vcortex MRI Vvglom/cortex Vg Biopsy Fulladosa X et al J Am Soc Nephrol 2003 ; 14: 2662

  25. Vren and Vcortex by means of a MRI

  26. Volumen renal VrenVolumen cortical Vcort

  27. Vglom/cortexy Vg Fulladosa X et al J Am Soc Nephrol 2003

  28. Estimación del número de Vcortex * Vvglom/cortexNg = __________________ Vg

  29. Characteristics of patientsSCr < 200 mmol/l and proteinuria < 1g/24h4m protocol biopsy (n=39) Mean  SD ______________________________________ N 39 Donor age 38 18 Donor sex (male / female) 26 / 13 Recipient age 46 14 Recipient sex (male / female) 24 / 15 Recipient BSAa (sqm) 1.74  0.19 Cold ischemia time (hours) 20  5 Delayed graft function (no / yes) 37 / 2 Serum Creatinine (mol/l) 12330 Proteinuria g/day 0.38  0.47 ______________________________________ Fulladosa X et al J Am Soc Nephrol 2003; 14: 2662

  30. 120 100 80 GFR (ml/min) 60 40 20 0 0 0.4 0.8 1.2 1.6 6 Ng-W&G (x 106) Relationship between Ng and GFR Fulladosa X et al J Am Soc Nephrol 2003; 51: 310

  31. Ng is a major determinant of GFR2GFR = 9 Ng

  32. Glomerular enlargement after transplantation(n=41) Vg Recipient biopsy Donor biopsy 0 4 Alperovich G et al, AJT 2004; 4 : 650

  33. Vg after transplantationVg Donor Biopsy Recipient Biopsy p _______________________________________________ Ah 0.150.42 0.290.56 NS cg 0.100.30 0.15 0.36 NS ci 0.190.45 0.49 0.64 0.0006 ct 0.15 0.42 0.49  0.67 0.0002 cv 0.02 0.16 0.19 0.60 0.087 Vg 4.1 1.4 5.1 2.4 0.021 _______________________________________________ Alperovich G et al, AJT 2004; 4 : 650

  34. Vg y FG a los 4m CrClml/min R=0.38, p=0.01 Vg (x1063) Alperovich G et al, AJT 2004; 4 : 650

  35. Glomerular enlargement may be a necessary condition to achieve a good renal function

  36. Epidemiological paradox

  37. ¿Graft Survival? GFR Graft Survival  Vg Graft Survival Glomerulosclerosis

  38. Vg, GFR and graft survivaln=144 patients, protocol biopsy at 4m Donor age (years) 37  16 (12 – 76) Donor gender (male/female) 101 / 43 Patient age (years) 47  13 (15 – 72) Patient gender (male/female) 95 / 49 Panel reactive antibodies (%) 7  18 (0 – 100) DR mismatches 0.6  0.6 (0 – 2) Cold ischemia time (hours) 22  5 (7 – 38) Delayed graft function (no/yes) 121 / 23 Acute rejection (no/yes) 114 / 30 Time of protocol biopsy (days) 125  52 (25 – 261) Serum creatinine (mol/l) 140  44 (72– 298) Proteinuria (g/day) 0.34  0.28 (0.03 – 1.00)

  39. Vg, FG y Sup injn=144 patients protocol biopsy at 4m RR IC p ________________________________ Vg > 5 x 1063 2.4 1.0-5.6 0.04 CrCl <60ml/min 3.5 1.0-11.9 0.04 ________________________________

  40. Vg, CrCl and Graft survivaln=144 biopsia de protocolo 6m > 10 glom  60ml/min/1.73m2 < 60 ml/min/1.73m2 High Low CrCl (Cockroft & Gault  5 x 1063 < 5 x 1063 Large Small Vg (Weibel & Gomez)

  41. Vg < 5 & GFR > 60 GS 95% Vg < 5 & GFR < 60 GS 78% Vg > 5 & GFR > 60 GS 73% Vg > 5 & GFR < 60 GS 45% Vg, FG, GS Cum. Survival 1 ,8 ,6 ,4 ,2 0 Time (months) 0 25 50 75 100 125 150 175 200

  42. Conclusion Glomerular volume and renal function are independent predictors of graft survival

  43. Summary

  44. Acknoledgements Francesc Moreso Xavier Fulladosa Miguel Hueso José Antonio Lopes Meritxell Ibernon Gabriela Alperovich Montserrat Gomà Marta Carrera Josep Maria Cruzado Salvador Gil-Vernet Josep Maria Grinyó

  45. Vg small CrCl high n=24 (17%) Vg small CrCl low n=60 (42%) Vg large CrCl high n=20 (20%) Vg large CrCl low n=31 (21%)

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