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Biopsias de protocolo:utilidad clínica. RSC & NCT. Diagnóstico precoz Valor predictivo independiente Variable de eficacia en ensayos clínicos. Estructura. Mediadores de lesión. T Renal adaptation after transplantation he kidney and the host.
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Biopsias de protocolo:utilidad clínica RSC & NCT Diagnóstico precoz Valor predictivo independiente Variable de eficacia en ensayos clínicos
Estructura Mediadores de lesión
T Renal adaptation after transplantation he kidney and the host
Glomerular number (Ng)Disector /fraccinator (n=56) 0.23-1.82 x 106 Hughson M et al Kidney Int 2003; 63: 2113
Ng and Vg in humans Ng/Vg/BSA Hoy WE et al, Kidney Int Suppl 2003; 83, S31
Number of Glomeruli per Kidney (Panel A) and Mean Glomerular Volume (Panel B) in 10 Patients with Hypertension and 10 Matched Normotensive Controls Nephron number in patients with primary hypertensionNumber of Glomeruli per Kidney (Panel A) and Mean Glomerular Volume (Panel B) in 10 Patients with Hypertension and 10 Matched Normotensive Controls Keller, G. et al. N Engl J Med 2003;348:101-108
Renal quality Alloimmunity Nephrotoxicity Renal adaptation IS T Renal adaptation after transplantation he kidney and the host Ng Vg
Baseline glomerular size as a predictor SCrglomerular MPA , n=96, follow up 7.52.5 Time r2 ________________ 6m 0.23 1y 0.42 2y 0.27 3y 0.34 4y 0.35 ________________ Abdi R et al, Transplantation 1998; 66: 329
CrCl (mL/min) 140 R=0.30 P=0.010 120 100 80 60 40 20 0 0 2 4 6 8 10 12 14 Vg (um3 x 106) Donor Vg and CrClJune 2000-Dec 2001, N = 77 (10 glom, 1 art) Lopes JA et al. Kidney Int 2005; 67:1595
Integration of macro and microscopic quantitative renal evaluation Morfometry Histology Radiology New parameters
Ng in vivo Vcortex MRI Vvglom/cortex Vg Biopsy Fulladosa X et al J Am Soc Nephrol 2003 ; 14: 2662
Vglom/cortexy Vg Fulladosa X et al J Am Soc Nephrol 2003
Estimación del número de Vcortex * Vvglom/cortexNg = __________________ Vg
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) 12330 Proteinuria g/day 0.38 0.47 ______________________________________ Fulladosa X et al J Am Soc Nephrol 2003; 14: 2662
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
Vg is a subordinate measure of NgNg is a major determinant of FG2GFR = 9 Ng
Glomerular enlargement after transplantation(n=41) Vg Recipient biopsy Donor biopsy 0 4 Alperovich G et al, AJT 2004; 4 : 650
Vg after transplantationVg Donor Biopsy Recipient Biopsy p _______________________________________________ Ah 0.150.42 0.290.56 NS cg 0.100.30 0.15 0.36 NS ci 0.190.45 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
Donor Vg and dVg VgR - VgD x106m3 7 5 3 1 -1 -3 -5 R=0.3, p=0.04 VgDx106m3 -7 1 2 3 4 5 6 7 8 9
Glomerular enlargement and CAN p=0.017 n=27 n=14
Vg & CrCl at 4m CrCl ml/min R=0.38, p=0.01 Vg (x1063) Alperovich G et al, AJT 2004; 4 : 650
Glomerular enlargement is a necessary condition to achieve an adequate renal function
mm * 18 10 13 7 7 Glom size and FGS in renal allografts Bathena. JASN 1993; 4: 1316
FG GS ¿GS? GS GS Vg
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) Azevedo F et al AJT in press
Vgn=144 patients, protocol biopsy at 4m Donor age r=0.23 DGF p=0.01 BMI r=0.17 CsA r=-0.18 CrCl r=0.17
Vg and graft survivalBest cut-off of Vg 4.0 4.5 5.0 5.5 6.0 (x1063) RR 2.4, CI 1.03-5.6
CrCl and graft survivalBest cut-off of CrCl 50 55 60 65 (ml/min) RR 3.3, CI 1.04-11.9
Vg, CrCl and Graft Survivaln=144 patients protocol biopsy at 4mMultivariate analysisadjusting for donor age, acute rejection, CAN RR IC ___________________________ Vg >5 x 1063 3.3 1.4-8.0 CrCl <60ml/min/1.73m2 4.9 1.4-17.0 ___________________________
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%)
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, CrCl, GS 1 ,8 ,6 ,4 ,2 0 Time (months) 0 25 50 75 100 125 150 175 200
Conclusion Vg a surrogate of nephron number an independent predictor of graft survival
Acknoledgements Francesc Moreso Xavier Fulladosa Gabriela Alperovich Fabio Azevedo José Antonio Lopes Meritxell Ibernon Montserrat Gomà Marta Carrera Miguel Hueso Josep Maria Cruzado Salvador Gil-Vernet Josep Maria Grinyó