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) x 10 6 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 hypertension Number 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:

Ng Vg T Renal adaptation after transplantation he kidney and the host Renal adaptation Alloimmunity Nephrotoxicity Renal quality IS

Baseline glomerular size as a predictor SCr glomerular MPA, n=96, follow up Abdi R et al, Transplantation 1998; 66: 329 Timer 2 ________________ 6m0.23 1y0.42 2y0.27 3y0.34 4y0.35 ________________

Donor Vg and CrCl June 2000-Dec 2001, N = 77 ( 10 glom, 1 art) Lopes JA et al. Kidney Int 2005; 67: 1595

Estimating Ng in vivo

Integration of macro and microscopic quantitative renal evaluation Radiology Histology Morfometry New parameters

Ng in vivo V cortex MRI V vglom/cortex Vg Biopsy Fulladosa X et al J Am Soc Nephrol 2003 ; 14: 2662

Vren and Vcortex by means of a MRI

Volumen renal Vren Volumen cortical Vcort

V glom/cortex y Vg Fulladosa X et al J Am Soc Nephrol 2003

Estimación del número de V cortex * V vglom/cortex Ng =__________________ Vg

Characteristics of patients SCr < 200 mmol/l and proteinuria < 1g/24h 4m protocol biopsy (n=39) Mean SD ______________________________________ N39 Donor age38 18 Donor sex (male / female)26 / 13 Recipient age46 14 Recipient sex (male / female)24 / 15 Recipient BSA a (sqm) Cold ischemia time (hours)20 5 Delayed graft function (no / yes)37 / 2 Serum Creatinine ( mol/l) Proteinuria g/day ______________________________________ Fulladosa X et al J Am Soc Nephrol 2003; 14: 2662

Donor age and Vg & Ng

Relationship between Ng and GFR Fulladosa X et al J Am Soc Nephrol 2003; 51: 310

Vg is a subordinate measure of Ng Ng is a major determinant of FG 2GFR = 9 Ng

¿Cómo se adaptan los glomérulos post TR?

Glomerular enlargement after transplantation (n=41) Donor biopsy Recipient biopsy Vg 04 Alperovich G et al, AJT 2004; 4 : 650

Vg after transplantation Vg Donor BiopsyRecipient Biopsyp _______________________________________________ Ah NS cg NS ci ct cv Vg _______________________________________________ Alperovich G et al, AJT 2004; 4 : 650

De que depende el crecimiento glomerular postrasplante?

Donor Vg and Vg VgR - VgD x VgDx R=0.3, p=0.04

Glomerular enlargement and CAN n=27 n=14 p=0.017

Vg & CrCl at 4m CrCl ml/min Vg (x ) Alperovich G et al, AJT 2004; 4 : 650 R=0.38, p=0.01

Glomerular enlargement is a necessary condition to achieve an adequate renal function

Glom size and FGS in renal allografts m * Bathena. JASN 1993; 4: 1316

Epidemiological paradox

Vg FG GS ¿GS?

Vg, GFR and graft survival n=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 – 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) (0.03 – 1.00) Azevedo F et al AJT in press

Vg n=144 patients, protocol biopsy at 4m Donor ager=0.23 DGFp=0.01 BMIr=0.17 CsAr=-0.18 CrClr=0.17

Vg and graft survival Best cut-off of Vg (x ) RR 2.4, CI

CrCl and graft survival Best cut-off of CrCl (ml/min) RR 3.3, CI

Vg, CrCl and Graft Survival n=144 patients protocol biopsy at 4m Multivariate analysis adjusting for donor age, acute rejection, CAN RR IC ___________________________ Vg >5 x CrCl <60 ml/min/1.73m ___________________________

Vg small CrCl highn=24(17%) Vg small CrCl lown=60(42%) Vg large CrCl highn=20(20%) Vg large CrCl lown=31(21%)

Vg, CrCl, GS Vg > 5 & GFR > 60 GS 73% Vg 60GS 95% Vg > 5 & GFR < 60GS 45% Vg < 5 & GFR < 60GS 78% Time (months) 0,2,4,6,

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