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 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;348:101-108

Ng

Vg

T Renal adaptation after transplantation he kidney and the host

Renal adaptation

AlloimmunityNephrotoxicity

Renal quality IS

Baseline glomerular size as a predictor SCr

glomerular MPA , n=96, follow up 7.52.5

Abdi R et al, Transplantation 1998; 66: 329

Time r2

________________6m 0.231y 0.422y 0.273y 0.344y 0.35________________

Donor Vg and CrClJune 2000-Dec 2001, N = 77 (10 glom, 1 art)

0

20

40

60

80

100

120

140

0 2 4 6 8 10 12 14

Vg (um3 x 106)

CrCl (mL/min)

R=0.30P=0.010

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

Vcortex MRI

Vvglom/cortex Vg Biopsy

Fulladosa X et al J Am Soc Nephrol 2003 ; 14: 2662

Vren and Vcortex by means of a MRI

Volumen renal VrenVolumen cortical Vcort

Vglom/cortex y Vg

Fulladosa X et al J Am Soc Nephrol 2003

Estimación del número de

Vcortex * Vvglom/cortex Ng = __________________

Vg

Characteristics of patientsSCr < 200 mmol/l and proteinuria < 1g/24h

4m protocol biopsy (n=39)Mean SD ______________________________________ N 39 Donor age 38 18Donor sex (male / female) 26 / 13Recipient age 46 14Recipient sex (male / female) 24 / 15Recipient BSAa (sqm) 1.74 0.19Cold ischemia time (hours) 20 5 Delayed graft function (no / yes) 37 / 2Serum Creatinine (mol/l) 12330Proteinuria g/day 0.38 0.47______________________________________

Fulladosa X et al J Am Soc Nephrol 2003; 14: 2662

Donor age and Vg & Ng

Relationship between Ng and GFR

0

20

40

60

80

100

120

0 0.4 0.8 1.2 1.6

Ng-W&G (x 106)6

GFR

(m

l/m

in)

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 biopsyVg

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 NScg 0.100.30 0.15 0.36 NSci 0.190.45 0.49 0.64 0.0006ct 0.15 0.42 0.49 0.67 0.0002cv 0.02 0.16 0.19 0.60 0.087Vg 4.1 1.4 5.1 2.40.021_______________________________________________

Alperovich G et al, AJT 2004; 4 : 650

De que depende

el crecimiento glomerular

postrasplante?

Donor Vg and Vg

-7

-5

-3

-1

1

3

5

7

1 2 3 4 5 6 7 8 9

VgR - VgD x1063

VgDx1063R=0.3, p=0.04

Glomerular enlargement and CAN

- 0,5

0

0,5

1

1,5

2

No CAN CAN

Delta Vg

n=27 n=14

p=0.017

Vg & CrCl at 4mCrCl ml/min

Vg (x1063)

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

0

50

100

150

200

250

Donor

Bx

no FGS

<2y

FGS

<2y

no FGS

>2y

FGS

>2y

Glom diameterm

18 10 13 7 7

*

Bathena. JASN 1993; 4: 1316

Epidemiological paradox

Vg

FG GS

GS GS

¿GS?

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

Vg n=144 patients, protocol biopsy at 4m

Donor age r=0.23DGF p=0.01BMI r=0.17CsA r=-0.18

CrCl r=0.17

Vg and graft survivalBest cut-off of Vg

4.04.55.05.56.0

(x1063)

RR 2.4, CI 1.03-5.6

CrCl and graft survivalBest cut-off of CrCl

50556065

(ml/min)

RR 3.3, CI 1.04-11.9

Vg, CrCl and Graft Survivaln=144 patients protocol biopsy at 4m

Multivariate analysis

adjusting for donor age, acute rejection, CAN

RR IC___________________________Vg >5 x 1063 3.3 1.4-8.0

CrCl <60 ml/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, CrCl, GS

Vg > 5 & GFR > 60 GS 73%

Vg < 5 & GFR > 60 GS 95%

Vg > 5 & GFR < 60 GS 45%

Vg < 5 & GFR < 60 GS 78%

Time (months)0

,2

,4

,6

,8

1

0 25 50 75 100 125 150 175 200

Conclusion

Vga surrogate of nephron number

an independent predictor of graft survival

AcknoledgementsFrancesc MoresoXavier FulladosaGabriela AlperovichFabio AzevedoJosé Antonio LopesMeritxell IbernonMontserrat GomàMarta CarreraMiguel HuesoJosep Maria CruzadoSalvador Gil-VernetJosep Maria Grinyó