Matrix Metalloproteinases & Their Inhibitors: Cadaveric Versus Live Related Allograft Recipients.

A K Ahmed 1*, E Khedr 1, M El Kossi, A M El Nahas 1 and T S Johnson 1.

1 Sheffield Kidney Institute (University of Sheffield), Northern General Hospital, Sheffield, United Kingdom .

Background:

ECM degradation occurs predominantly through the matrix metalloproteinase (MMP) system, which is regulated by Tissue inhibitors of MMP (TIMP). Reduced ECM degradation can lead to ECM accumulation and scarring. We have previously reported reduced MMP and elevated TIMP levels in implantation, acute and chronic rejected biopsies of cadaveric allograft recipients suggesting these changes may have a pre implantation cause. Here we have compared MMP and TIMP levels between cadaveric and live related allograft recipients to determine if pre harvest events or organ preservation is effecting the MMP system.

 

Patients and Methods:

Twenty-six renal biopsies from cadaveric graft recipients and 17 renal biopsies from live related graft recipients were diagnosed and scored to acute and chronic allograft nephropathy. Fourteen biopsies of focal segmental glomerulosclerosis (FSGS) with a similar scarring index were included to control for the effects of cyclosporin on the MMP system. The expression of MMPs 1, 2, 3, & 9 and TIMPs 2 & 3 were localised using immunohistochemistry and evaluated by point counting.

 

Results:

Point count analysis showed levels of all MMPs to be reduced and TIMPs elevated compared to normal sections. These changes were observed in acute and chronic rejection biopsies of both cadaveric and live related donors as well as in the FSGS biopsies. The reduction in MMPs was less in the live related group than the cadaveric groups, but this only reached significance for MMP1 (see table).

 

 

Normal

Acute Cadaveric

Chronic Cadaveric

Acute Live related

Chronic Live related

FSGS

MMP1

44.22 + 2.6%C

3.2 + 2%

5+ 3.2%

50.6+ 9.8%C

10.2+ 9.1%

25.1+ 7.4%

MMP2

68.4 + 3.8%B

32.8+ 5.9%

28.2+ 6.9%

40.7 + 4.1%

35.7 + 8.4%

29.7 + 4.6%

MMP3

44.5 + 9.1%B

17.9+4.5%

32.1+ 6.5 %

40.2 + 12.1%

37.7 + 7.5%

27.6 + 6.6%

MMP9

46.7+12. 5%B

21.8+5.9%

26.7 +7.8 %

35.7 + 12.3%

24.5 + 9.3%

20.3 + 5.6%

TIMP2

14.5+4.3%B

29. +4.6%

33.9+4.13%

38.4+11.4%

25.8+7.8%

34.3+4.5%

TIMP3

23.6+6.7 %A

40.3+5.7%

48.2+6.2%

49.5+5.3%

40.9+4.5%

42.2+4.6%

Data represents mean point count (% points) SEM. A= P<0.05 , B= P<0.01 ,C= P<0.001 from normal.

 

 

Conclusions:

The greater reduction in MMP 1 levels in allografts from a cadaveric donor than a live related donor suggesting that either pre harvest events or cold ischaemia influence MMP 1 expression. This may have implications for ECM processing and scarring in the allograft.