In Press, 1995, Transplantation Proceedings copyright by Appleton and Lange.

Glomerulosclerosis in Kidney Transplants: Pathophysiologic Mechanisms

L.C. Paul, J. Muralidharan, and H. Benediktsson

University of Toronto at St Michael's Hospital, Toronto and University of Calgary, Calgary.

 

Correspondence to:	L.C. Paul
			Division of Nephrology
			St Michael's Hospital
			30 Bond Street
			Toronto, Ontario M5B 1W8

Key Words: glomerulosclerosis; glomerular capillary pressure; anti-mesangial cell antibodies

 


With the introduction of powerful immunosuppressive drugs, the focus in clinical renal transplantation has shifted from improvement in the 1-year graft survival rate to prevention of late graft attrition. Elucidation of the mechanism(s) leading to late graft failure is needed to design the proper strategies to improve the long-term outcome. Several clinical studies have emphasized the correlation between acute rejection episodes and late graft dysfunction or chronic rejection but it is unknown whether these entities are causally related.

Proteinuria, the clinical hallmark of glomerular pathology, correlates with an adverse long-term prognosis [1]. The glomeruli in grafts with chronic dysfunction may show a variety of abnormalities, including wrinkling and collapse of the glomerular tuft [2], glomerular hypertrophy [3], mesangial matrix expansion with partial or complete collapse of the tuft, or focal glomerulosclerosis [4]. Although some of these lesions may result from recurrent or de-novo glomerulonephritis or from graft ischemia or cyclosporin exposure, most glomerular lesions seem related to chronic rejection. Hamburger et al were the first to describe rejection glomerulonephritis [5], a lesion characteristic of chronic rejection, that has also been named transplant glomerulopathy [6]. The early lesions are characterized by enlargement of the glomeruli, hypercellularity, mesangiolysis with widening of subendothelial zones and interposition of mesangial matrix and cells. Immunofluorescence staining show in most cases nonspecific segmental deposits of IgM and fibrin, sometimes associated with trace amounts of C3 albeit that some cases have transient linear deposits of IgG along the glomerular basement membrane (GBM) [7]. Immunohistochemistry with antibodies against extra-cellular matrix proteins has shown peripheral glomerular expansion of collagen type IV and fibronectin [8].

The pathophysiology of transplant glomerulopathy has remained elusive. We have recently demonstrated in rats the presence of antibodies against donor type glomerular basement membranes [9] and glomerular hypertension [10] in grafts with chronic rejection but the pathogenetic significance of these findings is unknown. Current experiments were designed to test the hypothesis that lowering of the intraglomerular pressure has a beneficial effect on the graft glomerular structure and function in chronic rejection.

 

Materials and Methods

F344 kidneys were transplanted into bilaterally-nephrectomized LEW recipients that were otherwise untreated (I) or received antihypertensive drug regimens consisting of (II) the combination of 0.5 mg/kg/day of reserpine, 8.0 mg/kg/ day of hydralazine, and 2.5 mg/kg/day of hydrochlorothiazide, (III) 20 mg/kg/day of the angiotensin-converting enzyme inhibitor cilazapril, or (IV) 3 mg/kg/day of the nonpeptide angiotensin II receptor antagonist L-158,809. Grafts were removed on day 50 for histological studies; sections were examined and scored semiquantitatively on a scale of 0-3 for interstitial inflammation, interstitial giant cells, tubulitis, tubular atrophy, vasculitis, arterial intima fibroplasia, glomerulitis, mesangiolysis and glomerulosclerosis. The data were analyzed using the Wilcoxon rank sum test; statistical significance was determined by comparing to a table of exact significance levels at a = 0.01.

 

Results and discussion

Treatment with antihypertensive drugs improved the day 50 graft survival rate from 55 % to 90 %, lowered the systemic and glomerular capillary pressure, decreased the amount of proteinuria and tended to improve graft function , compared with animals that did not receive anti-hypertensive medication (data not shown). Histopathological assessment of grafts removed from untreated recipient animals showed interstitial inflammation, tubulitis, tubular atrophy, a mild degree of vasculitis and arterial intima fibroplasia, glomerulitis, mesangiolysis [ Figure 1] and glomerulosclerosis. Treatment with triple therapy (group II) did not prevent any of the extra-glomerular lesions but ameliorated the glomerulosclerosis (a=0.005). Treatment with cilazapril (group III) or L-158,809 (group IV) showed more robust protection against mesangiolysis and glomerulosclerosis (a=0.001) while L158,809 treatment also inhibited graft atherosclerosis (a=0.001). None of these drugs prevented the tubulointerstitial manifestations of chronic rejection.

These data, as well as recent data from other investigators [11], are consistent with the hypothesis that glomerular hypertension is an important determinant of post-transplant glomerulosclerosis, which in turn seems closely associated with graft prognosis. Glomerular hypertension emerges as a result of loss of auto-regulatory capacity of the afferent arteriole in conjunction with glomerular hyperfiltration, as observed after loss of renal mass. However, the extent of graft glomerulosclerosis 4 or 8 weeks after transplantation of F344 kidneys into LEW recipients is more extensive than found 12 to 16 weeks after straightforward renal ablation, suggesting that glomerular hypertension alone cannot explain allograft glomerulosclerosis [10]. Consistent with this hypothesis is the observation that the degree of glomerulosclerosis observed in syngeneic F344 grafts is far less than in F344 grafts removed from allogeneic LEW recipients although syngeneic F344 grafts are also exposed to glomerular hypertension [10]. We recently found alloantibodies against cell surface antigens of cultured mesangial cells in LEW rats after transplantation of a F344 kidney [12]. Studies in the Thy-1.1 model of mesangial-proliferative glomerulonephritis in rats has shown that antibodies against mesangial cell surface antigens can produce many of the glomerular features of transplant glomerulopathy such as mesangiolysis, influx of mononuclear cells and glomerulosclerosis. The combination of immune reactivity against allogeneic determinants of glomerular mesangial cells, glomerular extracellular matrix proteins, and glomerular hypertension, possibly in conjunction with other factors such as hyperlipidemia, may lead to the tissue remodelling characteristic of transplant glomerulopathy and chronic rejection [13].

 

Literature cited

  1. Michielsen P, Vanrenterghem Y. Transplant Proc. 25, 2087,1993.

     

  2. Merrill JP. Transplant Proc. 1, 994,1969.

     

  3. Barrientos A, Portoles J, Herrero JA, et al. Transplantation. 57, 753,1994.

     

  4. Cheigh JS, Mouradian J, Soliman M, et al. Am J Kidney Dis. 2, 449,1983.

     

  5. Hamburger J, Crosnier J, Dormont JA. Ann N Y Acad Sci. 120, 558,1964.

     

  6. Zollinger HU, Moppert J, Thiel G, et al. Curr Top Pathol. 57, 1,1973.

     

  7. Habib R, Antigua C, Hinglais N, et al. Am J Kidney Dis. 10, 198,1987.

     

  8. Habib R, Zurowska A, Hinglais N, et al. Kidney Int. 44 (Suppl. 42), S104,1993.

     

  9. De Heer E, Davidoff A, Van der Wal A, et al. Lab Invest. 70, 494,1994.

     

  10. Kingma I, Chea R, Davidoff A, et al. Transplantation. 56, 53,1993.

     

  11. Mackenzie HS, Tullius SG, Heemann UW, et al. J Clin Invest. 94, 2148,1994.

     

  12. Paul LC, Manting EH, Muzaffar SA. 14 th Am Soc Transpl Physicians meeting. Chicago, Abstr 173,1995. (Abstract)

     

  13. Paul LC. Kidney Int. 47, 1491,1995.

 


Figure legend

(These figures are not available on our WWW server, however they will be available on our Banff Conference CD-ROM.)

Figure 1. Photomicrograph of a F344 glomerulus removed from a LEW recipient on day 50 after transplantation. There is mesangiolysis affecting a segment of the glomerulus. PAS x 200.

 


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