Glomerular hypertension—an under-appreciated aspect of chronic rejection

Leendert C. Paul

Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands

Introduction

Loss of renal mass results in an increase in renal blood flow and single-nephron glomerular filtration rate in the remaining renal tissue. Increased flow rates are accomplished through dilatation of the afferent and efferent arterioles. The former dilate more than the latter, however. This causes an increase in glomerular capillary hydrostatic pressure (PGC). Although this response is apparently beneficial to maintain homeostasis despite reduction in renal mass, a large body of evidence suggests that sustained elevated PGC ultimately results in proteinuria, glomerulosclerosis, and further loss of nephrons [1]. In clinical transplantation, most patients receive only one donor kidney that often has incurred injury during the agonal phase of the donor, the anoxic storage period, and after implantation. These multiple insults result in further reduction of renal mass and in elevation of single-nephron glomerular filtration and PGC, which in turn may contribute to graft failure. This editorial comment addresses the role of haemodynamic injury in kidney transplants.

Glomerular hypertension and chronic rejection: clinical studies

Glomerular pressure cannot be measured directly in human kidneys so its presence has to be deduced from other observations. An analysis of registry data has shown that the 3-year graft survival rate of transplants that came from female, black, very young, or very old donors is less than that of transplants from donors supposedly endowed with a larger nephron mass [2]. These observations are consistent with the presence of glomerular hypertension in grafts with presumed small functional renal mass. Studies that examined more directly the relationship of nephron mass, presumed recipient metabolic needs, and long-term outcome have reported inconsistent results, in part because of difficulties in assessing nephron mass. There is consensus, however, that a high recipient body weight is associated with shortened graft survival [35].

Dietary protein restriction in patients with chronic rejection results in rapid improvement of graft glomerular permselectivity characteristics without changes in systemic blood pressure, glomerular filtration rate, or renal plasma flow [6]. These observations are best explained by a reduction in PGC, induced by the low-protein diet as demonstrated in experimental animals [7]. Finally, comparison of glomerular surface areas in kidneys with or without chronic rejection have shown a skewed size distribution in chronic rejection towards higher glomerular sizes [8], a morphological feature consistent with glomerular hypertension. An argument against the presence of significant glomerular hypertension, however, is the observation that the histopathology of transplants with chronic rejection does not resemble the lesions induced by hyperfiltration and glomerular hypertension in native kidneys, i.e. focal segmental glomerulosclerosis.

Glomerular hypertension and chronic rejection: experimental studies

The F344 to LEW rat kidney transplant model has been used extensively to study chronic renal allograft rejection experimentally. Transplantation of a F344 kidney into a non-immunosuppressed LEW recipient results in an acute rejection episode and recipient death within two months in 50% of animals, whereas chronic rejection develops in the remaining ones. In the reverse combination, a LEW kidney transplanted into a F344 recipient, acute rejection also emerges but this reverses without developing into chronic rejection [9].

We measured the PGC in intact F344 and LEW rats, after subtotal renal ablation, and after transplantation [10]. Intact F344 rats had significantly higher PGC than intact LEW rats; following renal ablation, the PGC in remnant LEW kidneys remained unchanged but increased significantly in F344 kidneys. Transplantation of a LEW kidney into a bilaterally nephrectomized LEW or F344 recipient resulted in a slight but significant increase in PGC, which remained lower than in intact F344 rats. On the other hand, transplantation of a F344 kidney into either a syngeneic or an allogeneic recipient resulted in a significant increase in PGC [10], as also shown by others [11,12]. Thus, the PGC in transplanted kidneys resembles the PGC of the donor kidney after subtotal renal ablation. Because a F344 kidney transplanted into a syngeneic recipient develops glomerular hypertension but no chronic rejection, glomerular hypertension per se does not cause chronic rejection.

Interventions to lower the glomerular hydrostatic pressure

To further examine the role of the PGC in chronic rejection, we treated recipient animals prophylactically with either the immunosuppressive drug cyclosporin A (CsA) or various antihypertensive drugs such as the combination of hydralazine, reserpine, and hydrochlorothiazide, the long-acting ACE inhibitor cilazapril, or the angiotensin II receptor antagonist L-158,809 [9]. All treatment modalities resulted in lowering of PGC, systemic blood pressure, and proteinuria, a tendency towards improvement of function, and a significant improvement in survival. Histologically, CsA prevented all manifestations of acute or chronic rejection, whereas the antihypertensive drugs prevented the development of glomerulosclerosis but did not inhibit tissue inflammation. The ACE inhibitor and the AT2 receptor blocker also inhibited mesangiolysis, tubular atrophy and vascular fibro-intimal hyperplasia, although these effects were not as robust as the inhibition of the mesangiosclerosis.

The question is whether the protection related to anti-hypertensive treatment is caused by lowering the PGC or by lowering the systemic blood pressure. A renal allograft transplanted in the presence of an intact native kidney is protected from glomerular hypertension and glomerulosclerosis while there are no significant changes in the systemic arterial blood pressure [13]. The calcium channel blocker lacidipine, on the other hand, has no effect on proteinuria or survival, despite its beneficial effect on the systemic blood pressure [14]. Similarly inconsistent results of calcium-channel blockers with respect to lowering PGC and preventing glomerulosclerosis have also been noted in models where renal failure concerns the native kidneys. Thus it seems that the beneficial effect of anti-hypertensive medication results from lowering of the PGC rather than from their effect on the systemic blood pressure.

Beneficial effects of ACE inhibitors and AT2 receptor blockers on chronic renal allograft rejection have been reported by us and by others [1416]. In addition to their haemodynamic effects, these drugs decrease the glomerular permeability for macromolecules and favourably modulate the post-transplant immunological, inflammatory, and fibrous tissue reactions that play a role in chronic rejection [1719].

Conclusion

Several clinical observations are consistent with the hypothesis that kidneys that undergo chronic rejection are exposed to glomerular hypertension. Experimental studies in rats have provided direct evidence in support of this possibility. The increase in PGC depends on critical reduction of renal mass together with factors intrinsic to the kidney. Although glomerular hypertension also emerges in syngeneic grafts that do not develop chronic rejection, lowering of the graft PGC results in a significant prolongation of graft survival. Whereas chronic rejection depends on immunological reactions to various components of the graft [20], glomerular haemodynamic forces appear to play a role as a progression factor that controls the rate of decline to end-stage renal failure in chronic rejection.

Notes

Correspondence and offprint requests to: L. C. Paul, Department of Nephrology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands. Back

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