Nephrol Dial Transplant (2000) 15: 8-10
© 2000 European Renal Association-European Dialysis and Transplant Association
Editorial Comments
Hypertension and allograft nephropathy—cause, consequence, or both?
Department of Nephrology and Internal Intensive Care Medicine, Universitätsklinikum Charité, Campus Virchow Klinikum, Humboldt University, Berlin, Germany
Correspondence and offprint requests to: Ralf Schindler, MD, Department of Nephrology, Universitätsklinikum Charité, Campus Virchow Klinikum, Augustenburger Platz 1, D-13353 Berlin, Germany.
Hypertension is a risk factor for chronic allograft nephropathy
Chronic graft loss is one of the biggest problems after renal transplantation. Data from the United States Renal Data System [1] indicate that the projected median half life of renal allografts has been steadily improving over the past years, from 5.2 years in 1986–1987 to 10.2 years in 1994–1995. However, approximately 5% of renal transplants are lost every year. An ill defined entity called chronic rejection or chronic allograft nephropathy (CAN) remains the leading cause of graft loss after the first year of transplantation, particularly if death with a functioning graft is excluded as a cause of late graft failure [2]. Traditionally, the causes of CAN have been divided into alloantigen-dependent (immunological) and alloantigen-independent (non-immunological) factors. The former include MHC-mismatching [3] and acute rejection episodes [4], the latter include hyperfiltration [5], conditions of the brain-death donor [6], and hypertension of the recipient [7]. For many years, it has been known that hypertension is associated with graft failure. Cheigh et al. reported that graft survival was significantly inferior in hypertensive patients [7]. Modena et al. observed an association between systolic and diastolic blood pressure and the rate of deterioration of graft function [8]. Recently, Opelz and colleagues reported a highly significant correlation between post-transplant blood pressure and long-term graft outcome in more than 29000 patients [9].
Hypertension: cause or consequence of chronic allograft nephropathy?
An association between hypertension and deterioration of renal function does not prove a causal relationship. Hypertension after transplantation might simply be the result of a deterioration in graft function rather than vice versa. Retrospective studies [9–11] demonstrating an association between hypertension after transplantation and graft survival, cannot differentiate between cause and effect. The first evidence that hypertension per se may lead to graft damage was the observation that not only hypertension after transplantation, but also hypertension before transplantation is associated with later CAN [12]. Hypertension before transplantation increased the risk for later CAN by a factor of 3.4, the magnitude which was only surpassed by late (>60 days after transplantation) acute rejection episodes, which increased the risk for CAN by 5.5. A possible role of angiotensin-converting enzyme (ACE) gene polymorphism for CAN has been discussed, but the correlation between certain ACE-genotypes and CAN or hypertension was found to be weak in 30 transplant recipients [13]. Studies in animals support the concept of hypertension-induced graft damage. In two different hypertensive animal models (clipped native kidney plus allograft [14] or transplantation into spontaneous hypertensive rats [15]) it was shown that hypertension may aggravate graft damage.
To investigate the mechanisms by which hypertension contributes to CAN, experiments were performed in a model of Fisher to Lewis rat allografts [16]. Rats were either left normotensive, i.e. not treated, or were made hypertensive by treatment with deoxycorticosterone acetate (DOCA) and salt. Proteinuria was measured monthly, grafts were harvested at 3 and 6 months for semi-quantitative RT–PCR for smooth muscle cell-growth factors PDGF and TGF-ß and for immunohistology. Systolic blood pressure was markedly elevated in rats receiving DOCA/salt. Proteinuria was elevated in untreated allografts compared to isografts and was further raised in hypertensive animals. Expression of mRNA for PDGF was higher in allografts than in isografts and was highest in hypertensive animals. Similarly, significantly more tubular cells expressing the `proliferating cell nuclear antigen' as well as more extracellular matrix deposition were observed in hypertensive animals compared to untreated allografts. In addition, increased expression of MHC I and II was observed in hypertensive animals by both immunohistology and RT–PCR. Thus, hypertension may influence the immunogenicity of the graft.
These data indicate that hypertension of the recipient acts together with alloantigen-dependent factors on the expression of growth factors in the graft thought to be responsible for the morphological changes observed in CAN, particularly the vascular changes with proliferation of smooth muscle cells leading to neointimal proliferation.
Interaction between immunological and non-immunological factors in the pathogenesis of chronic allograft nephropathy
We suggest that alloantigen-dependent and alloantigen-independent factors share final pathways in the pathogenesis of CAN (Figure 1
). Initiation of the immune response with subsequent induction of growth factors traditionally caused, it is thought, by alloantigen-dependent factors such as acute rejection, may also be involved in the pathogenesis of graft injury by alloantigen-independent factors such as hypertension. Hypertension may initiate inflammatory pathways or act synergistically with alloantigen-dependent factors on graft injury. An interaction between alloantigen-dependent and alloantigen-independent factors is supported by observations that hypertension induces inflammatory changes also in native kidneys, such as expression of adhesion molecules ICAM-1 and interstitial leukocyte infiltration [17]. In the hypertensive rat remnant kidney model (an alloantigen-independent model of injury), expression of PDGF-B is observed before glomerulosclerosis develops [18]. The immunosuppressive drug mycophenolate mofetil is able to attenuate renal injury in this model [19], indicating that hypertension after renal ablation causes renal injury through immune mechanisms. On the other hand, renal damage in immunological-mediated renal diseases such as anti-GBM nephritis is aggravated by superimposed renovascular hypertension [20]. A synergy between hypertension and immunological mechanism of renal injury might not be restricted to allografts, but also valid for other types of renal diseases, since lowering of blood pressure by antihypertensive drugs reduces the rate of functional deterioration in renal diseases of diverse cause [21].
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Clinical consequences
The Collaborative Transplant Study reported that 55% of kidney transplant recipients had systolic blood pressures of 140 mmHg and higher [9]. In our own experience, 35% of patients receive more than two antihypertensive drugs 1 year after transplantation and still, in the majority of these patients, blood pressure is not well controlled [12]. There are no prospective clinical studies showing that aggressive lowering of blood pressure is suitable to reduce the rate of CAN. However, until these studies are performed, it is necessary from our present knowledge to emphasize the importance of controlling hypertension, maybe even more so after than before transplantation. The ideal level of blood pressure is not known, but data from the HOT study indicate that a diastolic pressure of 80–85 mmHg is safe [22]. It is also unknown which antihypertensive drugs should be used. Studies in animals have shown that angiotensin II receptor blockade (but not calcium channel blockade) protects from chronic rejection [23], but clinical data are scarce. Most patients, however, will need several classes of antihypertensives to control blood pressure adequately, and even bilateral removal of the native kidneys must be considered in selected cases.
Acknowledgments
We are indebted to Dr S. Tullius, Department of Surgery, Charité-Virchow Klinikum, for his help in performing the animal experiments. This work was supported by a grant from the Deutsche Forschungsgemeinschaft to R. S.
References
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