Journal of Human Hypertension (2004) 18, 835–836 & 2004 Nature Publishing Group All rights reserved 0950-9240/04 $30.00 www.nature.com/jhh
COMMENTARY
Hypertension after renal transplantation SC Textor Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA
Journal of Human Hypertension (2004) 18, 835–836. doi:10.1038/sj.jhh.1001766 Published online 23 September 2004
The relationships between blood pressure and kidney transplant recipients are complex. As more patients now reach end-stage kidney disease with large burdens of cardiovascular disease, more attention is being focused upon managing cardiovascular risk than ever before. Death with a functioning allograft, usually related to cardiovascular disease, is now one of the leading causes of graft loss.1 As a result, management of post-transplant hypertension has become an important component of the longterm medical care of the transplant recipient. How blood pressure relates to the function and durability of the transplanted kidney also is an important issue. Post-transplant hypertension appears to be a risk for both rejection2 and eventual graft loss.3 Immunosuppression based upon calcineurin inhibitors, such as cyclosporine (Sandimmune, Neoral, Gengraf, etc) or tacrolimus (Prograf), itself produces widespread vasoconstriction and hypertension, particularly when combined with steroids.4 These agents induce complex changes in endothelial function, circadian rhythms and sodium retention, sometimes precipitating microangiopathic haemolytic injury.5 Long-term exposure to calcineurin inhibitors induces permanent vascular injury and interstitial fibrosis. Recent studies with serial biopsies in patients treated with calcineurin inhibitors indicate that this is nearly universal.6 Whether selection of specific antihypertensive agents to treat post-transplant hypertension affects the outcomes of the allograft is not certain. For many years, dihydropyridine calcium channel blocking agents have been recognized to reverse contractile processes in vascular smooth muscle. Some reports favour preparing donor kidneys with these agents to minimize vasoconstriction associated with deceased-donor transplants.7,8 Application of these agents for treating post-transplant hypertension has been widely accepted based on principle and the results from short-term studies.9 Correspondence: SC Textor, Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA. E-mail:
[email protected] Published online 23 September 2004
In this issue, Premasathian et al10 present retrospective review of more than 1600 patients undergoing renal transplantation between 1994 and 2000. They stipulated that patients must have remained on the ‘index’ drug for at least nine continuous months following the initial 6 months of graft function. When patients were taking more than one ‘antihypertensive’ drug (defined as central alpha-agonists, peripheral alpha-antagonists, betablockers, calcium channel blockers (CCBs) drugs, and angiotensin antagonists (either ACE inhibitors or angiotensin receptor blockers), results were assigned to the first prescribed drug. The details of immunosuppression, diagnosis of rejection, and other management issues are relatively standard for reports of renal transplant patients. Importantly, the methods for assigning blood pressure outcomes, specific agents and intensity of therapy are moderately unorthodox for hypertension reports. For example, no information is presented regarding the use and role of diuretic therapy (which is not included as a class of antihypertensive agent here). No attempt is made to establish the severity of hypertension, for example, the intensity of drug therapy in each group (although 43% were taking multiple medications at 12 months). No mention is made regarding patient compliance. These limitations notwithstanding, the authors indicate that during follow-up periods ranging from 18 to 84 months, the largest cohort (n ¼ 673) received CCBs (primarily nifedipine or amlodipine). Overall, no relationship could be identified in this study regarding episodes of acute rejection and either blood pressure levels or specific antihypertensive drugs. However, average achieved blood pressure was related to ultimate graft loss (each 5 mm posed a relative risk of 1.12, P ¼ 0.016; 95% CI 1.03–1.21). Increased mean arterial pressures also posed a hazard for reduced patient survival (each 5 mm above 85 mmHg posed a relative risk of 1.16, P ¼ 0.041; CI 1.01–1.13). Remarkably, use of dihydropyridine CCBs as primary agents was associated overall with a reduced risk for graft loss, both for cyclosporineand tacrolimus-treated patients. These observations
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persisted during a multivariate analysis that included level of achieved blood pressure as a predictor of graft loss. No overall benefit was observed with ACE/ARB therapy, although some benefit was observed for patients with the highest levels of long-term arterial pressure. The ACE/ARB cohorts were the only group associated with reduction of urinary protein excretion, although this was only peripherally measured (changes in dipstick class). These data further support the principle that sustained hypertension after renal transplantation is a risk factor both for graft loss and patient death. Previous studies suggest that long-term risks of posttransplant hypertension at 1 year are independent of GFR.11 The data presented here indicate that use of dihydropyridine CCBs is not only safe and effective for such patients, but may provide improved allograft outcomes overall. The strength of this claim is subject, however, to the caveat that CCB assignment was not random, but seems to have been preferred from the outset. What prompted assignment to other drug classes as ‘primary’ drug therapy was neither randomized nor achieved in a standard manner. The authors recognize that the efficacy of CCBs is influenced strongly by their potency as antihypertensive agents. Nonetheless, these data support previous observations that vasoconstriction induced by calcineurin inhibitors is more effectively reversed with these agents than with others.12 They argue that posttransplant hypertension does, indeed, have distinguishing features, particularly regarding vascular injury to the kidney. The authors could not confirm their own previous report of slowed progression of declining renal function by ACE/ARBs in the group overall, although they emphasize the benefits of reducing proteinuria with these agents. Most importantly, they underscore once again the importance of meticulous attention to blood pressure
Journal of Human Hypertension
control, achieving clear benefits both to graft and patient survival even during short-term follow-up.
References 1 Pascual M et al. Strategies to improve long-term outcomes after renal transplantation. N Engl J Med. 2002; 346: 580–590. 2 Cosio FG et al. Renal allograft survival following acute rejection correlates with blood pressure levels and histopathology. Kidney Int 2000; 56: 1912–1919. 3 Mange KC, Cizman B, Joffe M, Feldman HI. Arterial hypertension and renal allograft survival. JAMA 2000; 283: 633–638. 4 Textor SC et al. Posttransplantation hypertension related to calcineurin inhibitors. Liver Transplant 2000; 6: 521–530. 5 Textor SC et al. Urinary endothelin and renal vasoconstriction with cyclosporine or FK506 after liver transplantation. Kidney Int 1995; 47: 1426–1433. 6 Nankivell BJ et al. The natural history of chronic allograft nephropathy. N Engl J Med 2003; 349: 2326–2333. 7 Neumayer HH, Kunzendorf U, Schreiber M. Protective effects of calcium antagonists in human renal transplantation. Kidney Int 1992; 41(Suppl 36): 87s–93s. 8 Palmer BF et al. Improved outcome of cadaveric renal transplantation due to calcium channel blockers. Transplantation 1991; 52: 640–645. 9 Mehrens T et al. The beneficial effects of calcium channel blockers on long-term kidney transplant survival are independent of blood pressure reduction. Clin Transplant 2000; 14: 257–261. 10 Premasathian NC et al. Blood pressure control in kidney transplantation: therapeutic implications. J Hum Hypertens 2004; 99: 9999. 11 Mange KC et al. Blood pressure and the survival of renal allografts from living donors. J Am Soc Nephrol 2004; 15: 187–193. 12 Textor SC et al. Systemic and renal effects of nifedipine in cyclosporine-associated hypertension. Hypertension 1994; 23(Suppl I): I-220–I-224.
