Patients with advanced and end-stage kidney disease have accelerated vascular disease, the hallmarks of which are arteriosclerosis and vascular calcification. The prevalence and severity depends on the duration of chronic kidney disease (CKD) (especially time spent on maintenance dialysis therapy) and older age. The functional consequences are increased vascular stiffness1 and, as a result, increased systolic blood pressure (SBP) and pulse pressure (PP) often accompanied by low or normal diastolic blood pressures (DBP). Although BP tends to improve after transplantation with the normalization of intravascular volume, structural vascular changes remain and hypertension is common.2 In patients receiving hemodialysis (eg, reference 3) there is a progressive relationship between SBP and cardiovascular outcomes, specifically cardiac death, but often a negative or U-shaped relationship with DBP. However, these associations are often weak, and PP may have a stronger association,3 although the determinants of vascular disease and calcification (eg, age and serum phosphate) are more significant determinants of cardiovascular (CV) disease. In the renal transplant population, post hoc analyses of clinical trials have examined the relationship between BP and outcomes. In the ALERT (Assessment of Lescol in Renal Transplantation) study, there was a highly significant progressive relationship between PP and fatal CV and non-CV events, a weaker association with SBP and a nonsignificant reverse relationship with DBP.4 Systolic blood pressure and PP were also significant determinants of graft failure, whereas DBP had no effect.5 In the FAVORIT (Folic Acid for Vascular Outcome Reduction in Transplantation) study,6 although PP was not reported, each 20-mm Hg increase in SBP was associated with a 32% increase in CV risk, whereas DBP above 70 mm Hg had no impact on CV risk and each 10 mm Hg below 70 mm Hg conferred a 31% increase in risk.
The relationship between blood pressure at 1 year after transplantation on graft survival was elegantly demonstrated by Opelz and colleagues7 almost 20 years ago, followed by an analysis that included the impact of changing blood pressure and patient outcomes.8 In this issue of Transplantation, the same group presents an analysis focused on PP, using the same Collaborative Transplant Study, registry data set.9
The present study describes the relationship between blood pressure levels 1 year after transplantation in 43 006 deceased donor transplant recipients, from 1995 to 2015. Subjects with BP recordings and a functioning graft 1 year after transplantation were followed up for a maximum of 10 years. The analyses were subgrouped by SBP less than 140 mm Hg, 140 to 159 mm Hg, and greater than 160 mm Hg; DBP less than 90 mm Hg, 90 to 99 mm Hg, greater than 100 mm Hg; PP less than 60 mm Hg, 60 to 69 mm Hg, greater than 70 mm Hg; and recipient age group 18 to 49 years, 50 to 59 years, older than 60 years. More than 80% of all patients were on antihypertensive therapy at 1 year, the proportion rising with age. All increased BP parameters were significantly associated with worsening death-censored graft survival and patient survival, except for DBP in the older patient group where there was a nonsignificant trend toward an inverse relationship between DBP and graft failure. High PP was associated with an increased risk of death in patients with SBP less than 140 mm Hg, who were otherwise at lower risk (significant, in the youngest and oldest cohorts). Perhaps the most striking observation is 48.4% of older patients had DBP less than 80 mm Hg compared with 29.5% of younger patients, whereas 34.1% of older patients had PP greater than 70 mm Hg compared with 10.5% of the younger patients. These observations are consistent with the patterns seen with ageing in the general population, but are more marked at an earlier age in patients with CKD.
Overall, the findings present a compelling relationship between PP and CV and renal outcomes. The observation that PP has a stronger association perhaps reflects a combination of the impact of low DBP and high SBP, which are features of advanced vascular stiffness and calcification, common among older patients. The fact that the impact of PP is strongest in older patients, where DBP has less prognostic value, supports this notion, presumably reflecting age and longer periods on hemodialysis.
It is difficult to see how PP could be used as a target in clinical practice. Antihypertensive agents reduce both SBP and DBP, and in practice, SBP becomes the target when the DBP is low or normal. It is well established that overaggressive reduction in DBP may lead to adverse outcomes, most probably through the reduction of diastolic coronary artery filling. Thus, PP is perhaps a useful parameter to identify risk, as a surrogate for vascular stiffness and calcification, rather than a therapeutic target.
One of the limitations of this study is the arbitrary categorization of BP levels, albeit based on established criteria for BP treatment. Although this may simplify the analysis, it limits our ability to identify thresholds for effect or underlying J- or U-shaped relationships between BP parameters and graft and patient outcomes. It would be interesting to see the results of a multivariate analysis that might better delineate this, incorporating BP measurements as continuous variables. It is also important to remember that this is a registry analysis. Such analyses have strength in large patient numbers and long follow-up, but they lack precision, and the authors have identified a lack of standardization in BP measurement. Although registry analyses reassure us that we continue to improve transplant outcomes,10 there are confounding influences, such as the relationship between poor allograft function and hypertension and the common practice to withdraw angiotensin-converting enzyme inhibitors in patients with poor or deteriorating graft function. These factors can make it difficult to translate observational data on BP and outcomes into clinical practice. Registry analyses are hypothesis generating and require to be tested in clinical trials. Once again, the authors remind us that there have been no clinical trials into the control of blood pressure in renal transplant recipients, at least none that have been completed,9 and we lack specific information on strategies or BP targets in this population. The fact that the 2 clinical trials of BP lowering were stopped early due to lack of end-points, and the observations in the present report, suggest that structural vascular disease is likely to more important than hypertension per se.
For the clinician and patient, the “take home” message in this important study is that elevated PP is clearly associated with adverse outcomes. Whether or not targeting PP improves outcomes remains to be tested. Meanwhile, clinicians should concentrate on limiting the development of vascular disease by early intervention in CKD and minimizing the time spent on maintenance dialysis.
1. London GM. Arterial stiffness in chronic kidney disease and end-stage renal disease. Blood Purif. 2018;45:154–158.
2. Jardine AG, Gaston RS, Fellstrom BC, et al. Prevention of cardiovascular disease in adult recipients of kidney transplants. Lancet. 2011;378:1419–1427.
3. Schneider A, Jardine AG, Schneider MP, et al. Determinants of cardiovascular risk in haemodialysis patients: post hoc analyses of the AURORA study. Am J Nephrol. 2013;37:144–151.
4. Jardine AG, Fellström B, Logan JO, et al. Cardiovascular risk and renal transplantation: post hoc analyses of the Assessment of Lescol in Renal Transplantation (ALERT) study. Am J Kidney Dis. 2005;46:529–536.
5. Fellström B, Holdaas H, Jardine AG, et al. Risk factors for reaching renal endpoints in the assessment of Lescol in renal transplantation (ALERT) trial. Transplantation. 2005;79:205–212.
6. Carpenter MA, John A, Weir MR, et al. BP, cardiovascular disease, and death in the folic acid for vascular outcome reduction in transplantation trial. JASN. 2014;25:1554–1562.
7. Opelz G, Wujciak T, Ritz E. Association of chronic kidney graft failure with recipient blood pressure. Collaborative transplant study. Kidney Int. 1998;53:217–222.
8. Opelz G, Döhler B; Collaborative Transplant Study. Improved long-term outcomes after renal transplantation associated with blood pressure control. Am J Transplant. 2005;5:2725–2731.
9. Kruger B, Dohler B, Opelz G, et al. Pulse pressure and outcome in kidney transplantation: results from the collaborative transplant study [published online September 4, 2018]. Transplantation. doi:10.1097/TP.0000000000002440
10. Keith DS, Vranic G, Nishio-Lucar A. Graft function and intermediate term outcomes of kidney transplants improved in the last decade: analysis of the United States Kidney Transplant Database. Transplant Direct. 2017;3:e166.