Impact of immunosuppressive therapy on arterial stiffness in kidney transplantation: are all treatments the same?

Impact of immunosuppressive therapy on arterial stiffness in kidney transplantation: are all... Arterial stiffness is a biologic process related to ageing and its relationship with cardiovascular risk is well established. Several methods are currently available for non-invasive measurement of arterial stiffness that provide valuable information to further assess patients’ vascular status in real time. In kidney transplantation recipients, several factors could accelerate the stiffness process, such as the use of calcineurin inhibitors (CNIs), the presence of chronic kidney disease and other classical cardiovascular factors, which would explain, at least in part, the high cardiovascular mortality and morbidity. Despite the importance of arterial stiffness as a biomarker of cardiovascular risk, and unlike other cardiovascular risk factors (e.g. left ventricular hypertrophy), only a few clinical trials or retrospective studies of kidney recipients have evaluated its impact. In this review we describe the clinical impact of arterial stiffness as a prognostic marker of cardiovascular disease and the effects of different immunosuppressive regimens on its progression, focusing on the potential benefits of CNI-sparing protocols and supporting the rationale for individualization of immunosuppression in patients with lower arterial elasticity. Among the immunosuppressive drugs, a belatacept-based regimen seems to offer better vascular protection compared with CNIs, although further studies are needed to confirm the preliminary positive results. Key words: arterial stiffness, augmentation index, immunosuppression, kidney transplantation, pulse wave velocity Introduction predictors of cardiovascular events in this population; in fact, High cardiovascular mortality and morbidity in kidney trans- the risk score calculators used for the general population usu- ally underestimate the cardiovascular risk in kidney recipients plant patients remains a great concern. Although the 1-year survival rates post-transplantation are high, cardiovascular risk [4]. Immunosuppressive therapy and other unconventional in these patients is higher than in healthy subjects [1, 2]. risk factors (such as arterial stiffness) could explain the failure Cardiovascular disease is the leading cause of death and in predicting cardiovascular events in this population. Among the second cause of graft loss in kidney recipients [3]. immunosuppressive drugs, steroids and calcineurin inhibitors However, classic cardiovascular risk factors are not reliable (CNIs) have a negative impact on the cardiovascular system Received: June 6, 2017. Editorial decision: September 6, 2017 V C The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/413/4654834 by Ed 'DeepDyve' Gillespie user on 20 June 2018 414 | E. Melilli et al. [5, 6], as they are potent vasoconstrictors that directly lead to The gold standard for measuring arterial stiffness is intra- vascular fibrosis [7]. Moreover, treatment regimens based on aortic arterial pressure measurement, an invasive method the use of CNIs and corticosteroids increase blood pressure requiring arterial catheterization [38]. Nowadays, there also (through salt retention and/or hyperactivation of the renin– exist several non-invasive methods for arterial stiffness angiotensin system) and low-density lipoprotein cholesterol assessment [39, 40], with PWV calculation being the most levels, thus indirectly affecting the vasculature [8, 9]. widely used. Since the aorta has elastic properties, after each Prednisone withdrawal and CNI-sparing therapy protocols systole, pressure is transmitted through the aortic wall and are tempting strategies to reduce the cardiovascular burden in branches, generating a forward wave with a propagation speed kidney transplant recipients, but these immunosuppressive (PWV) that depends on the wall elasticity, being faster in regimens might increase the risk of rejection, thereby limiting patients with greater stiffness [41]. When the wave reaches the their potential clinical benefit [10]. Instead, an individualized impedance points on the arterial tree, it generates a reflected, immunosuppressive protocol could improve outcomes in backward wave that, in presence of increased stiffness, selected patients with high cardiovascular and low immuno- reaches the aorta during the systole of the same cardiac cycle, logical risk. Biomarkers would be useful towards such per- thus causing an augmentation of the central aortic pressure sonalized medicine, but unfortunately they are still lacking. (AP) that can be quantified as the augmentation index (Aix), Consequently, transplant clinicians are looking for tools to defined as the percentage of the central pulse pressure attrib- predict and prevent cardiovascular events. uted to the reflected pulse wave [42]. In contrast to this discouraging scenario, some recent stud- Figure 1 shows how structural changes in the aorta, small ies have addressed the importance of arterial stiffness parame- arteries and arterioles modify the PWV, Aix and pulse pressure, ters as powerful predictive variables of cardiovascular events in the three parameters commonly evaluated in studies of arterial kidney transplant recipients [11, 12]. stiffness. Arterial stiffness is a biologic process related to ageing [13, A detailed description of the definition of arterial stiffness 14] and blood pressure [15], but also with inflammation [16, 17], and of the validity of all methods currently available for the arterial calcification [18] and stage of chronic kidney disease evaluation and measurement of aortic stiffness has been (CKD) [19]. In kidney transplant recipients, several studies have recently and exhaustively reviewed by Adenwalla et al. [43]. also associated arterial elasticity with donor age [20], donor vas- cular stiffness (in the case of living donors) [21], new-onset dia- Increased arterial stiffness in kidney betes post-transplantation [22], cold ischaemia time [23], renal graft function [glomerular filtration rate (GFR)] [24], hypomagne- transplant recipients is a powerful predictor of saemia [25] and resistance training [26]. In addition, CNI therapy cardiovascular events is known to contribute to vascular stiffness acceleration [27]. Results from PWV measurements should be evaluated based on Arterial stiffness in hypertensive patients has been studied the patient’s age. Although the 2007 European Society of in previous clinical trials [28, 29] that showed certain classes of Hypertension/European Society of Cardiology hypertension blood pressure–lowering drugs appear to decrease stiffness guidelines recommend a fixed threshold value of 12 m/s to more effectively than others, although this might be related to detect patients with high cardiovascular risk [44]. More recently, their better control of blood pressure [30]. In kidney transplant a consensus document has set this value at 10 m/s [45]. studies, except for a few minor studies that analysed the effect However, irrespective of the cut-off value, cardiovascular risk is of several immunosuppressive protocols on arterial stiffness, increased even at a lower threshold [44]. only two recent randomized clinical trials have introduced arte- In a Dutch study including a kidney transplant cohort of 330 rial stiffness as a secondary endpoint [31, 32]. patients, the PWV was found to be predictive of cardiovascular Here we provide a descriptive review of the literature focus- events and survival, irrespective of the patient’s age. ing on the usefulness of pulse wave velocity (PWV) as a predic- Interestingly, patients with a PWV of 7.5 m/s showed worse tor of cardiovascular events and on how immunosuppressive survival rates than those with a PWV <7.5 m/s [46]. therapy could modify arterial stiffness in kidney transplant In 2011, in a prospective study of a cohort of 512 kidney recipients. transplant recipients, PWV, together with central AP and Aix were measured at the time of kidney transplantation. After a Arterial stiffness evaluation in kidney mean follow-up of 5 years, PWV and AP were included in a transplantation model based on clinical variables and laboratory data to predict cardiovascular events. Adding PWV and AP data led to a net The three layers of the arterial wall contribute, each to a differ- reclassification improvement for cardiovascular events of ent extent, to its elastic property, which can be measured at 15.9%. Moreover, patients with a PWV of 8.1 m/s had worse both macro- and microscale levels [33]. With ageing and/or due cardiovascular survival compared with patients with a PWV to concurrent diseases (e.g. arteriosclerosis), the balance <8.1 m/s [11]. between elastin fibres and collagens tends to be disrupted in Lastly, a recent study from a Norwegian group including favour of the latter. This process involves several players, 1022 kidney transplant recipients showed that below a cut-off including matrix metalloproteinases [34–36], which degrade elastin fibres and the connections between them, calcium depo- value of 12 m/s, each increment in PWV of 1 m/s starting from 8 m/s was associated with a 36% increase in mortality risk [12]. sition in the tunica media and collagen glycosylation by The aforementioned studies demonstrate the powerful pre- advanced glycation end products (AGEs) [37]. Also, endothelial and vascular smooth muscle cells can affect the elastic property dictive value of PWV for cardiovascular events and mortality of the arterial wall, although the mechanisms are not well (see Table 1), irrespective of age and other clinical or laboratory understood [33]. All the aforementioned factors cause an accel- variables, thus confirming data obtained from other studies eration of arterial stiffness progression. involving different patient populations [47]. Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/413/4654834 by Ed 'DeepDyve' Gillespie user on 20 June 2018 kidney transplant, arterial stiffness and immunosuppression | 415 Fig. 1. Scheme of wave propagation according the PWV model. (A) Healthy subject/healthy artery: PWV is slow at the aortic level and fast at small (muscular) arteries. Each wave represents the sum of a unique forward wave (blue arrow) and multiple backward waves (black arrows). Backward waves are generated from reflection points located in the circulatory system: bifurcations (green dashes) and small arteries and arterioles (not shown in the figure). Due to the PWV gradient (i.e. the length and resistance at reflection points), backward waves reach, with a delay, the systolic peak of the forward wave, so there is no significant augmentation pressure (or Aix). (B) Patients with arterial stiffness: aortic media calcification and atherosclerotic plaque (red arrow - pulse presure) tend to increase the PWV at the aortic level. Moreover, changes in muscular tone and structure in small arteries and/or arteriolar hyalinosis (yellow arrows) increase resistance, amplifying the magnitude of reflected waves. As a consequence, more prominent backward waves reach the forward wave near the systolic peak, thus generating a notable increase in central AP, expressed as augmentation pressure. Table 1. Main studies on the predictive power of arterial stiffness for cardiovascular endpoints (mortality and event) Number Follow-up Independent predictive Independent predictive Source of patients (mean years) power for CV death: PWV power for CV death: Aix or AP Mitchel et al. 2010 [46] 330 3.8 YES NA Verbeke et al. 2011 [11] 512 5 YES YES Dahle et al. 2015 [12] 1040 4.2 YES NA Aix, augmentation index; AP, aortic pressure; CV, cardiovascular; PWV, pulse wave velocity. All studies used a Sphigmocor device for calculation of PWV and Aix or AP. Arterial stiffness and immunosuppression vasoconstriction at the arteriolar level is probably the cause of augmentation of certain stiffness parameters (Aix and AP) in As previously described, CNI toxicity on arteries is well known, patients treated with cyclosporine. Several factors seem to at least at the microcirculatory level. Two types of toxicity for play a role in this acute toxicity: hyperactivation of the renin– cyclosporine have been described: acute and chronic toxicity angiotensin system [50], upregulation of endothelin receptors [48]. Acute toxicity is a functional alteration due to an imbal- [51], endothelial cell injury [52], alteration in L-arginine nitric ance between vasoconstrictors and vasodilators, leading to a oxide production and hyperactivation of the sympathetic decrease in renal blood flow and to an increase in vascular resistance, particularly at the arteriolar level. Since arteriolar system [53]. Calcium antagonists and angiotensin receptor network resistance is the last barrier against pulsatile pressure blockers (ARBs) or angiotensin-converting enzyme inhibitors and represents the gate of the backward wave [49], this (ACEis) are known to mitigate the acute toxicity, which makes Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/413/4654834 by Ed 'DeepDyve' Gillespie user on 20 June 2018 416 | E. Melilli et al. Table 2. Main studies on the effect of IMS on arterial stiffness in kidney transplant recipients Source Design N IMS Results Limitation Zoungas et al. 2004 [63] Longitudinal 36 24 CYC PWV: no difference Small 12 TAC Aix: TAC ###/CYC # Ferro et al. 2002 [65] Transversal 250 146 CYC PWV: NA Design 62 TAC Aix: TAC # versus CYC Strzo ´ ecki et al. 2007 [66] Transversal 152 76 CYC PWV: TAC # versus CYC Design 76 TAC Aix: NA Seckinger et al. 2008 [67] Conversion CYC to EVR 27 10 CYC PWV: CYC "; EVR # Small 17 EVR Aix: NA Short follow-up Joannide `s et al. 2011 [68] Conversion CYC to SRL 44 21 CYC PWV: CYC "; SRL # Small 23 SRL Aix: CYC "; SRL # Selection criteria Gungor et al. 2011 [69] Transversal 81 47 CNI PWV: no difference Small 34 imTOR Aix: no difference Mixed CNI/imTOR Seibert et al. 2014 [70] Transversal 46 23 BLC PWV: no difference Small 23 CYC AP BLC # versus CYC Selection Melilli et al. 2015 [71] Transversal 40 20 BLC PWV <8.1: BLC 60%, CNI 40% Small 20 CNI Aix: NA CNI mixed Cruzado et al. 2016 [72] Conversion TAC to EVR 60 32 TAC PWV: no difference Normal PWV 28 EVR Small Holdaas et al. 2017 [31] Conversion CNI to EVR 164 95 CNI PWV: no difference Normal PWV 69 EVR Aix: NA CNI mixed Aix, augmentation index; AP, augmentation pressure; BLC, belatacept; CYC, cyclosporine; EVR, everolimus; IMS, immunosuppression; PWV, pulse wave velocity; SRL, sirolimus; TAC, tacrolimus. it difficult to understand how all these factors contribute to Table 3. Main effects of different immunosuppressive drugs on PWV, Aix and blood pressure acute vascular toxicity [54, 55]. Chronic toxicity is characterized by a structural change in Systemic blood vessels, particularly small arteries and arterioles [56]. Hyalinosis Drugs pressure PWV Aix or AP lesions on the arteriolar wall, a hallmark of CNI toxicity, are present in protocol biopsies at 10 years in the majority of Cyclosporine þþþ þþ þþ/þ patients receiving tacrolimus or cyclosporine [57]. Treatment Tacrolimus þ/þþ /þþ imTOR (everolimus  /þ using the mammalian target of rapamycin (mTOR) inhibitors or sirolimus) (imTORs) sirolimus and everolimus has been shown to attenu- BLC ate allograft vasculopathy in heart transplant recipients [58–60]. Mycophenolate mofetil  ?? Whether immunosuppressive drugs can modify PWV, directly Steroid þ ?? or indirectly influencing vasculature, remains largely speculative and difficult to demonstrate for the following reasons [61]. First, ?, stand for No Data. transplantation per se ameliorates arterial stiffness [22, 62, 63], probably as a result of recovery in renal function. Renal function is, in fact, closely related to PWV, as shown by Ford et al. [19]. In a small study, Covic et al. [73] showed that cyclosporine Moreover, transplantation allows better control of blood pressure, acutely decreased the Aix. However, the study lacked a control thus decreasing PWV, although Seibert et al. [64] showed that group and the decrease in Aix after cyclosporine uptake was high PWV was related to cardiovascular events after kidney related to a decrease in the timing of the reflected wave, which transplantation, regardless of peripheral blood pressure. Finally, could lead to an increased PWV in the long term. the majority of studies published so far are small-scale, retro- Interestingly, in the same period, a cross-sectional study spective and case–control (see Table 2). (including 250 stable kidney transplant recipients) showed Despite these limitations, there is some evidence of a protec- that cyclosporine increased Aix and blood pressure tive effect of CNI-sparing protocols on the progression of arterial considerably more than tacrolimus [65]. In 2007, Stro ´zecki et al. stiffness in kidney transplant recipients. Table 3 summarizes [66] compared the PWV in 76 patients taking cyclosporine with the impact of different immunosuppressive drugs on PWV, Aix 76 patients taking tacrolimus. The two study groups were and blood pressure. matched for main clinical characteristics (age, blood pressure, time on haemodialysis, diabetes). The cyclosporine group had CNIs and stiffness higher PWV values compared with the tacrolimus group (9.336 2.10 versus 8.546 1.35, respectively; P < 0.01). In Initial data on CNI effects on large arterial functions have been another study by the same group, stepwise multiple regression conflicting. In a prospective study, Zoungas et al. [63] compared analysis showed that age, male sex, mean arterial pressure PWV before and after kidney transplantation in 36 patients. At 12 months post-transplantation, PWV improved in all patients, (MAP), cyclosporine (versus tacrolimus) and fasting glucose irrespective of cyclosporine or tacrolimus use, although Aix concentration were independently associated with increased reduction was greater in patients treated with tacrolimus PWV [74]. The effect of cyclosporine on stiffness is probably (8.06 16.5% versus 27.46 18.2%; P ¼ 0.01). due to an increase in vascular tone or to impaired nitric- oxide Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/413/4654834 by Ed 'DeepDyve' Gillespie user on 20 June 2018 kidney transplant, arterial stiffness and immunosuppression | 417 vasodilation, although a study from Silverborn et al. [75]did not before and after conversion. The median time from transplanta- confirm this hypothesis. In their proof-of-concept study, 18 lung tion was 1.7 years for the tacrolimus group (25 patients) and transplant recipients (all treated with cyclosporine) were com- 1.3 years for the everolimus group (31 patients). At 24 months pared with patients waiting for lung transplantation and healthy from randomization, both groups had very well-controlled controls. Arterial resistance, non-endothelial-dependent relaxa- blood pressure, although the dipper status was preserved in more patients on everolimus (30% of tacrolimus-treated tion and arterial stiffness (by echo tracking) were analysed. Lung recipients had significantly less elastic arteries than healthy patients were non-dippers versus 22% of patients on everoli- mus). PWV values at baseline and 12 and 24 months were in the controls or patients on the transplant waiting list, even though no difference in blood pressure or endothelial response to nitric oxide normal range, with no significant differences between the two study groups [72]. was seen. Another ancillary study from a recent trial [31] evaluated Since cyclosporine was found to be related to higher PWV, PWV and blood pressure by ABPM. PWV data were obtained for conversion to tacrolimus could be an option to improve arterial 277, 223 and 184 patients at randomization and months 12 and stiffness. This hypothesis was tested in a small study where sta- 24, respectively. Patients converted to everolimus had a slight ble kidney recipients taking cyclosporine (>10 years) were con- decrease in PWV (month 12: 0.24 m/s; month 24: 0.03 m/s), verted to tacrolimus. PWV (by echo tracking) and ambulatory blood pressure monitoring (ABPM) were performed at baseline whereas patients on cyclosporine experienced a progressive increase in PWV (month 12: 0.11 m/s; month 24: 0.16 m/s). and repeated at 3 months post-conversion. No difference was Although the difference was not significant, one can argue that observed in blood pressure or PWV, probably due to the short baseline values were in the normal range (mean 7.8 m/s for the time span from conversion [76]. everolimus group and 7.6 m/s for the cyclosporine group). Despite the limitations in their study design, all the afore- Follow-up at 24 months confirmed the predictive value of PWV, mentioned studies suggest a possible negative impact of CNIs, since the incidence of cardiovascular events in the entire cohort and especially cyclosporine, on PWV. was low (2.8% in the everolimus group and 4.8% in the cyclo- sporine group). In such low-risk populations, a greater number imTORs and arterial stiffness of patients is necessary in order to show any benefit in a cardio- The imTORs everolimus and sirolimus are used in immunosup- vascular endpoint (or PWV) from any therapeutic intervention pressive regimens in kidney transplantation. Yet since their (such as conversion to an imTOR). Moreover, since such small first use, they have not shown superior efficacy in terms of variations (0.4–0.5 m/s) usually occur over a long time span, renal survival or prevention of rejection compared with follow-up at 24 months was probably too early a time point to tacrolimus [77, 78]. Beyond their immunosuppressive property, detect any significant change in PWV [82, 83]. imTORs exert certain pleiotropic effects on atherogenesis [79, Since patients with high PWV at baseline are susceptible to a 80] and fibrosis [81], so at least in theory, kidney transplant steeper increase in PWV [13], we cannot exclude the possibility recipients may benefit from the use of imTORs in terms of arte- that conversion to imTORs is beneficial for these patients. rial elasticity. In a randomized clinical trial, 17 of 27 patients were Co-stimulatory blockade and arterial stiffness switched from cyclosporine to everolimus 6 months after kid- ney transplantation. PWV remained stable in the everolimus The biologic immunosuppressant belatacept (BLC) is a fusion group (9.506 1.92 versus 9.136 1.62 m/s, DPWV 0.376 1.14 m/ protein comprising the common fragment Fc of human immu- s), whereas it was increased in the cyclosporine group noglobulin G (IgG) and CTL4, which, upon binding to CD80 and (9.936 1.94 versus 10.86 2.24 m/s, DPWV þ 0.896 1.47 m/s) [67]. CD86 receptors on antigen-presenting cells (APCs), inhibits co- In a substudy of the CONCEPT trial [68], 23 of 44 patients stimulatory signals essential for T-lymphocyte activation. In were converted from cyclosporine to sirolimus 12 weeks after the two non-inferiority clinical trials BENEFIT and BENEFIT-EXT kidney transplantation. PWV and Aix were evaluated at weeks [84, 85], BLC was demonstrated to have an anti-rejection effi- 12, 26 and 52. Patients in the sirolimus group experienced a cacy similar to cyclosporine. At the 3-year follow-up, patients decrease in PWV, whereas those in the cyclosporine group had treated with BLC showed better renal function, less renal fibro- an increase in PWV, with a significant difference at week 52. sis in protocol biopsies and a better cardiovascular profile [86]. Both groups experienced an increase in Aix, which was more In particular, at 12 months, systolic and diastolic blood pres- marked in the cyclosporine group. According to the authors, the sures were lower in patients treated with BLC than in those progressive decrease in PWV in the sirolimus group was a treated with cyclosporine, as shown in the BENEFIT and cause, rather than a consequence, of the better blood pressure BENEFIT-EXT trials, even though both treatment groups had the control. same baseline level of blood pressure. Moreover, in the BENEFIT Despite these encouraging results, a cross-sectional study by trial, both BLC regimens [more intensive (MI) and less intensive Gungor et al. [69] showed no benefit in terms of PWV or Aix in a (LI)] were associated with a 30% reduction in the odds of requir- group of patients treated with an imTOR (for at least 6 months, ing a higher number of antihypertensive medications at month with either sirolimus or everolimus) compared with treatment 12 (P¼ 0.02, BLC-LI versus cyclosporine A) [87]. with CNIs (cyclosporine or tacrolimus). In a linear regression Data analysis from these trials at different time points (12, analysis, only conventional risk factors (age, blood pressure, 36 and 84 months) also showed that patients treated with BLC cholesterol level and proteinuria) were predictive of arterial had a better GFR compared with patients treated with cyclo- stiffness. sporine [87]. A long-term analysis from the BENEFIT trial at More recently, a randomized clinical trial on the effect of late 7 years showed a 43% reduction in mortality risk or risk of graft conversion from CNIs (tacrolimus) to an imTOR (everolimus) loss with both the BLC-MI and BLC-LI regimens compared with showed a small benefit related to regression of left ventricular the cyclosporine regimen [88]. Since GFR is a powerful predictor hypertrophy in both groups. As secondary outcomes, changes of cardiovascular events and mortality in kidney transplant in blood pressure (measured by ABPM) and PWV were evaluated recipients [89, 90], these results were not unexpected. Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/413/4654834 by Ed 'DeepDyve' Gillespie user on 20 June 2018 418 | E. Melilli et al. In addition to better survival rates related to GFR, data from published studies on kidney transplantation do not report data other studies suggest improved control of arterial stiffness in BLC- on intra- or interobserver variability, making it difficult to based regimens. In an experimental model of hypertension assess and compare the data quality of each study. In fact, only induced by angiotensin or deoxycorticosterone acetate (DOCA)– a few studies on kidney transplantation have reported an salt, Vihn et al.[91] administered treatment infusion based on acceptable variation coefficient index (intraclass correlation CTLA4-Ig (a drug with effects mimicking genetic CD80/CD86 defi- coefficient) for operator variability [21, 76, 93]. There is also an ciency) in mice, thus preventing hypertension acceleration. A pos- extreme paucity of data on intrapatient variations in stiffness sible influence of the immune system on hypertension is not new, parameters. since the contribution of T cells in DOCA–salt-induced hyperten- Confounding factors represent another limitation relevant sion in thymectomized mice was shown >25 years ago [92]. In to arterial stiffness studies, including blood pressure and the mild hypertension, endothelial vessel damage causes the release duration of kidney disease, both closely related to arterial stiff- of damage-associated molecular patterns and altered self-proteins. ness. In kidney transplantation, studies published so far have Hypothetically these molecules could be recognized as antigens only reported the impact of time on dialysis [22, 25, 66], whereas presented by dendritic cells and thus trigger the immune system, data on the duration of disease and/or blood pressure are activating T cells and stimulating cytokine production and inflam- scarce. Moreover, most of these studies analysed only the rela- mation [93], the latter being closely associated with increased vas- tionship between a single determination of blood pressure and cular stiffness [16]. stiffness parameters. More rigorous blood pressure determina- From a clinical perspective, only two studies have analysed tions using ABPM and repeated arterial stiffness measurements the impact of BLC on arterial stiffness in kidney transplant recipi- are needed in order to confirm a possible independent effect of ents. In the first study, Seibert et al. [70], in a case–control retro- immunosuppression on arterial stiffness. Other confounding spective study, compared 23 patients treated with BLC with 23 factors such as diabetes and disorders of mineral and bone patients treated with cyclosporine. The two groups showed no metabolism are also related to arterial stiffness in kidney trans- significant differences with regard to gender distribution, age, plantation [25, 68, 96]. The use of vitamin D supplementation body mass index, time on dialysis prior to transplantation may produce a decrease in PWV in CKD patients [97], although and time since transplantation. After a mean follow-up of no data on vitamin D repletion in recipients are available. 88 months (all patients included had a minimum time from Nonetheless, paricalcitol did not seem to exert a reducing effect transplantation of 20 months and were first-kidney recipients), on PWV after 1 year of treatment, as shown by Pihlstrøm et al. augmentation pressure was significantly better in the BLC group [32] in a randomized trial on the effect of paricalcitol on para- [augmentation pressure 12.7 mmHg (range 8.3–16) versus 7.3 (2.3– thyroid hormone levels in kidney transplant recipients. 11.7); P¼ 0.048], despite no differences in systolic and diastolic In conclusion, all these confounders mask the true magnitude blood pressures (both peripheral and central). PWV mean values of the impact of immunosuppressive regimens on arterial stiffness. were identical in both groups (8.8 m/s). In the second study [71], our group compared 20 patients treated with BLC with 20 patients on CNIs (16 on tacrolimus and Open questions and ideas for future clinical 4 on cyclosporine). The control CNI group was matched for all studies the main variables affecting PWV. There were no differences in Measurements of PWV, Aix and AP usually take between 20 and median PWV between the two groups: 7.96 3.4 m/s (range 4.1– 30 min when performed by an experienced operator, which 12) in the CNI group and 7.46 4 m/s (range 5.2–15.5) in the BLC stands as one of the obstacles to widespread use of arterial stiff- group (P¼ 0.4). Due to the large discrepancy in age in our popu- ness evaluation in patients on transplant waiting lists or after lation study, we chose a value of 8.1 m/s of femoral-carotid PWV transplantation. Although magnetic resonance and/or certain as the cut-off value for high arterial stiffness, which was shown blood pressure devices can assess stiffness parameters, thus to correlate with an increased cardiovascular mortality risk in a rendering these tests less cumbersome, these parameters have recent retrospective study performed in a transplant population not yet been proven to be predictive of cardiovascular events [11]. In that study, 50% of patients in the CNI group had a PWV [43, 98, 99]. Moreover, measurement devices approved by >8.1 m/s versus 25% of patients in the BLC group (P¼ 0.08). regulatory agencies is often unaffordable in many health care Regression logistical analysis showed that age, renal resistive systems, thus restricting their use to research purposes only. index at 3–6 months after transplantation and BLC [odds ratio Sincebaselinehigh PWV values predict a higher cardiovascular 0.008 (95% confidence interval 0.004–0.890); P ¼ 0.045] were pre- risk, future trials in transplantation could include basal PWV as a dictive variables of PWV. biomarker to discriminate those patients at very high cardiovascu- Although these two studies have some limitations (transver- lar risk who could benefit from a CNI-free immunosuppressive reg- sal, lack of a baseline record of arterial stiffness measurements), imen (BLC-based, for example). Moreover, monitoring of PWV after data on PWV and augmentation pressure suggest that transplantation at different time points could identify those improvement in arterial stiffness could be obtained using BLC patients with rapid progression of arterial stiffness who could ben- as the main immunosuppressant. efit from conversion of CNIs to imTORs or who need tighter control of mineral and bone metabolism or blood pressure. Limitations Although the number of publications on arterial stiffness in kid- Conclusion ney transplantation is increasing, most studies present limita- tions that warrant caution in interpreting the results. As with Kidney transplant recipients with higher values of PWV are at increased cardiovascular and mortality risk. Preliminary data any method of measurement performed by an operator, there is a risk of high interobserver variation. Although the techniques from small studies indicate that CNIs, and especially cyclospor- used to measure arterial stiffness have been validated in terms ine, could increase PWV in renal transplant recipients. of reproducibility in healthy and CKD patients [29, 94, 95], most Although some studies suggest a possible protective effect of Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/413/4654834 by Ed 'DeepDyve' Gillespie user on 20 June 2018 kidney transplant, arterial stiffness and immunosuppression | 419 imTORs on arterial stiffness, data from two randomized trials 12. Dahle DO, Eide IA, Asberg A et al. Aortic stiffness in a mortal- ity risk calculator for kidney transplant recipients. have not shown significant differences after either early or late Transplantation 2015; 99: 1730–1737 conversion of CNIs to imTORs. The reduction in cardiovascular 13. Mitchell GF, Parise H, Benjamin EJ et al. Changes in arterial mortality risk shown by long-term results from BLC trials could stiffness and wave reflection with advancing age in healthy be due to a decrease in arterial stiffness, which warrants further men and women: the Framingham Heart Study. Hypertension investigation. 2004; 43: 1239–1245 14. Lee HY, Oh BH. Aging and arterial stiffness. Circ J 2010; 74: Acknowledgements 2257–2262 We thank Dr M. Goma ´ and Dr A. Vidal from the Pathology 15. Oliveras A, Segura J, Suarez C et al. Modification over time of pulse wave velocity parallel to changes in aortic BP, as well Unit of Bellvitge Hospital for their help with the vascular as in 24-h ambulatory brachial BP. J Hum Hypertens 2016; 30: image in Figure 1. No funding has been received for the 186–190 preparation of this manuscript. 16. Mahmud A, Feely J. Arterial stiffness is related to systemic inflammation in essential hypertension. Hypertension 2005; Conflict of interest statement 46: 1118–1122 17. 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Impact of immunosuppressive therapy on arterial stiffness in kidney transplantation: are all treatments the same?

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Abstract

Arterial stiffness is a biologic process related to ageing and its relationship with cardiovascular risk is well established. Several methods are currently available for non-invasive measurement of arterial stiffness that provide valuable information to further assess patients’ vascular status in real time. In kidney transplantation recipients, several factors could accelerate the stiffness process, such as the use of calcineurin inhibitors (CNIs), the presence of chronic kidney disease and other classical cardiovascular factors, which would explain, at least in part, the high cardiovascular mortality and morbidity. Despite the importance of arterial stiffness as a biomarker of cardiovascular risk, and unlike other cardiovascular risk factors (e.g. left ventricular hypertrophy), only a few clinical trials or retrospective studies of kidney recipients have evaluated its impact. In this review we describe the clinical impact of arterial stiffness as a prognostic marker of cardiovascular disease and the effects of different immunosuppressive regimens on its progression, focusing on the potential benefits of CNI-sparing protocols and supporting the rationale for individualization of immunosuppression in patients with lower arterial elasticity. Among the immunosuppressive drugs, a belatacept-based regimen seems to offer better vascular protection compared with CNIs, although further studies are needed to confirm the preliminary positive results. Key words: arterial stiffness, augmentation index, immunosuppression, kidney transplantation, pulse wave velocity Introduction predictors of cardiovascular events in this population; in fact, High cardiovascular mortality and morbidity in kidney trans- the risk score calculators used for the general population usu- ally underestimate the cardiovascular risk in kidney recipients plant patients remains a great concern. Although the 1-year survival rates post-transplantation are high, cardiovascular risk [4]. Immunosuppressive therapy and other unconventional in these patients is higher than in healthy subjects [1, 2]. risk factors (such as arterial stiffness) could explain the failure Cardiovascular disease is the leading cause of death and in predicting cardiovascular events in this population. Among the second cause of graft loss in kidney recipients [3]. immunosuppressive drugs, steroids and calcineurin inhibitors However, classic cardiovascular risk factors are not reliable (CNIs) have a negative impact on the cardiovascular system Received: June 6, 2017. Editorial decision: September 6, 2017 V C The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/413/4654834 by Ed 'DeepDyve' Gillespie user on 20 June 2018 414 | E. Melilli et al. [5, 6], as they are potent vasoconstrictors that directly lead to The gold standard for measuring arterial stiffness is intra- vascular fibrosis [7]. Moreover, treatment regimens based on aortic arterial pressure measurement, an invasive method the use of CNIs and corticosteroids increase blood pressure requiring arterial catheterization [38]. Nowadays, there also (through salt retention and/or hyperactivation of the renin– exist several non-invasive methods for arterial stiffness angiotensin system) and low-density lipoprotein cholesterol assessment [39, 40], with PWV calculation being the most levels, thus indirectly affecting the vasculature [8, 9]. widely used. Since the aorta has elastic properties, after each Prednisone withdrawal and CNI-sparing therapy protocols systole, pressure is transmitted through the aortic wall and are tempting strategies to reduce the cardiovascular burden in branches, generating a forward wave with a propagation speed kidney transplant recipients, but these immunosuppressive (PWV) that depends on the wall elasticity, being faster in regimens might increase the risk of rejection, thereby limiting patients with greater stiffness [41]. When the wave reaches the their potential clinical benefit [10]. Instead, an individualized impedance points on the arterial tree, it generates a reflected, immunosuppressive protocol could improve outcomes in backward wave that, in presence of increased stiffness, selected patients with high cardiovascular and low immuno- reaches the aorta during the systole of the same cardiac cycle, logical risk. Biomarkers would be useful towards such per- thus causing an augmentation of the central aortic pressure sonalized medicine, but unfortunately they are still lacking. (AP) that can be quantified as the augmentation index (Aix), Consequently, transplant clinicians are looking for tools to defined as the percentage of the central pulse pressure attrib- predict and prevent cardiovascular events. uted to the reflected pulse wave [42]. In contrast to this discouraging scenario, some recent stud- Figure 1 shows how structural changes in the aorta, small ies have addressed the importance of arterial stiffness parame- arteries and arterioles modify the PWV, Aix and pulse pressure, ters as powerful predictive variables of cardiovascular events in the three parameters commonly evaluated in studies of arterial kidney transplant recipients [11, 12]. stiffness. Arterial stiffness is a biologic process related to ageing [13, A detailed description of the definition of arterial stiffness 14] and blood pressure [15], but also with inflammation [16, 17], and of the validity of all methods currently available for the arterial calcification [18] and stage of chronic kidney disease evaluation and measurement of aortic stiffness has been (CKD) [19]. In kidney transplant recipients, several studies have recently and exhaustively reviewed by Adenwalla et al. [43]. also associated arterial elasticity with donor age [20], donor vas- cular stiffness (in the case of living donors) [21], new-onset dia- Increased arterial stiffness in kidney betes post-transplantation [22], cold ischaemia time [23], renal graft function [glomerular filtration rate (GFR)] [24], hypomagne- transplant recipients is a powerful predictor of saemia [25] and resistance training [26]. In addition, CNI therapy cardiovascular events is known to contribute to vascular stiffness acceleration [27]. Results from PWV measurements should be evaluated based on Arterial stiffness in hypertensive patients has been studied the patient’s age. Although the 2007 European Society of in previous clinical trials [28, 29] that showed certain classes of Hypertension/European Society of Cardiology hypertension blood pressure–lowering drugs appear to decrease stiffness guidelines recommend a fixed threshold value of 12 m/s to more effectively than others, although this might be related to detect patients with high cardiovascular risk [44]. More recently, their better control of blood pressure [30]. In kidney transplant a consensus document has set this value at 10 m/s [45]. studies, except for a few minor studies that analysed the effect However, irrespective of the cut-off value, cardiovascular risk is of several immunosuppressive protocols on arterial stiffness, increased even at a lower threshold [44]. only two recent randomized clinical trials have introduced arte- In a Dutch study including a kidney transplant cohort of 330 rial stiffness as a secondary endpoint [31, 32]. patients, the PWV was found to be predictive of cardiovascular Here we provide a descriptive review of the literature focus- events and survival, irrespective of the patient’s age. ing on the usefulness of pulse wave velocity (PWV) as a predic- Interestingly, patients with a PWV of 7.5 m/s showed worse tor of cardiovascular events and on how immunosuppressive survival rates than those with a PWV <7.5 m/s [46]. therapy could modify arterial stiffness in kidney transplant In 2011, in a prospective study of a cohort of 512 kidney recipients. transplant recipients, PWV, together with central AP and Aix were measured at the time of kidney transplantation. After a Arterial stiffness evaluation in kidney mean follow-up of 5 years, PWV and AP were included in a transplantation model based on clinical variables and laboratory data to predict cardiovascular events. Adding PWV and AP data led to a net The three layers of the arterial wall contribute, each to a differ- reclassification improvement for cardiovascular events of ent extent, to its elastic property, which can be measured at 15.9%. Moreover, patients with a PWV of 8.1 m/s had worse both macro- and microscale levels [33]. With ageing and/or due cardiovascular survival compared with patients with a PWV to concurrent diseases (e.g. arteriosclerosis), the balance <8.1 m/s [11]. between elastin fibres and collagens tends to be disrupted in Lastly, a recent study from a Norwegian group including favour of the latter. This process involves several players, 1022 kidney transplant recipients showed that below a cut-off including matrix metalloproteinases [34–36], which degrade elastin fibres and the connections between them, calcium depo- value of 12 m/s, each increment in PWV of 1 m/s starting from 8 m/s was associated with a 36% increase in mortality risk [12]. sition in the tunica media and collagen glycosylation by The aforementioned studies demonstrate the powerful pre- advanced glycation end products (AGEs) [37]. Also, endothelial and vascular smooth muscle cells can affect the elastic property dictive value of PWV for cardiovascular events and mortality of the arterial wall, although the mechanisms are not well (see Table 1), irrespective of age and other clinical or laboratory understood [33]. All the aforementioned factors cause an accel- variables, thus confirming data obtained from other studies eration of arterial stiffness progression. involving different patient populations [47]. Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/413/4654834 by Ed 'DeepDyve' Gillespie user on 20 June 2018 kidney transplant, arterial stiffness and immunosuppression | 415 Fig. 1. Scheme of wave propagation according the PWV model. (A) Healthy subject/healthy artery: PWV is slow at the aortic level and fast at small (muscular) arteries. Each wave represents the sum of a unique forward wave (blue arrow) and multiple backward waves (black arrows). Backward waves are generated from reflection points located in the circulatory system: bifurcations (green dashes) and small arteries and arterioles (not shown in the figure). Due to the PWV gradient (i.e. the length and resistance at reflection points), backward waves reach, with a delay, the systolic peak of the forward wave, so there is no significant augmentation pressure (or Aix). (B) Patients with arterial stiffness: aortic media calcification and atherosclerotic plaque (red arrow - pulse presure) tend to increase the PWV at the aortic level. Moreover, changes in muscular tone and structure in small arteries and/or arteriolar hyalinosis (yellow arrows) increase resistance, amplifying the magnitude of reflected waves. As a consequence, more prominent backward waves reach the forward wave near the systolic peak, thus generating a notable increase in central AP, expressed as augmentation pressure. Table 1. Main studies on the predictive power of arterial stiffness for cardiovascular endpoints (mortality and event) Number Follow-up Independent predictive Independent predictive Source of patients (mean years) power for CV death: PWV power for CV death: Aix or AP Mitchel et al. 2010 [46] 330 3.8 YES NA Verbeke et al. 2011 [11] 512 5 YES YES Dahle et al. 2015 [12] 1040 4.2 YES NA Aix, augmentation index; AP, aortic pressure; CV, cardiovascular; PWV, pulse wave velocity. All studies used a Sphigmocor device for calculation of PWV and Aix or AP. Arterial stiffness and immunosuppression vasoconstriction at the arteriolar level is probably the cause of augmentation of certain stiffness parameters (Aix and AP) in As previously described, CNI toxicity on arteries is well known, patients treated with cyclosporine. Several factors seem to at least at the microcirculatory level. Two types of toxicity for play a role in this acute toxicity: hyperactivation of the renin– cyclosporine have been described: acute and chronic toxicity angiotensin system [50], upregulation of endothelin receptors [48]. Acute toxicity is a functional alteration due to an imbal- [51], endothelial cell injury [52], alteration in L-arginine nitric ance between vasoconstrictors and vasodilators, leading to a oxide production and hyperactivation of the sympathetic decrease in renal blood flow and to an increase in vascular resistance, particularly at the arteriolar level. Since arteriolar system [53]. Calcium antagonists and angiotensin receptor network resistance is the last barrier against pulsatile pressure blockers (ARBs) or angiotensin-converting enzyme inhibitors and represents the gate of the backward wave [49], this (ACEis) are known to mitigate the acute toxicity, which makes Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/413/4654834 by Ed 'DeepDyve' Gillespie user on 20 June 2018 416 | E. Melilli et al. Table 2. Main studies on the effect of IMS on arterial stiffness in kidney transplant recipients Source Design N IMS Results Limitation Zoungas et al. 2004 [63] Longitudinal 36 24 CYC PWV: no difference Small 12 TAC Aix: TAC ###/CYC # Ferro et al. 2002 [65] Transversal 250 146 CYC PWV: NA Design 62 TAC Aix: TAC # versus CYC Strzo ´ ecki et al. 2007 [66] Transversal 152 76 CYC PWV: TAC # versus CYC Design 76 TAC Aix: NA Seckinger et al. 2008 [67] Conversion CYC to EVR 27 10 CYC PWV: CYC "; EVR # Small 17 EVR Aix: NA Short follow-up Joannide `s et al. 2011 [68] Conversion CYC to SRL 44 21 CYC PWV: CYC "; SRL # Small 23 SRL Aix: CYC "; SRL # Selection criteria Gungor et al. 2011 [69] Transversal 81 47 CNI PWV: no difference Small 34 imTOR Aix: no difference Mixed CNI/imTOR Seibert et al. 2014 [70] Transversal 46 23 BLC PWV: no difference Small 23 CYC AP BLC # versus CYC Selection Melilli et al. 2015 [71] Transversal 40 20 BLC PWV <8.1: BLC 60%, CNI 40% Small 20 CNI Aix: NA CNI mixed Cruzado et al. 2016 [72] Conversion TAC to EVR 60 32 TAC PWV: no difference Normal PWV 28 EVR Small Holdaas et al. 2017 [31] Conversion CNI to EVR 164 95 CNI PWV: no difference Normal PWV 69 EVR Aix: NA CNI mixed Aix, augmentation index; AP, augmentation pressure; BLC, belatacept; CYC, cyclosporine; EVR, everolimus; IMS, immunosuppression; PWV, pulse wave velocity; SRL, sirolimus; TAC, tacrolimus. it difficult to understand how all these factors contribute to Table 3. Main effects of different immunosuppressive drugs on PWV, Aix and blood pressure acute vascular toxicity [54, 55]. Chronic toxicity is characterized by a structural change in Systemic blood vessels, particularly small arteries and arterioles [56]. Hyalinosis Drugs pressure PWV Aix or AP lesions on the arteriolar wall, a hallmark of CNI toxicity, are present in protocol biopsies at 10 years in the majority of Cyclosporine þþþ þþ þþ/þ patients receiving tacrolimus or cyclosporine [57]. Treatment Tacrolimus þ/þþ /þþ imTOR (everolimus  /þ using the mammalian target of rapamycin (mTOR) inhibitors or sirolimus) (imTORs) sirolimus and everolimus has been shown to attenu- BLC ate allograft vasculopathy in heart transplant recipients [58–60]. Mycophenolate mofetil  ?? Whether immunosuppressive drugs can modify PWV, directly Steroid þ ?? or indirectly influencing vasculature, remains largely speculative and difficult to demonstrate for the following reasons [61]. First, ?, stand for No Data. transplantation per se ameliorates arterial stiffness [22, 62, 63], probably as a result of recovery in renal function. Renal function is, in fact, closely related to PWV, as shown by Ford et al. [19]. In a small study, Covic et al. [73] showed that cyclosporine Moreover, transplantation allows better control of blood pressure, acutely decreased the Aix. However, the study lacked a control thus decreasing PWV, although Seibert et al. [64] showed that group and the decrease in Aix after cyclosporine uptake was high PWV was related to cardiovascular events after kidney related to a decrease in the timing of the reflected wave, which transplantation, regardless of peripheral blood pressure. Finally, could lead to an increased PWV in the long term. the majority of studies published so far are small-scale, retro- Interestingly, in the same period, a cross-sectional study spective and case–control (see Table 2). (including 250 stable kidney transplant recipients) showed Despite these limitations, there is some evidence of a protec- that cyclosporine increased Aix and blood pressure tive effect of CNI-sparing protocols on the progression of arterial considerably more than tacrolimus [65]. In 2007, Stro ´zecki et al. stiffness in kidney transplant recipients. Table 3 summarizes [66] compared the PWV in 76 patients taking cyclosporine with the impact of different immunosuppressive drugs on PWV, Aix 76 patients taking tacrolimus. The two study groups were and blood pressure. matched for main clinical characteristics (age, blood pressure, time on haemodialysis, diabetes). The cyclosporine group had CNIs and stiffness higher PWV values compared with the tacrolimus group (9.336 2.10 versus 8.546 1.35, respectively; P < 0.01). In Initial data on CNI effects on large arterial functions have been another study by the same group, stepwise multiple regression conflicting. In a prospective study, Zoungas et al. [63] compared analysis showed that age, male sex, mean arterial pressure PWV before and after kidney transplantation in 36 patients. At 12 months post-transplantation, PWV improved in all patients, (MAP), cyclosporine (versus tacrolimus) and fasting glucose irrespective of cyclosporine or tacrolimus use, although Aix concentration were independently associated with increased reduction was greater in patients treated with tacrolimus PWV [74]. The effect of cyclosporine on stiffness is probably (8.06 16.5% versus 27.46 18.2%; P ¼ 0.01). due to an increase in vascular tone or to impaired nitric- oxide Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/413/4654834 by Ed 'DeepDyve' Gillespie user on 20 June 2018 kidney transplant, arterial stiffness and immunosuppression | 417 vasodilation, although a study from Silverborn et al. [75]did not before and after conversion. The median time from transplanta- confirm this hypothesis. In their proof-of-concept study, 18 lung tion was 1.7 years for the tacrolimus group (25 patients) and transplant recipients (all treated with cyclosporine) were com- 1.3 years for the everolimus group (31 patients). At 24 months pared with patients waiting for lung transplantation and healthy from randomization, both groups had very well-controlled controls. Arterial resistance, non-endothelial-dependent relaxa- blood pressure, although the dipper status was preserved in more patients on everolimus (30% of tacrolimus-treated tion and arterial stiffness (by echo tracking) were analysed. Lung recipients had significantly less elastic arteries than healthy patients were non-dippers versus 22% of patients on everoli- mus). PWV values at baseline and 12 and 24 months were in the controls or patients on the transplant waiting list, even though no difference in blood pressure or endothelial response to nitric oxide normal range, with no significant differences between the two study groups [72]. was seen. Another ancillary study from a recent trial [31] evaluated Since cyclosporine was found to be related to higher PWV, PWV and blood pressure by ABPM. PWV data were obtained for conversion to tacrolimus could be an option to improve arterial 277, 223 and 184 patients at randomization and months 12 and stiffness. This hypothesis was tested in a small study where sta- 24, respectively. Patients converted to everolimus had a slight ble kidney recipients taking cyclosporine (>10 years) were con- decrease in PWV (month 12: 0.24 m/s; month 24: 0.03 m/s), verted to tacrolimus. PWV (by echo tracking) and ambulatory blood pressure monitoring (ABPM) were performed at baseline whereas patients on cyclosporine experienced a progressive increase in PWV (month 12: 0.11 m/s; month 24: 0.16 m/s). and repeated at 3 months post-conversion. No difference was Although the difference was not significant, one can argue that observed in blood pressure or PWV, probably due to the short baseline values were in the normal range (mean 7.8 m/s for the time span from conversion [76]. everolimus group and 7.6 m/s for the cyclosporine group). Despite the limitations in their study design, all the afore- Follow-up at 24 months confirmed the predictive value of PWV, mentioned studies suggest a possible negative impact of CNIs, since the incidence of cardiovascular events in the entire cohort and especially cyclosporine, on PWV. was low (2.8% in the everolimus group and 4.8% in the cyclo- sporine group). In such low-risk populations, a greater number imTORs and arterial stiffness of patients is necessary in order to show any benefit in a cardio- The imTORs everolimus and sirolimus are used in immunosup- vascular endpoint (or PWV) from any therapeutic intervention pressive regimens in kidney transplantation. Yet since their (such as conversion to an imTOR). Moreover, since such small first use, they have not shown superior efficacy in terms of variations (0.4–0.5 m/s) usually occur over a long time span, renal survival or prevention of rejection compared with follow-up at 24 months was probably too early a time point to tacrolimus [77, 78]. Beyond their immunosuppressive property, detect any significant change in PWV [82, 83]. imTORs exert certain pleiotropic effects on atherogenesis [79, Since patients with high PWV at baseline are susceptible to a 80] and fibrosis [81], so at least in theory, kidney transplant steeper increase in PWV [13], we cannot exclude the possibility recipients may benefit from the use of imTORs in terms of arte- that conversion to imTORs is beneficial for these patients. rial elasticity. In a randomized clinical trial, 17 of 27 patients were Co-stimulatory blockade and arterial stiffness switched from cyclosporine to everolimus 6 months after kid- ney transplantation. PWV remained stable in the everolimus The biologic immunosuppressant belatacept (BLC) is a fusion group (9.506 1.92 versus 9.136 1.62 m/s, DPWV 0.376 1.14 m/ protein comprising the common fragment Fc of human immu- s), whereas it was increased in the cyclosporine group noglobulin G (IgG) and CTL4, which, upon binding to CD80 and (9.936 1.94 versus 10.86 2.24 m/s, DPWV þ 0.896 1.47 m/s) [67]. CD86 receptors on antigen-presenting cells (APCs), inhibits co- In a substudy of the CONCEPT trial [68], 23 of 44 patients stimulatory signals essential for T-lymphocyte activation. In were converted from cyclosporine to sirolimus 12 weeks after the two non-inferiority clinical trials BENEFIT and BENEFIT-EXT kidney transplantation. PWV and Aix were evaluated at weeks [84, 85], BLC was demonstrated to have an anti-rejection effi- 12, 26 and 52. Patients in the sirolimus group experienced a cacy similar to cyclosporine. At the 3-year follow-up, patients decrease in PWV, whereas those in the cyclosporine group had treated with BLC showed better renal function, less renal fibro- an increase in PWV, with a significant difference at week 52. sis in protocol biopsies and a better cardiovascular profile [86]. Both groups experienced an increase in Aix, which was more In particular, at 12 months, systolic and diastolic blood pres- marked in the cyclosporine group. According to the authors, the sures were lower in patients treated with BLC than in those progressive decrease in PWV in the sirolimus group was a treated with cyclosporine, as shown in the BENEFIT and cause, rather than a consequence, of the better blood pressure BENEFIT-EXT trials, even though both treatment groups had the control. same baseline level of blood pressure. Moreover, in the BENEFIT Despite these encouraging results, a cross-sectional study by trial, both BLC regimens [more intensive (MI) and less intensive Gungor et al. [69] showed no benefit in terms of PWV or Aix in a (LI)] were associated with a 30% reduction in the odds of requir- group of patients treated with an imTOR (for at least 6 months, ing a higher number of antihypertensive medications at month with either sirolimus or everolimus) compared with treatment 12 (P¼ 0.02, BLC-LI versus cyclosporine A) [87]. with CNIs (cyclosporine or tacrolimus). In a linear regression Data analysis from these trials at different time points (12, analysis, only conventional risk factors (age, blood pressure, 36 and 84 months) also showed that patients treated with BLC cholesterol level and proteinuria) were predictive of arterial had a better GFR compared with patients treated with cyclo- stiffness. sporine [87]. A long-term analysis from the BENEFIT trial at More recently, a randomized clinical trial on the effect of late 7 years showed a 43% reduction in mortality risk or risk of graft conversion from CNIs (tacrolimus) to an imTOR (everolimus) loss with both the BLC-MI and BLC-LI regimens compared with showed a small benefit related to regression of left ventricular the cyclosporine regimen [88]. Since GFR is a powerful predictor hypertrophy in both groups. As secondary outcomes, changes of cardiovascular events and mortality in kidney transplant in blood pressure (measured by ABPM) and PWV were evaluated recipients [89, 90], these results were not unexpected. Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/413/4654834 by Ed 'DeepDyve' Gillespie user on 20 June 2018 418 | E. Melilli et al. In addition to better survival rates related to GFR, data from published studies on kidney transplantation do not report data other studies suggest improved control of arterial stiffness in BLC- on intra- or interobserver variability, making it difficult to based regimens. In an experimental model of hypertension assess and compare the data quality of each study. In fact, only induced by angiotensin or deoxycorticosterone acetate (DOCA)– a few studies on kidney transplantation have reported an salt, Vihn et al.[91] administered treatment infusion based on acceptable variation coefficient index (intraclass correlation CTLA4-Ig (a drug with effects mimicking genetic CD80/CD86 defi- coefficient) for operator variability [21, 76, 93]. There is also an ciency) in mice, thus preventing hypertension acceleration. A pos- extreme paucity of data on intrapatient variations in stiffness sible influence of the immune system on hypertension is not new, parameters. since the contribution of T cells in DOCA–salt-induced hyperten- Confounding factors represent another limitation relevant sion in thymectomized mice was shown >25 years ago [92]. In to arterial stiffness studies, including blood pressure and the mild hypertension, endothelial vessel damage causes the release duration of kidney disease, both closely related to arterial stiff- of damage-associated molecular patterns and altered self-proteins. ness. In kidney transplantation, studies published so far have Hypothetically these molecules could be recognized as antigens only reported the impact of time on dialysis [22, 25, 66], whereas presented by dendritic cells and thus trigger the immune system, data on the duration of disease and/or blood pressure are activating T cells and stimulating cytokine production and inflam- scarce. Moreover, most of these studies analysed only the rela- mation [93], the latter being closely associated with increased vas- tionship between a single determination of blood pressure and cular stiffness [16]. stiffness parameters. More rigorous blood pressure determina- From a clinical perspective, only two studies have analysed tions using ABPM and repeated arterial stiffness measurements the impact of BLC on arterial stiffness in kidney transplant recipi- are needed in order to confirm a possible independent effect of ents. In the first study, Seibert et al. [70], in a case–control retro- immunosuppression on arterial stiffness. Other confounding spective study, compared 23 patients treated with BLC with 23 factors such as diabetes and disorders of mineral and bone patients treated with cyclosporine. The two groups showed no metabolism are also related to arterial stiffness in kidney trans- significant differences with regard to gender distribution, age, plantation [25, 68, 96]. The use of vitamin D supplementation body mass index, time on dialysis prior to transplantation may produce a decrease in PWV in CKD patients [97], although and time since transplantation. After a mean follow-up of no data on vitamin D repletion in recipients are available. 88 months (all patients included had a minimum time from Nonetheless, paricalcitol did not seem to exert a reducing effect transplantation of 20 months and were first-kidney recipients), on PWV after 1 year of treatment, as shown by Pihlstrøm et al. augmentation pressure was significantly better in the BLC group [32] in a randomized trial on the effect of paricalcitol on para- [augmentation pressure 12.7 mmHg (range 8.3–16) versus 7.3 (2.3– thyroid hormone levels in kidney transplant recipients. 11.7); P¼ 0.048], despite no differences in systolic and diastolic In conclusion, all these confounders mask the true magnitude blood pressures (both peripheral and central). PWV mean values of the impact of immunosuppressive regimens on arterial stiffness. were identical in both groups (8.8 m/s). In the second study [71], our group compared 20 patients treated with BLC with 20 patients on CNIs (16 on tacrolimus and Open questions and ideas for future clinical 4 on cyclosporine). The control CNI group was matched for all studies the main variables affecting PWV. There were no differences in Measurements of PWV, Aix and AP usually take between 20 and median PWV between the two groups: 7.96 3.4 m/s (range 4.1– 30 min when performed by an experienced operator, which 12) in the CNI group and 7.46 4 m/s (range 5.2–15.5) in the BLC stands as one of the obstacles to widespread use of arterial stiff- group (P¼ 0.4). Due to the large discrepancy in age in our popu- ness evaluation in patients on transplant waiting lists or after lation study, we chose a value of 8.1 m/s of femoral-carotid PWV transplantation. Although magnetic resonance and/or certain as the cut-off value for high arterial stiffness, which was shown blood pressure devices can assess stiffness parameters, thus to correlate with an increased cardiovascular mortality risk in a rendering these tests less cumbersome, these parameters have recent retrospective study performed in a transplant population not yet been proven to be predictive of cardiovascular events [11]. In that study, 50% of patients in the CNI group had a PWV [43, 98, 99]. Moreover, measurement devices approved by >8.1 m/s versus 25% of patients in the BLC group (P¼ 0.08). regulatory agencies is often unaffordable in many health care Regression logistical analysis showed that age, renal resistive systems, thus restricting their use to research purposes only. index at 3–6 months after transplantation and BLC [odds ratio Sincebaselinehigh PWV values predict a higher cardiovascular 0.008 (95% confidence interval 0.004–0.890); P ¼ 0.045] were pre- risk, future trials in transplantation could include basal PWV as a dictive variables of PWV. biomarker to discriminate those patients at very high cardiovascu- Although these two studies have some limitations (transver- lar risk who could benefit from a CNI-free immunosuppressive reg- sal, lack of a baseline record of arterial stiffness measurements), imen (BLC-based, for example). Moreover, monitoring of PWV after data on PWV and augmentation pressure suggest that transplantation at different time points could identify those improvement in arterial stiffness could be obtained using BLC patients with rapid progression of arterial stiffness who could ben- as the main immunosuppressant. efit from conversion of CNIs to imTORs or who need tighter control of mineral and bone metabolism or blood pressure. Limitations Although the number of publications on arterial stiffness in kid- Conclusion ney transplantation is increasing, most studies present limita- tions that warrant caution in interpreting the results. As with Kidney transplant recipients with higher values of PWV are at increased cardiovascular and mortality risk. Preliminary data any method of measurement performed by an operator, there is a risk of high interobserver variation. Although the techniques from small studies indicate that CNIs, and especially cyclospor- used to measure arterial stiffness have been validated in terms ine, could increase PWV in renal transplant recipients. of reproducibility in healthy and CKD patients [29, 94, 95], most Although some studies suggest a possible protective effect of Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/413/4654834 by Ed 'DeepDyve' Gillespie user on 20 June 2018 kidney transplant, arterial stiffness and immunosuppression | 419 imTORs on arterial stiffness, data from two randomized trials 12. Dahle DO, Eide IA, Asberg A et al. Aortic stiffness in a mortal- ity risk calculator for kidney transplant recipients. have not shown significant differences after either early or late Transplantation 2015; 99: 1730–1737 conversion of CNIs to imTORs. The reduction in cardiovascular 13. Mitchell GF, Parise H, Benjamin EJ et al. 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Clinical Kidney JournalOxford University Press

Published: Nov 23, 2017

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