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Antihypertensive Treatment in Kidney Transplant Recipients—A Current Single Center Experience

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Antihypertensive Treatment in Kidney Transplant Recipients—A Current Single Center Experience Journal of Clinical Medicine Article Antihypertensive Treatment in Kidney Transplant Recipients—A Current Single Center Experience Ulrich Jehn 1 , Katharina Schütte-Nütgen 1, Markus Strauss 2, Jan Kunert 1, Hermann Pavenstädt 1, Gerold Thölking 1 , Barbara Suwelack 1 and Stefan Reuter 1,* 1 Department of Medicine D, Division of General Internal Medicine, Nephrology and Rheumatology, University Hospital of Münster, 48149 Münster, Germany; [email protected] (U.J.); [email protected] (K.S.-N.); [email protected] (J.K.); [email protected] (H.P.); [email protected] (G.T.); [email protected] (B.S.) 2 Department of Medicine C, Division of Cardiology and Angiology, University Hospital of Münster, 48149 Münster, Germany; [email protected] * Correspondence: [email protected]; Tel.: +49-251-83-47540; Fax: +49-251-83-56973 Received: 16 October 2020; Accepted: 3 December 2020; Published: 7 December 2020 Abstract: Arterial hypertension affects the survival of the kidney graft and the cardiovascular morbidity and mortality of the recipient after kidney transplantation (KTx). Thus, antihypertensive treatment is necessary for a vast majority of these patients. Long-term data on antihypertensive drugs and their effects on allograft function after KTx is still limited, and further investigation is required. We retrospectively analyzed a cohort of 854 recipients who received a kidney transplant at our transplant center between 2007 and 2015 with regard to antihypertensive treatment and its influence on graft function and survival. 1-y after KTx, 95.3% patients were treated with antihypertensive therapy. Of these, 38.6% received mono- or dual-drug therapy, 38.0% received three to four drugs and 8.1% were on a regimen of 5 drugs. Beta-blockers were the most frequently used antihypertensive ≥ agents (68.1%). Neither the use of angiotensin-converting enzyme inhibitor/angiotensin receptor blockers (51.9%) and calcium channel blockers (51.5%), nor the use the use of loop diuretics (38.7%) affected allograft survival. Arterial hypertension and the number of antihypertensive agents were associated with unfavorable allograft outcomes (each p < 0.001). In addition to the well-known risk factors of cold ischemic time and acute rejection episodes, the number of antihypertensive drugs after one year, which reflects the severity of hypertension, is a strong predictor of unfavorable allograft survival. Keywords: kidney transplantation; post-transplant care; arterial hypertension; antihypertensives; allograft failure 1. Introduction Cardiovascular disease (CVD) is the leading cause of mortality and morbidity in kidney transplant (KTx) recipients [1]. Thus, arterial hypertension (AHT) is a significant risk factor that affects a large proportion of this patient population (50–80% of adult recipients) [2]. Increased systolic and diastolic blood pressure are associated with allograft failure [3]. However, it has been shown that target systolic blood pressures below 120 mmHg in KTx recipients, as recommended for patients at a high risk for cardiovascular events [4], does not negatively affect allograft function [5], favoring the need for strict blood pressure control in KTx recipients. Most kidney transplant recipients have a long-term history of chronic kidney disease (CKD) associated with vascular pathologies leading to elevated systolic blood pressure (SBP) and increased pule J. Clin. Med. 2020, 9, 3969; doi:10.3390/jcm9123969 www.mdpi.com/journal/jcm J. Clin. Med. 2020, 9, 3969 2 of 14 pressure [6]. After KTx, additional factors occur that are capable of inducing AHT. First, the unavoidable use of immunosuppressants, especially calcineurin inhibitors (CNIs), and steroids is implied to induce or promote AHT [7]. Second, volume overload is a common issue in patients with renal (allograft) insufficiency, and induces elevated blood pressure [8]. Third, renal insufficiency following KTx can also cause AHT, since the allograft and also the diseased autologous kidneys can trigger AHT, mainly via altered sodium regulation and the activation of the renin–angiotensin–aldosterone system (RAAS) [9]. Fourth, transplant renal artery stenosis accounts for 1–5% of cases of post-transplant AHT [10]. Fifth, post-transplant weight gain and obesity are common and lead to a significantly increased prevalence of the metabolic syndrome, both of which favor AHT [11]. In KTx recipients, donor factors such as the donor’s pre-existing AHT, higher donor age, poor allograft quality and genetic donor factors can also influence the recipient’s blood pressures [2]. To date, there have not been randomized controlled trials on optimal blood pressure limits or favorable treatment strategies in patients after KTx [2]. Therefore, the Kidney Disease Improving Global Outcomes (KDIGO) and National Kidney Foundation guidelines for the management of AHT in patients with CKD are widely followed when AHT is treated in KTx recipients [12], targeting a blood pressure <130/80 mmHg. Nevertheless, there are substantive differences in the treatment of non-transplant patients, as, for example, some of the factors mentioned above that contribute to AHT in KTx recipients are transplant-specific. A recent cross-sectional study from Poland showed that beta-blockers were the most commonly used antihypertensive agents, followed by Calcium channel blockers (CCB), angiotensin-converting enzyme inhibitors (ACE-I)/Angiotensin-II-receptor-blockers (ARB), and diuretics [13]. The remaining drug classes, such as alpha1-receptor-antagonists, anti-sympathotonics and vasodilators are usually prescribed as reserve antihypertensives. In CKD patients, the blockage of RAAS has been proved to slow down the progression of diabetic and non-diabetic (protein-rich) kidney disease [14,15]. Several years ago, we observed in our KTx cohort that the use of ACE-I/ARB and CCB promoted long-term graft survival in KTx recipients [16]. A recent meta-analysis of 71 randomized controlled trials by Pisano et al. also supports the preferred use of CCB, as they were found to improve graft function as well as graft survival [17]. In this meta-analysis, ACE-I and ARB treatment was associated with worsening effects on allograft function and a 3-fold higher risk for hyperkalaemia—nevertheless there is some evidence for improvement of graft survival regarding RAAS inhibitors [17]. To date, however, there is no data demonstrating an association between the use of beta-blockers or diuretics and the long-term outcome of kidney allografts and KTx recipients although both drug classes are widely used. The frequent co-incidence of different therapeutic indications especially for beta-blockers and/or diuretics in addition to the treatment of AHT in the KTx setting, e.g., treatment of congestive heart failure or atrial fibrillation, is a problematic pitfall in this matter [18,19]. Especially for loop diuretics, the evidence for their perioperative use in KTx is still controversial [20]. The present study was conducted in order to shed some light on the relationship between antihypertensive drugs and long-term outcomes for KTx recipients in the present era, taking into account that former studies are predominantly ten to twenty years old and KTx recipient outcome has changed rapidly within the last years [21]. Our analyses focused on how AHT treatment in the first year predicted the subsequent allograft survival. 2. Materials and Methods 2.1. Study Design and Population We analyzed the data of 850 adult patients (follow-up of 4109.5 patient years, median follow-up 4.2 years) who were transplanted at our center between 1 January 2007 and 31 December 2015. The demographics and clinical characteristics of the patients were recorded at the time of KTx, J. Clin. Med. 2020, 9, 3969 3 of 14 and written informed consent was obtained from all patients to record their data. The data was taken from the patients’ files, and the personal information was made anonymous prior to the analysis. This study was performed in accordance with the Declaration of Helsinki and the International Conference on Harmonization of Good Clinical Practice guidelines and approved by the local ethics committee (Ethik Kommission der Ärztekammer Westfalen-Lippe und der Medizinischen Fakultät der Westfälischen Wilhelms-Universität, 2014-381-f-N). Induction therapy was chosen based on the immunological risks of the patients. The triple immunosuppressive standard regimen consisted of tacrolimus (6–10 ng/mL), mycophenolate mofetil and steroids (Table1). Estimated glomerular filtration rate (eGFR) was calculated using the CKD–EPI formula [22]. 2.2. Blood Pressure Monitoring and Antihypertensive Medication Blood pressure was measured manually during the outpatient one-year routine follow-up according to the 2013 European Society of Hypertension (ESH)/European Society of Cardiology (ESC) Guidelines for the management of AHT [23] and the antihypertensive medication that each patient was taking at the time of the one-year follow-up was simultaneously recorded. We categorized antihypertensive medication into ACE-I/ARB, CCB and diuretics, subclassified into loop diuretics, thiazids and aldosterone-antagonists, beta-receptor-blockers, alpha1-receptor-antagonists, anti-sympathotonics and vasodilators. 2.3. Statistical Analysis The data was analyzed with IBM SPSS Statistics 26 (IBM Corp., Armonk, New York, USA). The results are expressed as a mean with standard deviation, median with interquartile range (IQR) or number/percent. The categorical
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