Gorriz et al. BMC Nephrology (2021) 22:110 https://doi.org/10.1186/s12882-021-02313-1 RESEARCH ARTICLE Open Access Cardiovascular risk factors and the impact on prognosis in patients with chronic kidney disease secondary to autosomal dominant polycystic kidney disease José Luis Gorriz1*, David Arroyo2, Luis D’Marco1, Roser Torra3, Patricia Tomás1, María Jesús Puchades1, Nayara Panizo1, Jonay Pantoja4, Marco Montomoli1, José Luis Llisterri5, Vicente Pallares-Carratalá6*† and José Manuel Valdivielso7† Abstract Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent hereditary renal disease. There is an increased rate of cardiovascular disease (CVD) in ADPKD. In this study, we evaluate the prevalence of cardiovascular risk factors, the achievement rates for treatment goals and cardiovascular events (CVE) in ADPKD and their relations with asymptomatic CVD in CKD from other etiologies (CKDoe) and controls. Methods: We evaluated 2445 CKD patients (2010–2012). The information collected was: clinical, anthropometric and analytical parameters, treatments and CVD evaluation (intima-media thickness (IMT), atheromatous plaque presence and ankle-brachial index (ABI)). Laboratory, vital status, CVE and hospitalizations were collected for 4 years. Results: ADPKD patients had a worse renal function and worst achievement of blood pressure, higher parathormone levels but lower proteinuria compared to CKDoe. ADPKD patients presented lower IMT values than other groups, however, an intermediate rate of pathologic ABI and atheromatous plaque was present. More than half of the patients received statins, achieving LDL-c levels < 100 only in 50 and 39.8% of them (ADPKD and CKDoe respectively). The number of CVE during the follow-up period was low. In adjusted Cox regression model, ADPDK had the lowest occurrence of CVE of all three groups (HR:0.422, 95%CI 0.221–0.808, p = 0.009). Conclusion: ADPKD patients show intermediate control rates of CVD. A better control of CVD risk seems to be related with a lower load of CVD compared to other groups, which may lead in the long term to a better prognosis. Further investigation is necessary to determine cardiovascular prognosis in ADPKD. Keywords: Autosomal dominant polycystic kidney disease, Chronic kidney disease, Cardiovascular disease, Nephropathy * Correspondence: jlgorriz@senefro.org; pallares.vic@gmail.com † Vicente Pallares-Carratalá and José Manuel Valdivielso share senior authorship. 1 Department of Nephrology, University Clinic Hospital, INCLIVA, University of Valencia, Av Blasco Ibañez 17, 46010 Valencia, Spain 6 Health Surveillance Unit, Castellon Mutual Insurance Union, Castellon, Spain. Department of Medicine, Jaume I University, Castellon, Spain Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Gorriz et al. BMC Nephrology (2021) 22:110 Page 2 of 10 Introduction diabetic or hypertensive nephropathy, there is an in- Cardiovascular disease (CVD) is the leading cause of creased in the rate of CVD in ADPKD patients being the death in patients with chronic kidney disease (CKD) first cause of death (Fig. 1) [5, 6]. It should be noted that from earlier stages of the disease compared to the there is evidence that asymptomatic CVD predicts the general population [1, 2]. Consequently, CKD has been incidence of CVE [7], but data on evaluation and man- considered an important cardiovascular risk factor in agement of cardiovascular risk in ADPKD are limited. several international guidelines. In this regard, several This study evaluates the prevalence of classic cardio- factors have been postulated to contribute to this vascular risk factors in ADPKD, its relationships to increased risk, mainly, age at CKD initiation and comor- asymptomatic CVD and treatment trends in ADPKD bidities such as arterial hypertension and diabetes, patients in a large cohort of CKD patients and controls followed by other related conditions such as obesity or without previous CVD. dyslipidemia [3]. On the other hand, CKD per se produces several alterations that have a direct impact on Material and methods vascular health, such as proteinuria, anemia, metabolic Study design and participants acidosis or mineral bone disease (MBD). These lastly is This study is a sub-analysis of the NEFRONA project, known as non-traditional or uremic related factors. which consists of a large prospective multicenter cohort Some of these factors may partially explain the higher designed to evaluate asymptomatic CVD in patients at rates of both asymptomatic CVD and cardiovascular different stages of CKD without previous CVE. Extensive events (CVE) among CKD patients. information on methodology and initial results has been Autosomal dominant polycystic kidney disease (ADPK published previously [8, 9]. In summary, from October D) is the most frequent hereditary renal disease and 2010 to June 2012, 2445 patients with CKD (937 CKD accounts for approximately 6 to 10% of the patients stage 3, 820 CKD stages 4–5 and 688 in dialysis) were initiating renal replacement therapies (RRT) worldwide enrolled in 81 hospitals and dialysis units throughout [2, 4]. Although ADPKD is not usually associated with Spain, along with 559 patients without CKD used as Fig. 1 Pathophysiological mechanisms associated with the initiation and progression of chronic kidney disease in autosomal dominant polycystic kidney disease. This schematic figure shows the negative influence of classical and renal or uremic-related cardiovascular risk factors in patients affected by ADPKD. The key to management these patients depend of the optimal approach and good control of these associated risk factors. The uses of novel therapies as vasopressin V2-receptor antagonist (Tolvaptan) may delay the progression of the renal disease specifically at the first step of the pathophysiological mechanisms related to proliferation and expansion of the cyst. Finally, if these measures are not taking in the early stages of ADPKD, a cascade of events can develop serious consequences. In addition, an activation of SRAA and SNS may produce vascular damage, increase the vascular resistance and renal fibrosis. All these activated mechanisms induce a chronic and irreversible damage in the kidneys. Abbreviations: SRAA, renin – angiotensin – aldosterone system; SNS, sympathetic nervous system; ADPKD, autosomal dominant polycystic kidney disease; CVD, cardiovascular disease; CKD, chronic kidney disease Gorriz et al. BMC Nephrology (2021) 22:110 Page 3 of 10 controls, also without previous CVE selected from 14 cardiovascular events and hospitalizations were collected Spanish primary care centers. Controls did not have every 2 years and at the end of the study (48 months). CKD but were not completely healthy subjects, as they Patients with ADPKD were compared to non-CKD attended primary care due to different comorbidities. patients and patients with CKDoe. In order to assess the A biannual follow-up was conducted over 4 years. The specific impact of ADPKD and exclude the added effect patients signed the informed consent and the study of advanced CKD, a secondary analysis was performed protocol was approved by the Ethics Committee of the comparing only patients with CKD stage 3 an ADPKD Arnau de Vilanova University Hospital. with controls. For this sub-study, 1192 patients with diabetes or on The adequacy of cardiovascular risk factors control dialysis were excluded to avoid the confusing effect of across groups was compared (hypertension, dyslipidemia, these circumstances. Finally, a total of 1.751 patients obesity, and treatment with statins and renin-angiotensin- were included: 132 patients with ADPKD were com- aldosterone system [RAAS] blockade). Adequate blood pared with 1121 patients with CKD of other etiologies pressure control was considered when the office blood (CKDoe) and 498 controls (Fig. 2). pressure was < 140/90 mmHg [10]. Proper cholesterol control was considered when LDL-cholesterol was < 155 Clinical data mg/dL in non-CKD patients or < 100 mg/dL in CKD The information collected at the baseline and at 24 patients [11]. months was as follow: clinical and anthropometric data, analytical parameters (including renal function, meta- Statistical analysis bolic profiles, anemia, CKD-related MBD and inflamma- Statistical analyses were performed with SPSS version tion parameters), pharmacological treatments and the 20.0 software (Chicago, Ill, USA). Mean value ± standard evaluation CVD using the intima-media thickness deviation is used for quantitative data, while absolute (IMT), the presence of carotid atheromatous plaque and and relative frequencies are used for qualitative variables. the ankle-brachial index (ABI). All anthropometric and The Kolmogorov-Smirnoff test was used to confirm the cardiovascular evaluations were performed using a stan- normal distribution. The Χ2 test was used to compare dardized method by three experienced itinerant teams. categorical data, Student’s t-test for continuous data The occurrence of fatal and non-fatal CVE was evaluated between two groups and ANOVA for multinomial com- biannually, as well as the death from other causes and parisons. Cox regression analysis was used for temporal kidney transplantation. Laboratory data, vital status, events. A significance level of 0.05 was accepted. Fig. 2 Flowchart describing the patient selection. Abbreviations: ADPKD, autosomal dominant polycystic kidney disease; CKD, chronic kidney disease; CKDoe, CKD of etiologies other than ADPKD Gorriz et al. BMC Nephrology (2021) 22:110 Page 4 of 10 Results peripheral vascular disease, presence of carotid atheroma- ADPKD patients compared to CKDoe patients tous plaque and obesity. Several differences in serum blood The differences between patients with ADPKD and and urinary parameters were detected. The patients with those with CKDoe and controls are summarized in ADPKD included in the study had worse renal function Table 1 and supplemental Table 1 (S1). In the ADPKD (worse mean estimated by glomerular filtration rate [eGFR], group, the distribution by age and gender was similar to more in patients with CKD stage 4) and consequence lower the controls, while patients with CKDoe, who were older hemoglobin levels, higher parathormone levels but lower and with a higher prevalence of males. In terms of proteinuria compared to CKDoe. It should be note that in comorbidities, patients with CKDoe showed more the evaluation of asymptomatic CVD, patients with ADPK Table 1 Comparison between controls, ADPKD patients and patients with CKD from other etiologies. The first “p” value corresponds to the comparison between the three groups and the second value corresponds to the comparison between ADPKD and patients with CKD from other etiologies (CKD stages 3, 4 and 5 not on dialysis) Controls ADPKD CKDoe P P n = 498 (28.4%) n = 132 (7.5%) n = 1121 (64.1%) Comparison ADPKD vs CKDoe three groups Age (years) 53.69 ± 1163 53.60 ± 11.09 59.56 ± 12.22 < 0.001 < 0.001 Male gender 262 (52.5%) 67 (50.8%) 700 (62.1%) < 0.001 0.012 BMI (Kg/m2) 27.82 ± 4.40 27.55 ± 4.65 28.56 ± 4.94 0.003 0.02 Obesity (BMI > 30 Kg/m2) 131 (26.3%) 35 (26.5%) 251 (34.9%) 0.010 0.03 Active smoking 100 (20.0%) 34 (25.7%) 212 (18.7%) NS NS Hypertension 163 (32.7%) 123 (93.2%) 1017 (90.2%) < 0.001 NS Dyslipidemia 157 (31.5%) 82 (62.1%) 762 (67.6%) < 0.001 NS CKD stage 3 0 (0.0%) 57 (43.2%) 635 (56.3%) < 0.001 0.004 CKD stages 4–5 0 (0.0%) 75 (56.8%) 493 (43.7%) < 0.001 0.004 Creatinine (mg/dL) 0.84 ± 0.15 3.00 ± 1.77 2.37 ± 1.18 < 0.001 < 0.001 eGFR (mL/min/1.73m2) 91.82 ± 16.94 27.50 ± 14.09 33.46 ± 14.05 < 0.001 < 0.001 Hemoglobin (g/dL) 14.54 ± 1.41 12.82 ± 1.49 13.3 ± 1.73 < 0.001 0.024 Albumin (g/dL) 4.36 ± 0.30 4.08 ± 0.43 4.09 ± 0.45 < 0.001 NS Uric acid (mg/dL) 5.05 ± 1.45 7.00 ± 1.30 6.86 ± 1.57 < 0.001 NS Phosphate (mg/dL) 3.46 ± 0.52 4.02 ± 0.77 3.64 ± 0.76 < 0.001 NS iPTH (pg/mL) 53.54 ± 15.34 172.26 ± 141.96 128.37 ± 110.75 < 0.001 < 0.001 25-hydroxi-vitamin D (ng/mL) 20.58 ± 8.39 18.13 ± 8.21 16.75 ± 7.47 < 0.001 NS FGF23 (pg/mL) 53.97 ± 62.88 96.77 ± 78.44 97.71 ± 84.06 < 0.001 NS Potassium (mEq/L) 4.47 ± 0.40 4.71 ± 0.51 4.75 ± 0.53 < 0.001 NS Proteinuria (g/day) 0.07 ± 0.12 0.32 ± 0.38 0,98 ± 1.4 < 0.001 0.04 Urine albumin to creatinine 34 ± 46 214 ± 507 427 ± 894 < 0.001 0.002 ratio (mg/g) SBP (mmHg) 132.45 ± 17.44 140.83 ± 19.56 142.99 ± 20.73 < 0.001 NS DBP (mmHg) 79.84 ± 9.66 85.14 ± 10.34 82.49 ± 10.86 < 0.001 0.006 IMT (mm) 0.70 ± 0.12 0.66 ± 0.11 0.72 ± 0.14 < 0.001 < 0.001 Pathologic ABI (< 0.9 or > 1.4) 62 (12.4%) 19 (14.4%) 244 (21.8) < 0.001 0.027 Ischemic ABI (< 0.9) 56 (11.4%) 14 (11.0%) 184 (17.4%) 0.004 0.041 Plaque presence 248 (49.7%) 71 (53.8%) 752 (66.7%) < 0.001 0.003 Cardiovascular event 11 (2.2%) 1 (0.8%) 73 (6.5%) < 0.001 0.008 Cardiovascular death 0 (0.0%) 0 (0.0%) 13 (1.2%) 0.026 NS Non-cardiovascular death 3 (0.6%) 3 (2.3%) 38 (3.4%) 0.004 NS Abbreviations: ABI ankle brachial index, ADPKD autosomal dominant polycystic kidney disease, BMI body mass index, CKD chronic kidney disease, CKDoe CKD of etiologies other than ADPKD, DBP diastolic blood pressure, eGFR estimated glomerular filtration rate with the CKD-EPI formula, FGF-23 fibroblast growth factor 23, IMT intima-media thickness, iPTH intact parathyroid hormone, NS not statistically significant, SBP systolic blood pressure Gorriz et al. BMC Nephrology (2021) 22:110 Page 5 of 10 D had lower IMT values than the other groups, however, in the three groups (HR 0.422, 95%CI 0.221–0.808, there was an intermediate rate of pathological ABI and p = 0.009) (Fig. 3). atheromatous plaque. When the control of classic cardiovascular risk factors Stage 3 ADPKD patients compared to non-CKD subjects was evaluated, patients with ADPKD had the worst (control group) achievement of blood pressure targets (Table 1 and A second analysis was performed, comparing only Supplemental Figure 1). The rates of overweight and ADPKD with stage 3 CKD to non-CKD subjects, in obesity were like non-CKD patients. It should be note order to better observe the specific effect of ADPKD in- that obesity was present in 34.9% of patients with stead of the effect of severe loss of eGFR (Table 2 and CKDoe, in 26.5% of patients with ADPKD and also in Supplemental Table 3). In this comparison, there were 26.3% of controls. Finally, it is also particularly note- no significant differences in age, gender, overweight, and worthy the low percentage of statins treatment in obesity; however, patients with ADPKD had higher rates patients with CKD (Supplemental Table 2 (S2)). Only of hypertension and dyslipidemia. As expected, due to slightly more than half of the patients received statins, their mild CKD, patients with ADPKD had lower levels reaching LDL-c levels < 100 in only 50 and 39.8% of of hemoglobin and serum albumin, and higher levels of them (ADPKD and CKDoe respectively). If we consider potassium, parathormone, and uric acid. Interestingly, an LDL-c target < 70 mg/dL, the percentage of patients no differences were found in phosphate or calcium who achieve this target is only 11 and 9.7% respectively. levels. In general, the number of CVE during the 4 year of There was a lower lipid control rate among patients follow-up was very low (Tables 1 and 2). In a Cox with ADPKD, despite a higher number of patients in regression model adjusted for age, sex, obesity, and statins treatment (Supplemental Table 4). Interestingly, tobacco use, ADPDK had the lowest incidence of CVE and despite their CKD, this was not associated to higher Table 2 Comparison between controls and ADPKD patients with stage 3 CKD Controls ADPKD stage 3 CKD p n = 498 (89.7%) n = 57 (10.3%) Age (years) 53.69 ± 11.63 54.54 ± 11.73 NS Male gender 262 (52.5%) 30 (52.6%) NS Hypertension 163 (32.7%) 52 (91.2%) < 0.001 Dyslipidemia 157 (31.5%) 37 (64.9%) < 0.001 Creatinine (mg/dL) 0.84 ± 0.15 1.69 ± 0.35 < 0.001 eGFR (mL/min/1.73m2) 91.82 ± 16.94 41.13 ± 8.52 < 0.001 Macroalbuminuria 0 (0.0%) 5 (13.2%) < 0.001 Total cholesterol (mg/dL) 204.41 ± 35.63 187.42 ± 40.68 0.001 HDL-cholesterol (mg/dL) 54.36 ± 15.38 49.05 ± 12.37 0.020 LDL-cholesterol (mg/dL) 128.73 ± 32.74 111.12 ± 31.93 < 0.001 Triglycerides (mg/dL) 112.32 ± 66.08 132.82 ± 64.99 0.030 Hemoglobin (g/dL) 14.54 ± 1.41 13.56 ± 1.35 < 0.001 Albumin (g/dL) 4.36 ± 0.30 4.23 ± 0.32 0.008 Uric acid (mg/dL) 5.05 ± 1.45 6.80 ± 1.28 < 0.001 iPTH (pg/mL) 53.54 ± 15.34 96.79 ± 46.94 < 0.001 Potassium (mEq/L) 4.47 ± 0.40 4.61 ± 0.45 0.017 DBP (mmHg) 79.84 ± 9.66 83.53 ± 9.35 0.006 2 Overweight (BMI 25.1–30 Kg/m ) 236 (47.3%) 23 (46.9%) < 0.001 Target LDL-cholesterol 349 (80.4%) 23 (46.9%) < 0.001 Cardiovascular event 11 (2.2%) 0 (0.0%) NS Cardiovascular death 0 (0.0%) 0 (0.0%) – Non cardiovascular death 3 (0.6%) 1 (1.8%) NS Abbreviations: ABI ankle brachial index, ADPKD autosomal dominant polycystic kidney disease, BMI body mass index, CKD chronic kidney disease, DBP diastolic blood pressure, eGFR estimated glomerular filtration rate with the CKD-EPI formula, FGF-23 fibroblast growth factor 23, HDL high density lipoprotein, IMT intima- media thickness, iPTH intact parathyroid hormone, LDL low density lipoprotein, NS not statistically significant, SBP systolic blood pressure Gorriz et al. BMC Nephrology (2021) 22:110 Page 6 of 10 Fig. 3 Adjusted Cox regression model of cardiovascular event free time: controls vs. ADPKD vs. CKD of other etiologies. Kaplan Meier analysis: log rank test: p < 0.001. Abbreviations: ADPKD, autosomal dominant polycystic kidney disease; CKD, chronic kidney disease. Cox regression model adjusted to age, sex, obesity and tobacco use percentages of asymptomatic CVD: no difference was compared to others causes of end-stage kidney disease found on IMT, the presence of plaque or pathologic (ESKD), patients with ADPKD continued to have higher rates of ABI. The low number of CVE during the follow- cardiovascular morbidity and mortality [12]. A direct up (11 in the control group and none in the ADPKD link between ADPKD and metabolic abnormalities lead- group) did not allow for comparison. ing to CVD has been proposed [13]. In addition, total kidney volume has been shown to be a predictor of CVE Discussion [14]. Hypertension occurs early in the course of the dis- To the best of our knowledge, this is the first study to ease, among other causes due to local hyperactivation of assess the adequacy of the control of traditional cardio- the RAAS (Fig. 1) [15]. vascular risk factors in ADPKD, and their impact on When a CVE occurs, it is expected to be more severe asymptomatic CVD. In this large national prospective than in the general population. A study that analyzed cohort, patients with ADPKD have an intermediate risk episodes of acute myocardial infarction showed that factors control rate, with a variable impact on subclinical patients with ADPKD had a higher rate of ST-segment atheromatosis but with a lower event rate compared to elevation, multi-vessel involvement, and secondary patients with CKDoe. Patients with ADPKD in CKD sudden death [16]. However, most studies have focused stage 3 have a similar blood pressure control, while they on the evaluation and progression of CKD [17, 18]. have a larger prevalence of hypertension and worse lipid Strict control blood pressure (BP) has been shown not control than patients without CKD, but a similar rate of to slow the progression of CKD, but to improve the asymptomatic CVD risk factors. It is to be noted that damage in target organs [12]. However, The HALT PKD the classic cardiovascular risk factors are not optimally trial carried out in an early population with ADPKD controlled. showed that intensive control of systolic BP to 95–110 Patients with ADPKD tend to be younger and health- mmHg was associated with a 14% slower rate of kidney ier than patients with CKD who are affected from other volume growth compared to standard control [19]. Of etiologies. Although cardiovascular morbidity is lower interest, other sub analysis of this trial found that Gorriz et al. BMC Nephrology (2021) 22:110 Page 7 of 10 sodium restriction is beneficial in the management of Lipid control also appears to affect the progression of ADPKD [20]. CKD in ADPKD; however, the actual pleiotropic effect In our study, patients with ADPKD CKD stage 3 of statins remains unclear [17, 31]. Other studies have showed a cardiovascular profile similar to controls, with shown worse lipid control and higher uric acid levels similar results in ABI and even a better subclinical ather- and inflammatory markers, also not associated with omatosis profile measured by ITM in both groups of the worse IMT or ABI [30]. These results could be influ- study with an identical mean age. This may be related to enced not only by serum lipid levels, but also by deeper early and regular monitoring in patients with ADPKD. lipid disturbances, such as lipid particle number, size Being a hereditary condition, early diagnosis is frequent, and density. These alterations have been related to CVD leading to an early control of cardiovascular risk and the in CKD of other etiologies [32], and recently preliminary intensification of treatments for cardiovascular preven- data have been published in this regard in patients with tion. While this is not usually the case in the general ADPKD [33]. population, as has been shown in the control group. The small differences between patients with ADPKD Data on cardiovascular risk and evaluation and pre- at stage 3 of CKD and controls support the hypothesis vention of CVD in patients with ADPKD is scarce. IMT that the main cause for CVD in the ADPKD population represent an early marker of vascular dysfunction [21]. is CKD rather than the disease itself. While recognizing Several studies have shown higher IMT values in ADPK that the control population is not completely healthy, its D than in healthy controls, even before the development cardiovascular status is similar to that of patients with of hypertension [22–26]. In our cohort, patients with CKD stage 3 ADPKD, suggesting that a good control of ADPKD had the lowest IMT, while patients with ADPK the risk factors for CV in ADPKD should allow ESKD to D CKD stage 3 presented a similar IMT to controls. be achieved in a good cardiovascular health. Previous studies have shown very similar values of IMT, Therefore, there is scope to improve cardiovascular although they were performed in patients with ADPKD risk control in ADPKD, although most indications have with normal renal function [23]. This difference can be a low level of evidence based on expert opinions [34, 35]. explained by the fact that, for the present study, the con- Recent CVD guidelines [36] have established the CKD trols were not completely healthy subjects, but patients condition as high or very high risk with the BP target recruited from primary care with different comorbidities. below 140/90 with a tendency to a systolic BP of 130 in The presence of plaque in the carotid or femoral arter- CKD if tolerated [36]. In our study, only half of the ies may be considered established CVD, a late-stage or patients achieved the less strict BP target. Recently asymptomatic CVD [27]. In our study, patients with the ESC/EAS Guidelines for the management of ADPKD had an intermediate rate of plaque presence dyslipidemias have also considered CKD patients as between controls and subjects with CKDoe, while stage high or very high risk with LDL cholesterol objectives 3 CKD ADPKD was not associated with higher rates of of 70 mg/dL and 55 mg/dL respectively [37], being atheromatous plaques than controls. As far as we know, these levels far from the data shown in our study. no other study has reported similar findings. Asymptom- The high prevalence of overweight and obesity in atic peripheral vascular disease is relatively common in patients with CKD, including patients with ADPKD, CKD [28]. ABI is a proved marker of CVD, and both coupled with the lack of achievement of BP and lipid low and high values have shown to predict CVE in pa- targets means that much remains to be done. These tients with CKD [29]. Pathologic rates of ABI values data show the need to increase awareness about intensify- were lower in patients with ADPKD than in CKDoe, and ing the control of classic cardiovascular risk factors in similar to controls without CKD. A previous study patients with ADPKD. It does not make much sense to showed a normal ABI value in patients with ADPKD use expensive disease modifying drugs without using with an eGFR > 60 mL/min [30]. effective adjuvant therapies that prevent CVE. In this cohort, BP and weight control were not lower A deeper view of CVD and atheromatous disease is than controls or patients with CKDoe, as long as BP needed in the near future. In this study, patients with control is understood as for general CKD patients, not ADPKD-derived CKD showed a similar or even lower as for the intense control recommended for ADPKD long-term cardiovascular risk than those with or without patients [17]. Despite more frequent use of statins, LDL CKD. Given the condition of hereditary disease, in most control was lower than controls and similar to other cases patients with ADPKD have benefited from routine patients with CKD. One possible explanation could be vascular evaluation tests because they have begun their the use of insufficient statin doses. In general terms, the follow-up from the early stages. This have demonstrated adequacy of the control of cardiovascular risk factors in a prognostic effect, as we have shown in our study. patients with ADPKD observed in our study may be However, we are still far from achieving the optimal ob- responsible for the low rates of asymptomatic CVD. jectives for the control of cardiovascular risk factors. Gorriz et al. BMC Nephrology (2021) 22:110 Page 8 of 10 Finally, a major effort must be made to look beyond Torrecardenas (Almería); Diaz-Tejeiro Izquierdo, Rafael. Hospital Virgen de la the prevention of the progression of CKD, towards a Salud (Toledo); Dotori, Marta. USP Marbella (Málaga); Duarte, Verónica. Hospital de Terrassa (Barcelona); Estupiñan Torres, Sara. Hospital Universitario more intense management of cardiovascular risk, which Canarias (Santa Cruz de Tenerife); Fernández Reyes, Mª José. Hospital de should lead to a reduction in CVE, especially if it could Segovia (Segovia); Fernández Rodríguez, Mª Loreto. Hospital Príncipe de be implemented early in the course of the disease. Asturias (Madrid); Fernández, Guillermina. Clínica Santa Isabel (Sevilla); Galán Serrano, Antonio. Hospital General Universitario de Valencia (Valencia); García Our study has several limitations. The main one is the Cantón, Cesar. Hospital Universitario Insular de Gran Canaria (Las Palmas); existence of an intentional selection bias: since patients García Herrera, Antonio L. Hospital Universitario Puerto Real (Cádiz); García with previous CVE were excluded from the study, Mena, Mercedes. Hospital San Juan de Dios (Zaragoza); Gil Sacaluga, Luis; Aguilar, Maria. Hospital Virgen del Rocío (Sevilla); Górriz, José Luis. Hospital included patients had a starting lower cardiovascular Universitario Doctor Peset (Valencia); Huarte Loza, Emma. Hospital San Pedro profile. Besides, non-CKD patients are not matched (Logroño); Lerma, José Luis. Hospital Universitario Salamanca (Salamanca); healthy controls. However, the control group had a Liebana Cañada, Antonio. Hospital de Jaén (Jaén); Marín Álvarez, Jesús Pedro. Hospital San Pedro de Alcántara (Cáceres); Martín Alemany, Nàdia. Hospital mean age like those in the ADPKD group. Finally, there Josep Trueta (Girona); Martín García, Jesús. Hospital Nuestra Señora de were many dropouts through the follow-up, mainly due Sonsoles (Ávila); Martínez Castelao, Alberto. Hospital Universitari de Bellvitge to kidney transplantation. Another limitation is related (Barcelona); Martínez Villaescusa, María. Complejo Hospitalario Universitario de Albacete (Albacete); Martínez, Isabel. Hospital Galdakao (Bilbao); Moina to relatively low patients with ADPKD included. The Eguren, Iñigo. Hospital Basurto (Bilbao); Moreno Los Huertos, Silvia. Hospital study also has important strengths, being the main its Santa Bárbara (Soria); Mouzo Mirco, Ricardo. Hospital El Bierzo, Ponferrada large sample, and its multicenter and prospective nature. (León); Munar Vila, Antonia. Hospital Universitari Son Espases (Palma de Mallorca); Muñoz Díaz, Ana Beatriz. Hospital Virgen del Consuelo (Valencia); In conclusion, patients with ADPKD show intermedi- Navarro González, Juan F. Hospital Universitario Nuestra Señora de Candelaria ate control rates of cardiovascular comorbidities, when (Santa Cruz de Tenerife); Nieto, Javier; Carreño, Agustín. Hospital General compared to non-CKD subjects and other etiologies of Universitario de Ciudad Real (Ciudad Real); Novoa Fernández, Enrique. Complexo Hospitalario de Ourense (Ourense); Ortiz, Alberto; Fernandez, CKD. Better control of cardiovascular risk factors Beatriz. IIS-Fundación Jiménez Díaz (Madrid); Paraíso, Vicente. Hospital appears to be associated with a lower burden of CVD, Universitario del Henares (Madrid); Pérez Fontán, Miguel. Complejo which may lead in the long term to a better prognosis. Hospitalario Universitario A Coruña (A Coruña); Peris Domingo, Ana. Hospital Francesc de Borja (Valencia); Piñera Haces, Celestino. Hospital Universitario However, we are still far from achieving the optimal Marqués de Valdecilla (Santander); Prados Garrido, Mª Dolores. Hospital goals for the control of cardiovascular risk factors in Universitario San Cecilio (Granada); Prieto Velasco, Mario. Hospital de León patients with ADPKD. Further investigation is needed to (León); Puig Marí, Carmina. Hospital d’Igualada (Barcelona); Rivera Gorrín, Maite. Hospital Universitario Ramón y Cajal (Madrid); Rubio, Esther. Hospital deepen our knowledge about the course of CVD in Puerta del Hierro (Madrid); Ruiz, Pilar. Hospital Sant Joan Despí Moisès Broggi ADPKD and to determine the usefulness of specific (Barcelona); Salgueira Lazo, Mercedes; Martínez Puerto, Ana Isabel. Hospital therapeutic measures to improve cardiovascular progno- Virgen Macarena (Sevilla); Sánchez Tomero, José Antonio. Hospital Universitario de la Princesa (Madrid); Sánchez, José Emilio. Hospital Universitario Central de sis in ADPKD. Asturias (Oviedo); Sans Lorman, Ramon. Hospital de Figueres (Girona); Saracho, Ramon. Hospital de Santiago (Vitoria); Sarrias, Maria; Prat, Oreto. Hospital Universitari Vall d’Hebron (Barcelona); Soler, María José; Barrios, Clara. Hospital Supplementary Information del Mar (Barcelona); Sousa, Fernando. Hospital Rio Carrión (Palencia); Toran, Dan- The online version contains supplementary material available at https://doi. iel. Hospital General de Jerez (Cadiz); Tornero Molina, Fernando. Hospital de org/10.1186/s12882-021-02313-1. Sureste (Arganda del Rey); Usón Carrasco, José Javier. Hospital Virgen de la Luz (Cuenca); Valera Cortes, Ildefonso. Hospital Virgen de la Victoria (Málaga); Additional file 1. Vilaprinyo del Perugia, Mª Merce. Institut Catala d’Urologia i Nefrologia (Barcelona); Virto Ruiz, Rafael C. Hospital San Jorge (Huesca). Acknowledgments Authors’ contributions The authors would like to thank the NEFRONA team (Eva Castro, Virtudes All authors contribute equally in this investigation. The author(s) read and María, Teresa Molí, Meritxell Soria) and the Biobank of RedInRen for their approved the final manuscript. invaluable support. The NEFRONA study investigator group is composed by the following: Aladrén Regidor, Mª José. Hospital Comarcal Ernest Lluch (Calatayud); Almirall, Jaume; Ponz, Esther. Corporació Parc Taulí (Barcelona); Funding Arteaga Coloma, Jesús. Hospital de Navarra (Pamplona); Bajo Rubio, Mª The NEFRONA study is funded by a research grant from AbbVie and the Auxiliadora, Hospital La Paz (Madrid); Belart Rodríguez, Montserrat. Sistemes Spanish government RETIC (RD12/0021) and FIS PS10/00946. Renals (Lleida); Bielsa-García. Sara, Hospital Obispo Polanco (Teruel); Bover Torra R research is funded by the Instituto de Salud Carlos III/Fondo Europeo Sanjuan, Jordi. Fundació Puigvert. IIB Sant Pau (Barcelona); Bronsoms Artero, de Desarrollo Regional (FEDER) funds, RETIC REDINREN RD16/0009 FIS FEDER Josep. Clínica Girona (Girona); Cabezuelo Romero, Juan B; Muray Cases, FUNDS (PI15/01824, PI18/00362). Salomé. Hospital Reina Sofía (Murcia); Calviño Varela, Jesús. Hospital Universitario Lugus Augusti (Lugo); Caro Acevedo, Pilar. Clínica Ruber Availability of data and materials (Madrid); Carreras Bassa, Jordi. Diaverum Baix Llobregat (Barcelona); Cases All data generated or analyzed during this study are included in this Amenós, Aleix; Massó Jiménez, Elisabet. Hospital Clínic (Barcelona); Castilla published article. Pérez, Jesús. Hospital de la Defensa (Zaragoza); Cigarrán Guldris, Secundino; López Prieto, Saray. Hospital Da Costa (Lugo); Comas Mongay, Lourdes. Declarations Hospital General de Vic (Barcelona); Comerma, Isabel. Hospital General de Manresa (Barcelona); Compte Jové, Mª Teresa, Hospital Santa Creu Jesús (Tar- Ethics approval and consent to participate ragona); Cuberes Izquierdo, Marta. Hospital Reina Sofía (Navarra); de Álvaro, Patients signed the informed consent, and the study protocol was approved Fernando; Hevia Ojanguren, Covadonga. Hospital Infanta Sofía (Madrid); de by the Ethics Committee of the Arnau de Vilanova University Hospital. All the Arriba de la Fuente, Gabriel. Hospital Universitario Guadalajara (Guadalajara); study was conducted in accordance with relevant guidelines and del Pino y Pino, Mª Dolores. Complejo Hospitalario Universitario regulations. Gorriz et al. BMC Nephrology (2021) 22:110 Page 9 of 10 Consent for publication 13. Chirumamilla R, Mina D, Siyahian S, MPark. Subclinical metabolic and Not applicable cardiovascular abnormalities in autosomal dominant polycystic kidney disease. 2018;90:237–45. 14. Sans L, Pascual J, Radosevic A, Quintian C, Ble M, Molina L, et al. Renal Competing interests volume and cardiovascular risk assessment in normotensive autosomal Authors declares no competing interests in this investigation. dominant polycystic kidney disease patients. Medicine. 2016;95(49):e5595. 15. Ecder T, Schrier RW. Cardiovascular abnormalities in autosomal-dominant Author details polycystic kidney disease. Nat Rev Nephrol. 2009;5:221–8. 1 16. Yang B, Wang Q, Wang R, Xu T. Clinical manifestation, management and Department of Nephrology, University Clinic Hospital, INCLIVA, University of Valencia, Av Blasco Ibañez 17, 46010 Valencia, Spain. 2Department of prognosis of acute myocardial infarction in autosomal dominant polycystic Nephrology, Hospital General Universitario Gregorio Marañón, Madrid, Spain. kidney disease. Kidney Blood Press Res. 2018;43(6):1806–12. https://doi.org/1 3 0.1159/000495638. Inherited Kidney Diseases, Nephrology Department, Fundació Puigvert, Instituto de Investigaciones Biomédicas Sant Pau (IIB-Sant Pau), Medicine 17. Schrier RW, Brosnahan G, Cadnapaphornchai MA, Chonchol M, Friend K, Gitomer Department-Universitat Autónoma de Barcelona, REDinREN, nstituto de B, et al. Predictors of autosomal dominant polycystic kidney disease progression. Investigación Carlos III, Barcelona, Spain. 4Department of Nephrology, J Am Soc Nephrol. 2014;25:2399–418 American Society of Nephrology. University Dr Peset Hospital, Valencia, Spain. 5Clinica Vallada, Calle San 18. Gansevoort RT, Arici M, Benzing T, Birn H, Capasso G, Covic A, et al. Ramón 2, 46691 Valencia, Spain. 6Health Surveillance Unit, Castellon Mutual Recommendations for the use of tolvaptan in autosomal dominant Insurance Union, Castellon, Spain. Department of Medicine, Jaume I polycystic kidney disease: a position statement on behalf of the ERA-EDTA University, Castellon, Spain. 7Vascular and Renal Translational Research Group, Working Groups on Inherited Kidney Disorders and European Renal Best UDETMA, REDinREN del ISCIII, IRBLleida, Lleida, Spain, 2 Statistics Department, Practice. Nephrol Dial Transplant. 2016;31:337–48 Oxford University Press. University of Lleida, Lleida, Spain. 19. Brosnahan GM, Abebe KZ, Moore CG, Bae KT, Braun WE, Chapman AB, et al. Determinants of progression in early autosomal dominant polycystic kidney Received: 18 December 2020 Accepted: 16 March 2021 disease: is it blood pressure or renin-angiotensin-aldosterone- system blockade? Curr Hypertens Rev. 2018;14(1). 20. Torres VE, Abebe KZ, Schrier RW, Perrone RD, Chapman AB, Yu AS, et al. Dietary salt restriction is beneficial to the management of autosomal References dominant polycystic kidney disease. Kidney Int. 2017;91(2). 1. Saran R, Robinson B, Abbott KC, et al. US renal data system 2019 annual 21. Raggi P, D’Marco L. Imaging for detection of vascular disease in chronic data report: epidemiology of kidney disease in the United States. Am J kidney disease patients. In: Oxford textbook of clinical nephrology. 4th ed; Kidney Dis. 2019;19. 2015. p. 1–23. Available from: http://www.oxfordmedicine.com/view/10.1 2. Go AS, Chertow GM, Fan D, Mcculloch CE, Hsu C-Y. Chronic kidney disease 093/med/9780199592548.001.0001/med-9780199592548. and the risks of death, cardiovascular events, and hospitalization. N Engl J 22. Kocaman O, Oflaz H, Yekeler E, Dursun M, Erdogan D, Demirel S, et al. Med. 2004;351 Available from: www.nejm.org. Endothelial dysfunction and increased carotid intima-media thickness in 3. Major RW, Cheng MRI, Grant RA, Shantikumar S, Xu G, Oozeerally I, et al. patients with autosomal dominant polycystic kidney disease. Am J Kidney Cardiovascular disease risk factors in chronic kidney disease: a systematic Dis. 2004;43(5):854–60. https://doi.org/10.1053/j.ajkd.2004.01.011. review and meta-analysis. PLoS One. 2018;13(3). 23. Turkmen K, Oflaz H, Uslu B, Cimen AO, Elitok A, Kasikcioglu E, et al. Coronary 4. Spithoven EM, Kramer A, Meijer E, Orskov B, Wanner C, Abad JM, et al. Renal flow velocity reserve and carotid intima media thickness in patients with replacement therapy for autosomal dominant polycystic kidney disease autosomal dominant polycystic kidney disease: from impaired tubules to (ADPKD) in Europe: prevalence and survival - an analysis of data from the impaired carotid and coronary arteries. Clin J Am Soc Nephrol. 2008;3(4): ERA-EDTA registry. Nephrol Dial Transplant. 2014;29:iv15–25. 986–91. https://doi.org/10.2215/CJN.02330607. 5. Kuo IY, Chapman AB. Polycystins, ADPKD, and cardiovascular disease. Kidney 24. Rong S, Jin X, Ye C, Chen J, Mei C. Carotid vascular remodelling in patients Int Rep. 2020;5:396–406 Elsevier Inc. with autosomal dominant polycystic kidney disease. Nephrology. 2009;14(1): 6. Martínez V, Comas J, Arcos E, Díaz JM, Muray S, Cabezuelo J, et al. Renal 113–7. https://doi.org/10.1111/j.1440-1797.2008.01049.x. replacement therapy in ADPKD patients: A 25-year survey based on the 25. Salk I, Yildiz G, Egilmez H, Atalar MH, Candan F, Cetin A. Carotid artery Catalan registry. BMC Nephrol. 2013;14(1). Doppler ultrasonography in patients with chronic kidney disease. Med Sci 7. Valdivielso JM, Betriu A, Martinez-Alonso M, Arroyo D, Bermudez-Lopez M, Monit. 2014;20:11–7. Fernandez E. Factors predicting cardiovascular events in chronic kidney 26. Coban M, Inci A, Yllmaz U, Asilturk E. The association of fibroblast growth disease patients. Role of subclinical atheromatosis extent assessed by factor 23 with arterial stiffness and atherosclerosis in patients with vascular ultrasound. PLoS ONE. 2017;12(10). autosomal dominant polycystic kidney disease. Kidney Blood Press Res. 8. Junyent M, Martínez M, Borràs M, Coll B, Valdivielso JM, Vidal T, et al. 2018;43(4):1160–73. https://doi.org/10.1159/000492244. Predicting cardiovascular disease morbidity and mortality in chronic 27. D’Marco L, García I, Vega C. Acido úrico, aterosclerosis y calcificaciones kidney disease in Spain. The rationale and design of NEFRONA: a vasculares en enfermedad renal crónica. Investig Clin. 2012;53(1):52–9. prospective, multicenter, observational cohort study. 2010. Available 28. Arroyo D, Betriu A, Valls J, Gorriz JL, Pallares V, Abajo M, et al. Factors from: http://www.nefrona.es. influencing pathological ankle-brachial index values along the chronic 9. Arroyo D, Betriu A, Martinez-Alonso M, Vidal T, Valdivielso JM, Fernández E. kidney disease spectrum: the NEFRONA study. Nephrol Dial Transplant. Observational multicenter study to evaluate the prevalence and prognosis 2017;32(3):513–20. of subclinical atheromatosis in a Spanish chronic kidney disease cohort: 29. Matsushita K, Sang Y, Ballew SH, Shlipak M, Katz R, Rosas SE, et al. Subclinical baseline data from the NEFRONA study. BMC Nephrol. 2014;15(1). atherosclerosis measures for cardiovascular prediction in CKD. J Am Soc 10. Torres VE, Abebe KZ, Chapman AB, Schrier RW, Braun WE, Steinman TI, Nephrol. 2015;26(2):439–47. https://doi.org/10.1681/ASN.2014020173. et al. Angiotensin blockade in late autosomal dominant polycystic 30. Lai S, Mastroluca D, Matino S, Panebianco V, Vitarelli A, Capotosto L, et al. kidney disease. N Engl J Med. 2014;371(24):2267–76. https://doi.org/10.1 Early markers of cardiovascular risk in autosomal dominant polycystic kidney 056/NEJMoa1402686. disease. Kidney Blood Press Res. 2017;42(6):1290–302. https://doi.org/10.11 11. Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, et al. 59/000486011. 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid 31. Torres VE, Grantham JJ, Chapman AB, Mrug M, Bae KT, King BF, et al. modification to reduce cardiovascular risk. Atherosclerosis. 2019;290:140– Potentially modifiable factors affecting the progression of autosomal 205. Available from: https://linkinghub.elsevier.com/retrieve/pii/S002191501 dominant polycystic kidney disease. Clin J Am Soc Nephrol. 2011;6(3):640–7. 9314595. https://doi.org/10.1016/j.atherosclerosis.2019.08.014. https://doi.org/10.2215/CJN.03250410. 12. Perrone RD, Ruthazer R, Terrin NC. Survival after end-stage renal disease in 32. Bermudez-Lopez M, Forne C, Amigo N, Bozic M, Arroyo D, Bretones T, et al. autosomal dominant polycystic kidney disease: contribution of extrarenal An in-depth analysis shows a hidden atherogenic lipoprotein profile in non- complications to mortality. Am J Kidney Dis. 2001;38(4):777–84. https://doi. diabetic chronic kidney disease patients. Expert Opin Ther Targets. 2019; org/10.1053/ajkd.2001.27720. 23(7):619–30. https://doi.org/10.1080/14728222.2019.1620206. Gorriz et al. BMC Nephrology (2021) 22:110 Page 10 of 10 33. Kim K, Trott JF, Gao G, Chapman A, Weiss RH. Plasma metabolites and lipids associate with kidney function and kidney volume in hypertensive ADPKD patients early in the disease course. BMC Nephrol. 2019;20(1). 34. Bolignano D, Palmer SC, Ruospo M, Zoccali C, Craig JC, Strippoli GFM. Interventions for preventing the progression of autosomal dominant polycystic kidney disease. Cochrane Database Syst Rev. 2015;2015 John Wiley and Sons Ltd. 35. Chebib FT, Torres VE. Recent advances in the management of autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol. 2018;13:1765– 76 American Society of Nephrology. 36. Cosentino F, Grant PJ, Aboyans V, Bailey CJ, Ceriello A, Delgado V, et al. 2019 ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J. 2020 Jan 1;41(2): 255–323. https://doi.org/10.1093/eurheartj/ehz486. 37. Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, et al. 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020;41:111–88 Oxford University Press. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.