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. 2015 Aug 21;17(12):963–969. doi: 10.1111/jch.12634

Inflammation and Atherosclerosis Are Associated With Hypertension in Kidney Transplant Recipients

Maria A Azancot 1, Natalia Ramos 1, Irina B Torres 1, Clara García‐Carro 1, Katheryne Romero 1, Eugenia Espinel 1, Francesc Moreso 1, Daniel Seron 1,✉
PMCID: PMC8032044  PMID: 26293391

Abstract

The aim of the current study was to evaluate risk factors associated with hypertension in kidney transplant recipients. The authors recruited 92 consecutive kidney transplant recipients and 30 age‐matched patients with chronic kidney disease without history of cardiovascular events. Twenty‐four–hour ambulatory blood pressure monitoring, pulse wave velocity, and carotid ultrasound were performed. Serum levels of log‐transformed interleukin 6 (Log IL‐6), soluble tumor necrosis factor receptor 2, and intercellular adhesion molecule 1 were determined. Twenty‐four–hour systolic blood pressure (SBP) (P=.0001), Log IL‐6 (P=.011), and total number of carotid plaques (P=.013) were higher, while the percentage decline of SBP from day to night was lower in kidney transplant recipients (P=.003). Independent predictors of 24‐hour SBP were urinary protein/creatinine ratio and circulating monocytes (P=.001), while Log IL‐6, serum creatinine, and total number of carotid plaques (P=.0001) were independent predictors of percentage decline of SBP from day to night. These results suggest that subclinical atherosclerosis and systemic inflammation are associated with hypertension after transplantation.

Hypertension is a risk factor for cardiovascular events and progression of chronic kidney disease (CKD).1, 2 The prevalence and severity of hypertension is closely associated with the degree of renal impairment.3 In kidney transplant recipients, hypertension is present in more than 80% of patients4 and is associated with patient survival and decreased allograft survival.5, 6

Ambulatory blood pressure (BP) monitoring (ABPM) constitutes the most accurate measure to evaluate BP. In patients with CKD, ABPM detects patients at risk for cardiovascular events and progression of renal insufficiency better than office BP.2 In kidney transplant recipients, reverse dipping ABPM pattern has been associated with outcome evaluated by means of a composite variable consisting of the combination of any cardiovascular event and graft failure for any reason.7 However, in a study comparing ABPM between transplant and CKD patients with similar renal function, transplantation was an independent predictor of the severity of hypertension, especially for sleep systolic BP (SBP) once corrected for confounding factors.8 The reason for this difference between transplant and CKD patients has not been studied. The use of calcineurin inhibitors in transplant recipients may partly explain this difference since their use is associated with endothelial dysfunction,9, 10 systemic vasoconstriction11 and hypertension.12, 13 However, other reasons can be suggested for this difference. Kidney transplant recipients, in comparison with CKD patients with similar renal function, have a longer history of renal insufficiency and the majority of them have received dialysis treatment during a variable period of time. Accordingly, longer exposure to renal insufficiency may be responsible for a more severe atherosclerotic burden in kidney transplant recipients14, 15 that can contribute to more severe hypertension.16

Different autoimmune diseases, such as rheumatoid arthritis, lupus erythematosus, inflammatory bowel disease, and psoriasis, characterized by increased systemic inflammation are associated with a higher prevalence of cardiovascular disease,17, 18, 19, 20 suggesting that tissue inflammation may favor systemic inflammation that in turn will contribute to endothelial dysfunction21 and hypertension.22, 23 The majority of diseases leading to graft dysfunction and/or proteinuria are characterized by severe allograft inflammation such as cellular rejection, antibody‐mediated rejection, or polyomavirus infection.24 Thus, renal allograft patients might display more severe systemic inflammation than CKD patients with similar renal function, and this difference may contribute to the severity of hypertension.

The aim of the present study was to characterize risk factors associated with hypertension in stable kidney transplant recipients.

Material and Methods

Patients

Between June 2011 and September 2011, consecutive kidney transplant recipients with the following criteria were included: (1) age 18 years and older and 70 years and younger; (2) no history of cardiovascular events (angina, myocardial infarction, heart failure, stroke, or peripheral vascular disease); (3) stable renal function defined as variability of estimated glomerular filtration rate <10% between the current and previous visit; (4) absence of renal transplant artery stenosis according to arterial echo Doppler performed at least 2 years before; and (5) signed informed consent. Patients with active infection or neoplasia except nonmelanoma skin cancer were excluded. CKD patients with similar age, sex, renal function, and proteinuria were recruited at the same time period and served as controls. Patients with CKD treated with steroids or immunosuppressant agents were not considered. This study was approved by the ethical committee of Hospital Universitari Vall d'Hebron.

Clinical Variables

At entry, the following variables were recorded: age, sex, height and weight, body mass index (BMI) calculated as weight divided by squared height, active smoking (yes/no), time since diagnosis of renal disease, time on dialysis, time since transplant, number and class of antihypertensive drugs, and immunosuppressive treatment in renal transplant.

Laboratory Tests

The following parameters were determined at entry: hemoglobin (g/dL), leucocytes (×109/L), lymphocytes (×109/L), monocytes (×109/L), total cholesterol (mg/dL), triglycerides (mg/dL), serum creatinine (mg/dL), serum calcium (mg/dL), serum phosphate (mg/dL), serum parathyroid hormone (pg/dL), urinary protein/creatinine ratio (g/g), 24‐hour urine sodium (mEq/24 h), and 24‐hour urine potassium (mEq/24 h). In patients without a history of diabetes mellitus, a 2‐hour oral glucose tolerance test after administration of 75 g of anhydrous glucose was performed.

Patients undergoing antidiabetic treatment or with fasting glucose ≥126 mg/dL, random glucose determination ≥200 mg/dL, oral glucose tolerance ≥200 mg/dL, or glycated hemoglobin ≥6.5% were diagnosed as having diabetes according to American Diabetes Association criteria 2010.25

Inflammation Markers

Serum samples for interleukin 6 (IL‐6), soluble tumor necrosis factor receptor 2 (sTNFR2), and intercellular adhesion molecule 1 (ICAM‐1) were obtained in a fasting blood sample before taking immunosuppressive drugs and were stored at −80°C in aliquots until analysis. Measurement of serum IL‐6 and ICAM‐1 were determined in duplicate using enzyme‐linked immunosorbent assay (ELISA) according to the manufacturers’ instructions (Aushon BioSystem, Billerica, MA) and were read by an ELISA processor (SearchLight Plus CCD Imaging System, Aushon BioSystem). sTNFR2 was measured using ELISA according to the manufacturers’ instructions (R&D System, Minneapolis, MN) and was read with the ELX800 Universal Microplate Reader (Biotek Instruments, Winooski, VT).

Carotid echography was performed in both carotid arteries with a high‐frequency (8–12 MHz) linear transducer (Esaote, 7300, Florence, Italy) in the supine position by the same observer. Intima‐media thickness (IMT) was determined in 10 mm before carotid bifurcation in the posterior arterial wall of the common carotid artery. The number of plaques in the common carotid artery, internal and external, were recorded. A plaque was defined as a focal structure protruding 0.5 mm into the lumen, or 50% of the surrounding IMT value, or an increased thickness >1.5 mm from the media‐adventitia to the intima‐lumen interface.26 IMT was expressed as the mean value obtained in both common carotid arteries and the total number of plaques was expressed as the addition of the number of plaques in both carotids. Carotid‐femoral pulse wave velocity (PWV; m/s) was determined by pulse tonometry (SphygmoCor EM3; AtCor, West Ryde, Australia ) as previously described.27 Ankle‐brachial pressure index was classified as normal (>0.9 and ≤ 1.3), abnormally high (>1.3) or suggestive of the presence of peripheral artery disease (≤ 0.9).

ABPM was measured using an overnight‐automated ABPM monitor (Spacelab 90207; Spacelabs Healthcare, Snoqualmie, WA) with appropriate cuff sizes for each patient as previously described.8 The percentage decline of BP from day to night was calculated as ([awake SBP–sleep SBP]/awake SBP) × 100.

Statistical Analysis

This is an exploratory cohort study and no formal power calculation was performed to estimate minimum sample size. Continuous normally distributed variables are presented as mean±standard deviation. To compare categorical and continuous normally distributed variables, chi‐square and Student t test were employed, respectively. For non‐normally distributive variables, Mann‐Whitney U test was applied. Since IL‐6, sTNFR2, and ICAM‐1 were not normally distributed, they were log‐transformed. Stepwise multivariate regression analysis was employed to evaluate variables associated with 24‐hour SBP and percentage decline of SBP from day to night. Logistic regression analysis was employed to analyze risk factors associated with reverse dipping pattern. All tests were two‐tailed and a P value <.05 was considered significant.

Results

Demographic Characteristics of Patients

During the study period, a total of 100 consecutive kidney transplant recipients were studied. In eight transplant recipients, 24‐hour ABPM was not adequately obtained. Finally, 92 transplant recipients were included. A total of 30 CKD patients served as controls.

Demographic characteristics of patients are summarized in Table 1. Renal function, proteinuria, and sodium intake evaluated by 24‐hour urinary sodium excretion were similar between transplant and CKD patients. As expected, time of diagnosis of renal disease was higher in kidney transplant recipients.

Table 1.

Demographic Characteristics of Patients

Transplantation (n=92) CKD (n=30) P Value
Age, y 52.5±11.3 53.8±10.3 .567
Caucasian race, No. (%) 87 (94.6) 29 (97.7) .644
Male sex, No. (%) 68 (73.9) 19 (63.3) .266
Body mass index, kg/m2 26.8±4.7 26.4±4.1 .663
Time of renal disease, mo 199.4±119.8 160.2±159.0 .022
Time after transplantation, mo 73.7±78.3 –
Dialysis vintage, mo 22.7±26.1 –
Smoking, No. (%) 14 (15.2) 8 (26.7) .157
Pack/years of smoking, No. 12.4±21.2 17.4±25.9 .300
Diabetes mellitus, No. (%) 18 (19.6) 7 (23.3) .657
Hemoglobin, g/dL 12.8±1.6 13.3±1.7 .193
Leukocytes, ×109/L 7.06±2.04 6.94±2.26 .792
Lymphocytes, ×109/L 1.94±0.84 1.67±0.73 .116
Monocytes, ×109/L 0.58±0.17 0.53±0.24 .213
Total cholesterol, mg/dL 189.4±34.6 189.4±28.2 .995
Triglycerides, mg/dL 169.8±95.6 166.7±142.6 .890
Serum calcium, mg/dL 9.48±0.54 9.46±0.59 .891
Serum phosphate, mg/dL 3.41±0.72 3.65±0.73 .120
PTH, pg/dL 87.14±45.06 90.34±81.04 .786
Creatinine, mg/dL 1.8±0.6 1.8±0.6 .824
Urinary protein/creatinine ratio, g/g 0.49±0.85 0.50±0.90 .999
24‐h urinary sodium, mEq/24 h 161.52±78.55 133.40±69.20 .116
24‐h urinary potassium, mEq/24 h 59.04±24.31 64.71±28.76 .337
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Abbreviations: CKD, chronic kidney disease; PTH, parathyroid hormone. Bold value indicates significance.

A total of 69 transplant recipients were receiving tacrolimus, 18 cyclosporine, and six an inhibitor of the mammalian target of rapamycin. At the time of the study, 83 were receiving mycophenolate mofetil and 64 were receiving steroids.

Ambulatory BP Monitoring

BP characteristics are summarized in Table 2. ABPM showed significantly higher BP values in kidney transplant recipients. A percentage decline in SBP from day to night was lower and the proportion of patients with a reverse dipping pattern was higher in kidney transplant recipients. The mean number of antihypertensive drugs per patient was not different between groups. The proportion of patients treated with diuretics was lower and the proportion of patients treated with β‐blockers was higher in kidney transplant recipients while the proportion of patients treated with angiotensin‐converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs) and calcium channel blockers were similar between groups.

Table 2.

Blood Pressure Characteristics

Transplantation (n=92) CKD (n=30) P Value
24‐h SBP, mm Hg 133.9±14.3 120.5±14.6 .0001
24‐h DBP, mm Hg 79.8±10.4 73.8±10.2 .007
Awake SBP, mm Hg 135.6±15.2 123.8±15.7 .0001
Awake DBP, mm Hg 81.7±11.2 76.6±10.7 .028
Sleep SBP, mm Hg 131.2±16.2 113.6±14.3 .0001
Sleep DBP, mm Hg 75.9±11.3 67.8±10.9 .001
Decline in SBP from day to night, % −3.1±8.2 −8.1±7.5 .003
Dipper and nondipper/reverse dipper 67/25 26/4 .122
Antihypertensive drugs, No. 1.6±1.1 1.4±1.0 .539
ACE inhibitors/ARBs, % 48 (52.2) 20 (66.7) .165
Diuretics, % 20 (21.7) 12 (40) .048
Calcium receptor blockers, % 32 (34.8) 6 (20) .129
β‐Blockers, % 30 (32.6) 3 (10) .015
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Abbreviations: ACE, angiotensin‐converting enzyme; ARBs, angiotensin receptor blockers; CKD, chronic kidney disease; DBP, diastolic blood pressure; SBP, systolic blood pressure.

Bold values indicate significance.

Biomarkers of Inflammation and Endothelial Activation

Log IL‐6 was higher in transplant patients than in CKD patients (0.89±0.33 vs 0.71±0.31, P=.011), while Log sTNFR2 and Log ICAM‐1 were not different between groups (Figure 1).

Figure 1.

Figure 1

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Biomarkers of inflammation and endothelial activation in transplant recipients and patients with chronic kidney disease (CKD). Log IL‐6 indicates log‐transformed interleukin 6; Log TNFR‐2, log‐transformed soluble tumor necrosis factor receptor 2; Log ICAM‐1, log‐transformed intercellular adhesion molecule 1.

Subclinical Atherosclerosis

The proportion of patients with atherosclerotic plaques in carotid arteries was higher in transplant patients in comparison with CKD patients (55.4% vs 30%, P=.016) as well as the total number of carotid plaques (1.17±1.48 vs 0.53±1.07, P=.013). On the contrary, we did not find any difference between transplant and CKD patients in IMT (0.768±0.139 vs 0.761±0.126 mm, P=.134), PWV (7.98±1.75 vs 8.17±1.84, P=.628), and ankle‐brachial pressure index, which was normal in 67 (72.8%) transplant and 20 (66.6%) CKD patients, abnormally high in 21 (22.8%) transplant and eight (26.6%) CKD patients. Peripheral artery disease was present in four (4.3%) transplant and two (6.6%) CKD patients (P=.804). There was no association between total number of carotid plaques or IMT and Log IL‐6, Log‐sTNFR2, and Log ICAM‐1 in kidney transplant recipients. We did not find any association between the use of steroids and the total number of carotid plaques, IMT, Log IL‐6, Log sTNFR2, and Log ICAM‐1.

Variables Associated With 24‐Hour SBP

The variables associated with 24‐hour SBP in the univariate analysis were urinary protein/creatinine ratio (r=0.288, P=.005), PWV (r=0.217, P=.043), and circulating monocytes (r=0.218, P=.037). In multivariate regression analysis, urinary protein/creatinine and circulating monocytes were independent predictors of 24‐hour SBP (Table 3a).

Table 3.

Independent Predictors of 24‐Hour, and Percentage Decline of SBP From Day to Night in Kidney Transplant Recipients

β (CI 95%) R R 2 P Value
(a) Predictors of 24‐hour SBP
Urinary protein/creatinine ratio, g/g 5.33 (2.20–8.47) 0.335 0.112 .001
Circulating monocytes, ×109/L 0.017 (0.002–0.033) 0.399 0.159 .035
(b) Predictors of percentage decline of SBP from day to night
Log IL‐6 6.09 (1.16–11.01) 0.327 0.107 .016
Serum creatinine, mg/dL 3.48 (0.67–6.29) 0.405 0.164 .016
Carotid plaques, No. 1.10 (0.04–2.16) 0.450 0.202 .042
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Abbreviations: CI, confidence interval; Log IL‐6, log‐transformed interleukin 6; SBP, systolic blood pressure.

Variables Associated With Percentage Decline of SBP From Day to Night

The variables associated with percentage decline of SBP from day to night in the univariate analysis were Log IL‐6 (r=0.327, P=.001) (Figure 2), serum creatinine (r=0.307, P=.003), Log sTNFR2 (r=0.300, P=.004), total number of carotid plaques (r=0.248, P=.017), and serum phosphate (r=0.207, P=.048). In multivariate analysis, Log IL‐6, serum creatinine, and total number of carotid plaques were independent predictors of percentage decline of SBP from day to night (Table 3b).

Figure 2.

Figure 2

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Correlation between percentage decline of systolic blood pressure (SBP) from day to night in relation to log‐transformed interleukin 6 (Log IL‐6).

To further characterize the relationship between the circadian rhythm of BP and subclinical atherosclerosis and inflammation markers, multivariate logistic regression was performed to analyze variables associated with BP reverse dipping pattern. This analysis confirms that total number of carotid plaques (relative risk [RR], 1.52; 95% confidence interval [CI], 1.03–2.34; P=.036) and Log IL‐6 (RR, 6.65; 95% CI, 1.00–44.21; P=.050) were associated with reverse dipping pattern.

Discussion

In a previous study we described increased 24‐hour ABPM in kidney transplant recipients compared with CKD patients with similar renal function, but the reason for this difference remains unclear.8 In the present study, we observed an increased number of carotid plaques and increased IL‐6 levels in kidney transplant recipients. Risk factors associated with 24‐hour SBP were proteinuria and number of circulating monocytes, while the number of carotid plaques and IL‐6 levels were associated with reduced percentage decline of BP from day to night and with reverse dipping pattern.

Proteinuria has been associated with 24‐hour ABPM in kidney transplant recipients,8, 28 while its relationship with circulating monocytes has not been described. In spontaneously hypertensive rats29 and in hypertensive patients, the number of circulating monocytes is increased.30 After kidney transplantation, the proportion of peripheral proinflammatory CD16+ monocytes increases as well as their capacity to produce proinflammatory cytokines in culture such as IL‐1β, tumor necrosis factor α, and interferon γ.31 Furthermore, MCP1/CCL2, a chemokine mobilizing monocyte to inflamed tissues through stimulation of the CCR2 receptor, is increased in urine samples of patients displaying inflammation in 6‐month renal allograft surveillance biopsies compared with patients with normal histology, suggesting that the inflamed allograft contributes to monocyte mobilization.32 In a study evaluating biopsies for cause, peripheral blood mononuclear cells were obtained at the time of biopsy and cultured to measure cytokines. Patients displaying glomerulitis showed increased IL‐6 and IL1β secretion compared with patients without glomerulitis.33 Taken together, these data suggest that kidney allograft inflammation favors mobilization, activation, and enhanced production of proinflammatory cytokines that, in turn, might favor endothelial dysfunction and hypertension.

On the other hand, serum IL‐6 was significantly higher in renal transplant recipients and was an independent predictor of percentage decline of SBP from day to night and reverse dipping pattern, pointing out that increased systemic inflammation in transplant recipients may contribute to the modification of the circadian BP pattern. An association between IL‐6 and BP has been described in healthy men34 and in patients with essential hypertension.35 However, there is a close association between renal function and IL‐6 levels.36 They are highest in hemodialysis patients and decrease after transplantation, remaining elevated in comparison with those in healthy controls.37, 38 The mechanism linking increased serum IL‐6 levels and hypertension is not well understood. In experimental studies, infusion of angiotensin II increases IL‐6 levels and, in IL‐6–deficient mice, the hypertensive response to angiotensin infusion is attenuated or abolished.39, 40 Infusion of IL‐6 in normal pregnant rats is associated with hypertension, while blockade of angiotensin II receptor with losartan abolishes the hypertensive effect of IL‐6.41 In healthy and hypertensive volunteers, infusion of angiotensin II also increases BP and IL‐6 levels.35 Furthermore, an association between elevated IL‐6 levels and cardiovascular mortality has been described in a large observational study in kidney transplant patients.42 Since in our study renal function and proteinuria were similar in transplant and CKD patients, we interpret that increased IL‐6 levels in kidney transplant recipients may be related to a particular condition of the transplanted patient. Surveillance biopsies performed in stable grafts display mild to moderate subclinical inflammation.43, 44 Since tissue inflammation constitutes a trigger of systemic inflammation, we suggest that increased IL‐6 in renal transplant recipients might be the consequence of renal inflammation. An alternative explanation for increased IL‐6 in kidney transplant recipients may be increased atherosclerotic burden compared with CKD patients. An association between IL‐6 and IMT has been described in hemodialysis patients.45 However, in our study we did not observe any association between IL‐6, sTNFR2, or ICAM‐1 and total number of carotid plaques or IMT in kidney transplant recipients.

Apart from IL‐6, total number of carotid plaques was an independent predictor of percentage decline of SBP from day to night and reverse dipping pattern. Subclinical carotid plaques not only represent an early marker of atherosclerosis but are also associated with endothelial dysfunction,46 which, in turn, is a marker of nondipping pattern.47 A direct association between increased media thickness as well as plaque prevalence and a nondipping pattern has been described in the general population.48 In a large cross‐sectional epidemiological study including hypertensive and nonhypertensive populations, IMT was associated with nondipping pattern regardless of conventional risk factors and antihypertensive or lipid‐lowering medications.49

Despite the major contribution of sodium intake to hypertension, the mean number of antihypertensive drugs and 24‐hour urinary sodium and potassium excretion were not different between transplant and CKD patients in our study. However, diuretics were more often employed in CKD patients while β‐blockers were more frequently employed in kidney transplant recipients. These variables were neither associated with 24‐hour SBP nor percentage decline of SBP from day to night.

Study Limitations

The present study has limitations and accordingly these results should be interpreted with caution. This was an exploratory study and the sample size was relatively small. Moreover, the associations between IL‐6, number of carotid plaques, and BP are relatively week. The cross‐sectional design does not allow defining the temporal sequence of the associations between variables, and long‐term follow‐up of this cohort will be necessary to further evaluate the contribution of inflammation and subclinical atherosclerosis to hypertension in renal transplant recipients.

Conclusions

Our data suggest that systemic inflammation and subclinical atherosclerosis are associated with hypertension in kidney transplant recipients.

Disclosure

The authors have no conflicts of interest to disclose.

Author contributions

M.A. Azancot contributed to the study design, performed echocardiography, determined pulse wave velocity, collected clinical variables, and participated in data analysis and writing of the paper. N. Ramos contributed to the study design, collected clinical variables, and participated in data analysis and writing of the paper. I. Torres, C. Garcia, and K. Romero collected clinical variables and contributed to data analysis. F. Moreso, E. Espinel, and D. Seron contributed to the study design and critical revision of the paper.

Acknowledgments

This work was supported by the Instituto Carlos III grants PI10/2496, PIE13/00027, and PI14/01383 and Red de Investigación renal REDinREN grant 12/0021/0013. M.A. Azancot was supported by a predoctoral grant from the Instituto Carlos III (FI11/0246) and I.B. Torres by a predoctoral grant from the Vall d'Hebron Research Institute (VHIR).

J Clin Hypertens (Greenwich). 2015;17:963–969. DOI: 10.1111/jch.12634. © 2015 Wiley Periodicals, Inc.

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