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Original Clinical Science

Prevalence and Risk Factors of Noncontrolled


and Resistant Arterial Hypertension in Renal
Transplant Recipients
Vetromile Fernando,1 Pernin Vincent,1 Szwarc Ilan,1 Garrigue Valrie,1 Delmas Sylvie,1 Mourad Georges,1
and Fesler Pierre2

Background. Arterial hypertension (HT) is common in renal transplant recipients (RTRs). Control of HT is not optimal in this high-
risk population despite recommendations for target blood pressure levels under 130/80 mm Hg. Methods. We performed a
cross-sectional analysis of the prevalence of uncontrolled HT, and using a Cox regression model, we identified the risk factors as-
sociated with resistant HT. Results. Eight hundred eleven RTRs (>1 year after transplantation) were included. A total of 10.5%
were normotensive (<130/80 mm Hg without treatment), 41% had controlled HT, 32.5% uncontrolled HT, and 16% resistant HT.
In univariate analysis, compared to controlled HT, the RH group had significantly higher body mass index and older donors,
delayed graft function, prevalence of metabolic syndrome (69.2 vs. 51.9%), fast glycemia and glycated hemoglobin, albumin-
uria, triglycerides and uric acid levels, and worse measured glomerular filtration rate (mGFR). In multivariate analysis, recipient
age (P < 0,001), mGFR (P = 0.037), albuminuria (P < 0.001), and metabolic syndrome (P = 0.007) were significantly asso-
ciated with RH. Association of metabolic syndrome with RH was much stronger than each of its components. Conclusion.
Our data show that despite the recommendations issued by scientific societies, blood pressure control in RTRs is far from the rec-
ommended targets. At least a third of our patients (uncontrolled HT) did not receive optimal treatment and suffered therapeutic
inertia. Decreased mGFR, metabolic syndrome, and urinary albumin excretion emerged as strong predictors of poor HT control.
Whether prevention and management of the metabolic syndrome and reduction of albuminuria could help to more consistently
reach the blood pressure recommended targets deserves further investigation.

(Transplantation 2015;99: 10161022)

A rterial hypertension (HT) is a common complication af-


ter renal transplantation, whatever the posttransplant
period. Using classic blood pressure (BP) targets (lower than
for nonproteinuric patients.9 Subsequently, the seventh report
of the JNC in 200310 and the ESH in 200711 recommended
target BP less than 130/80 mm Hg for patients with chronic
140 and 90 mm Hg), its prevalence is between 50% and kidney disease (CKD) and for diabetics. Because most RTRs
80% of recipients during the first year after transplanta- have CKD, the French Health Authority in 200712 as well as
tion.1-4 In renal transplant recipients (RTRs), it was already the KDIGO guidelines in 200913 recommended to reduce blood
demonstrated that elevated BP and pulse pressure result in pressure levels in RTRs to less than 130/80 mm Hg.
decreased allograft survival1,5 and left ventricular hypertro- In the general population with HT, some patients are not
phy, a well-known risk factor for heart failure and death.6,7 treated at all, and among the treated patients, measured BP
There is no universal agreement as to optimal BP targets is over the recommended targets in a majority of them. Simi-
in RTRs. In 2000, the AST recommended target BP levels larly, it was reported that control of BP was not optimal in
lower than 130/80 mm Hg,8 whereas in 2002, the European RTRs, despite the regular surveillance in transplant clinics. In
Best Practice Guidelines recommended a BP goal of less than a previous report, only 5% of RTRs were normotensive (NT)
125/75 mm Hg for proteinuric and less than 130/80 mm Hg measured by ambulatory BP measurement.14 In fact, BP levels
are not required in the majority of national transplant registries,
Received 12 May 2014. Revision requested 27 May 2014.
Accepted 26 August 2014. participated in design of the study, data collection and writing of the article. F.P.
1
Department of Nephrology, Dialysis and Transplantation, Hpital Lapeyronie, participated in design of the study and statistical analysis.
Universit de Montpellier, Montpellier, France. Correspondence: Georges Mourad, MD, Service de Nphrologie, Dialyse et Trans-
2
Department of Medicine and Hypertension, Hpital Lapeyronie, Universit de plantation, Hpital Lapeyronie, University of Montpellier, Montpellier 05, France.
Montpellier, Montpellier, France. (g-mourad@chu-montpellier.fr)

The authors declare funding or no conflicts of interest. Supplemental digital content (SDC) is available for this article. Direct URL citations
appear in the printed text, and links to the digital files are provided in the HTML text
G.M. and P.F. cotutored this study. of this article on the journals Web site (www.transplantjournal.com).
V.F. participated in collection of the data and writing of the article. P.V. participated in Copyright 2014 Wolters Kluwer Health, Inc. All rights reserved.
collection of the data and discussion of the results. S.I. participated in statistical
analysis. G.V. participated in collection of the data and discussion of the results. ISSN: 0041-1337/15/9905-1016
D.S. participated in collection of the data and discussion of the results. M.G. DOI: 10.1097/TP.0000000000000467

1016 www.transplantjournal.com Transplantation May 2015 Volume 99 Number 5

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2014 Wolters Kluwer Fernando et al 1017

and it is difficult to estimate the magnitude of posttransplant of metabolic syndrome was 47.5%. Measured glomerular
HT prevalence and quality of its control. filtration rate (mGFR) was 53.520.8 mL per min per
The aim of the present study was to analyze in a large 1.73 m2. Characteristics of the whole population are listed
cohort of RTRs the prevalence of uncontrolled HT (UH) in Table 1.
and resistant HT (RH) using the current recommendations
(<130/80 mm Hg) and to identify the risk factors associated Prevalence of Posttransplant HT
with RH.
Using the recommended targets of 130/80 mm Hg, only
85 (10.5%) recipients had normal BP without treatment (NT).
RESULTS Controlled HT (CH) was observed in 333 (41%) patients.
Three hundred ninety-three (48.5%) recipients were not con-
Patients Demographics trolled: 265 (32.5%) had UH and 128 (16%) had RH. So,
Of the 811 subjects who fulfilled the inclusion criteria, the majority of RTRs with HT were not receiving optimal
755 (93%) recipients were from cadaver and 56 (7%) from treatment. When using the classic BP levels of 140/90 mm Hg,
living donors. Incidences of delayed graft function and acute the population stratification was as follows: 109 (13.5%) NT,
rejection were 16% and 18.5%, respectively, and incidence 483 (59.5%) CH, 134 (16.5%) UH, and 85 (10.5%) RH.

TABLE 1.
Patients characteristics at baseline and comparison of NT versus all HT patientsa

All patients (811) NT (85) All HT (726) Pb


Variable
Recipients
Age, yr 52.5712.4 41.7314.95 53.8411.77 <0.001
Sex (male), % 64.1 40 66.9 <0.001
Past or current tobacco use, % 33.7 27.1 34.4 ns
Body mass index, kg/m2 25.364.64 22.473.65 25.704.63 <0.001
Time in dialysis, mo 23 (743) 17 (233) 23 (943) 0.092
Donors
Cadaveric donor, % 93.1 95.3 92.8
Donor age, yr 46.0016.54 35.5713.99 47.2016.39 <0.001
Delayed graft function, % 15.8 10.6 16.4 ns
Acute rejection, % 18.5 18.8 18.5 ns
Transplantation delay, mo 48 (2495) 48 (2495) 48 (2495) ns
Immunosuppression
Cyclosporin, % 41.8 24.7 43.8 <0.001
Tacrolimus, % 42.34 61.2 40.2 <0.001
mTOR inhibitors, % 11 7.1 11.4 ns
Steroids, % 55.6 56.5 55.5 ns
Metabolic profile
Metabolic syndrome, % 47.5 6 52.5 <0.001
Waist circumference, cm 90.8613.72 79.2811.82 92.2113.29 <0.001
Glycemia, mmol/L 5.752.30 5.041.03 5.842.39 0.003
Hb A1C, % 6.190.97 5.770.65 6.240.99 <0.001
Total cholesterol, mmol/L 1.900.41 1.830.36 1.910.42 ns
High density cholesterol, mmol/L 0.470.13 0.500.13 0.470.13 0.032
Triglycerides, mmol/L 1.380.89 1.030.45 1.420.92 <0.001
Uric acid, mol/L 450.00118.00 402.8193.24 455.19119.40 <0.001
Diabetic status (no diabetes/diabetes 77.6/9.1/13.3 91.8/0/8.2 75.9/10.2/13.9 0.002
before transplantation/diabetes
after transplantation), %
Renal parameters
mGFR (Tc-DTPAa; ml/min) 53,4820,86 53.4820.86 60.2621.24 52.6820.68 0.002
Serum creatinine, mol/L 137.0053.00 118.0046.00 138.9853.45 <0.001
eGFR (MDRD) 53.0021.00 61.0022.00 52.1620.78 <0.001
Urinary albumin excretion, g/min
Log albuminuria 1.420.68 1.110.63 1.450.68 <0.001
Urinary sodium excretion 145.4370.15 127.4064.31 147.4470.53 0.017
Values presented in boldface are statistically significant.
a
Values are expressed as meanSD, median (interquartile range) or percentage as appropriate.
b
NT vs. HT.
NT, normotensive patients; HT, hypertensive patients; mGFR, measured glomerular filtration rate; eGFR, estimated GFR; HbA1c, European best practice guidelines for renal transplantation. Section IV: long-term
management of the transplant; mTOR, mammalian target of rapamycin; Tc-DTPA, technetium-labeled diethylene-triamino-pentaacetic acid.

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1018 Transplantation May 2015 Volume 99 Number 5 www.transplantjournal.com

Normotensive Versus Hypertensive Groups 1.990.89; P<0.001). There was no difference in the other
Characteristics of the NT group were strikingly different parameters (Table 2).
from the whole HT group (Table 1). The NT recipients were
significantly younger and from the female sex, received grafts RH Versus CH Groups
from younger donors, and had significantly less metabolic
In univariate analysis, compared to CH, those with RH
syndrome (MS) (6 vs. 52.5%; P<0.001). Of note, use of ste-
were significantly older, had higher body mass index, and re-
roids was not associated with the presence of MS.
ceived kidneys from older donors. They experienced more
DGF, had higher blood glucose and glycated hemoglobin,
UH Versus CH Groups higher prevalence of metabolic syndrome (69.2% vs. 51.9%;
Renal transplant recipients with UH had higher glycated P=0.003), higher triglycerides, and higher uric acid levels. They
hemoglobin and log-urinary albumin excretion and interest- had significantly lower renal function (mGFR, 44.5918.62 vs.
ingly received less antihypertensive drugs (1.410.84 vs. 55.0621.22; P<0.001 and estimated glomerular filtration rate

TABLE 2.
Univariate analysis: controlled versus uncontrolled versus resistant HT

CH (333) UH (265) CH vs. UHa RH (128) CH vs. RHa UH vs. RHa F or b Pb


Variable
Recipients
Age, yr 52.2612.25 53.511.8 ns 58.628.76 <0.001 <0.001 14 <0.001
Sex (male), % 64.9 67 ns 72.7 ns ns 2.27 0.13
Tobacco use, % 33.9 33.6 ns 37.5 ns ns 0.33 ns
Body mass index, kg/m2 25.464.76 25.74.6 ns 26.984.53 0.004 0.004 6 0.002
Time in dialysis, mo 23 (840) 23 (1047) 0.1 26 (845) ns ns 2.27 0.1
Antihypertensive drugs (n) 1.990.89 1.410.84 <0.001 3.380.49 <0.001 <0.001 250 <0.001
Angiotensin system inhibitors, % 65 48 <0.001 81 <0.001 <0.001 42.2 <0.001
Beta blockers, % 44 37 ns 80 <0.001 <0.001 66 <0.001
Calcium channel blockers, % 50 36 <0.001 77 <0.001 <0.001 57.3 <0.001
Diuretics, % 40 20 <0.001 100 <0.001 <0.001 227.4 <0.001
Donors
Cadaver donor, % 92.2 93.4 ns 94.5 ns ns 0.19 ns
Donor age, yr 45.6617.03 46.515.8 ns 52.6314.73 <0.001 0.010 8.9 <0.001
Delayed graft function, % 12.9 17.7 ns 22.7 0.030 ns 3.5 0.03
Acute rejection, % 18.3 18.5 ns 18.8 ns ns 0.006 ns
Transplantation delay, mo 48 (2495) 48 (2495) ns 47 (2486) ns ns 1.44 ns
Immunosuppression
Cyclosporin, % 42.3 44.9 ns 45.3 ns ns 0.27 ns
Tacrolimus, % 42.9 40.4 ns 32.8 0.140 ns 3.95 0.14
mTOR, % 9.9 10.9 ns 11 0.160 ns 3.95 0.14
Steroids, % 52 59.6 ns 56.3 ns ns 3.55 ns
Metabolic profile
Metabolic syndrome, % 51.9 45.4 ns 69.2 0.003 <0.001 9.43 <0.001
Waist circumference, cm 92.2113.29 91.312.8 ns 97.0612.52 ns ns 1.64 ns
Fast glycemia, mmol/L 5.622.38 5.912.23 ns 6.252.69 0.030 ns 3.32 0.04
Hb A1C, % 6.070.82 6.291.08 0.02 6.561.08 <0.001 0.030 12.5 <0.001
Total cholesterol, mmol/L 1.890.41 1.930.4 ns 1.920.46 ns ns 0.75 ns
High density cholesterol, mmol/L 0.460.13 0.480.14 ns 0.450.13 ns <0,05 3.14 <0.05
Triglycerides, mmol/L 1.350.82 1.370.77 ns 1.711.29 0.001 <0.001 7.94 <0.001
Uric acid, mol/L 452.80121.34 438111 ns 496.98120.96 0.001 <0.001 10.9 <0.001
Diabetic status (no diabetes/diabetes 81.7/5.1/13.2 72.8/12.5/14.7 ns 67.2/18.8/14.1 ns ns 2.74 0.07
before transplantation/diabetes
after transplantation)
Renal parameters
mGFR (DTPA-Tca), mL/min 55.0621.22 53.620 ns 44.5918.62 <0.001 <0.001 12.5 <0.001
e GFR (MDRD), mL/min/1.73 m2 54.0021.00 52.719.6 ns 47.0021.00 0.002 0.010 6.12 0.002
Albuminuria, g/min 16 (640) 26.2 (9.72127) 49 (20178)
Log albuminuria 1.250,58 1.550.72 <0.001 1.750.68 <0.001 0.01 30.5 <0.001
Urinary sodium 145.0769.06 14767 ns 155.1280.69 ns ns 0.92 ns
Values presented in boldface are statistically significant.
a
P value, Tukey, or Mann-Whitney U test with Bonferroni correction post hoc analysis.
b
ANOVA or Kruskal-Wallis.
ns, no statistical difference; HT, hypertension; HbA1c, glycated hemoglobin; mGFR, measured glomerular filtration rate; eGFR, estimated GF; ANOVA, analysis of variance; mTOR, mammalian target of rapamycin.

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2014 Wolters Kluwer Fernando et al 1019

DISCUSSION
Our study shows that although at high risk of CV morbid-
ity and death, RTRs are not in the BP targets because 48.5%
of them have UH or RH, when using the recommended tar-
gets of less than 130/80 mm Hg. Even if we apply the targets
recommended in the general population, 27% of our cohort
are still noncontrolled, suggesting that better control of HT
remains a goal in the renal transplant population. The fact
that treated hypertensive patients are not in the recommended
range is relatively common: when analyzing data in the gen-
eral population with HT, HT control remains disappointingly
lower than that in controlled trials. For instance, in the large
Antihypertensive and Lipid-Lowering Treatment to Prevent
FIGURE 1. Risk factors for RH in the multivariate analysis. RH, Heart Attack trial, 55% of participants had their blood pres-
resistant hyper tension. sure controlled less than 140/90 mm Hg at the first annual
visit, and 66% were at this target 4 years later.15 In marked con-
[eGFR]; P=0.002) and higher log-albuminuria (1.750.68 vs. trast, several studies indicate that up to two thirds of hyper-
1.250.58; P<0.001). As expected, there was a significant tensive subjects from the general population may be untreated
difference in the number of antihypertensive drugs (3.4 vs. or undertreated. Longitudinal data from the Framingham
1.99; P<0.001). There was no difference in donor sex, tobacco Heart Study indicate that more than half of individuals with
use, history of HT, donor serum creatinine, donor eGFR UH will continue to have inadequate control after 4 years.16
(modification of the diet in renal disease [MDRD] or Cockroft- In a multinational survey among hypertensive subjects aged
Gault), donor cause of death and deceased versus living 35 to 64 years, 29% in the United States, 17% in Canada, and
donor transplantation. There was no difference in other re- less than 10% in European countries had their blood pres-
cipient parameters (Table 2) and particularly doses and sure down to the 140/90 mm Hg level.17,18 Suboptimal con-
concentrations of various immunosuppressive drugs (Table S1, trol of HT is also highly prevalent (48%) in patients with
SDC, http://links.lww.com/TP/B79). CKD,19 although the recent analysis of data from the National
Health and Nutrition Examination Survey 1999 to 2006 indi-
cated that some improvement occurred over time.20
RH Versus UH Groups Blood pressure control is also obviously suboptimal in
The differences observed between these two groups should RTRs. As early as 1997, using ambulatory BP measurement,
be interpreted with caution because the UH group did not it was reported in a pediatric population that only 18% to
benefit of appropriate anti-HT treatment titration to reach 53% of children demonstrated well-controlled HT.21 In
the recommended BP targets. However, recipients with RH 2003, Wodarczyk et al.22 reported that the rate of control
and their donors were older, had higher body mass index, of BP (<140/90) in their transplant cohort was only 25%.
higher percentage of metabolic syndrome (69.2% vs. 45.4%; Similarly, Kasiske et al.23 found in 2004 that 51% of their
P<0.001), worst blood glucose and glycated hemoglobin, RTRs were HT (>140 mm Hg) at 1 year after transplantation,
and higher levels of triglycerides and uric acid. Also, renal despite treatment with antihypertensive medications. Despite
function and log-albuminuria were significantly different. the recommendations issued in 2002 in Europe,9 in 2003 in
Diabetic status and immunosuppressive regimens did not the United States,10 and later in 2004 (Kidney Disease Out-
differ from one group to the other (Table 2 and Table S1, comes Quality Initiative), Tutone et al.24 reported in 2005 that
SDC, http://links.lww.com/TP/B79).

Multivariate Analysis TABLE 3.


In the multivariate analysis, the factors significantly asso- Odds ratio for resistant hypertension (multivariate
ciated with RH were recipient age (odds ratio [OR], 1.83 logistic regression)
[1.272.65]; P<0.001), mGFR (OR, 0.73 [0.550.98];
The reference category is:
P=0.037), urinary albumin excretion (UAE; log UAE, OR, controlled HT
2.25 [1.702.99]; P<0.001), and the presence of metabolic
syndrome (OR, 2.08 [1.213.55]; P<0.007) (Fig. 1). Of Model r2= Exp(B) coefficient (95% CI)
interest, duration of dialysis, delay after transplantation, Recipient age (per 13 yr) 1.837 (1.2732.650)
donor age, DGF, and urinary sodium excretion were not Donor age (per 17 yr) 0.929 (0.6761.275)
significantly associated with RH (Table 3). When we re- Transplantation delay (median) 0.860 (0.5021.472)
place the MS by its components, the basal glycemia (P=0.04, Time in dialysis (6 mo) 0.781 (0.4321.409)
[1.01.17]), triglycerides levels (P=0.04, [1.011.52]), and dia- mGFR (Tc-DTPA; mL/min/1.73 m2) 0.738 (0.5540.982)
betes status (P=0.047; [1.02.9] were significant but much Delayed graft function (%) 1.727 (0.9123.267)
less than the MS, whereas HDL cholesterol and waist circum- Albuminuria ( per 0.7 log) 2.255 (1.7012.99)
ference were not. Urinary sodium (per 70/mmol/24 hr) 1.265 (0.9981.603)
In another multivariate analysis, the risk factors for UH Metabolic syndrome (yes vs. no) 2.080 (1.2183.550)
were only albuminuria (P<0.001) and metabolic syndrome HT, hypertension; 95% CI, 95% confidence interval; Tc-DTPA, technetium-labeled diethylene-
(P=0.043). triamino-pentaacetic acid.

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1020 Transplantation May 2015 Volume 99 Number 5 www.transplantjournal.com

still 32% of their RTRs had BP levels higher than 140 mm Hg impact in the control of HT and eventually improvement of
and certainly a higher percentage over 130/80 mm Hg. We patient and graft survivals.
report approximately similar percentages in our cohort: Concerning the relation of renal function (mGFR, eGFR,
27% over 140/90 and 48.5% over 130/80 mm Hg. The find- serum creatinine, albuminuria) and HT, our work is in line
ing of a high prevalence of UH or RH in this specific group with previous reports, showing essentially an association be-
of patients, who has the privilege to be submitted to a regular tween decreased GFR, increased albuminuria, and HT. How-
surveillance by transplant physicians or transplant surgeons, ever, although decreased mGFR was a significant risk factor
is surprising. for the presence of RH, serum creatinine and eGFR (MDRD)
Several factors associated with poor blood pressure con- were not significant. In RTRs, the reported associations be-
trol have been identified and divided, somewhat arbitrarily, tween control of HT and renal function are different between
into patient-related and physician-related factors.25 Among ambulatory BP monitoring and office measurements. For in-
patient-related factors, noncompliance with antihypertensive stance, Covic et al.29 observed that for each 10% reduction in
medications probably plays a significant role because these nocturnal systolic blood pressure, the GFR may be higher by
patients have a big number of pills to ingest everyday includ- 4.5 mL per min per 1.73 m2. In contrast, Jacobi et al.30 ob-
ing immunosuppressant, antihypertensive and hypolipemiant served that casual BP values did not correlate with 6-month
drugs, proton-pomp inhibitors, and aspirin or anticoagulants. serum creatinine concentrations. Although eGFR (MDRD)
Unfortunately, we have no precise information about com- is usually significantly correlated with mGFR in RTRs, one
pliance with antihypertensive drugs in our cohort, but it can speculate that the better precision of mGFR was required
was already reported that noncompliance with immunosup- to show a significant association between RH and graft func-
pressive regimen is a common finding in RTRs,26 suggesting tion. Using the results from the intervention as a goal in
that this may be also the case with antihypertensive med- Hypertension Treatment (INSIGHT) trial, de Leeuw et al.31
ications. Physicians practices are also responsible for poor reported in the general population that both proteinuria
blood pressure control, including essentially a reluctance to and elevated serum creatinine concentration significantly re-
make therapeutic changes and to increase antihypertensive duced responsiveness to antihypertensive treatment, and this
treatment (clinical inertia), possibly because physicians are is essentially similar to the results we observe in our trans-
not confident in the BP values collected during office visits, plant population.
or because self-blood pressure measurement was reported to We recognize that our study has several limitations. First,
be in the target values, and this behavior may explain why although the data are prospectively collected, the study is
only 16% of our cohort received three or more antihyperten- retrospective, cross-sectional, and reflects only the prac-
sive drugs. Whether systematic use of 24-hr ambulatory BP tices of our center. Second, information on antihyperten-
monitoring or self BP monitoring would improve these re- sive treatment was collected from patient declarations
sults deserves further investigation. It is also possible that and charts, and this reflects more the medical prescription
some physicians disagree with guidelines, particularly when rather than the actual treatment really taken by the patients.
the evidence from properly done clinical trials supporting Finally, BP measurements were done for 3 to 4 hr in the
the low BP levels recommended remains questionable.27 morning, and these values may not precisely reflect the ambu-
In addition to patient and physician behaviors related to latory 24-hr values and do not give any information about
recommendations, medical treatment, and possible noncom- the nycthemeral cycle.
pliance, it is well known that some patients characteristics In conclusion, our study confirms that BP control in RTRs
like age, sex, ethnicity, or comorbidities (diabetes, obesity, left is far from the recommended targets and suggests that
ventricular hypertrophy, or renal disease) may participate to management of HT should be improved in this cardiovas-
resistance to adequate therapy. In the retrospective study of cular high-risk population. Among many others, metabolic
Kasiske et al.23 including 1,666 patients, correlates of higher syndrome and urinary albumin excretion emerged as strong
BP included male sex, recipient and donor age, diabetes, body predictors of poor HT control. Whether prevention, early diag-
mass index, the presence of native kidneys, and delayed graft nosis, and management of the metabolic syndrome and re-
function. Our study shows that recipient age, metabolic syn- duction of albuminuria could help to more consistently reach
drome, decreased mGFR, and increased UAE are significant the BP recommended targets deserves further investigations.
risk factors for RH.
In a recent study conducted in 3,370 patients with HT MATERIALS AND METHODS
across 12 European countries, poor BP control was observed
in 53.5% of patients without MS or diabetes, 72.4% of pa- Patients
tients with MS but not diabetes, 77.7% of patients with We included in our study all consecutive RTRs attending
diabetes but not MS, and 95.3% of patients with both con- our outpatient clinic between January 1, 2007, and December
ditions; in multivariate analysis, MS conveyed an OR of 31, 2011, for their annual evaluation. We only excluded
2.56 for uncontrolled BP.28 A striking finding in the pres- 41 recipients with the following characteristics: age younger
ent study is that MS was associated with an OR of 2.08 than 18 years (n = 2), transplantation duration less than
for RH, whereas no or weak independent association was 1 year (n = 19), measured glomerular filtration rate less than
found between any single component of the MS and RH. 15 mL per min per 1.73 m2 (n = 7), pregnancy (n = 2), combined
Those results suggest a powerful but harmful synergy be- transplantation (n = 9), and 3 transplantations (n = 2).
tween the different components of MS on poor BP control According to the French Law, noninterventional studies do
and suggest that prevention and management of MS, which not require approval by institutional review board ethics
was observed in as many as 47.5% of the total cohort and committee (article L1121-1 du code de la sant publique). In
52.5% of the HT group could have a significant positive fact, data of all our transplant patients are recorded in an

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2014 Wolters Kluwer Fernando et al 1021

academic database, and we have approval of institutional re- of plasma radioactivity and hematocrit. The GFR value
view board to use these data for scientific purposes (Cohorte was the average of four measurements.
DIMTP, Ref : 13_334). For the present study, we have no
Hypertension Groups
written informed consent, but patients are informed that we
collect their data for potential publication. Although patients were on the supine position for the
determination of renal function, after a 10-min period of
Immunosuppression and Clinical Follow-Up rest, BP was measured on the arteriovenous fistula free arm
Patients were regularly followed-up as usual calendar of all every 5 min, and reported values are the average of at least
transplanted patients in our center. From month 3 onward, 20 measurements. We used the mean of these values to clas-
clinical examination and biochemical analyses were recorded sify patients depending on their BP control:
bimonthly until month 6, monthly until month 12, and every NT: BP less than 130/80 mm Hg without any treatment.
3 months thereafter: a check for glycemia is done every CH: BP less than 130/80 mm Hg with use of one or more an-
3 months and for lipids every 6 months. Blood pressure is tihypertensive drugs.
measured at each visit in the supine position after 10 min of UH: systolic BP greater than 130 mm Hg or diastolic BP
rest: the choice and adaptation of anti-HT treatment was greater than 80 mm Hg, despite the use of one or more antihy-
pertensive drugs.
under the responsibility of the consultant physician, who
RH: systolic BP greater than 130 mm Hg or diastolic BP
was encouraged to follow the KDIGO recommendations greater than 80 mm Hg despite the use of at least three antihy-
for the care of transplant patients.13 Metabolic syndrome was pertensive drugs, including one diuretic.
managed through optimization of its constitutive parame-
ters following specific guidelines, targeting an LDL choles-
terol less than 2.6 mmol/L and a glycated haemoglobin Statistical Analysis
less than 7%. SPSS for Windows version 11.0 software (SPSS Inc., Chicago,
Maintenance immunosuppressive protocol usually includes IL) was used for statistical analysis. Data are presented as
mycophenolic acid in association with a calcineurin in- mean standard deviation for continuous and normally dis-
hibitor with or without steroids. Acute rejection episodes tributed variables, as median (interquartile range) for continu-
(biopsy-proven or clinically suspected) are treated with ous non-normally distributed variables and as percentages for
three intravenous methylprednisolone boluses of 500 mg categorical variables. Because of skewed distribution, urinary
per day each. albumin was log-transformed before comparison of groups.
Differences between HT versus NT patients were assessed
Annual Evaluation by the Student t test for parametric data and by the chi-square
Patients were admitted in the morning with a 24-hr urine analysis for categorical data.
collection. Weight, height, and waist circumference were mea- The potential differences between the HT groups were
sured, and immunosuppressive and antihypertensive medica- tested using an analysis of variance or a Kruskal-Wallis test
tions were recorded. Arterial pressure was measured with (as appropriate), and if a significant effect was found, a Tukey
an automatic device (Model Dinamap V100; GE Healthcare, post hoc analysis or a Mann-Whitney U test with Bonferroni
Little Chalfont, UK).32 correction was performed.
Glomerular filtration rate was measured with an isotopic Variables identified as significant correlates of the control
method. Arterial pressure was monitored for 3 to 4 hr, and of BP in this univariate analysis were then included in a mul-
blood and urine were collected for analysis. tivariate logistic regression model. Because those variables
have different distributions, the OR were computed for one
Metabolic Syndrome standard deviation of the variables. To avoid the regres-
Search for the presence of MS is part of our annual evalua- sion to the mean phenomenon, baseline values of GFR
tion. Metabolic syndrome was defined, according to recently were entered into the model. In the multivariate analysis,
revised criteria, using a regional cutpoint for waist circumfer- we only included CH versus RH groups: we considered that
ence.33 A patient was classified as having MS if at least three a multivariate analysis of risk factors could be misleading
of the following criteria were present : (1) abdominal obesity in patients who did not receive an optimal treatment,
(defined as men waist circumference 94 cm, women waist which is the case in the UH group. Two-tailed P value less
circumference 80 cm); (2) triglycerides of 150 mg/dL or than 0.05 was considered statistically significant.
greater; (3) HDL cholesterol: men less than 40 mg/dL,
women less than 50 mg/dL; (4) BP of 130/85 mm Hg or
greater; (5) fasting blood glucose of 5.6 mmol/L or higher. REFERENCES
1. Opelz G, Wujciak T, Ritz E. Association of chronic kidney graft failure with
Determination of Renal Function recipient blood pressure. Collaborative Transplant Study. Kidney Int
Glomerular filtration rate was estimated by urinary clear- 1998;53:217.
2. Kasiske BL. Cardiovascular disease after renal transplantation. Semin
ance of technetium-labeled diethylene-triamino-pentaacetic
Nephrol 2000;20:176.
acid, using the constant infusion technique as previously 3. Campistol JM, Romero R, Paul J, et al. Epidemiology of arterial hypertension
described.34 Briefly, after the induction of water diuresis in renal transplant patients: changes over the last decade. Nephrol Dial
and a 90-min equilibration period, four 20-min to 30-min Transplant 2004;19(Suppl 3):62.
urine collections were obtained by spontaneous voiding. At 4. Levey AS, Beto JA, Coronado BE, et al. Controlling the epidemic of
cardiovascular disease in chronic renal disease: What do we know?
the end of each clearance period, patients drank a volume What do we need to learn? Where do we go from here? National Kidney
of water equal to the preceding urine volume. At midpoint of Foundation Task Force on Cardiovascular Disease. Am J Kidney Dis
each clearance period, blood was drawn for the determination 1998;32:853.

Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved.


1022 Transplantation May 2015 Volume 99 Number 5 www.transplantjournal.com

5. Vetromile F, Szwarc I, Garrigue V, et al. Early high pulse pressure is 19. Jafar TH, Stark PC, Schmid CH, et al; AIPRD Study Group. Progression
associated with graft dysfunction and predicts poor kidney allograft of chronic kidney disease: the role of blood pressure control, proteinuria,
survival. Transplantation 2009;88:1088. and angiotensin-converting enzyme inhibition: a patient-level meta-
6. Rigatto C, Foley R, Jeffery J, et al. Electrocardiographic left ventricular analysis. Ann Intern Med 2003;139:244.
hypertrophy in renal transplant recipients: prognostic value and impact 20. Plantinga LC, Miller ER 3rd, Stevens LA, et al. Blood pressure control
of blood pressure and anemia. J Am Soc Nephrol 2003;14:462. among persons without and with chronic kidney disease: US trends and
7. Mange KC, Feldman HI, Joffe MM, et al. Blood pressure and the survival of risk factors 19992006. Centers for Disease Control and Prevention
renal allografts from living donors. J Am Soc Nephrol 2004;15:187. Chronic Kidney Disease Surveillance Team. Hypertension 2009;54:47.
8. Kasiske BL, Vazquez MA, Harmon WE, et al. Recommendations for the 21. Lingens N, Dobos E, Witte K, et al. Twenty-four-hour ambulatory blood
outpatient surveillance of renal transplant recipients. American Society of pressure profiles in pediatric patients after renal transplantation. Pediatr
Transplantation. J Am Soc Nephrol 2000;11(Suppl 15):S1. Nephrol 1997;11:23.
9. EBPG Expert Group on Renal Transplantation. European best practice 22. Wodarczyk Z, Glyda M, Kocianska L, et al. Prevalence of arterial
guidelines for renal transplantation. Section IV: long-term management of hypertension following kidney transplantationa multifactorial analysis.
the transplant recipient. IV.5.2. Cardiovascular risks. Arterial hypertension. Ann Transplant 2003;8:43.
Nephrol Dial Transplant 2002;17(Suppl 4):25. 23. Kasiske BL, Anjum S, Shah R, et al. Hypertension after kidney
10. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint transplantation. Am J Kidney Dis 2004 ; 43:1071.
National Committee on Prevention, Detection, Evaluation, and Treatment 24. Tutone VK, Mark PB, Stewart GA, et al. Hypertension, antihypertensive
of High Blood Pressure. Joint National Committee on Prevention, Detection, agents and outcomes following renal transplantation. Clin Transplant
Evaluation, and Treatment of High Blood Pressure. National Heart, Lung, 2005;19:181.
and Blood Institute; National High Blood Pressure Education Program 25. Wang TJ, Vasan RS. Epidemiology of uncontrolled hypertension in the
Coordinating Committee. Hypertension 2003;42:1206. United States. Circulation 2005;112:1651.
11. Mancia G, De Backer G, Dominiczak A, et al. 2007 Guidelines for 26. Denhaerynck K, Dobbels F, Cleemput I, et al. Prevalence, consequences,
the Management of Arterial Hypertension: The Task Force for the and determinants of non-adherence in adult renal transplant patients: a
Management of Arterial Hypertension of the European Society of literature review. Transpl Int 2005;18:1121.
Hypertension (ESH) and of the European Society of Cardiology (ESC). 27. Flynn C, Bakris GL. Blood pressure targets for patients with diabetes or
J Hypertens 2007;25:1105. kidney disease. Curr Hypertens Rep 2011;13:452.
12. Haute Autorit de Sant. Recommandations professionnelles. Suivi 28. Kjeldsen SE, Naditch-Brule L, Perlini S, et al. Increased prevalence of
ambulatoire de ladulte transplant rnal au-del de 3 mois aprs metabolic syndrome in uncontrolled hypertension across Europe: the
transplantation. Recommendations November 2007. www.has-sante.fr. global cardio-metabolic risk profile in patients with hypertension disease
13. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work survey. J Hypertens 2008;26:2064.
Group. KDIGO clinical practice guideline for the care of kidney transplant 29. Covic A, Gusbeth-Tatomir P, Mardare N, et al. Dynamics of the
recipients. Am J Transplant 2009;9(Suppl 3): S1. circadian blood pressure profiles after renal transplantation. Transplantation
14. Paoletti E, Gherzi M, Amidone M, et al. Association of arterial hypertension 2005;80:1168.
with renal target organ damage in kidney transplant recipients: the 30. Jacobi J, Rockstroh J, John S, et al. Prospective analysis of the value
predictive role of ambulatory blood pressure monitoring. Transplantation of 24-hour ambulatory blood pressure on renal function after kidney
2009;87:1864. transplantation. Transplantation 2000;70:819.
15. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative 31. De Leeuw PW, Ruilope LM, Palmer CR, et al. Clinical significance of renal
Research Group. Major outcomes in high-risk hypertensive patients function in hypertensive patients at high risk. Results from the INSIGHT
randomized to angiotensin-converting enzyme inhibitor or calcium channel trial. Arch Intern Med 2004;164:2459.
blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to 32. Reinders A, Reggiori F, Shennan AH. Validation of the DINAMAP ProCare
Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288:2981. blood pressure device according to the international protocol in an adult
16. Lloyd-Jones DM, Evans JC, Larson MG, et al. Treatment and control population. Blood Press Monit 2006;11:293.
of hypertension in the community: a prospective analysis. Hypertension 33. Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the metabolic
2002;40:640. syndrome: a joint interim statement of the International Diabetes Federation
17. Wolf-Maier K, Cooper RS, Kramer H, et al. Hypertension treatment and Task Force on Epidemiology and Prevention; National Heart, Lung, and
control in five European countries, Canada, and the United States. Blood Institute; American Heart Association; World Heart Federation;
Hypertension 2004;43:10. International Atherosclerosis Society; and International Association for the
18. Wang YR, Alexander GC, Stafford RS. Outpatient hypertension Study of Obesity. Circulation 2009;120:1640.
treatment, treatment intensification, and control in Western Europe and 34. Mimran A, Deschodt G. The role of the rennin-angiotensin system in
the United States. Arch Intern Med 2007;167:141 Erratum in: Arch the hormonal and renal responses to tilt in normal man. Ren Physiol
Intern Med. 2007;167:648. 1983;6:36.

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