CE: ; JH-D-18-00510; Total nos of Pages: 9;

JH-D-18-00510

Original Article

Malignant hypertension: diagnosis, treatment and

prognosis with experience from the Bordeaux cohort
Sébastien Rubin a, Antoine Cremer b, Romain Boulestreau b, Claire Rigothier a
Sophie Kuntz b, and Philippe Gosse b

Background: Malignant hypertension, the most severe

INTRODUCTION

M
form of hypertension, is defined by high blood pressure alignant hypertension (MHT) is the most severe
and acute ischemic organ damage. It has a worse form of hypertension, resulting in acute ischemic
prognosis than other forms of hypertension, especially in damages on target organs (e.g. eye, brain, kidney
black patients. New tools to assess organ damage, and heart). MHT remains a current medical problem. Despite
especially that of the heart and brain, are now available improvement of hypertension management, the frequency
and may contribute to a better evaluation of these of MHT has failed to decrease in the last 30 years [1], and it has
patients. This report improves knowledge of the increased recently in the USA [2]. In Birmingham (UK),
characteristics of involved organs to facilitate diagnosis and incidence of MHT is 6/100 000 per year [3]. Five-year survival
to evaluate the effectiveness of our treatment protocol. of patients with MHT is 90% [4], and 10–35% of them require
Method: The Bordeaux registry, started in 1995, recruited dialysis or kidney transplantation. These poor outcomes
168 patients. In addition to evaluations of their eyes and contrast with chronic hypertension and show why MHT
kidneys, these patients had a systematic evaluation of their should still be a topic of interest for the medical community.
hearts with ECG and echocardiography and, since 2007, a Black people are often more affected than other groups and
systematic brain MRI. have worst prognoses. For example, van den Born et al. [5]
found that approximately 50% of the MHT registry in Amster-
Results: Blood pressure was lowered with a protocol
dam (the Netherlands) consisted of black people. However,
based on blockers of the renin–angiotensin system
low income may explain some of these results because 25%
started at a very low-dose with forced titration over 48 h.
of blacks were uninsured, and only 2% of whites. This
Only an oral route was used for antihypertensive
situation is worse in African countries [6]. In the Birmingham
medication. Systematic MRIs found significant brain
cohort, median survival after MHT was 121 months for whites
damage in 93% of patients. Heart involvement was highly
and only 20.4 months for blacks [4]. However, other factors
prevalent: 82% had left ventricular mass more than 60 g/
like genetic predisposition can affect prognosis. For exam-
m2.7, and 56% had systolic dysfunction (estimated by
ple, the South Asian ethnicity is associated with better out-
global longitudinal strain). Renal involvement and
comes than white or African people in the United Kingdom
thrombotic microangiopathy were respectively present in
[7]. Because of frequency and seriousness, particularly in
55 and 15% of patients. Median follow-up was 48
developing countries, modern challenges for MHT are to
months. Renal survival at 5 years was 90.8%, similar to
have easy diagnosis criteria available at bedside and to
other studies.
implement cost-effective treatment worldwide. Previously,
Conclusion: Malignant hypertension is a systemic MHT had been defined according to the classical definition of
disease causing severe damage to the brain, heart, kidneys high blood pressure (BP) level and malignant hypertensive
and eyes, even in absence of symptoms. Renin– retinopathy (MHR) [8]. However, fundus examinations are
angiotensin system blockers seem to be the cornerstone of now often performed only by ophthalmologists, who not
treatment. available everywhere, especially in small hospitals or
Keywords: hypertension, malignant hypertension, renin–
angiotensin system, thrombotic microangiopathy
Journal of Hypertension 2018, 36:000–000
Abbreviations: ACEI, angiotensin convertor enzyme a
Service de Néphrologie, Transplantation, Dialyse et Aphérèses, Hôpital Pellegrin and
inhibitor; ESRD, end-stage renal disease; GLS, global b
Service d’Hypertension Artérielle, ESH Hypertension Excellence Center, Hôpital Saint-
longitudinal strain; LVH, left ventricular hypertrophy; MHR, André, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
malignant hypertensive retinopathy; MHT, malignant Correspondence to Sébastien Rubin, Service de Néphrologie, Transplantation, Dialyse
hypertension; MOD, multi-organ damage; RAS, renin– et Aphérèses, Hôpital Pellegrin, Centre Hospitalier Universitaire de Bordeaux, Place
Amélie Raba Léon, 33 076 Bordeaux Cedex, France. E-mail: sebastien.rubin@chu-
angiotensin system; TMA, thrombotic micro angiopathy; bordeaux.fr
WML, white matter lesions Received 24 May 2018 Accepted 26 July 2018
J Hypertens 36:000–000 Copyright ß 2018 Wolters Kluwer Health, Inc. All rights
reserved.
DOI:10.1097/HJH.0000000000001913

Journal of Hypertension www.jhypertension.com 1

Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
CE: ; JH-D-18-00510; Total nos of Pages: 9;
JH-D-18-00510

Rubin et al.

developing countries. Moreover, BP levels are not correlated Heart involvement was assessed by troponin dosage, ECG
with mortality in MHT [9], and the eye should not be the only and echocardiography. Troponin and ECG were performed
target organ evaluated for damage to define MHT. Therefore, immediately after admission, and echocardiography was
a new definition including all involved organs is necessary. performed in the first 2 days by a trained cardiologist. Heart
Considering this situation, a group of clinicians with exper- involvement was categorized as important left ventricular
tise in MHT management has proposed diagnostic criteria for hypertrophy (LVH) [left ventricular (LV) mass index >60 g/
each organ, using the term ‘hypertension MOD’ (multi-organ m2.7] and/or impaired systolic function [ejection fraction
damage) [10]. This approach, which considers a minimum of <50% or global longitudinal strain (GLS) >14%] and/or
three involved organs, including heart, brain, kidneys and ischemic heart disease (repolarization abnormalities on ECG
endothelium [defined by mechanical hemolysis secondary to and/or troponin elevation without signs of ongoing infarc-
thrombotic micro angiopathy (TMA)], may facilitate a diag- tion) [10]. GLS has been measured using Vivid 7 and 9 and by
nosis of MHT when fundus examination was not immedi- using ECHOPAC PC (General Electrics, Boston, Massachu-
ately available. Moreover, the Bordeaux cohort has used this setts, USA) in all patients since 2008.
systemic approach since 1995 and thus collected much data, Brain involvement was categorized using an MRI (if
especially for heart and brain damage. Therapeutic manage- available) or brain scanner as acute stroke (ischemic or
ment of MHT has typically not been reported in the different hemorrhagic) and/or posterior regressive encephalopathy
published cohorts – probably because of management het- syndrome and/or extensive white matter lesions (WML)
erogeneity. In Bordeaux (France) since 1995, patients and microbleeds if patient has less than 60 years old. Since
with MHT or hypertension MOD have been treated the same 2007, we have tried to perform brain MRIs on all patients
way, starting with oral renin–angiotensin system (RAS) with MHT, even in the absence of any neurological sign and
blockers. The main aim of this report is to describe the with the limits of MRI availability and of patient agreements.
initial characteristics of MHT or hypertension MOD at admis- Before 2007, brain scans were only performed in symptom-
sion to facilitate early recognition of these patients and atic neurological patients.
improve knowledge of organ damage. The second aim is Kidney involvement was categorized according to Kid-
to evaluate the evolution of these patients using our system- ney Disease Improving Global Outcomes (KDIGO) guide-
atic management. lines [12] as creatinine elevation more than 0.3 mg/dl
(26.5 mmol/l) or more than 1.5 time baseline if available
METHODS or the presence of proteinuria/creatinuria more than 50 mg/
mmol or in the absence of creatinine anteriority by a
Bordeaux registry of malignant hypertension creatinine more than 130 mmol/l in the absence of another
The Bordeaux registry of MHT was started in 1995 in the cause at admission.
Bordeaux hypertension unit (European Society of Hyper- TMA, defined by reduced platelets count concomitant
tention Excellence Center). Patients were referred from the with haptoglobin decrease at admission, was considered as
emergency department, ICU, neurological unit or by their another sign of organ damage.
general practitioner (GP) to the hypertension unit. During
the first 10 years, patients’ inclusion in the registry was based Management
on the association of high BP (>180/110 mmHg) and the At admission, in addition to assessment of target organ
classical definition of MHR. Since 2004, patients with high BP damage, renal artery Doppler was performed to exclude
and acute damage involving at least three organs according bilateral stenosis renal arteries prior to the introduction of
to the modern definition and our previous publication [10,11] RAS inhibitors. When the registry was started, bilateral renal
were also entered in the registry, even if there was no MHR. artery stenosis contraindicated the use of angiotensin renin
Patients who no longer had high BP (>160/100 mmHg) at system inhibitors. This contraindication explains this strat-
admission in our unit with treatments initiated in a previous egy, which no longer seems indispensable because the use
department, patients who needed specific BP management of this drug class is possible in this situation as long as
to maintain cerebral perfusion pressure (acute ischemic or kaliemia and renal functions are closely monitored. The
hemorrhagic stroke for example) or patients known to be oral route was the only method used for antihypertensive
intolerant to inhibitors of the RAS were excluded. A nurse medication. Based on pathogenesis [13], the first drug class
trained in BP measurement took initial BP about 30 min after was a RAS blocker, starting with a very low dose (such as
admission to the hypertension unit using an auscultatory ramipril 1.25 mg) with forced titration by doubling dosage
method, with the patient in a lying position. Three measure- every 6 h until reaching a maximum of twice the standard
ments were taken, and their mean was recorded. We cate- dosage (20 mg for ramipril) with a target SBP between 140
gorized patients who did not know they were hypertensive and 180 mmHg in the first 48 h. When the maximum RAS
to have de novo hypertension. Patients with known hyper- blocker dose was reached, a calcium channel blocker was
tension, previously treated or not, were categorized as hav- added if BP remained more than 140/90 mmHg. The third
ing long-standing hypertension. drug class was a thiazide diuretic, and, if necessary, we used
spironolactone. This protocol is summarized in Table 1.
Assessment of target organ damage Beta blockers were introduced or continued if required by
MHR was a level 3 or 4 according to the Keith and Wagener specific indication. Renal function and potassium levels
classification. Fundus examination was performed by an were monitored every day. Saline infusion (0.9%) used in
ophthalmologist in the ophthalmology department from the case of an RAS blocker-induced severe decrease of renal
the university hospital of Bordeaux. function at clinicians’ discretion.

2 www.jhypertension.com Volume 36  Number 1  Month 2018

Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
CE: ; JH-D-18-00510; Total nos of Pages: 9;
JH-D-18-00510

Malignant hypertension: patients characteristics

TABLE 1. Treatment protocol used in our unit were defined as acute coronary syndrome, stroke or
1. STOP intravenous antihypertensive medication if any aortic dissection.
2. Titration RAS blocker (e.g. ramipril, another RAS blocker can be used) Renal-event-free survival was defined by survival with-
140 mmHg < Target < 180 mmHg
H0: Ramipril 1.25 mg
out ESRD. Event-free survival was defined by survival
H6: Ramipril 2.5 mg without ESRD or major cardiovascular event. BP during
H12: Ramipril 5 mg the follow-up was measured by physicians working in the
H24: Ramipril 10 mg hypertension unit using mercury sphygmomanometer.
H36: Ramipril 10 mg twice a day
If blood pressure remains >140/90 mmHg after 48 h then Occurrence of ESRD, worsening renal function or major
3. Introduce calcium channel blockers cardiovascular events of all patients were evaluated in 2017
4. Double dosage of calcium channel blockers if tolerated or add beta blocker by using hospital records for patients still followed in our
5. Add thiazide diuretic
6. Add spironolactone 25 mg
unit or by phone call with the patients and their GP.
RAS, renin–angiotensin system.
Statistics
Statistical analysis was done using SPSS25 (Release 25, 2017;
Follow-up IBM Corp., Armonk, New York, USA) software. Descriptive
Patients returned 1 month after discharge to the hyperten- statistics included mean (SD). Quantitative variables were
sion unit and then every 3 months for 1 year. A secondary compared using t test, and qualitative variables, using x2
hypertension assessment was performed during initial hos- test. Renal survival was studied with the Kaplan–Meier
pitalization or during follow-up with at least an adrenal scan curve. Survival curves were compared using a log-rank
and metanephin, cortisol and thyroid stimulating hormone test. P less than 0.05 was considered statistically significant.
dosages for every patient. The search for hyperaldosteron-
ism was performed 6–12 months after the acute phase RESULTS
(because it is requiring to stop for 2 weeks RAS blockers).
Resistant hypertension was defined as uncontrolled Since 1995, 168 patients were enrolled (Fig. 1), 42 between
clinic BP (>140/90 mmHg) after treatment with at least 1995 and 2004, 85 between 2005 and 2014 and 41 between
three antihypertensives agents included a diuretic. 2015 and the end of November 2017. Among these patients,
Significant renal function worsening was defined as the 153 had MHR, and 15 had normal ocular fundus but with at
occurrence of end-stage renal disease (ESRD) or as a least three others target organs damaged, thus fulfilling the
decrease of estimated glomerular filtration rate (eGFR) (using criteria for hypertension MOD [10]. Twenty-nine percent
modification of diet in renal disease formula) between dis- were less than 40 years old. For a large proportion of these
charge and follow-up more than 40%, according to National patients [101/168 (60%)], hypertension had not been
Kidney Foundation–Food and Drug Administration Scien- detected or treated before this acute event. Baseline char-
tific Workshop guidelines [14]. Major cardiovascular events acteristics are presented in Table 2. Patients with malignant

FIGURE 1 Yearly inclusions from 1995 to November 2017. MHR, patients with malignant hypertension retinopathy; MOD, hypertension multi-organ damage (patients
without malignant hypertensive retinopathy).

Journal of Hypertension www.jhypertension.com 3

Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
CE: ; JH-D-18-00510; Total nos of Pages: 9;
JH-D-18-00510

Rubin et al.

TABLE 2. Baseline characteristics: comparison of patients with TABLE 4. Causes of hypertension

malignant hypertension and patients without
malignant hypertension n %

MHT, MODHTN, P Essential 125 74

n ¼ 153 n ¼ 15 Estrogen contraception 18 11
Primary hyperaldosteronism 10 6
Age (years) 46.5  12.5 50.6  15.8 NS
Renal artery stenosis 7 4
Male 104 (68%) 13 (87%) NS
IgA nephropathy 3 2
Diabetes 11 (8%) 0 NS
Other nephropathy 4 2.5
Smoker 44 (29%) 7 (47%) NS
Pheochromocytoma 1 0.5
De novo hypertension 63 (41%) 5 (33%) NS
Essential hypertension 101 (73%) 10 (83%) NS
Entry SBP (mmHg) 211  33.4 200.8  28.4 NS
Entry DBP (mmHg) 118.4  20.3 112.5  14.8 NS we propose, heart damage was present in 138 of 168 (82%)
Entry creatinine (mmol/l) 173.1  165 163.1  115 NS of patients.
Entry proteinuria/creatinuria 104  160 156  160 NS Before brain MRI was systematically performed, brain dam-
(mmol/mmol)
age was found in 14 of 49 (29%) of patients by using a brain
Entry potassium (mmol/l) 3.5  0.6 3.5  0.6 NS
LVM/h2.7 (g/m2.7) 83.1  26 102.5  39 0.01
scanner. Since September 2007 when MRI was introduced in
Troponin I (ng/ml) 0.19  0.4 1  2.3 0.001 our systematic evaluation, more than two-thirds of patients had
GLS (%) 13.6  3.9 11.6  4.1 NS brain MRIs during this period [81/119 (68%)] – this prevalence
LVEF (%) 55.9  11.4 40.7  16.8 <0.001 has dramatically increased: the MRIs performed revealed that 75
of 81 (93%) patients had brain damage. Brain lesion character-
Baseline characteristics: because of the different inclusion criteria, the subgroup of
patients corresponding to the classical definition of malignant hypertension and those istics are summarized in Table 5.
corresponding to the definition of multi-organ damage hypertension are compared. GLS, Renal involvement was found in 55% of patients (10%
global longitudinal strain; h, height, LVM, left ventricular mass; LVEF, left ventricular
ejection fraction; MHT, malignant hypertension; MODHTN, multi-organ damage had only proteinuria and no eGFR decrease). Despite acute
hypertension.
kidney injury, potassium levels remained normal or low
retinopathy had similar kidney or brain damage but less (mean: 3.5  0.60 mmol/l; range 2.3–5.7). A mild protein-
heart damage (LV mass was 83.6  26 vs. 102.5  39 g/m2.7, uria was frequent [average proteinuria/creatinine was
P ¼ 0.01, and LV ejection fraction was 55.9  11.4 vs. 110  160 mg/mmol (range 0–889)]. Only one patient
40.7  16.8, P < 0.001). Patients with secondary hyperten- required dialysis immediately after admission. Eleven
sion were more likely to be female and to have recognized patients had kidney biopsy. Six of them (54.5%) had only
hypertension before MHT (Table 3). malignant nephroangiosclerosis, two had IgA nephropathy
Reasons for admission were high BP in 34 (20%) patients. and three had unspecific vascular lesions. No patient
For the remaining 80%, admission was due to a complica- required dialysis after starting our management protocol.
tion [visual impairment n ¼ 42 (25%), stroke n ¼ 35 (21%), TMA was found in 15% of patients with a mean platelets
heart failure n ¼ 16 (10%)] or unspecific signs like head- count of 119 000  28 900/ml (ranges 46 000–149 000).
aches, dizziness, anorexia, asthenia [n ¼ 28 (17%)]. Causes Organs damages are summarized in Table 5.
of hypertension are summarized in Table 4. At discharge, on average 8  3 days after admission,
Although echocardiography was systematically per- office SBP was significantly reduced (141  15 vs.
formed on all these patients, measurements were not of 211  33 mmHg, P < 0.001) and creatinine was stable
sufficient quality in all patients (Table 5). With the criteria (172  161 vs. 162  113 mmol/l, NS). All patients were
treated with RAS blockers [116 (69%) angiotensin convertor
TABLE 3. Baseline characteristics: comparison of patients with enzyme inhibitor (ACEI), 52 (31%) angiotensin -receptor
essential or secondary hypertension antagonist]. Calcium antagonist was used in 128 (76%)
Essential Secondary patients, and 83 (49%) had a thiazide diuretic, 62 (37%) a
hypertension, hypertension, beta blocker, 60 (36%) spironolactone, 15 (9%) an alpha
n ¼ 125 n ¼ 43 P blocker. The number of different antihypertensive classes
Age (years) 46.7  12.9 504  12.8 NS
was only one class for four (2%), two classes for 33 (20%),
Male 97 (78%) 20 (47%) 0.0002 three classes for 42 (25%), four classes for 45 (27%), five
Diabetes 9 (7%) 2 (5%) NS classes in 32 (19%) and six classes for 12 (7%).
Smoker 38 (30%) 13 (30%) NS
De novo hypertension 57 (46%) 11 (26%) 0.03
Evolution
Entry SBP (mmHg) 211  33 209  34 NS
Entry DBP (mmHg) 120  21 113  16 NS
Follow-up data were obtained from 154 of the 168 patients.
Entry creatinine (mmol/l) 160.8  127.5 204.8  230.6 NS With a median follow-up of 48 months, 28 patients (18%)
Entry proteinuria/creatinuria 100.8  148.3 135.8  190.2 NS developed ESRD, major cardiovascular events or death
(mmol/mmol) (Table 6).
Entry potassium (mmol/l) 3.6  0.7 3.3  0.7 NS
Worsening renal function was observed in 22 patients
LVM/h2.7 (g/m2.7) 86.2  28.6 81.0  26.6 NS
Troponin I (ng/ml) 0.2  0.5 0.4  1.5 NS
(14%). At 5 years, renal-event-free survival was 90.8%, and
GLS (%) 13.3  4.1 13.6  3.4 NS event-free survival was 83.6% (Fig. 2). There was no differ-
LVEF (%) 55.4  13.1 52  11.1 NS ence between patients with secondary hypertension and
those with essential hypertension (Fig. 3).
Baseline characteristics: comparison between patients suffering from secondary or
essential hypertension. GLS, global longitudinal strain; h, height; LVM, left ventricular Follow-up BP was significantly reduced at an average of
mass; LVEF, left ventricular ejection fraction. 131  17/81  1 mmHg. Follow-up SBP was less than

4 www.jhypertension.com Volume 36  Number 1  Month 2018

Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
CE: ; JH-D-18-00510; Total nos of Pages: 9;
JH-D-18-00510

Malignant hypertension: patients characteristics

TABLE 5. Details of target organ damage

Organ Method Criteria Patients with available measures Positive
2.7
Cardiac Echocardiography LVMI > 60 g/m 146 120 (82%)
Cardiac Echocardiography LVEF < 50% 147 46 (31%)
Cardiac Echocardiography GLS > 14% 105 59 (56%)
Cardiac Blood test Troponin >0.04 116 73 (63%)
Cardiac ECG Abnormal repolarization 135 85 (63%)
Brain Scanner Ischemic stroke 81 25 (31%)
Brain Scanner Hemorrhagic stroke 81 10 (12%)
Brain scanner lacunae 81 11 (14%)
Brain MRI PRES 83 42 (51%)
Brain MRI Abnormal WML 83 22 (27%)
Brain MRI Microbleeds 83 12 (14%)
Brain MRI Ischemic stroke 83 10 (12%)
Brain MRI Hemorrhagic stroke 83 6 (7%)
Kidney Blood test Creatinine >130 mmol/l 168 77 (46%)
Kidney Blood test Kaliemia 3.5 168 86 (51%)
Kidney Blood test Creatinine >130 mmol/l and Kaliemia 3.5 168 37 (22%)
TMA Blood test Platelets count  150 000 (/m3) 138 25 (18%)
TMA Blood test Haptoglobin  0.15 (g/l) 45 15 (33%)

GLS, global longitudinal strain; LVEF, left ventricular ejection fraction; LVMI, left ventricular mass index; PRES, posterior reversible encephalopathy syndrome; TMA, thombotic
microangiopathy; WML, white matter lesions.

140 mmHg in 98 of 144 patients (68%). We failed to obtain Beginning in 2004, we chose to include in our MHR
SBP follow-up measurement in our clinic for 10 patients. All registry patients who did not have MHR but who had at least
patients were treated with a RAS blocker: ACEI for 106 three other organs involved [among brain, heart, kidney or
patients (69%) and ACEI or angiotensin II receptor antago- biological TMA (Fig. 1)]. This practice is now in accordance
nist for 52 patients (34%). One hundred and fifteen (75%) with the most recent definition of MHT (used, for example,
patients had a calcium antagonist, 80 (52%) had a thiazide by the European Society of Hypertension [11] and with the
diuretic, 64 (42%) had spironolactone and 44 (29%) had a opinion of the main experts of MHT [10]). The 15 patients
beta blocker. The number of different antihypertensive we reported without MHR were similar to the others except
classes was one class for eight patients (5%), two classes for having more sever cardiac involvement (Table 2).
for 32 (21%), three classes for 53 (34%), four classes for 39 Unfortunately, we did not have enough patients to compare
(25%), five classes for 14 (9%) and six classes for eight (5%). renal survival or cardiovascular events in these two sub-
At the last follow-up, 44 of 144 (31%) patients had groups.
resistant hypertension. In the first years, brain damage was not systematically
assessed in patients without neurological symptoms. In the
DISCUSSION last 10 years we performed systematic brain MRIs on these
patients. Systematic brain MRIs in 81 of our patients showed
Malignant hypertension has not disappeared, but rather has an unexpected high prevalence of damage (more than
recently increased. This trend is evident in our experience 90%). Posterior reversible encephalopathy syndrome prev-
with almost twice as many cases admitted to our unit from alence was 51%, and other WML were found in 27%. These
2005 to 2014 as compared with 1995 to 2004. This increase is lesions have been associated with a higher risk of cognitive
also reflected in the number of new cases admitted in the dysfunction [15]. Long-term follow-up will be necessary to
last 3 years. In a lot of patients, hypertension had never see whether this is true in patients with MHT, but these
been detected or treated before the acute event triggering patients should be considered as having some risk of
admission. developing cognitive decline many years after the acute
MHT [16,17]. On the contrary, MRIs were not effectively
performed in all patients and we could overestimated the
prevalence of brain involvement in our series because the
TABLE 6. Events summary of 154 patients pressure to perform brain MRIs was certainly greater in
symptomatic neurological patients than in asymptomatic
ESRD 9 (6%)
Stroke 7 (4.5%)
ones. However, this very high prevalence is certainly a new
Coronary event 2 (1.3%) finding and should result in considering systematic brain
Aortic dissection 1 (0.6%) MRIs for these patients.
Death 9 (6%) Heart involvement was systematically assessed in our
Cardiovascular event 6 patients and appears even more frequent than renal dam-
Cancer 2 age with severe LVH (Fig. 4), systolic dysfunction and
Unknown 1
impaired coronary perfusion explaining increased troponin
Total (n ¼ 154) 28 (18%)
levels and ECG repolarization abnormalities and contribut-
ESRD, end-stage renal disease. ing to systolic dysfunction. We previously reported that

Journal of Hypertension www.jhypertension.com 5

Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
CE: ; JH-D-18-00510; Total nos of Pages: 9;
JH-D-18-00510

Rubin et al.

FIGURE 2 Event-free survival curve.

Follow-up me (months) 0 12 24 36 48 60 72 .

Paents at risk 154 124 93 94 74 58 48
Event-free survival (survival without end-stage renal disease or major cardiovascular event), ESRD, end-stage renal disease.

these anomalies regress quite rapidly in most cases [18]. before starting RAS blocker, despite frequent hypovolemia
However, one of our patients showed persistent LV dys- [19]. Saline infusion may be used in the case of rapid and
function function (ejection fraction <20% after 2 years) in significant BP reduction or in the case of a major increase in
the absence of any other detectable cause. The demonstra- blood creatinine (>30%), but this did not happen in our
tion of frequent LV function impairment explains why we population. In practice, and in the absence of echocardi-
chose to avoid systematic saline infusion in these patients ography, heart involvement can be considered by using

FIGURE 3 Event-free survival curves in patients with essential or secondary hypertension.

Follow-up me (months) 0 12 24 36 48 60 72

Essenal hypertension 119 98 82 74 57 46 39 .

Secondary hypertension 35 26 11 20 17 12 9
Event-free survival (survival without end-stage renal disease or major cardiovascular event): Comparison between patients suffering from secondary or essential hyperten-
sion. ESRD, end-stage renal disease.

6 www.jhypertension.com Volume 36  Number 1  Month 2018

Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
CE: ; JH-D-18-00510; Total nos of Pages: 9;
JH-D-18-00510

Malignant hypertension: patients characteristics

FIGURE 4 Echocardiography from a man suffering from malignant hypertension. Note the severe concentric left ventricular hypertrophy. (a) Left parasternal long axis. (b)
Left ventricle short axis. (c) M-mode of left ventricle short axis.

ECG at bedside. Severe cardiac hypertrophy and repolari- Because of renal TMA, patients with MHT show hyper-
zation abnormalities are often found (Fig. 5). aldosteronism secondary to renin activation [13], and the
Renal failure has long been considered as the most kidneys continue to excrete potassium. In practice, acute
frequent organ involvement in MHT and has greatly influ- kidney injury with high BP and hypokalemia should indi-
enced prognoses. This is also true in our cohort. Some of cate MHT or TMA. Proteinuria was not very high in our
our patients had severe renal failure at admission. Never- patients (average 110 mg/mmol of creatinuria equivalent at
theless, potassium levels remained normal or low, which is about 1 g/day) as described in other series [3]. A very high
rather uncommon in the case of acute kidney injury. proteinuria persisting after BP control (1 month in our

FIGURE 5 ECG (same patients from Fig. 4) showing left ventricular hypertrophy and repolarization abnormalities.

Journal of Hypertension www.jhypertension.com 7

Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
CE: ; JH-D-18-00510; Total nos of Pages: 9;
JH-D-18-00510

Rubin et al.

experience) should result in kidney biopsy to avoid missing after starting treatment in the acute phase. However, this
primary kidney disease. Because the hypertension center protocol is not applicable for MHT when severe acute stroke
was not in the same hospital as the renal unit, it is possible occurs or when BP must be monitored continuously at a
that patients suffering from the most severe form of kidney precise range to maintain cerebral perfusion pressure
injury were admitted directly to the renal unit and could not according to recommendations [26].
be included in this study. We found that 14% of patients had Physicians could be reluctant to use RAS blockers in the
impaired renal function, defined as a more than 40% case of MHT because of the risk of renal artery stenosis. In
decrease in eGFR between discharge and last follow-up. our cohort, only 4% of patients had renal artery stenosis-
The 40% threshold has been validated in the nephrological induced MHT. In 1995, RAS blockers were not used for
community [14]. However, it is more rigorous to identify bilateral renal artery stenosis, and we performed renal
impaired renal function at a preestablished follow-up date artery Doppler before starting RAS blockers. We have never
for all patients (e.g. 2 years) rather than at the last follow-up. found bilateral renal artery stenosis. Nevertheless, this is no
We did not have it for all patients, so the proportion of 14% longer the case and RAS blockers can be used regardless of
should be interpreted with caution due to the wide vari- the condition of the renal arteries. Therefore, performing a
ability in follow-up time. However, it does indicate that, renal artery Doppler is not mandatory before starting RAS
over a median follow-up of 4 years, a significant number of blocking. Moreover, RAS blockers are now considered to be
patients showed impaired renal function. the first-line treatment in the case of renal artery stenosis-
The original description of MHT gave special importance induced hypertension with regular monitoring of renal
to eye involvement (MHR initially being called retinitis) for function and potassium levels [27]. Finally, RAS blockers
simplification purposes. However, the occurrence of malig- are already used for scleroderma renal crisis (SRC), which is
nant forms of hypertension without this retinal picture had similar to MHT in terms of kidney damage: histologic
already been noticed [8] in the first studies on MHT. Because lesions are the same and pathogenesis is renin-dependent
MHT is a systemic disease, its definition should not rely on for both [28]. The use of RAS blockers in SRC decreased the
the damage of a single organ. Today, the assessment of mortality rate from 90% at 1 year to about 10–30%. Despite
heart and brain can easily be performed to identify any severe acute kidney failure, RAS blockers are systematically
potential damage of these two organs. This is a strong used even if patients require dialysis at the acute phase.
argument in favor of a new definition of MHT that takes Many patients recover in a couple of weeks [29]. These data
into account MOD. are in accordance to the utilization of RAS blockers in MHT.
Using our protocol management of MHT, survival with- We recognized that a controlled trial would be much better
out ESRD at 5 years is in accordance to others studies [3]. For to confirm the efficacy and safety of our oral protocol, but
example, Lip et al. [4] studied the biggest cohort of MHT in none of the therapeutic recommendations on the treatment
Birmingham (UK) and found that the survival rate without of MHT are based on something other than the experience
ESRD was 90.1% at 5 years. In a Madrid cohort, the survival of clinicians. Moreover, most of the published registries of
rate was slightly worse (84%) [20], but those patients likely MHT do not even report the way patients were treated.
had worse kidney function when admitted to the renal unit. Long-term follow-up of these patients remains impor-
Our choice not to use intravenous antihypertensive drugs tant. At follow-up, most of these patients required three or
may appear uncommon. Because MHT certainly generates more antihypertensive drugs to lower their BP, and resistant
anxiety for both the patient and the physician, the use of hypertension was found in one-third of patients. Resistant
intravenous drugs is often preferred [21,22]. Many publica- hypertension is one of the most important cardiovascular
tions recommend progressively decreasing BP and advise risk factors and can help to explain why these patients had
carefully monitoring these patients in an ICU. The intrave- so many cardiovascular events [30].
nous drug appears to be safer and more flexible in this To summarize our recommendations regarding the daily
condition. However, our study indicates that these patients practice of diagnosis and management, malignant hyper-
can also be treated by only using oral medication, especially tension should be considered in the presence of severe
RAS blockers, according to the pathogenesis [13,23,24]. RAS hypertension (>180/110 mmHg) and unspecific clinical
blockers are required to be introduced at a very low dose signs (e.g. asthenia, dizziness, visual acuity drop, weight
because these patients usually present with hypovolemia. loss). At bedside, ECG and simple biological analyses (e.g.
Initial saline infusion before starting antihypertensive med- creatinine, kaliemia, proteinuria, troponin, blood count,
ications is sometimes recommended to avoid drastic haptoglobin, schizocytes) and fundus examination (if avail-
decreases in BP in these patients. In our experience, starting able) are often sufficient to confirm the diagnostic hypoth-
with low-dose RAS blockers followed by forced titration esis. Treatment with RAS blockers should be started without
every 6 h is well tolerated and efficient. For us, the corner- delay but at very low dose with forced titration and close
stone of MHT treatment is to promptly and completely block follow-up of BP and creatinine levels. In addition, a brain
RAS using high doses of RAS blockers. We recently published MRI and echocardiography can be done without changing
the case of a patient suffering from beta interferon-induced the therapeutic strategy.
MHT [25]. Despite good BP control, hemolysis failed to In conclusion, malignant hypertension is a systemic
recover but was improved only when RAS blockers were disease causing severe damage to the heart, brain, kidney
introduced. Moreover, our protocol is certainly more cost and eye. A systematic evaluation of the brain and heart
effective than intravenous drugs and could be easier to use in shows that these two organs are probably more often
countries with limited access to ICUs. Moreover, this protocol damaged than usually believed. Malignant hypertension
appears to be safe in our study as no patient required dialysis remains a serious illness, with much higher incidence of

8 www.jhypertension.com Volume 36  Number 1  Month 2018

Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
CE: ; JH-D-18-00510; Total nos of Pages: 9;
JH-D-18-00510

Malignant hypertension: patients characteristics

renal and cardiovascular events as compared with common 12. Khwaja A. KDIGO clinical practice guidelines for acute kidney injury.
Nephron Clin Pract 2012; 120:c179–c184.
hypertension. Malignant hypertension can be easily recog- 13. van den Born BJ, Koopmans RP, van Montfrans GA. The renin–
nized by the physician at bedside using simple criteria, such angiotensin system in malignant hypertension revisited: plasma renin
as symptomatic hypertension, acute kidney failure and activity, microangiopathic hemolysis, and renal failure in malignant
hypokalemia, LVH and repolarization abnormalities on hypertension. Am J Hypertens 2007; 20:900–906.
ECG, biological hemolysis and hypertensive retinopathy. 14. Levey AS, Inker LA, Matsushita K, Greene T, Willis K, Lewis E, et al. GFR
decline as an end point for clinical trials in CKD: a scientific workshop
These patients are the true hypertensive emergencies. In sponsored by the National Kidney Foundation and the US Food and
our experience, immediate treatment using RAS blockers Drug Administration. Am J Kidney Dis 2014; 64:821–835.
appears to be safe, efficient and cost effective. 15. Postma IR, Slager S, Kremer HP, de Groot JC, Zeeman GG. Long-term
consequences of the posterior reversible encephalopathy syndrome in
ACKNOWLEDGEMENTS eclampsia and preeclampsia: a review of the obstetric and nonobstetric
literature. Obstet Gynecol Surv 2014; 69:287–300.
We thank Pr BJ Van-den-Born for his valuable advice on 16. Jacquot C, Glastonbury CM, Tihan T. Is posterior reversible encepha-
lopathy syndrome really reversible? Autopsy findings 4.5 years after
this article. radiographic resolution. Clin Neuropathol 2015; 34:26–33.
17. Kaffashian S, Soumaré A, Zhu Y-C, Mazoyer B, Debette S, Tzourio C.
Conflicts of interest Long-term clinical impact of vascular brain lesions on magnetic
All authors declare a lack of conflicts of interest with this resonance imaging in older adults in the population. Stroke 2016;
47:2865–2869.
article. There was no support funding for this article. 18. Gosse P, Coulon P, Papaioannou G, Litalien J, Lemetayer P. Impact
of malignant arterial hypertension on the heart. J Hypertens 2011;
REFERENCES 29:798–802.
1. Lip GY, Beevers M, Beevers G. The failure of malignant hypertension to 19. Barraclough MA. Sodium and water depletion with acute malignant
decline: a survey of 24 years’ experience in a multiracial population in hypertension. Am J Med 1966; 40:265–272.
England. J Hypertens 1994; 2:1297–1305. 20. Gonzalez R, Morales E, Segura J, Ruilope LM, Praga M. Long-term renal
2. Polgreen LA, Suneja M, Tang F, Carter BL, Polgreen PM. Increasing survival in malignant hypertension. Nephrol Dial Transplant 2010;
trend in admissions for malignant hypertension and hypertensive 25:3266–3272.
encephalopathy in the United States. Hypertension 2015; 65: 21. van den Born BJH, Beutler JJ, Gaillard CAJM, de Gooijer A, van den
1002–1007. Meiracker AH, Kroon AA. Dutch guideline for the management of
3. Lane DA, Lip GY, Beevers DG. Improving survival of malignant hypertensive crisis – 2010 revision. Neth J Med 2011; 69:248–255.
hypertension patients over 40 years. Am J Hypertens 2009; 22:1199– 22. Marik PE, Varon J. Hypertensive crises: challenges and management.
1204. Chest 2007; 131:1949–1962.
4. Lip GY, Beevers M, Beevers DG. Complications and survival of 23. Kawazoe N, Eto T, Abe I, Takishita S, Ueno M, Kobayashi K, et al.
315 patients with malignant-phase hypertension. J Hypertens 1995; Pathophysiology in malignant hypertension: with special reference to
13:915–924. the renin–angiotensin system. Clin Cardiol 1987; 10:513–518.
5. van den Born BJ, Koopmans RP, Groeneveld JO, van Montfrans GA. 24. Fleming S. Malignant hypertension – the role of the paracrine renin–
Ethnic disparities in the incidence, presentation and complications of angiotensin system. J Pathol 2000; 192:135–139.
malignant hypertension. J Hypertens 2006; 24:2299–2304. 25. Rubin S, Lacraz A, Galantine V, Gosse P. Malignant hypertension and
6. Kadiri S, Olutade BO, Osobamiro O. Factors influencing the develop- interferon-beta: a case report. J Hum Hypertens 2014; 28:340–341.
ment of malignant hypertension in Nigeria. J Hum Hypertens 2000; 26. Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC,
14:171–174. Becker K, et al., American Heart Association Stroke Council. 2018
7. Shantsila A, Shantsila E, Beevers DG, Lip GYH. Predictors of Guidelines for the early management of patients with acute ischemic
5-year outcomes in malignant phase hypertension. J Hypertens 2017; stroke: a guideline for healthcare professionals from the American
35:2310–2314. Heart Association/American Stroke Association. Stroke 2018; 49:e46–
8. Keith NM, Wagener HP. The syndrome of malignant hypertension. e110.
Arch Intern Med 1928; 41:141–188. 27. Herrmann SMS, Saad A, Textor SC. Management of atherosclerotic
9. Shantsila A, Lane DA, Beevers DG, Lip GYH. Lack of impact of pulse renovascular disease after cardiovascular outcomes in renal athero-
pressure on outcomes in patients with malignant phase hypertension: sclerotic lesions (CORAL). Nephrol Dial Transplant 2015; 30:366–375.
the West Birmingham Malignant Hypertension study. J Hypertens 2012; 28. Mouthon L, Bussone G, Berezné A, Noël L-H, Guillevin L. Scleroderma
30:974–979. renal crisis. J Rheumatol 2014; 41:1040–1048.
10. Cremer A, Amraoui F, Lip GYH, Morales E, Rubin S, Segura J, et al. From 29. Penn H, Howie AJ, Kingdon EJ, Bunn CC, Stratton RJ, Black CM, et al.
malignant hypertension to hypertension-MOD: a modern definition Scleroderma renal crisis: patient characteristics and long-term out-
for an old but still dangerous emergency. J Hum Hypertens 2016; comes. QJM 2007; 100:485–494.
30:463–466. 30. Muntner P, Davis BR, Cushman WC, Bangalore S, Calhoun DA, Pressel
11. ESH/ESC Task Force for the Management of Arterial Hypertension. SL, et al., ALLHAT Collaborative Research Group. Treatment-resistant
2013 Practice guidelines for the management of arterial hypertension of hypertension and the incidence of cardiovascular disease and end-
the European Society of Hypertension (ESH) and the European Society stage renal disease: results from the Antihypertensive and Lipid-Low-
of Cardiology (ESC): ESH/ESC Task Force for the Management of ering Treatment to Prevent Heart Attack Trial (ALLHAT). Hypertension
Arterial Hypertension. J Hypertens 2013; 31:1925–1938. 2014; 64:1012–1021.

Journal of Hypertension www.jhypertension.com 9

Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.