Systemic Vasculitis: an Important and Underestimated Cause of Malignant Hypertension

Home , Nutcracker syndrome, Secondary hypertension

Vol. 4 No. 2 (2019) 99–108 Cardiovascular Innovations and Applications ISSN 2009-8618 DOI 10.15212/CVIA.2019.0009

RESEARCH PAPER

Systemic Vasculitis: An Important and Underestimated Cause of Malignant Hypertension

Qing Zhu, MD1, Shasha Liu, MD1, Mulalibieke Heizhati, MD1, Xiaoguang Yao, PhD1, Menghui Wang, MD1, Qin Luo, MD1, Lei Wang, MD1, Delian Zhang, PhD1, Guijuan Chang, MD1 and Nanfang Li, PhD, MD1

1The Center for Hypertension of the People’s Hospital of Xinjiang Uygur Autonomous Region, Hypertension Institute of Xinjiang Uygur Autonomous Region, Urumqi, China Received: 29 June 2018; Revised: 28 January 2019; Accepted: 30 January 2019

Abstract Objectives: Malignant hypertension (MHT) is defined as severe hypertension accompanied by ischemic failure of one or more organs. The aims of this study were to evaluate the current clinical and etiologic profiles of MHT. Methods: As a retrospective study, we selected all patients admitted to our center from January 2013 to December 2016. Seventy patients with MHT were included. Results: The average age of the patients was 40 years, and more than half of the patients were male (78.57%). There were 24 patients with essential hypertension, accounting for 34.29% of the patients, and 46 with secondary hypertension, accounting for 65.71% of the patients. For secondary MHT, systemic vasculitis (25.57%) was the most common cause, followed by severe obstructive sleep apnea syndrome (15.71%), primary renal parenchymal hypertension (11.43%), primary aldosteronism (7.14%), and Cushing syndrome (1.43%) and nutcracker phenomenon (1.43%). Twenty patients with systemic vasculitis were characterized by severe hypertension accompanied by damage to two or more target organs of differing severity. The levels of white blood cells, hypersensitive C-reactive protein, serum creatinine, and 24-hour urinary protein were above their normal range. Conclusion: Systemic vasculitis may be one of the main causes of MHT, and has been underestimated in the past. In future clinical work, clinicians need to pay more attention to patients with systemic vasculitis.

Keywords: malignant hypertension; cause; systemic vasculitis

Significance Statement: Malignant hypertension (MHT) is a life-threating manifestation of hypertension, and the underlying cause of MHT needs to be identified as early as possible. However, systemic vasculitis was one of the main causes of MHT in our study, and was ignored in the past. In future clinical work, clinicians need to pay more attention to patients with systemic vasculitis and actively treat them.

Correspondence: Nanfang Li, PhD, MD, The Center for Introduction Hypertension of the People’s Hospital of Xinjiang Uygur Malignant hypertension (MHT) is a condition char- Autonomous Region, Hypertension Institute of Xinjiang Uygur Autonomous Region, No. 91 Tianchi Road, Urumuqi, acterized by severe hypertension and can cause reti- 830001 Xinjiang, China, Tel.: +86-13999179937, nal, neurologic, renal, and cardiac complications. Fax: +86-09918564816, E-mail: [email protected] If MHT is not treated, mortality is very high, the

2-year mortality being 80% [1]. Despite the avail- Patients for etiologic screening of hypertension admitted to our ability of a vast range of antihypertensive agents, center between January 2013 and December 2016 (n = 11,792) MHT continues to be a significant clinical chal- lenge. Although its prevalence is very low, the abso- Patients with bilateral retinopathy with hemorrhages and/or cotton wool spots or exudates, with or without papilledema lute number of new cases has not changed in recent (n = 765) decades [2, 3]. Since the clinical manifestations of

MHT are not specific, when patients present with Patients with DBP ≥120 mmHg (n = 137) acute renal failure the underlying causes of MHT are difficult to identify. Generally, the causes of MHT are primary or secondary hypertension. A few stud- Patients with renal insufficiency and/or proteinuria and/or hematuria (n = 70) ies showed that about 1–5% of cases of essential hypertension may develop into MHT [4] because Patients who fulfilled the criteria for MHT (n = 70) of patients not taking antihypertensive medications or abruptly stopping taking antihypertensive Figure 1 Flow Chart of Patients with Malignant medications. For the secondary causes of MHT, Hypertension (MHT). some clinical case reports and studies showed that DBP, Diastolic blood pressure. such secondary hypertension can lead to MHT as in primary aldosteronism (PA), pheochromocytoma, Cushing syndrome, obstructive sleep apnea syn- found to have high blood pressure through physical drome (OSAS), renal hypertension (including renal examination, some had headache, dizziness, palpi- vascular hypertension), hypothyroidism, and preg- tation, fatigue, and other uncomfortable symptoms, nancy [5–10]. Recent studies have indicated that the and some appeared to have experienced stoke, myo- immune system may also play an important role in cardial infarction, chronic renal insufficiency, and the development of this condition [11]. There is an other complications due to long-term hypertension. increasing amount of literature on vasculitis indi- So they were admitted to our center. cating that various types of vasculitis can also cause We selected patients who fulfilled the criteria for MHT [12–14]. Therefore, our aims were to evaluate MHT, including (1) elevated diastolic blood pres- the current clinical and etiologic profiles of MHT. sure (≥120 mmHg), (2) presence of grade III or IV hypertensive retinopathy (bilateral retinopathy Participants and Methods with hemorrhages and/or cotton wool spots or exudates, with or without papilledema), and (3) renal complications (increased creatinine concentration Ethics Approval of the Study Protocol and/or proteinuria and/or hematuria) (Figure 1). This study was approved by the Ethics Committee of Patients younger than 18 years, pregnant women, the People’s Hospital of Xinjiang Uygur Autonomous and patients who were already undergoing dialysis Region (Urumqi, China). It was conducted according before admission were excluded. to the standards of the Declaration of Helsinki. Diagnostic Criteria Participants Essential Hypertension We reviewed all patients admitted to our center for screening for the cause of hypertension between Patients were considered to have essential hyper- January 2013 and December 2016. Our hyperten- tension if they fulfilled the criteria for the diagnosis sion center is the biggest hypertension center in of MHT and secondary hypertension was excluded. China, and has 180 inpatient beds. Thousands of patients are referred to the center from all over Primary Aldosteronism China each year, and we have successfully identified the cause of secondary hypertension in more The screening of patients for and the diagnosis of than 10,000 patients. Of these patients, some were PA were conducted by a standard process based Q. Zhu et al., Systemic Vasculitis and Malignant Hypertension 101 on the current guidelines as in a previous study vasculitis (AAV), granulomatosis with polyangiitis from our center [15]. An elevated aldosterone level (GPA), eosinophilic granulomatosis with polyangiitis (>12 ng/L) and suppressed plasma renin activity (EGPA), and microscopic polyangiitis (MPA)]. For (<1.0 μg/L h) or an aldosterone-to-renin ratio (the the classification of PAN and other necrotizing vas- ratio of plasma aldosterone concentration to plasma culitides, we referred to the consensus algorithm that renin activity) greater than 20 ng/dL per nanogram was proposed by combination of ACR and CHCC per milliliter per hour was considered as PA. PA criteria, ANCA testing, and surrogate markers of was confirmed by a saline loading test (postinfusion vascular inflammation, including clinical, laboratory, plasma aldosterone concentration >5 ng/dL). neurophysiologic, and imaging tests (Figure 2) [22].

Cushing Syndrome Takayasu Arteritis The diagnosis was on the basis of symptoms, signs, A patient was considered have TA if at least three serum cortisol and ACTH levels and CT/MRI find- of these six criteria: (1) age <40 years, (2) claudica- ings. The qualitative diagnosis and localization tion of an extremity, (3) decreased brachial artery diagnosis of Cushing syndrome were according to pulse, (4) >10 mmHg difference in systolic pressure the Endocrine Society guideline [16]. between arms, (5) a bruit over subclavian arteries or aorta and (6) angiographic evidence of narrowing Primary Renal Parenchymal Hypertension or occlusion of the aorta or its primary or proximal branches were present [17]. The presence of three Hypertension was diagnosed after a history of or more of these six criteria demonstrated sensitiv- renal disease and was confirmed by kidney biopsy, ity of 91% and specificity of 98%. excluding secondary glomerular lesions.

Systemic Vasculitis Polyarteritis Nodosa The diagnosis of systemic vasculitis was based on A patient was considered to have PAN if at least the patient’s clinical manifestations (such as malaise, three of these ten criteria: (1) Weight loss 24 kg; weight loss, fever, arthralgia, and myalgia), labora- (2) Livedo reticularis; (3) Testicular pain or tory test results (such as elevated erythrocyte sedi- tenderness; (4) Myalgias, weakness, or leg ten- mentation rate and levels of C-reactive protein and derness; (5) Mononeuropathy or polyneuropathy; other acute-phase reactants, proteinuria, hematuria, (6) Diastolic BP >90 mmHg; (7) Elevated BUN or and increased creatinine concentration), and typi- creatinine; (8) Hepatitis B virus; (9) Arteriographic cal imaging findings (such as artery occlusion and abnormality; (10) Biopsy of small or medium-sized stenosis or arterial saccular or fusiform microaneu- artery containing polymorphonuclear neutrophils rysms) and pathologic biopsy findings (such as vas- were present [18]. The presence of three or more of cular wall thickening, bursal stenosis, surrounded these ten criteria demonstrated sensitivity of 82.2% by inflammatory cell infiltration, but the lack of and specificity of 86.6%. immune complex deposition). Diagnosis was confirmed by a rheumatologist and was in accordance ANCA-Associated Vasculitis with the 1990 American College of Rheumatology The diagnosis was on the basis of symptoms, signs, (ACR) criteria or the revised 2012 Chapel Hill laboratory indicators, detection of ANCA, and Consensus Conference (CHCC) nomenclature of pathology examination according to the related crite- vasculitis [17–21]. Systemic vasculitis, according to ria. “ANCA-associated vasculitis” (AAV) is a collec- the CHCC definition, is divided into seven catego- tive term for three diseases: MPA, GPA, and EGPA. ries. It mainly includes large-vessel vasculitis [giant cell arteritis and Takayasu arteritis (TA)], medium- Obstructive Sleep Apnea Syndrome vessel vasculitis [Kawasaki disease and polyarteritis nodosa (PAN)], and small-vessel vasculitis [antineu- All patients with snore underwent full-night trophil cytoplasmic antibody (ANCA)-associated polysomnography. OSAS was defined as an 102 Q. Zhu et al., Systemic Vasculitis and Malignant Hypertension

Meets ACR EGPA criteria or CHCC EGPA definition Yes EGPA

Meets ACR GPA criteria or CHCC GPA definition or CHCC MPA definition but with clinical findings typical of GPA or Yes GPA no histologic biopsy but clinical findings typical of GPA in addition to PR3 or MPO ANCA positivity

Clinical and histologic biopsy features of small-vessel vasculitis without findings typical of GPA or no histologic biopsy features. No Yes MPA findings typical of GPA. PR3 or MPO ANCA positive in addition to clinical findings typical of MPA

Meets ACR PAN criteria or CHCC PAN definition or angiographic or Yes histologic biopsy features typical of PAN PAN

Unclassifiable

Figure 2 Consensus Algorithm Proposed by Watts et al. [22] for the Classification of Eosinophilic Granulomatosis with Polyangiitis (EGPA), Granulomatosis with Polyangiitis (GPA), Microscopic Polyangiitis (MPA), and Polyarteritis Nodosa (PAN). Findings typical of GPA include but are not limited to imaging evidence of fixed pulmonary infiltrated nodules or cavita- tions, bronchial stenoses, bloody nasal discharge and crusting, nasal ulceration, chronic sinusitis, otitis media or mastoiditis, retro-orbital mass, subglottic stenosis, and saddle-nose deformity. Findings typical of MPA include alveolar hemorrhage and hematuria associated with red cell casts or 10% dysmorphic erythrocytes or proteinuria. ACR, American College of Rheumatology; ANCA, antineutrophil cytoplasmic antibodies; CHCC, Chapel Hill Consensus Conference; MPO, myeloper- oxidase: PR3, proteinase 3. (Adapted from [22]). apnea-hypopnea index (AHI) of more than five polyneuropathy); central nervous system involve- events per hour and was further subclassified ment; urologic and renal involvement (orchitis, into mild OSAS (AHI = 5–15), moderate OSAS dialysis, peripheral limb edema, and recent-onset (AHI = 16–30), and severe OSAS (AHI > 30). or severe hypertension); cutaneous symptoms (nodules, purpura, erythema, and livedo reticula- Nutcracker Syndrome ris); alimentary manifestations (nausea, vomiting, abdominal pain, hemorrhage, pancreatitis, and The diagnosis of nutcracker syndrome was based peritonitis); cardiovascular involvement (pectoral- on clinical examination, followed by Doppler ultra- gia, cardiomyopathy, pericarditis, and ischemia); sonography and phlebography with measurement ophthalmologic involvement (retinal vasculitis/ of the renocaval pressure gradient [23]. exudates, visual impairment, conjunctivitis, kera- titis, and uveitis); pulmonary involvement (cough, Data Collection and Measurements hemoptysis, dyspnea, pleural effusion, and lung infiltrates). All the clinical data came from the patients’ medi- The biological parameters recorded were blood cal records during hospitalization (including demo- cell counts, renal parameters (proteinuria, hematu- graphics and clinical, biological, imaging, and ria, 24-hour urinary protein level, and serum creati- biopsy findings). nine concentration), erythrocyte sedimentation rate, The following clinical manifestations were C-reactive protein level, hypersensitive C-reactive recorded: general symptoms (fever, weakness, protein level, and the presence of ANCA as tested asitia, myalgia and arthralgia, and weight loss); by indirect immunofluorescence and enzyme-linked peripheral neuropathy (mononeuritis multiplex, or immunosorbent assay. Q. Zhu et al., Systemic Vasculitis and Malignant Hypertension 103

The diagnosis of renal vascular hypertension, Table 1 Characteristics of 70 Patients with Malignant TA, and PAN mostly requires vascular ultrasonog- Hypertension. raphy, vascular CT angiography, or angiography. The angiography results were judged as abnormal Index Data when the blood vessels were sparse, there was Male sex, n 55 (78.57%) irregular stenosis, and/or there were microaneu- Age (years), mean ± SD 40 ± 9 rysms. The chest X-ray was judged as abnormal if it ≤ 45years, n 51 (72.86%) 2 showed nodules, infiltrating lesions, and/or cavita- BMI (kg/m ), mean ± SD 26.46 ± 4.43 tion. The result was determined by two radiologists. Pulse (beats/min), mean ± SD 89.36 ± 15.20 Biopsy is often required for the diagnosis of renal SBP (mmHg), mean ± SD 196.71 ± 24.54 hypertension and small-vessel vasculitis. When DBP (mmHg), mean ± SD 135.00 ± 14.10 hypertension from these two causes is considered, Disease course ≤5years, n 48 (68.57%) renal and/or skin biopsy should be performed for a Grade III hypertensive 63 (90.00%) retinopathy, n clear diagnosis. Inflammatory cell infiltration and/or Grade IV hypertensive 7 (10.00%) formation of a crescent was present in small-vessel retinopathy, n and medium-vessel vasculitis. Immunofluorescence Serum creatinine (mmol/L), 128.70 (107.28, demonstrated no or little immune complex deposi- median (25%, 75%) 203.00) tion in the mesangial area, vascular loops, or small Plasma aldosterone (ng/dL), 23.65 (16.69, 32.70) vascular walls. The result was determined by two median (25%, 75%) pathologists. Plasma renin activity 4.63 (3.07, 8.41) (ng/mL h), median (25%, 75%) Statistical Analysis 24-hour urinary protein (g), 0.902 (0.225, 1.544) median (25%, 75%) Data analysis was performed with SPSS Statistics Proteinuria, n 50 (71.43%) for Windows (version 17.0; SPSS, Chicago, IL, Renal insufficiency, n 60 (85.71%) USA). All continuous variables are expressed as the Cerebrovascular diseases, n 44 (62.86%) mean ± standard deviation (for data that were nor- Cardiovascular diseases, n 14 (20.00%) mally distributed) or the median and interquartile BMI, Body mass index; DBP, diastolic blood pressure; SBP, range (for data that were not normally distributed). systolic blood pressure; SD, standard deviation. The frequencies of categorical data are presented as percentages. Table 2 The Cause Distribution for 70 Patients with Malignant Hypertension.

Results Disease Number Frequency (%) A total of 11,972 patients were admitted to our center Essential hypertension 24 34.29 between January 2013 and December 2016, and 70 Secondary hypertension 46 65.71 patients fulfilled the criteria for MHT. The clinical Systemic vasculitis 20 28.57 characteristics of the patients with MHT are shown Severe obstructive sleep 11 15.71 in Table 1. The average age was 40 years, and the apnea syndrome patients were mainly male (78.57%). They had high Primary renal 8 11.43 blood pressure and a short disease course. Sixty-three hypertension patients had grade III hypertensive retinopathy and Primary aldosteronism 5 7.14 seven patients had grade IV hypertensive retinopathy. Cushing syndrome 1 1.43 Besides renal involvement, most patients presented Nutcracker phenomenon 1 1.43 with cardiac and cerebrovascular complications. A detailed breakdown of the details of the 70 patients can be found online in the Supplementary Table S1. diagnosed in 24 patients, accounting for 34.29% Table 2 shows the cause distribution for the 70 of the patients, while secondary hypertension was patients with MHT. Essential hypertension was diagnosed in 46 patients, accounting for 65.71% of 104 Q. Zhu et al., Systemic Vasculitis and Malignant Hypertension the patients. For secondary MHT, systemic vasculi- manifestations (livedo reticularis, tender subcutane- tis (25.57%) was the most common cause, followed ous nodules) in 15% of patients. There were otolar- by severe OSAS (15.71%), primary renal paren- yngologic manifestations, mainly rhinitis, sinusitis, chymal hypertension (11.43%), PA (7.14%), and tinnitus, and otitis media, in 40% of patients. Cushing syndrome (1.43%) and nutcracker phe- Table 4 shows the laboratory examination find- nomenon (1.43%). Among the 20 cases of vasculi- ings for 20 patients. The levels of white blood cells, tis, ten cases were PAN, four cases were TA, and six hypersensitive C-reactive protein, serum creatinine, cases were AAV (including one case of GPA, two and 24-hour urinary protein were above their nor- cases of EGPA, and three cases of MPA). mal range. Other indicators were normal. From Table 3, we see that 20 patients with systemic vasculitis were characterized by severe hyper- Discussion tension accompanied by damage to two or more target organs of differing severity. Among the clini- MHT is the severest form of hypertension and is a life- cal manifestations, neurologic, cardiac, and renal threatening condition. Although survival of MHT has manifestations were common. However, general considerably improved with the advent of antihyper- symptoms, mainly weakness and weight loss, were tensive medication, end-stage renal disease remains present in 20% of patients. There were cutaneous a significant cause of morbidity and death [24, 25]. In addition, there are the irregular treatment and lack of individualized treatment, whether there are other Table 3 The Clinical Features of 20 Patients with Systemic reasons for it. Patients often stop or discontinue tak- Vasculitis. ing the medicine by themselves because they have no discomfort or no money. Moreover, studies have Index Data suggested that some patients continue to develop Male sex, n 15 (75%) progressive renal failure despite a good degree of Age (years), mean ± SD 41 ± 9 blood pressure control [26]. The reasons may be that BMI (kg/m2), mean ± SD 25.72 ± 4.27 the potential cause and the pathogenesis of MHT SBP (mmHg), mean ± SD 199.25 ± 24.15 are not clear. While the roles of the activation of the DBP (mmHg), mean ± SD 132.95 ± 12.22 renin-angiotensin-aldosterone system and endothelial Target organ damage dysfunction in the pathogenesis of MHT have been Two organs, n 1 (5%) well described, recent studies have indicated that the Three organs, n 4 (20%) immune system (particularly T cells) may also play Four organs, n 8 (40%) an important role in the development of MHT and Five organs, n 7 (35%) MHT-related kidney injury [4, 27, 28]. They are coin- Clinical manifestations cident with the pathogenesis of systemic vasculitis. General manifestations, n 4 (20%) Systemic vasculitis is characterized by inflamma- Cutaneous manifestations, n 3 (15%) tion and damage of vessels, with a severe clinical Otolaryngologic manifestations, n 8 (40%) course. Although the cause of vasculitis is unclear, Respiratory manifestations, n 3 (15%) some studies have shown that immune-mediated Cardiac manifestations, n 9 (45%) complement activation and endothelial dysfunction Gastrointestinal manifestations, n 6 (30%) are responsible for its pathogenesis [29]. Systemic Urologic and renal manifestations, n 8 (40%) vasculitis often mainly involves the skin, kidneys, Neurologic manifestations, n 12 (60%) lungs, nervous system, etc., and has complex and Abdominal vascular murmurs, n 8 (40%) varied clinical manifestations and causes multiple The target organ includes heart (left ventricular hypertrophy, organ dysfunction in patients. When the kidneys ischemia, infarction, heart failure arrhythmia), carotid artery are involved, systemic vasculitis can lead to hyper- (endometrium thickening, plaque formation), brain (stroke), tension (especially high diastolic blood pressure). kidney (proteinuria, increased creatinine concentration), and fundus (hemorrhage, papilledema). Studies have shown that TA can lead to renal failure BMI, Body mass index; DBP, diastolic blood pressure; SBP, and renovascular hypertension in 60% of patients, systolic blood pressure; SD, standard deviation. PAN in 25% of patients, and AAV in 12% of patients. Q. Zhu et al., Systemic Vasculitis and Malignant Hypertension 105

Table 4 Laboratory Examination Findings for 20 Patients.

Index Data Normal range/status Blood White blood cells (/L), mean ± SD 9.05 × 109 ± 3.30 × 109 3.5 × 109–9.5 × 109 Hemoglobin (g/L), mean ± SD 135.00 ± 17.65 130–175 Platelets (/L), median (25%, 75%) 223 × 109 (151 × 109, 248 × 109) 125 × 109–350 × 109 Neutrophils (%), mean ± SD 69.60 ± 6.47 40–75 Eosinophils (%), median (25%, 75%) 2.1 (1.43, 2.59) 0.4–8.0 Urine Urinary protein, n 17 (85%) Negative Hematuria, n 5 (25%) Negative 24-hour urinary protein (g), median (25%, 75%) 1.12 (0.37, 1.79) 0.028–0.141 Inflammatory indicators ESR (mm/h), median (25%, 75%) 24 (12, 44) 0–15 Hypersensitive C-reactive protein (mg/L), 5.4 (2.94, 10.9) 0–5 median (25%, 75%) C-reactive protein (mg/L), median (25%, 75%) 5.95 (3.34, 20.45) 0–8 Biochemical indicators Albumin (g/L), mean ± SD 39.35 ± 2.99 40–55 Globulin (g/L), mean ± SD 28.59 ± 4.57 20–30 ALT (U/L), median (25%, 75%) 21 (16.24, 32.4) 16 AST (U/L), median (25%, 75%) 18.12 (15, 23) 11 BUN (mmol/L), median (25%, 75%) 8.14 (5.48, 10.76) 2.9–8.2 Creatinine (μmol/L), median (25%, 75%) 146 (115.25, 196.43) 59–104 (male) 45–84 (female) Glucose (mmol/L), median (25%, 75%) 4.59 (4.41, 5.44) 3.9–6.1 TG (mmol/L), median (25%, 75%) 1.73 (1.23, 2.11) 0–1.7 TC (mmol/L), mean ± SD 4.69 ± 0.99 2.59–6.47 HDL (mmol/L), mean ± SD 1.00 ± 0.29 >1.04 LDL (mmol/L), median (25%, 75%) 2.80 (1.02, 3.25) 0–3.37 Potassium (mmol/L), mean ± SD 3.54 ± 0.57 3.5–5.3 Sodium (mmol/L), mean ± SD) 140.81 ± 2.34 137–147 Calcium (mmol/L), mean ± SD 2.35 ± 0.17 2.08–2.6 Immune indicators ANA, n 6 (30%) Negative ANCA, n 0 Negative IgG (g/L), mean ± SD 11.84 ± 2.59 7.51–15.60 IgA (g/L), median (25%, 75%) 1.68 (1.02, 2.46) 0.82–4.53 IgM (g/L), mean ± SD 1.44 ± 0.47 0.46–3.04 C3 (g/L), mean ± SD 1.16 ± 0.14 0.79–1.52 C4 (g/L), mean ± SD 0.32 ± 0.06 0.16–0.38 ALT, Alanine aminotransferase; ANA, antinuclear antibodies; ANCA, antineutrophil cytoplasmic antibodies; AST, aspartate aminotransferase; BUN, blood urea nitrogen; ESR, erythrocyte sedimentation rate; HDL, high-density lipoprotein; LDL, low- density lipoprotein; SD, standard deviation; TC, total cholesterol; TG, triglyceride.

A recent single-center study showed that arterial The pathophysiologic mechanisms for the devel- hypertension is common during TA (45.8%) [30]. opment of hypertension or MHT by vasculitis are In our study, for secondary MHT, most patients had as follows: (1) large vascular lesions involving the a diagnosis of systemic vasculitis (43.48%). renal artery trunk and main branches, which lead to 106 Q. Zhu et al., Systemic Vasculitis and Malignant Hypertension

Systemic vasculitis

Lesions involving renal artery Systemic endothelial Lesions involving renal trunk and main branches dysfunction arterioles

Vascular wall full-layer Coagulation enhancement, Glomerular, renal tubule, inflammation complement activation and interstitial tissue damage

Elastic fiber damage, fibrous Renal parenchymal ischemic Thrombosis and renal immune tissue granulation, tissue necrosis, degeneration, and injury hyperplasia fibrosis

Thickening of the vessel wall Renal ischemia GFR

Renal artery stenosis, Na+/H O discharge occlusion, aneurysm 2 Vasodilation material

(PGE2, PGA2) + Renal blood flow Na /H2O retention

Activate RAAS Blood volume

Hypertension or MHT

Figure 3 The Possible Pathophysiologic Mechanisms for the Development of Hypertension or Malignant Hypertension (MHT) by Vasculitis.

GFR, Glomerular filtration rate; PGA2, prostaglandin A2; PGE2, prostaglandin E2; RAAS, renin-angiotensin-aldosterone system. renal artery stenosis and occlusion aneurysm, cause and serologic markers of vasculitis were not spe- renal blood flow to decrease and activate the renin- cific, and because angiography and histopathology angiotensin-aldosterone system, thereby leading to were limited by segmental and traumatic lesions, a high blood pressure, such as renal vascular hyper- large number of patients were often missed and there tension caused by PAN, TA, etc; (2) small vascu- was misdiagnosis and delayed treatment. Because lar lesions involving renal arterioles, which lead the pathologic characteristics of MHT (hyperplas- to damage of glomerular, renal tubule, and inter- tic arteriolosclerosis and necrotizing arteriolitis, stitial tissue, causing renal parenchymal ischemic mainly involving the kidney) are similar to those of necrosis, degeneration, and fibrosis, thereby reduc- systemic vasculitis, especially small-vessel vasculi- ing the glomerular filtration area and causing renal tis, systemic vasculitis was not well identified in the ischemia, leading to hypertension, such as renal hypertensive population. parenchymal hypertension caused by allergic gran- Although uncommon, early diagnosis of sys- ulomatous vasculitis, microscopic polyangiitis, temic vasculitis is required to preserve the function etc; (3) vascular endothelial cell damage, which of the affected organs and to decrease mortality. If leads to coagulation enhancement and activation systemic vasculitis is not diagnosed, evaluated, and of complement and immune regulation, results in treated properly, the outcome will be very poor. thrombosis and renal immune injury, causing high From the follow-up of our patients with vasculitis, blood pressure (Figure 3). In addition, macrovas- there were five cases of adverse events (one death, cular lesions lead to narrowing of the aorta or the one cerebral hemorrhage, one massive hemoptysis, abdominal aorta, redistributed blood flow, and one abdominal aortic aneurysm rupture, and one upper limb blood pressure significantly higher than repeated fundus hemorrhage) in the 20 patients, lower limb blood pressure. Furthermore, the inter- and the prognosis was very poor. Therefore, if action of these mechanisms may result in higher patients have unexplained renal atrophy, proteinu- blood pressure. ria, hematuria, deterioration of renal function, mul- In the past, because of the lack of understanding tiple organ involvement, increased inflammatory of vasculitis, because the clinical manifestations indexes, and/or antinuclear antibody and ANCA Q. Zhu et al., Systemic Vasculitis and Malignant Hypertension 107 positivity, they should be highly suspected of hav- Conclusions ing vasculitis. Together with skin, ear, nose, throat, eye, and other symptoms, these manifestations can Systemic vasculitis may be one of the main causes help in the diagnosis of vasculitis. of MHT, and was underestimated in the past. Despite clinical manifestations and laboratory indicators of systemic vasculitis not being specific, the target organ Limitations damage is great. In future clinical work, clinicians need to pay more attention to these patients with sys- This is a single-center study in a hypertension temic vasculitis and more actively treat them. center and so there might be some specialist bias. Because of the cross-sectional nature of the study, a causal relationship between MHT and vasculitis Acknowledgments could not be determined. Some scholars consider We sincerely thank all the staff of the Center of that vasculitis reflects target organ damage caused Hypertension in Xinjiang for their support with the by MHT or as a consequence of markedly elevated medical examinations and demographic data col- blood pressure, whereas others think the otherwise. lection. This study was supported by the Special However, because our center is a specialty center Foundation of Autonomous Region Key Laboratory for secondary hypertension, most of the patients of China (grant number 2014KL014) and the enrolled in this study were hospitalized because of National Natural Science Foundation of China markedly increased blood pressure with high levels (grant number 81360051). of inflammatory factors, antinuclear antibody and ANCA positivity, and severe target organ damage and were found to share vasculitis as the common Conflict of Interest cause. In the future, we will confirm the relationship between MHT and systemic vasculitis through The authors declare that they have no conflicts of follow-up outcomes. interest.

References

1. Keith NM, Wagener HP, Barker 5. Michelli A, Bernardi S, Grillo A, Prieto A, et al. Severe hypertension NW. Some different types of essen- Panizon E, Rovina M, Bardelli M, and hypokalemia as first clinical tial hypertension: their course et al. A case report of malignant manifestations in ectopic Cushing’s and prognosis. Am J Med Sci hypertension in a young woman. syndrome. Arq Bras Endocrinol 1974;268(6):336–45. BMC Nephrol 2016;17:65. Metabol 2008;52:1066–70. 2. Guzik T, Prejbisz A, Miko B, 6. Prejbisz A, Klisiewicz A, 9. Ramdoo K, Salam M, Warakaulle Jczyk T, Osmenda G, Januszewicz Januszewicz A, Lenders JW, D, Liong WC. Subintimal renal W. Malignant hypertension: Pregowska-Chwala B, Józwik- artery angioplasty in a case of renal new aspects of an old clini- Plebanek K, et al. 22-year-old patient artery stenosis leading to malignant cal entity. Pol Arch Med Wewn with malignant hypertension associ- hypertension. JRSM Short Rep 2016;126(1–2):86–93. ated with primary aldosteronism. J 2012;3:18. 3. Lane DA, Lip GY, Beevers DG. Hum Hypertens 2013;27:138–40. 10. Moroz LA, Simpson LL, Rochelson Improving survival of malig- 7. Kumar UM, Pande P, Savita SS, B. Management of severe hyperten- nant hypertension patients Ashwin PK, Yelikar BR. An extra- sion in pregnancy. Semin Perinatol over 40 years. Am J Hypertens adrenal pheochromocytoma pre- 2016;40:112–8. 2009;22:1199–204. senting as malignant hypertension- 11. Rodriguez-Iturbe B. Autoimmunity 4. Huang H, Luo Y, Liang Y, Long X, a report of two cases. J Clin Diagn in the pathogenesis of hypertension. Peng Y, Liu Z, et al. CD4+CD25+ Res 2013;7:1177–9. Hypertension 2016;67:477–83. T cells in primary malignant hyper- 8. Fernández-Rodríguez E, Villar- 12. Patel B, Tiwari A, Dubey SR, Bhatt tension related kidney injury. Sci Taibo R, Pinal-Osorio I, Cabezas- GC, Tiwari P, Bhan BD. Takayasu Rep 2016;6:27659. Agrícola JM, Anido-Herranz U, arteritis presenting with malignant 108 Q. Zhu et al., Systemic Vasculitis and Malignant Hypertension

hypertension; a rare manifestation et al. The American College of hypertension: a retrospective cohort of a rare disease: a case report and Rheumatology 1990 criteria for study. BMC Nephrol 2012;13:71. review of the literature. Trop Doct the classification of Churg-Strauss 26. Mitchell HC, Graham RM, Pettinger 2017;47:60–3. syndrome (allergic granulomato- WA. Renal function during long- 13. Blaustein DA, Kumbar L, Srivastava sis and angiitis). Arthritis Rheum term treatment of hypertension with M, Avram MM. Polyarteritis nodosa 1990;33:1094–100. minoxidil: comparison of benign presenting as isolated malignant 20. Leavitt RY, Fauci AS, Bloch DA. The and malignant hypertension. Ann hypertension. Am J Hypertens American College of Rheumatology Intern Med 1980;93:676–81. 2004;17:380–1. 1990 criteria for the classification of 27. Januszewicz A, Guzik T, Prejbisz 14. Kettritz R, Luft FC. Severe hyper- Wegener’s granulomatosis. Arthritis A, Mikołajczyk T, Osmenda G, tension with large-vessel arteritis. Rheum 1990;33:1101–7. Januszewicz W. Malignant hyper- Hypertension 2012;59:179–83. 21. Jennette JC, Falk RJ, Bacon PA, tension: new aspects of an old 15. Luo Q, Li NF, Yao XG, Zhang DL, Basu N, Cid MC, Ferrario F, et al. clinical entity. Pol Arch Med Wewn Abulikemu SF, Chang GJ, et al. 2012 revised International Chapel 2016;126:86–93. Potential effects of age on screening Hill Consensus Conference nomen- 28. Mathew RO, Nayer A, Asif A. for primary aldosteronism. J Hum clature of vasculitides. Arthritis The endothelium as the common Hypertens 2016;30:53–61. Rheum 2013;65:1–11. denominator in malignant hyper- 16. Nieman LK, Biller BM, Findling 22. Watts R, Lane S, Hanslik T, Hauser tension and thrombotic micro- JW, Newell-Price J, Savage MO, T, Hellmich B, Koldingsnes W, et al. angiopathy. J Am Soc Hypertens Stewart PM, et al. The diagno- Development and validation of a 2016;10:352–9. sis of Cushing’s syndrome: an consensus methodology for the clas- 29. Strizhakov LA, Moiseev S, Endocrine Society clinical practice sification of the ANCA-associated Semenkova EN, Kuznetsova EI. guideline. J Clin Endocrinol Metab vasculitides and polyarteritis nodosa Cardiovascular complications and 2008;93:1526–40. for epidemiological studies. Ann endothelial dysfunction in primary 17. Arend WP, Michel BA, Bloch Rheum Dis 2007;66(2):222.e7. vasculitis. Ter Arkh 2012;84:31–5. DA, Hunder GG, Calabrese LH, 23. Ananthan S, Onida AH. Davies. 30. Mammeria A, Guermazb R, Hatrib Edworthy SM, et al. The American Nutcracker syndrome: an update A, Kessalb F, Taharboucht S, College of Rheumatology 1990 on current diagnostic criteria and Hamrour F, et al. Hypertension dur- criteria for the classification of management guidelines. Eur J Vasc ing Takayasu’s disease: an Algerian Takayasu arteritis. Arthritis Rheum Endovasc Surg 2017;53:886–94. single center experience of 279 1990;33:1129–34. 24. Van den Born BJ, Honnebier UP, patients. Ann Cardiol Angeiol 18. Lightfoot RW, Michel BA, Bloch DA, Koopmans RP, van Montfrans 2017:66:154–8. Hunder GG, Zvaifler NJ, McShane GA. Microangiopathic hemoly- DJ, et al. The American College of sis and renal failure in malig- Rheumatology 1990 criteria for the nant hypertension. Hypertension Supplementary Material: Supple classification of polyarteritis nodosa. 2005;45:246–51. mentary material for this paper can Arthritis Rheum 1990;33:1088–93. 25. Amraoui F, Bos S, Vogt L, van be found at http://cvia-journal.org/ 19. Masi AT, Hunder GG, Lie JT, den Born BJ. Long-term renal out- wp-content/uploads/2019/07/Systemic- Michel BA, Bloch DA, Arend WP, come in patients with malignant Vasculitis-TABLE_1.pdf.