Renovascular hypertension associated with JAK2 V617F positive myeloproliferative neoplasms treated with angioplasty: 2 cases and literature review

Abstract

Myeloproliferative neoplasms (MPNs) with Janus kinase 2 (JAK2) mutation are associated with a high risk for occlusive vascular diseases. We report 2 cases of renovascular hypertension associated with JAK2 V617F mutation‐positive MPNs and provide a literature review. In Case 1, a 63‐year‐old woman had resistant hypertension, massive proteinuria, and erythrocytosis. Evaluations revealed right renal artery stenosis causing renovascular hypertension and polycythemia vera with JAK2 V617F mutation. Renin‐angiotensin system inhibitors and subsequent angioplasty controlled the blood pressure and the proteinuria resolved. In Case 2, a 74‐year‐old woman had resistant hypertension and thrombocytosis. Evaluations confirmed left renal artery stenosis and essential thrombocythemia with JAK2 V617F. Angioplasty cured the hypertension. A literature review of 18 cases revealed the following as the most common characteristics of MPN‐associated renovascular hypertension: manifests primarily in women; is associated with untreated polycythemia vera and essential thrombocythemia, concomitant leukocytosis, and JAK2 mutation positivity; and is responsive to angioplasty. This report demonstrates that JAK2 mutation‐positive MPNs are a less common but important underlying cause of adult renovascular hypertension.

1. INTRODUCTION

Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders characterized by expansion of one or more myeloid cell lineages. In the genesis of MPNs, a tyrosine kinase Janus kinase 2 (JAK2) pathway exhibits a significant role, especially in polycythemia vera (PV) and essential thrombocythemia (ET). Acquired mutations in JAK2 (JAK2 V617F and exon 12 mutations) have been identified in almost all patients with PV and in 60% of those with ET.1 The mutations result in a constitutive activation of the JAK2‐STAT pathway and lead to the unregulated expansion of the affected hematopoietic precursor cells.2, 3

In subtypes of MPNs, PV and ET create a high risk for thrombotic events and occlusive vascular diseases, including myocardial infarction and stroke. These complications are the main cause of death among patients with MPNs. Highlighting the importance of their prevention and management. Mechanistically, in addition to the hyperviscosity by increased blood cell counts, constitutive activation of JAK2 signaling has been suggested.4 In addition to cardiovascular events, peripheral arterial occlusive diseases can occur in patients with MPNs.5, 6

Several cases of renovascular hypertension and renal artery stenosis in patients with MPNs have been described in the literature since the 1980s. However, they have been sporadic reports, leaving us unable to recognize the clinical characteristics. In addition, diagnostic modalities for MPNs and treatment strategies for renovascular hypertension have progressed. Thus, the common clinical manifestations of patients with MPN‐associated renovascular hypertension have been unclear. Also, optimal treatments for the renovascular lesion in such patients have not been determined.

We report 2 cases of renovascular hypertension associated with JAK2 mutation‐positive MPNs, in which renal artery angioplasty effectively ameliorated the hypertension. In addition, we conducted a literature review of cases of MPN‐associated renovascular hypertension, which has revealed the common clinical characteristics of the affected patients

2. METHODS

We searched the MEDLINE, PubMed, EMBASE, Web of Science, Scopus, and Japan Medical Abstracts Society (ICHUSHI) databases for literature on cases of renovascular hypertension associated with MPNs. We excluded meeting abstracts, resulting in 13 articles describing 16 cases.7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 The clinical characteristics of the 16 cases from the literature and our 2 patients were examined for a total of 18 cases.

2.1. Case 1

A 63‐year‐old woman was referred for evaluation of severe hypertension with massive proteinuria. Although her blood pressure had been controlled below 130/70 mm Hg with amlodipine 5 mg for the previous 10 years, it had gradually increased in the preceding 2 years and reached 200/110 mm Hg 2 months prior. On admission, her blood pressure was 190/110 mm Hg despite receiving antihypertensive medications (amlodipine 10 mg). Her pulse rate was 83 beats/min in a regular rhythm. Laboratory results showed marked urinary protein of 24 g/g creatinine (gCr), excessively high plasma renin activity (23.2 ng/mL/h, reference range 0.3‐2.9) and aldosterone level (715 pg/mL, reference 30‐160), with a normal level of serum creatinine (0.6 mg/dL). A contrast‐enhanced computed tomography (CT) angiographic scan revealed a severe stenosis in the proximal portion of the right renal artery, resulting in ischemia of the affected kidney with collateral flow (Figure 1A). The right kidney was atrophic (long diameter, 86 mm) and the contralateral kidney was enlarged (130 mm) (Figure 1B). We diagnosed renovascular hypertension caused by atheromatous stenosis. However, except for the hypertension, she had no conventional risk factors for atherosclerosis, such as smoking, diabetes, severe dyslipidemia, obesity, or past or family history of cardiovascular diseases or thrombotic events.

Figure 1.

Radiographic images and clinical course of Case 1. (A, B) Computed tomography angiographic scan showing stenosis of the right renal artery (arrows) and collateral supply (dotted arrow). The right kidney was atrophic and the left kidney was enlarged. (C) Clinical course of blood pressure and urine protein. PRA, plasma renin activity; Ald, plasma aldosterone concentration; PTRA, percutaneous transluminal renal angioplasty. (D) Angiographic images of the right renal artery before and after the angioplasty. The nearly occluded lesion was revascularized with stent implantation (arrows)

The laboratory examination results were indicative of pancytosis: white blood cell count 13 100/μL, red blood cell count 509 × 10⁴/μL, hemoglobin 17.0 g/dL, hematocrit 49.5%, and platelet count 54.8 × 10⁴/μL. Serum erythropoietin (10.2 mIU/mL) was within the normal range of < 29 mIU/mL. A bone marrow biopsy showed trilineage hyperplasia. Cytogenetic analysis of her blood samples detected JAK2 V617F allele without BCR‐ABL transcript. These findings led to the diagnosis of PV, which was considered the underlying cause of the renal artery stenosis.

To control her blood pressure, the antihypertensive medication was replaced with controlled‐release nifedipine (calcium channel blocker) and bunazosin (alpha blocker) in combination with the renin‐angiotensin inhibitors temocapril and olmesartan; blood pressure fell to about 140/90 mm Hg (Figure 1C). Urinary protein was also reduced to 4 g/gCr but remained moderately elevated (Figure 1C). Therefore, we attempted transluminal angioplasty for revascularization of the stenotic lesion. Renal angiography confirmed a nearly occluded severe stenosis in the right renal artery (Figure 1D). Subsequent balloon dilatation and stent implantation resolved the stenosis, resulting in revascularization of the right kidney (Figure 1D). One week later, her blood pressure was controlled at approximately 130/80 mm Hg, urinary protein was reduced to 0.9 g/gCr, and hyperreninemia was also resolved (Figure 1C). Three months later, urinary protein was further reduced to 0.3 g/gCr. During the following 3 years, her blood pressure was maintained at approximately 120/70 mm Hg with olmesartan and amlodipine treatment, and no findings of restenosis were observed in the follow‐up evaluation by Doppler ultrasonography. For the management of PV, aspirin and intermittent phlebotomy were initially started; however, 3 years later, hydroxyurea was administered because of the progression of polycythemia.

2.2. Case 2

A 74‐year‐old woman was referred for evaluation of hypertension with concomitant thrombocytosis. She had been normotensive until 1 year previously, but the hypertension as well as an increased platelet count had emerged during the preceding year. She had an episode of pruritus triggered by contact with water. On admission, her blood pressure was 142/94 mm Hg while on treatment with amlodipine 5 mg and irbesartan 100 mg/d. To control her blood pressure, trichlormethiazide 1 mg (thiazide diuretic) was added. Laboratory test results showed a leukocytosis and thrombocytosis: white blood cell count 19 800/μL, platelet count 75.3 × 10⁴/μL, hemoglobin 12.3 g/dL, and hematocrit 50%. Serum creatinine was 0.9 mg/dL and urinary protein was 0.14 g/Cr. Active renin concentration was high (71.7 pg/mL, reference range 2.5‐21.4) and the aldosterone level was 132 pg/mL; these levels were measured when the patient was prescribed the antihypertensive medications. A CT angiographic scan revealed splenomegaly and severe stenosis in the proximal portion of the left renal artery, resulting in atrophy of the affected kidney (Figure 2A). Blood tests were positive for JAK2 V617F, and the patient was diagnosed with ET. Similar to Case 1, she had no conventional risk factors for atherosclerosis except the hypertension; the ET was considered to be the cause of the renal artery stenosis.

Figure 2.

Radiographic images and clinical course of Case 2. (A) Computed tomography angiographic scan showing stenosis of the left renal artery (arrow). (B) Angiographic images of the right renal artery before and after the angioplasty. The treated lesion is indicated by arrows. (C) Clinical course of blood pressure. Prescribed three antihypertensive medications are amlodipine 5 mg, irbesartan 100 mg, and trichlormethiazide 1 mg/d

To resolve the stenotic lesion, we performed transluminal renal angioplasty (Figure 2B). Two days after the treatment, her blood pressure decreased to 110/64 mm Hg without any antihypertensive agents (Figure 2C). The ET was initially treated with aspirin and hydroxyurea. However, because of the worsening of the pruritic itching, the hydroxyurea was replaced with a JAK inhibitor, ruxolitinib. Over the following 8 months, she remained normotensive (110/60 mm Hg) with no findings of restenosis. The renin and aldosterone levels were also maintained within a normal range (active renin concentration, 6.8 pg/mL; aldosterone, 89 pg/mL).

2.3. Literature review of renovascular hypertension associated with MPNs

Including our 2 cases, we reviewed a total of 18 cases of MPN‐associated renovascular hypertension (Table). Overall, the mean age at the time of diagnosis of renovascular hypertension was 45 ± 15 years (range 27‐74 years). A total of 89% (16/18) of the patients were women. The types of MPNs were ET in 9 patients (50%), PV in 8 patients (44%), and occult MPNs in 1 patient. However, some cases that were reported as ET with concomitant polycythemia, such as cases #5 and #9, are now considered to be PV based on the current classification criteria for MPNs.20 Leukocytosis (> 10 000/μL) was present in 13 (87%) of 15 cases in which white blood cell counts were obtained. In 16 cases (89%), MPNs were first recognized in the untreated condition, when the renovascular hypertension was diagnosed. In only 2 cases (#11 and #16), before the appearance of renovascular hypertension, MPNs had been treated with hydroxyurea for several years. JAK2 V617F mutation was identified in all 7 cases that were analyzed after the first report of the mutation in 2005.2

Table 1.

Literature review of the case of renovascular hypertension associated with MPNs

References	#	Age Sex	Type of MPNs	JAK2 mutation	WBC (/μL)	Ht (%)	Hb (g/dL)	Plt (x104/μL)	Diagnostic time of MPNs	Renal artery lesion	Treatment of RVH	Hypertension management after PTRA
Yuno71979	1	52 F	PV	N.A.	11 500	64	20.8	82	Same	Uni.	Medication	‐
Biggs8 1983	2	47 M	PV	N.A.	11 700	‐	18.3	50.5	Same	Bil.	Nephrectomy	‐
Higashijima9 1984	3	57 F	PV	N.A.	11 100	53.4	19.0	31	Same	Uni.	PTRA	Became controllable with medication
Lagrue10 1986	4	20 F	ET	N.A.	‐		‐	60	Same	Uni.	Medication	‐
	5	40 F	ET	N.A.	12 000	‐	16	100	Same	Bil.	Reimplantation	‐
	6	42 F	ET	N.A.	‐	‐	15	80	Same	Uni.	Reimplantation	‐
Bruch11 1988	7	40 F	ET	N.A.	13 200	42	‐	66‐150	Same	Bil.	Reimplantation	‐
	8	27 F	ET	N.A.	16 400	50	‐	63	Same	Uni.	Medication	‐
Arnar12 1993	9	36 M	ET	N.A.	‐	49.9	16.7	82.8	Same	Bil.	PTRA	Uncontrollable with 3 drugs → controllable with 2
Hur13 2005	10	28 F	ET	N.A.	6300	‐	12.3	75.7	Same	Uni.	PTRA	Remission of hypertension
Ozben14 2006	11	54 F	ET	N.A.	13 110	44.1	14.8	67.6	−12 y	Uni.	PTRA	Became controllable with medication
Tabaczewski15 2009	12	72 F	Occult MPN	V617F	Mild leukocytosis	‐	Normal	Normal	Same	Uni.	PTRA	(Occlusion by in‐stent thrombosis after 10 d)
Bhadauria16 2011	13	40 F	PV	V617F	45 000	56	16.4	54	Same	Uni.	PTRA	Decrease in number of drugs from 6 to 2
Kim17 2014	14	30 F	PV	V617F	22 500	66.9	22.5	40	Same	Uni.	PTRA	Became controllable with 1 drug
Zahra18 2014	15	31 F	PV	V617F	12 890	53.8	18.2	55.2	Same	Bil.	Medication	‐
Gavriilaki19 2014	16	52 F	PV	V617F	8300	44.4	14.4	23.8	−7 y	Uni.	PTRA	Became controllable with medication
Case 1	17	63 F	PV	V617F	13 600	49.5	17.0	54.8	Same	Uni.	PTRA	Became controllable with 2 drugs
Case 2	18	74 F	ET	V617F	19 800	39.2	12.3	75.3	Same	Uni.	PTRA	Remission of hypertension

Bil. bilateral; ET, essential thrombocythemia; Hb, hemoglobin; Ht, hematocrit; MPNs, myeloproliferative neoplasms; N.A, not available; Plt, platelet; PTRA, percutaneous transluminal renal angioplasty; PV, polycythemia vera; RVH, renovascular hypertension; Same, at the same time of the diagnosis of RVH; Uni, unilateral; WBC, white blood cells.

#11 and #16 had been treated with hydroxyurea. Reimplantations were right renal artery reimplantation and splenorenal arterial anastomosis (#5), right renal artery reimplantation (#6), and bilateral renal artery reimplantation (#7).

Stenotic lesions of the renal artery were unilateral in 13 patients (72%) and were bilateral in 5 patients (28%). For the treatment of renovascular lesion, transluminal angioplasty was performed in 11 patients (61%). In most cases treated with angioplasty, the intervention achieved remission or improvement of hypertension, including a decreased number of antihypertensive agents needed to control blood pressure.

3. DISCUSSION

We described 2 cases of renovascular hypertension due to renal artery stenosis associated with JAK2 V617F‐positive MPNs, in which hypertension was successfully ameliorated with angioplasty. The literature review revealed that the common clinical characteristics of MPN‐associated renovascular hypertension are as follows: predominant occurrence in women, associated with untreated PV or ET, JAK2 mutation positive, concomitant leukocytosis, and high therapeutic response to angioplasty. Thus, when a middle‐aged or elderly patient has renovascular hypertension with blood cell abnormalities, JAK2 mutation‐positive MPNs should be considered as an underlying disorder.

In the present 2 cases, the stenotic lesions in the renal arteries were radiographically considered to be thrombotic plaque or intimal hyperplasia, which would be associated with PV and ET. PV and ET can lead to intraluminal thrombus formation and arterial intimal proliferation via multiple mechanisms, such as hyperviscosity from increased hematocrit, activation of leukocytes and platelets, and abnormalities in coagulation systems and vascular endothelium functions.21 In addition, a constitutive activation of the JAK‐STAT pathway is proposed as another possible mechanism. JAK2 signaling activates STAT and subsequently drives activation of platelets and leukocytes and accelerates hyperplasia of the vascular cells, leading to atherosclerotic plaque and intimal hyperplasia.21 Indeed, increases in the JAK2 V617F allele burden in peripheral blood cells have been reported as a risk factor for thrombotic events in patients with MPNs.22 Similarly, a high JAK2 V617F allele burden may be associated with the risk of renovascular hypertension in patients with MPNs; however, we did not evaluate the allele burden in the present cases.

In the reviewed cases, the mean age of the diagnosis was relatively young (46 years) compared with the population of MPNs patients, as the median age at diagnosis of PV and ET is approximately 60 years.23, 24 Additionally, in most of the cases, the MPNs were first recognized in the untreated condition, when the renovascular hypertension was diagnosed. These findings suggest that renovascular hypertension appears to be an early complication of untreated MPNs, particularly with PV and ET. Emerging abnormalities in blood cells and vascular function during the early phase may be involved in the pathogenesis of the occlusive lesions in the renal artery.

Both cases responded to revascularization by angioplasty. Especially in Case 2, angioplasty completely alleviated the hypertension. Similarly, in most of the reviewed cases, angioplasty was an effective treatment to control the blood pressure. However, when atherosclerosis is the main pathogenic factor for renal artery stenosis, angioplasty is often ineffective. Randomized clinical trials for atherosclerotic renal artery stenosis have not demonstrated significant benefits of angioplasty over medical management in controlling blood pressure and preserving renal function.25, 26 This ineffectiveness is considered to be caused by the remaining ischemia in the kidney due to concomitant aortic stiffening and arteriosclerosis in the intrarenal small arteries. By contrast, in patients with MPNs, the arterial stenosis seems not to be derived from simple atherosclerosis. Thus, the degree of aortic stiffening and arteriosclerosis has not progressed in these patients with MPN‐associated renovascular hypertension compared with those with atherosclerotic renal artery stenosis. Therefore, angioplasty would be a recommended intervention for the MPN‐associated renovascular hypertension unless the patient shows findings of progressed atherosclerosis. In general, reduction in viscosity by cytoreductive drugs such as hydroxyurea can lower the blood pressure to some extent in patients with MPNs. However, in the pathophysiology of renovascular hypertension, the primary cause of blood pressure elevation is excessive activation of the renin‐angiotensin system. Therefore, the blood pressure‐lowering effect of cytoreductive therapy would be limited in cases of MPN‐associated renovascular hypertension.

Case 1 had massive proteinuria, which nearly disappeared after treatment with renin‐angiotensin system inhibitors and subsequent angioplasty. Previous reports have shown that unilateral renovascular hypertension occasionally causes a nephrotic range of gross proteinuria.27 In such cases, it is known that the urinary proteins are derived from a contralateral kidney without a stenotic lesion.28 In the pathophysiology, the contralateral kidney undergoes hyperperfusion and glomerular hyperfiltration associated with an activated renin‐angiotensin system, leading to the proteinuria.28 In these cases, resolution of stenosis by angioplasty has been reported to be effective in reducing the proteinuria,29 as in the present case. In Case 1, mild proteinuria (0.3 g/gCr) persisted after the resolution of stenosis by percutaneous transluminal renal angioplasty (PTRA). In addition to the renovascular diseases, glomerulopathy such as focal segmental glomerulosclerosis has been reported as a renal complication in patients with MPNs.30 Thus, persistent mild proteinuria might be attributed to MPN‐related glomerulopathy. The erythropoietin level in Case 1 was not suppressed despite a high hemoglobin level (17.0 mg/dL) before the angioplasty. This may be because of erythropoietin production due to renal ischemia in the affected kidney as the hemoglobin level was slightly decreased from 17.0 mg/dL to 15.0 mg/dL after revascularization.

In the present review, the patients were predominantly female. Although there is a preponderance of women with ET, with a female‐to‐male incidence ratio of 2:1,31 there is no significant difference in PV with regard to sex. In addition, previous reports have shown that MPN‐related other cardiovascular events and peripheral artery diseases occurred predominantly in males.5, 32 Thus, why there are more women with MPN‐related renovascular hypertension is still unknown. Moreover, because the pathophysiology of MPN‐associated renovascular disease has not been commonly known, clinicians might have overlooked underlying MPNs in male patients with renovascular hypertension, for example, by erroneously considering it as smoking‐related secondary polycythemia.

In summary, JAK2 mutation‐positive MPNs are a less common but important cause of adult renovascular hypertension. When blood cell abnormalities are concomitantly observed, clinicians should consider a possibility of underlying MPNs in the patients with renovascular hypertension, especially middle‐aged or elderly patients lacking conventional risk factors for atherosclerosis. In such cases, renal angioplasty would be a useful option for control the blood pressure. The relationship between MPNs and renovascular hypertension adds to the body of knowledge of onco‐nephrology.

CONFLICT OF INTEREST

The authors declare no conflicts of interest to disclose.

Mishima E, Suzuki T, Takeuchi Y, et al. Renovascular hypertension associated with JAK2 V617F positive myeloproliferative neoplasms treated with angioplasty: 2 cases and literature review. J Clin Hypertens. 2018;20:798–804. 10.1111/jch.13257