HIV Vasculopathy of the Renal Artery Manifesting as Severe Hypertension in a Young Female: Case Report and Review

Abstract

The burden of HIV infection, particularly in Sub-Saharan Africa, is well documented. The consequences are far-reaching and go beyond those of opportunistic infection and malignancy and into the realm of chronic diseases of lifestyle, with an increasing risk of cardiovascular disease in HIV-positive individuals. In this report we explore the case of a young black female with HIV who was referred with severe early-onset hypertension and was found, on further investigation, to have unilateral renal artery stenosis and bilateral renal artery aneurysms. We will also look at the clinicopathological entity of large- and medium-vessel vasculopathy associated with HIV.

VASCULAR DISEASE MANAGEMENT 2011;8(2):E40–E44

Key words: HIV vasculopathy; hypertension; renal artery stenosis

Introduction

The severity of the HIV/AIDS (human immunodeficiency virus/acquired immune deficiency syndrome) epidemic in South Africa is well documented. True prevalence figures are difficult to ascertain, but Statistics South Africa estimates that around 5.24 million out of a population of 50 million people were living with HIV in 2010,1 and it is predicted that the number will exceed 6 million by 2015.² In South Africa, much of the original focus of HIV infection has been centered on the treatment and prevention of life-threatening opportunistic infections and neoplasms. With the introduction of highly active antiretroviral therapy (HAART), long-term survival of HIV-infected individuals has become a reality, and attention has turned to the long-term cardiovascular3 and metabolic complications of therapy, which is compounded by the burgeoning epidemic of chronic diseases of lifestyle in our population. As early as 1987, a unique type of vascular disease was reported in patients with HIV infection that was associated with both occlusive and aneurysmal involvement of the cerebral, peripheral and visceral circulations. This has been termed HIV vasculopathy. In this case, we report the unusual involvement of the renal artery by HIV vasculopathy resulting in severe hypertension with target organ damage, requiring multiple antihypertensive drugs.

Case Report

The patient was a 34-year-old black female who was referred for investigation of early-onset severe hypertension. She was known to be HIV-positive since her first pregnancy in 2004. She developed hypertension during this pregnancy, and in a further two pregnancies, all of which terminated in second trimester miscarriages. Antihypertensive therapy was not continued between pregnancies; details of her blood pressure during these periods were not known. In October 2009, her CD4 count was 341 cells/μl and she was not receiving HAART according to the National Guidelines on the Treatment of HIV in South Africa at the time. In December 2009, she was diagnosed with hypertension at her primary care clinic. Antihypertensive treatment was commenced and escalated to enalapril 5 mg twice daily, amlodipine 10 mg daily and hydrochlorothiazide 12.5 mg daily. She was referred to our hypertension clinic for further evaluation.

The patient was previously using medroxyprogesterone acetate as contraception, which was stopped in January 2010 due to menorrhagia. There was a strong family history of hypertension, with both parents deceased due to hypertensive complications. Her mother also had Type 2 diabetes mellitus. She had two siblings, both of whom were healthy. She was a non-smoker, did not use alcohol and had no history of substance abuse. Examination revealed an obese woman with a body mass index of 34 kg/m², without features of Cushing’s syndrome. Her blood pressure was 152/98 mmHg, similar in both arms. Heart rate was 74 beats/min and regular. All pulses were palpable and equal, with no carotid, femoral or renal artery bruits or radio-femoral delay. Clinically, there was evidence of left ventricular hypertrophy (LVH), and fundoscopy revealed hypertensive changes with arteriovenous nipping and silver-wiring of the vessels. The kidneys were impalpable and the dipsticks urine was negative. The electrocardiogram showed voltage criteria for left ventricular hypertrophy and the patient’s creatinine was 94 μmol/l, with an estimated glomerular filtration rate (GFR) of 76 ml/min by MDRD formula. Her potassium was 4.3 mmol/L, total cholesterol 3.7 mmol/L, random glucose 4.0 mmol/L, uric acid 0.27 mmol/L, urine albumin/creatinine ratio 0.9 mg/mmol and C-reactive protein

Discussion

An unusual form of vascular disease affecting the large and medium-sized arteries in patients with HIV was first described in 1987⁴ and was later termed HIV vasculopathy. The disease shares several clinicopathological similarities with Takayasu’s disease.⁴ It typically affects younger patients, with multiple aneurysms and occlusive disease involving larger vessels.⁴ Aneurysmal degeneration and occlusive disease appear to be different expressions of a similar underlying pathology.⁵ In contrast to Takayasu’s disease, there is a male predominance,^4,6 and pathologically there is a proliferation of slit-like vascular spaces in the adventitia, the absence of prominent intimal proliferation and atherosclerosis, and pronounced leucocytoclastic vasculitis of the vasa vasora.⁴ Aneurysms are found in atypical sites, with a predilection for the carotid, popliteal and superficial femoral arteries.⁷ They are usually multiple (average of 3 per patient in one series)⁷ and most often saccular.⁶ Laboratory features include hypoalbuminemia, hyperglobulinemia^7,8 and low CD4 count^7–10 with an inverted CD4:CD8 ratio.^7,8 Nair et al described the histological features of aneurysmal disease in a series of 10 patients.⁸ Active and inactive lesions were seen, both of which were centered on the vasa vasora. The acute inflammatory lesions showed neutrophils surrounded by a cuff of plasma cells and lymphocytes, with occasional hemosiderin-laden macrophages. There was marked endothelial swelling of the vasa vasora, with disruption, necrosis and fibrin deposition. This resulted in occlusion of the vessel lumen. In the areas of most severe acute inflammation, focal transmural necrosis was noted. The areas of acute inflammation were surrounded by chronic, inactive lesions with fibrosis, hemosiderin deposition, fragmentation of medial elastic fibers, loss of smooth muscle and intimal fibromuscular hyperplasia.⁸ Chetty et al reported similar findings, but in addition, noted a proliferation of slit-like vascular channels within and between the adventitial collagen in non-aneurysmal parts of the arteries.⁴

Occlusive disease is less well studied, but shares similar clinical features with aneurysmal disease (young age, low CD4 count, hypoalbuminemia and hypergammaglobulinemia).⁵ Patients usually have occlusive disease involving the limbs and present with either critical ischemia and rest pain, or acute thrombosis with no antecedent claudication.⁹ Duplex Doppler studies show a characteristic “string of beads” pattern in the vessel wall^9,11 (also observed in HIV-associated arterial aneurysms), and angiographic studies show normal proximal and contralateral vessels with poor run-off due to thrombosis into the smaller vessels.⁹ At surgery, Nair et al noted that the arterial walls were macroscopically normal, with no evidence of atherosclerosis.⁵ Histologically, the major inflammatory changes were concentrated in the adventitia, with a leucocytoclastic vasculitis involving the vasa vasora — almost identical to the pathology seen in aneurysmal disease.⁵ There is no evidence to suggest that either atherosclerosis or hypercoagulability is implicated in the pathogenesis of occlusive disease. Typical risk factors for atherosclerosis were generally lower than in the general population¹² and the coagulation profile including international normalized ratio (INR), platelet count, protein C and S levels, serum fibrinogen level and antiphospholipid antibodies were typically normal.^9,11 In contrast, in HIV positive patients with venous thromboembolic disease, various abnormalities in coagulation have been demonstrated.¹³

The pathogenesis of HIV vasculopathy is unknown. Several mechanisms have been suggested,¹⁴ however, the exact pathogenesis remains an enigma. Direct action of the virus itself could cause vessel wall weakening.⁸ HIV protein has been found in the lymphocytes within vasculitic lesions, but this is true throughout the body in HIV-infected individuals.⁶ Receptors on vascular endothelial and smooth muscle cells that allow viral entry and replication are typically absent. In one study, immunohistochemical studies were negative for the gp-41 viral protein, which would tend to refute direct HIV-related damage to the vessel wall.⁸ The role of opportunistic infection, e.g., Salmonella, Hemophilus or mycobacteria, was explored in a series of 92 aneurysms.7 Positive tests were found in only 3 of the 92 aneurysms. One aneurysm cultured mixed organisms including Escherichia coli, Staphylococcus aureus and Enterococcus fecalis. This was a case of a ruptured aneurysm and thought to be due to skin-surface contamination. One patient had serological evidence of current Salmonella typhi infection, and one patient had evidence of ongoing syphilitic infection. Salmonella was cultured from two of the aneurysms.⁷ It has also been suggested that infection, as a result of immunodeficiency, could increase exposure to endogenous and exogenous elastases, causing disruption of the medial elastic fibers.⁸ The failure to isolate an infecting organism could be due to technical aspects of collection, staining and culture or the possibility that infectious agents present earlier in the disease process had been eradicated.⁸ Further evidence in support of a possible infectious etiology has been provided by a case in which a child developed extensive cerebral aneurysmal disease as part of immune reconstitution syndrome shortly after starting antiretroviral therapy. This suggests that vasculopathy may be due to an immune-mediated response to chronic infection.¹⁵ HIV vasculopathy could potentially be related to immune-complex deposition due to chronic infection or immune system dysregulation, but this has never been demonstrated.^4,8 Angiogenesis with proliferation of slit-like vascular spaces in the adventitia may be related to a synergistic relationship between HIV, cytokines and growth factors.⁴ Inflammatory cytokines such as tumor necrosis factor α (TNFα), interleukin-1β (IL-1β), IL-6 and interferon γ (IFN-γ) are released by HIV-infected immune cells and activate viral gene expression and replication. They also affect the normal properties of vascular endothelium, leading to endothelial cell activation and production of angiogenic factors.¹⁶

It has been shown that expression of vascular endothelial growth factor-A (VEGF-A) is increased in chronically HIV-infected T-lymphocytes, and that inflammatory cytokines induce expression of VEGF-A in uninfected T-cells via a paracrine mechanism.¹⁶ In addition, trans-acting transcription factor (Tat), which is essential for viral replication and is produced early after infection, activates the tyrosine kinase receptor encoded by VEGF in endothelial cells and induces vascular leakage and proliferation of endothelial cells. Tat may also compete with fibroblast growth factor for binding to heparin sulphate proteoglycans, resulting in endothelial cell activation.¹⁷ Also, the aforementioned cytokines have been shown to be responsible for increased adhesion of mononuclear cells to the endothelium in HIV-infected patients (via E-selectin and VCAM-1).¹⁸ These factors may lead to the generalized vascular activation, proliferation and permeability seen in HIV-infected individuals, and may contribute to the development of HIV-vasculopathy as well as Kaposi sarcoma.¹⁶

Renal artery involvement in HIV appears to be rare. There are 3 cases reported in the literature. One case had a polyarteritis nodosa-like syndrome with bilateral perirenal hematomas and an angiogram showing multiple renal intraparenchymal microaneurysms, together with hepatic microaneurysms. The diagnosis of polyarteritis nodosa (PAN) was confirmed on histology. This patient had tested negative for hepatitis B, hepatitis C, Epstein Barr virus, parvovirus and cytomegalovirus, but positive for HIV, which was thought to be the etiological factor for the PAN.¹⁹ Nair et al reported 1 case of renal artery involvement in a large institutional series. This 18-year-old patient presented with severe hypertension and was found to have a large suprarenal abdominal aortic aneurysm (AAA) with renal artery occlusion and a non-functioning left kidney. This patient underwent elective repair of her AAA with nephrectomy of the non-functioning kidney and multiple side-arm grafts to the remaining visceral vessels. She later succumbed to renal failure due to occlusion of the renal artery graft.⁷ The third case was that of a 38-year-old male who was found to have bilateral renal artery aneurysms with right renal artery stenosis. There was also aneurysmal dilatation and subsequent occlusion of the left hypogastric artery and an aneurysm of the right superficial femoral artery. The patient’s blood pressure was not reported in this case.¹⁴ The diagnosis of HIV vasculopathy is suggested by the presence of multiple aneurysms in unusual sites or occlusive disease in a young HIV-positive patient with a low CD4 count and the absence of other risk factors for cardiovascular disease. Ideally, histological confirmation of a leucocytoclastic vasculitis of the vasa vasorum should be obtained from surgical specimens. Other forms of large- and medium-vessel vasculitis need to be excluded, for example, Takayasu’s arteritis, giant cell arteritis and polyarteritis nodosa. Serological investigations for Hepatitis B virus, Hepatitis C virus as well as syphilis should be performed. Aneurysms are best demonstrated by CT angiography, and the presence of an aneurysm in one location should lead to a search for aneurysms elsewhere.⁹ Due to the multicentric nature of the disease, large amounts of contrast may be required¹⁴ and appropriate hydration and prophylaxis against thrombosis are advised.¹⁴ In occlusive disease involving the limbs, duplex ultrasound examination confirming thrombosis with the “string of beads” sign, the absence of distal run-off and normal proximal and contralateral vessels is sufficient for diagnosis.¹¹ Further imaging with digital subtraction angiography does not contribute to the information obtained from ultrasound.¹¹

The treatment of HIV vasculopathy has three main objectives: to control HIV replication, treat the underlying vasculitis and manage vascular complications.²⁰ HIV vasculopathy should be considered an AIDS-defining illness and it is recommended that HAART be instituted in all cases. It is important to note that there are no data on the influence of HAART on vascular disease, but it is theorized that control of the underlying viral replication may arrest the underlying vasculitic process. One must be aware of the potential for antiretroviral therapy to cause superimposed atherosclerotic disease due to adverse metabolic effects, and modification of risk factors for atherosclerosis should be instituted. As previously discussed, HIV vasculopathy is a vasculitic process involving the vasa vasora. There is also the entity of a small-vessel systemic vasculitis involving the skin, peripheral nerves and central nervous system.²¹ In this disease, suppression of inflammation with steroids and cytotoxic drugs is a therapeutic strategy, but remains controversial as it may stimulate viral replication.^19,20 Guillevin et al performed plasma exchange in patients with small-vessel vasculitis associated with HIV, in conjunction with HAART, in an attempt to avoid steroids and cytotoxic agents.²¹ This approach was based on the theory that circulating immune complexes were responsible for the immune-mediated vascular damage. The first 8 patients who were treated with this regimen showed improvement and remission. This strategy was also effective in those co-infected with HIV and hepatitis B or C viruses.²¹ Sagcan et al commented that the combination of HAART and plasma exchange can cure HIV-related small-vessel vasculitis in a manner analogous to that seen in Hepatitis virus-related PAN.¹⁹ It remains to be explored whether this approach would be of use in the treatment of large- and medium-vessel vasculitis, where the inflammation is centered on the vasa vasora which are, in essence, small vessels.

Vascular emergencies with rupture or threatened rupture of aneurysms or acute thrombosis due to occlusive disease must be treated urgently with appropriate vascular intervention.^10,14 In non-urgent cases, intervention should be delayed in order to improve the immunological and nutritional status of the patient and to control opportunistic infection.¹⁰ These patients are at high risk for post-operative sepsis, and there may be a role for prophylactic antibiotics beyond the scope of those usually used (e.g., fungal prophylaxis, and cotrimoxazole to prevent opportunistic infections).^12,17 The risk of venous thromboembolism is also high and prophylactic heparin is recommended.¹⁴ There are several surgical options for the treatment of HIV vasculopathy: bypass procedures, endovascular procedures, thrombectomy and primary amputation (the latter two options for occlusive disease). Long-term mortality for patients with aneurysmal disease has been found to be significantly worse than those with occlusive disease.¹⁷ It has also been found that the results of procedures in HIV-associated occlusive disease were much worse than those in atherosclerotic disease.¹⁷

There are many problems with the use of endovascular procedures and revascularization in occlusive disease due to HIV. Many patients have long-segment arterial occlusion that precludes the use of endovascular procedures.⁵ Late presentation with advanced tissue necrosis is common, and requires primary amputation rather than revascularization.^5,9,12 The poor distal run-off that is seen in the disease also limits the use of bypass surgery.^9,17 When bypass surgery is performed, autogenous venous grafts are preferred to prosthetic material.⁸ This approach is, however, not always possible, due to concomitant DVT in the long saphenous vein, due to compression by lower limb aneurysms, or the hypercoagulability seen in HIV positive patients,⁸ or due to thrombophlebitis.¹² Silver impregnated grafts have also been used where there is a high probability of infection.¹² However, one study showed a failure rate of > 75%for bypass surgery.¹⁷ Endovascular therapy was used with success in occlusive disease in the series by Robbs et al.⁹ However, sepsis was again a concern, leading to death in 1 patient.⁹ Scholtz suggests that due to the underlying inflammatory nature of the disease process, a similar treatment approach to that used in patients with Takayasu’s disease should be used, i.e., the surgical route rather than the endoluminal route.¹⁴ However, there are no data comparing the two approaches, and there is a suggestion that endoluminal procedures should be considered an option, especially where surgical procedures are known to have a high mortality rate, e.g., repair of thoracic aortic aneurysms.¹⁴ Studies investigating the use of thrombectomy in HIV-associated occlusive disease have shown disappointing outcomes with the procedure.^11,17 A search of the literature revealed no guidelines as to the optimal treatment of renal artery stenosis caused by HIV vasculopathy. Intervention presumably needs to be based on the risk of rupture, potential for occlusion leading to renal ischemia and blood pressure control. In our case, the blood pressure was well controlled on three agents, and a decision regarding intervention is awaited from our vascular surgeons.

Overview

Vasculopathy associated with HIV infection was first described in children in 1987. Excluding drug reactions, the incidence of HIV-related vasculitis is low (22 however, the range of vascular diseases associated with HIV is broad. A classification of HIV-related vascular disease is shown in Table 1.^22,23

Conclusion

In South Africa two major epidemics, namely HIV and non-communicable diseases like hypertension, are colliding. HIV infection and hypertension are likely to coexist in the same patient, and this may be due to underlying essential hypertension, the adverse metabolic effects of HAART or rarely due to HIV vasculopathy with renal artery stenosis. It is suggested that severe hypertension or treatment-resistant hypertension should prompt investigation for HIV vasculopathy. The effect of HAART on the prevention and treatment of vasculopathy is unknown, but it is likely that the earlier roll-out of HAART in HIV-positive patients with higher CD4 counts may have substantial impact on this disease. The treatment of HIV vasculopathy beyond the immediate surgical complications is not known.

Acknowledgments. We would like to thank Dr. S. Candy and Dr. N. Ahmed for their assistance with the interpretation of the radiographic and the CT images, together with Miss R. Ahmed for obtaining the computer images.

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From the Division of Nephrology and Hypertension, University of Cape Town, Cape Town, South Africa. The authors report no conflicts of interest regarding the content herein. Address for correspondence: Brian Rayner, MBChB, FCP MMed, E13 Groote Schuur Hospital, Observatory, 7925, South Africa. E-mail: brian.rayner@uct.ac.za