Hyperreninemic hypertension secondary to a subcapsular perinephric hematoma in a patient with polyarteritis nodosa

Hyperreninemic Hypertension Secondary to a Subcapsular Perinephric Hematoma in a Patient With Polyarteritis Nodosa Thomas J. Pintar, MD, and Stephen Zimmerman, MD ● Page kidney is the name ascribed to a rare syndrome of hyperreninemic hypertension caused by unilateral compressive perinephritis. Blood or fluid that accumulates in the perinephric subcapsular space compresses the renal parenchyma leading to ischemia. This syndrome is analogous to the description of cellophane-induced perinephritis by Page in 1939. Page kidney typically presents in healthy young men after blunt trauma to the flank or abdomen, although cases have been noted after medical or surgical interventions. We report a case of a Page kidney in a young man with hepatitis B virus–associated polyarteritis nodosa. The patient presented with severe hypertension, hypokalemia, hyperreninemia, and radiographic evidence of a unilateral subcapsular hematoma. Perinephric hemorrhage developed because of necrotizing vascular inflammation and spontaneous or traumatic vascular rupture. In patients who present with new-onset hypertension and hypokalemia with a history of trauma or coexisting vasculitis, the presence of a Page kidney should be considered. r 1998 by the National Kidney Foundation, Inc. INDEX WORDS: Page kidney; polyarteritis nodosa; secondary hypertension; hyperreninemia; renal trauma; perinephric hematoma; hypokalemia.

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OLYARTERITIS NODOSA (PAN) is a systemic necrotizing vasculitis that occurs in association with hepatitis B virus infection. Manifestations of PAN are often subtle, and it can be difficult to diagnose. Perirenal or subcapsular hemorrhage is a rare but well-known complication of PAN. We describe a patient who presented with a Page kidney: renovascular hypertension secondary to unilateral subcapsular perinephric hematoma. The cause of the Page kidney could be related to either spontaneous microaneurysmal rupture or a remote history of abdominal/flank trauma with aneurysm rupture. Therapy with angiotensin-converting enzymes (ACE) inhibitors, awaiting spontaneous resolution of the hematoma, and treatment for hepatitis B virus PAN led to improvement in the patient’s condition. New-onset hypertension or hypokalemia in patients with a recent or remote history of abdominal or flank trauma should prompt an evaluation for compressive perinephritis. CASE REPORT

A 25-year-old man presented to the emergency department with right-sided flank pain, fever, and headache. He complained of a gradual 12-kg weight loss, fatigue, migratory arthralgias, and testicular pain over the preceding 7 months. He also admitted to intravenous drug use (IVDU) and a motor vehicle accident 5 months earlier. Medical history was notable for a meningocele repair, depression, a prior suicide attempt, and tobacco and alcohol abuse. Medications included amitriptyline, buspirone, and ibuprofen. Physical examination showed an alert young man in acute distress. Temperature was 101.3°C; blood pressure, 198/106 mm Hg; and heart rate was 98 beats/min and regular. Skin, pulmonary, and neurological examination were normal. Car-

diac examination showed a dynamic precordium, regular rhythm, and a 2/6 midsystolic nonradiating murmur at the left sternal border. The abdomen was soft, nondistended, and remarkable for right costovertebral angle tenderness with a palpable right flank mass. Initial laboratory evaluation included a white blood cell count of 21.3 ⫻ 103/mm3 with normal differential. Hematocrit was 39.7%, and hemoglobin 14.2 g/dL. Electrolytes showed sodium, 133 mmol/L; potassium, 2.7 mmol/L; bicarbonate, 30 mmol/L; chloride, 91 mmol/L; blood urea nitrogen, 12 mg/dL; and creatinine, 1.2 mg/dL. Other laboratory tests were within normal limits, except albumin, 2.8 g/dL; total protein, 6.3 g/dL; and lactate dehydrogenase, 291 U/L. Urinalysis showed 2⫹ protein, 25 to 35 red blood cells high-power field (hpf) 3 to 5 white blood cells/hpf but nocasts. The patient was admitted for further evaluation of his fever, right flank pain, and hypertension. Blood and urine cultures were negative. An intravenous pyelogram showed no evidence of nephrolithiasis or obstruction. Abdominal ultrasound showed a right perinephric fluid collection and inflammatory changes consistent with severe pyelonephritis. Computed tomography (CT) scan of the abdomen showed a right subcapsular perinephric hematoma and evidence of bilateral striated cortical attenuation consistent with severe pyelonephritis versus embolic necrosis (Fig 1). To investigate whether bacterial endocarditis had contributed to the changes on CT scan, a transthoracic echocardiogram was done that showed no valvular vegetation or regurgitation.

From the University of Wisconsin Madison Hospital and Clinics, Madison, WI. Received December 5, 1997; accepted in revised form March 24, 1998. Address reprint requests to Thomas J. Pintar, MD, J5/230, University of Wisconsin Madison Hospital and Clinics, 600 Highland Ave, Madison, WI 53792. E-mail: tj.pintar@hosp. wisc.edu

r 1998 by the National Kidney Foundation, Inc. 0272-6386/98/3203-0022$3.00/0

American Journal of Kidney Diseases, Vol 32, No 3 (September), 1998: pp 503-507

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Fig 1. CT scan with contrast shows a large crescentshaped nonenhancing right subcapsular hematoma with parenchymal compression and displacement of the kidney posteriorly. Also, bilateral striated cortical attenuation is seen.

Studies investigating causes of secondary hypertension showed a supine aldosterone of 40.2 ng/dL and plasma renin activity of greater than 60 ng/mL/h. Selective renal vein renin analysis lateralized to the right kidney in a 1:1.5 ratio. Abdominal arteriography showed multiple microaneurysms in the right and left renal and hepatic arteries consistent with a systemic vasculitis (Fig 2). Subsequently, serologies for hepatitis B virus were found to be consistent with a recent infection (Table 1). The patient was diagnosed with acute hepatitis B virus infection associated with polyarteritis nodosa vasculitis. A concomitant right subcapsular hematoma and perinephritis contributed to the patient’s hyperreninemic hypertension. Treatment was initiated with ACE inhibition (ACEI) and beta-blockers for blood pressure control. Pulse methylprednisolone was administered for treatment of the vasculitis. Antiviral therapy with lamivudine was initiated as well, given the acute nature of the hepatitis B infection. Treatment for the vasculitis led to rapid resolution of pain and constitutional symptoms, and resolution of the subcapsular hematoma correlated with improvement in blood pressure control and normokalemia (Fig 3). At 10-month followup, the patient’s weight had increased 18 kg, and his blood pressure was 120/70 mm Hg on low-dose lisinopril and labetolol. Serum electrolytes and liver function were within normal limits. However, hepatitis B surface and e antigen remained positive without evidence of seroconversion, and thus low-dose prednisone and lamivudine treatment were continued.

Fig 2. Right renal digital subtraction arteriogram shows multiple aneurysms in the distal renal vasculature. The right subcapsular artery is displaced superiorly secondary to the presence of a large subcapsular hematoma.

gous to the arterial hypertension induced in dogs after unilateral renal encasement in cellophane.1 This original experiment was an attempt to halt the development of renal cortical collateral circulation. The use of cellophane was noted to contribute to an intense subcapsular proliferative reaction that induced arterial hypertension. Selective nephrectomy or bilateral adrenalectomy alleviated the hypertension completely. The earliest description of Page kidney in humans was in a young man with a posttraumatic subcapsular hematoma.2 Since then, numerous case reports have appeared3-8 with Page kidney typically developing in otherwise healthy young athletic men suffering blunt abdominal or flank trauma, Table 1. Hepatitis Panel

DISCUSSION

Page kidney is a rare, potentially reversible form of secondary hypertension. An encasing perinephric hematoma or perirenal fibrous capsule leads to a compressive perinephritis and renal cortical ischemia. This syndrome is analo-

Hepatitis BsAg Hepatitis BeAg Anti-HBc IgM Anti-HBs IgG Anti-HBc IgG Hep B viral DNA

Positive Positive Positive Negative Negative 540 pg/mL

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Fig 3. CT scan without contrast, 4-month follow-up examination, shows complete resolution in the large right subcapsular hematoma.

for example, American football, or motor vehicle accidents.6 Our patient presented with flank pain, fever, hypertension, and hypokalemia. Initially, pyelonephritis and nephrolithiasis were suspected; however, intraveneous pyelography and urine cultures were negative. The history of IVDU and a new heart murmur prompted evaluation for bacterial endocarditis; however, blood cultures and the echocardiogram were normal. The patient continued to be hypokalemic and hypertensive, prompting further studies including a CT scan that showed a large subcapsular hematoma. Hyperreninemia was confirmed, lateralizing to the affected organ, leading to the diagnosis of Page kidney. A unifying diagnosis of the patient’s underlying illness was made only after angiography showed microaneurysms in the renal and hepatic arterial system resulting in a diagnosis of PAN. PAN is a systemic panmural necrotizing vasculitis of unknown origin with manifestations occurring in multiple organ systems. Kussmaul and Maier26 first described this difficult-to-diagnose entity in 1866. The incidence of PAN has been estimated to be 0.7 to 6/100,000, occurring most commonly in middle-aged men.8 An association with hepatitis B virus infection is well documented in 7% to 36% of cases of PAN.15 This infection may trigger an immune-complex– induced mechanism for the vasculitis8,9,17-19 by impairing clearance or increasing the burden of

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hepatitis surface antigen.19 Clinical renal involvement occurs in 60% to 75% of patients, and hypertension is observed typically in 50%.9,11 Our patient fulfilled the clinical criteria for diagnosing PAN15 (Table 2), including weight loss greater than 4 kg, testicular pain, myalgia, hypertension, hepatitis B seropositivity, and microaneurysms on arteriography. The presence of three or more criteria has been shown to have a sensitivity of 82% and specificity of 86%.15 Perirenal and retroperitoneal hemorrhage occur in PAN either because of spontaneous arterial thrombosis or rupture of microaneurysms.9,10,13,16 This pathological picture is virtually diagnostic for PAN.9,10,13 One third of patients will have small vessel involvement only with glomerulonephritis and, often, a positive p-ANCA.8 PAN has been shown to be associated with a hyperreninemic state. Parenchymal ischemia either secondary to the arteritis and arterial occlusion,11,12 or JG cell hyperplasia in affected areas of renal parenchyma, lead to increased renin release.14 In our patient, the elevation in plasma renin activity confirmed his hyperreninemic state in the setting of PAN. Localizing the increase in renin to the affected kidney, however, gave credence to the diagnosis of Page kidney. To our knowledge, this is the first report of Page kidney syndrome caused by hepatitis B virus PAN. It is likely that the subcapsular hematoma developed as a result of spontaneous microaneurysmal rupture from the necrotizing arteritis, or possibly as a result of the patient’s motor vehicle accident 5 months earlier. PAN also has been described in patients with familial Mediterranean fever (FMF)—paroxysmal familial polyserositis.27-29 Interestingly, in the rare instance that patients with FMF develop PAN, a perirenal or subcapsuTable 2. 1990 ACR Criteria for the Classification of Polyarteritis Nodosa 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

Weight loss ⬎4 kg Livedo reticularis Testicular pain Myalgias, weakness, or polyneuropathy Mononeuropathy or polyneuropathy Diastolic BP ⬎90 mm Hg Elevated BUN or creatinine Hepatitis B virus positive Arteriographic abnormality Biopsy of small- or medium-sized artery containing PMNs

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lar hematoma is the presenting condition in greater than 50% of cases. The renal vascular hemorrhage occurs in the absence of amyloid deposition and has been speculated to be secondary to immune complex formation as a sequela of streptococcal infection,29 similar to the immunologic mechanism proposed in the development of hepatitis B PAN. The diagnosis of Page kidney depends on the presence of a surrounding renal hematoma, or a fibrous capsule encasing the kidney.2,6 Multiple imaging techniques, including ultrasound, CT scan, and magnetic resonance imaging (MRI) have all been shown to assist in this diagnosis.23-25 Ultrasound has the advantage of being minimally invasive, safe, and inexpensive but is limited in its resolution.23 Our patient had an ultrasound that showed a large nonspecific perirenal fluid collection. CT scan allows for improved resolution of the retroperitoneum, along with detection of a fibrous or calcified perinephric capsule.24 The use of MRI in diagnosing Page kidney has the added advantage of potentially determining the age of the hematoma and the state of the renal vasculature.25 In our patient, however, the angiogram provided a unifying diagnosis for the patient’s illness with the presence of multiple microaneurysms. Current therapeutic approaches for Page kidney are based on case reports and retrospective data. Because it is a rare form of secondary hypertension, no prospective data have been acquired. Most reports focus on the medical management of the hyperreninemic state with ACE inhibitors.6,7,11 Patience while waiting for spontaneous resolution of the hematoma, at times, has been successful therapy.6 However, depending on the cause of Page kidney and the presence of an organized fibrous capsule, percutaneous drainage, capsulotomy, and nephrectomy also have been used as treatment strategies for Page kidney.6 In cases of fibrous capsule formation, longstanding secondary hypertension may contribute to persistence of elevated blood pressure secondary to arteriolar damage in the nontraumatized kidney.5 In our patient, treatment with ACE inhibitors and beta-blockers resulted in excellent blood pressure control. Follow-up CT scan also showed complete resolution of subcapsular hematoma (Fig 3), yet hypertension continued to require treatment, suggesting that the duration of

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the initial insult could have led to permanent arteriolar damage. Treatment for PAN has encompassed highdose corticosteroids, immunosuppressive drugs, and plasma exchange.8,9,17-22 These agents have improved the survival rate from 10% in untreated patients to 82% in patients treated with corticosteroids and cyclophosphamide.8,17-19 The treatment of patients with hepatitis B virus– associated PAN is challenging. Conventional treatment with corticosteroids and immunosuppressive agents places the patient at risk for perpetuating the hepatitis B infection. These treatments enhance viral replication and favor development of a chronic hepatitis infection that increases the risk for cirrhosis and hepatocellular carcinoma.17-22 The use of plasma exchange to remove the circulating hepatitis B surface antigen has been shown to be useful in life-threatening PAN.19 Recently, the use of pulse immunosuppression and plasma exchange followed shortly thereafter by antiviral agents enhanced rates of HBeAg/anti-HBeAb seroconversion from a baseline of 12% to greater than 50%.17,19 The rapid taper of steroids is thought to induce a rebound immunologic clearance of hepatitis B virus (HBV)-infected hepatocytes and favor seroconversion to anti-eAb and anti-sAb. Seroconversion has been shown to be associated with resolution of polyarteritis vasculitis. Our patient received the antiviral drug lamivudine in addition to prednisone. The use of lamivudine in chronic hepatitis B has been shown to be well tolerated and able to reduce HBV DNA to undetectable levels.22 In a 10-month period, we have not yet noted seroconversion of the HBV. Most patients who seroconvert do so within the first several weeks, though late seroconversion of up to 1 year has been reported.17 Until this occurs, the patient continues to be at risk for recurrent PAN vasculitis, as well as progression to chronic hepatitis, cirrhosis, and hepatocellular carcinoma.17 SUMMARY

PAN in association with HBV infection presenting as a Page kidney to our knowledge has not been described. The cause of our patient’s unilateral perinephric hematoma could be related to either spontaneous microaneurysmal rupture or a remote history of abdominal/flank trauma with aneurysm rupture. Conservative medical

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therapy with ACE inhibitors, awaiting spontaneous resolution of the hematoma, and treatment for hepatitis B virus PAN led to improvement in the patient’s condition. The need for continued antihypertensive medications may reflect arteriolar damage induced in the nontraumatized kidney. Absence of hepatitis e antigen seroconversion in our patient despite antiviral treatment does increase the risk of relapse of PAN in addition to further sequelae from chronic hepatitis. Onset of new hypertension or hypokalemia in patients with a history of vasculitis and abdominal or flank trauma should prompt an evaluation for compressive perinephritis. ACKNOWLEDGMENT The authors thank Dr Bryan Becker for his thoughtful comments and suggestions during the preparation of this manuscript. In addition, the authors would like to acknowledge Dr Bennett Vogelman, who as internal medicine program director gave the gracious time, encouragement, and support necessary to complete this project during chief residency year.

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artery aneurysm in polyarteritis nodosa: Critical review of the literature and report of a case. Am J Med 87:464-467, 1989 14. Graham PC, Lindop GBM: The renin-secreting cell in polyarteritis: An immunohistochemical study. Histopathology 16:339-345, 1990 15. Lightfoot RW, Michael BA, Bloch DA, Hundar GG, Zvaifler NJ, McShane DJ, Arend WP, Calabrese LH, Leavitt RY, Lie JT, Masi AT, Mills JA, Stevens MB: The American College of Rheumatology 1990 Criteria for the classification of Polyarteritis Nodosa. Arthritis Rheum 33:1088-1093, 1990 16. Tocci PE, Lankford RW, Lynne CM: Spontaneous rupture of the kidney secondary to polyarteritis nodosa. J Urol 113:860-863, 1975 17. Guillevin L, Lhote F, Cohen P, Sauvaget F, Jarrousse B, Lortholary O, Noel LH, Trepo C: Polyarteritis nodosa related to hepatitis B virus: A prospective study with longterm observation of 41 patients. Medicine 74:238-253, 1995 18. Guillevin L, Lhote F, Gayraud M, Cohen P, Jarrousse B, Lortholary O, Thibult N: Prognostic factors in polyarteritis nodosa and Churg-Strauss syndrome: A prospective study in 342 patients. Medicine 75:17-28, 1996 19. Guillevin L, Lhote F, Leon A, Fauvelle F, Vivitski L, Trepo C: Treatment of polyarteritis nodosa related to hepatitis B virus with short term steroid therapy associated with antiviral agents and plasma exchanges: A prospective trial in 33 patients. J Rheumatol 20:289-298, 1993 20. Clemence D, Lortholary O, Cohen P, Brauner M, Guillevin L: Regressing microaneurysms in 5 cases of hepatitis B virus related polyarteritis nodosa. J Rheumatol 22:876-880, 1995 21. Simsek H, Telatar H: Successful treatment of hepatitis B virus-associated polyarteritis nodosa by interferon alpha alone. J Clin Gastroenterol 20:263-265, 1995 22. Dienstag JL, Perrillo RP, Schiff ER, Bartholomew M, Vicary C, Rubin M: A preliminary trial of lamivudine for chronic hepatitis B infection. N Engl J Med 25:1657-1661, 1995 23. Conrad MR, Freedman M, Weiner C, Freeman C, Sanders RC: Sonography of the Page kidney. J Urol 116:293296, 1976 24. Takahoshi M, Tamakawa Y, Shibata A, Fukushima Y: Computed tomography of the ‘‘Page kidney.’’ J Comput Assist Tomogr 1:344-348, 1977 25. Williams RD, Hricak H: Magnetic resonance imaging in urology. J Urol 132:641-649, 1984 26. Kussmaul A, Maier R: Ueber eine bisher nicht beshriebine eigenthumliche arterienerkrankung, die mit morbus brightii und rapid fortscheitender allgemeiner muskellahmungeinhergeht. Dtsch Arch Klin Med 1:483-518, 1866 27. Ozen S, Saatci U, Balkanci F, Besbas N, Bakkaloglu A, Tacal T: Familial Mediterranean fever and polyarteritis nodosa. Scand J Rheumatol 21:312-313, 1992 28. Schlesinger M, Oren S, Fano M, Viskoper JR: Perirenal and renal subcapsular haematoma as presenting symptoms of polyarteritis nodosa. Postgrad Med J 65:681-683, 1989 29. Glikson M, Galun E, Schlesinger M, Cohen D, Haskell L, Rubinow A, Eliakim M: Polyarteritis nodosa and familial Mediterranean fever: A report of 2 cases and review of the literature. J Rheum 16:536-539, 1989