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Jul 28, 2006 - uneventful pregnancy and she had no history of hypertension (blood pressure was 120/66 mmHg. 2 weeks before admission). Upon admission ...

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Adverse outcomes of renovascular hypertension during pregnancy Bjorg Thorsteinsdottir, Garvan C Kane, Michael J Hogan, William J Watson, Joseph P Grande and Vesna D Garovic* S U M M A RY Background A 26-year-old primigravida, with no history of hypertension,

presented at 20 weeks of gestation with severe pre-eclampsia. A pelvic ultrasound revealed intrauterine fetal death, probably caused by placental abruption. The pregnancy was terminated by induction with oxytocin, followed by a vaginal breech delivery. The patient remained hypertensive for 8 weeks after delivery. Investigations Physical examination, laboratory investigation, renal angiogram and renal-vein renin sampling. Diagnosis An atrophic right kidney secondary to an occluded right renal artery, probably caused by dissected fibromuscular dysplasia; a contralateral high-grade stenosis secondary to fibromuscular dysplasia. Management Right nephrectomy and angioplasty of the left renal artery. KEYWORDS hypertension, pre-eclampsia, pregnancy outcomes, renal artery stenosis, renovascular hypertension

CME

B Thorsteinsdottir is a senior associate consultant in Community Internal Medicine, Mayo Clinic, and Instructor in Medicine, Mayo Medical School, Rochester, MN, USA. GC Kane is a fellow in Cardiovascular Diseases at Mayo Clinic and Instructor in Medicine, Mayo Medical School, Rochester, MN, USA. MJ Hogan is an attending physician in Regional International Medicine and Program Director for Clinical Reviews at Mayo Clinic, Scottsdale, AZ, USA. WJ Watson is Chief of the Division of Maternal and Fetal Medicine, Mayo Clinic and Professor in Obstetrics and Gynecology, Mayo Medical School, Rochester, MN, USA. JP Grande is Professor in Laboratory Medicine and Pathology and Associate Dean for Academic Affairs, Mayo Medical School, Rochester, MN, USA. VD Garovic is an attending physician in Nephrology and Hypertension at Mayo Clinic and Assistant Professor of Medicine, Mayo Medical School, Rochester, MN, USA. Correspondence *Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA [email protected] Received 16 April 2006 Accepted 28 July 2006 www.nature.com/clinicalpractice doi:10.1038/ncpneph0310

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This article offers the opportunity to earn one Category 1 credit toward the AMA Physician’s Recognition Award. THE CASE

A 26-year-old primigravida was transferred to our institution at 20 weeks of gestation for an emergency delivery following placental abruption and intrauterine fetal demise. The vaginal bleeding had prompted admission to another hospital 4 days earlier. She had had an otherwise uneventful pregnancy and she had no history of hypertension (blood pressure was 120/66 mmHg 2 weeks before admission). Upon admission, her blood pressure was 207/104 mmHg and her predicted 24 h protein excretion, as determined by the protein-to-osmolality ratio in a random urine specimen, was 1.1 g. Her kidney function was normal with a blood urea nitrogen (BUN) level of 7.85 mmol/l and a serum creatinine concentration of 70.72 μmol/l (0.8 mg/dl). Laboratory evaluation revealed a decreased hemoglobin concentration (106 g/l), low platelet count (79 × 109/l), and an elevated serum aspartate aminotransferase level, which peaked at 79 U/l. Clinical and laboratory findings were consistent with severe pre-eclampsia and possibly HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count). The patient received two doses of 5 mg hydralazine hydrochloride intravenously. Oxytocin was given as a continuous infusion, and the dose varied from 2 U/h to 10 U/ h over the course of 8 h, which resulted in the breech delivery of a 260 g stillborn male infant. Her predicted 24 h protein excretion decreased to 369 mg within the first week after delivery, but she remained hypertensive, with systolic blood pressures ranging between 130 mmHg and 170 mmHg, and was treated with labetalol hydrochloride, 200 mg twice daily. Six weeks postpartum, the patient’s hypertension persisted and her blood pressure regimen was changed to amlodipine 5 mg twice daily, atenolol 50 mg once daily, and doxazosin 2 mg daily. Physical examination revealed a

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A

B

C

Figure 1 Renal arteriograms with contrast showing (A) occluded right renal artery, (B) fibromuscular dysplasia of the middle left renal artery and (C) successful treatment with angioplasty.

Figure 2 Histology of the surgically removed right kidney showing: ischemic wrinkling and thickening of the glomerular basement membrane with mild mesangial matrix expansion (white arrow); thickening of the tubular basement membranes (black arrow) with patchy lymphocytic interstitial infiltrate. Hematoxylin and eosin stain; original magnification ×100.

continuous systolic–diastolic bruit in the periumbilical area. Despite the three-drug regimen, her hypertension was inadequately controlled, with systolic pressures of 174–190 mmHg and diastolic pressures of 94–106 mmHg. Renal artery stenosis was suspected. A renal angiogram showed an occluded right renal artery with an atrophic right kidney (Figure 1A), measuring approximately 7 cm along its length; the left kidney measured 11.2 cm along its length, with evidence of fibromuscular dysplasia in the midportion of the left renal artery (Figure 1B). Renal-vein renin measurements1 showed a right renal-vein renin activity of 545.10 pmol/l/h versus a left renal-vein renin activity of 35.55 pmol/l/h with a ratio of 15.3, lateralizing

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to the right, atrophic kidney. The right kidney was removed surgically. Histological findings were consistent with ischemic nephropathy (Figure 2). The patient tolerated the procedure well and her blood pressure improved, averaging 130/80 mmHg on the same three-drug regimen. Two months later, she underwent a left renal artery angioplasty (Figure 1C), after which her blood pressure normalized without medication and her 24 h urine collection showed no significant proteinuria (54 mg/24 h). One year later, the patient remained normotensive and delivered a healthy infant after an uneventful pregnancy. DISCUSSION OF DIAGNOSIS Initial diagnosis

Pre-eclampsia is a pregnancy-specific disorder, clinically characterized by hypertension (blood pressure ≥140/90 mmHg) and proteinuria (≥300 mg in a 24 h urine collection).2 The condition affects both women who were normotensive before their pregnancies (‘pure’ pre-eclampsia) and those with a history of chronic hypertension, defined as a blood pressure ≥140/90 mmHg before pregnancy or before the 20th week of gestation. Chronic hypertension can also occur for the first time during pregnancy. In these women, hypertension develops for the first time during the second half of pregnancy as gestational hypertension; subsequent failure of blood pressure to normalize by 12 weeks postpartum leads to the diagnosis of chronic hypertension. Compared with normotensive pregnant women, the risk of developing pre-eclampsia is significantly higher in women with a history of chronic hypertension, affecting 25% of these patients (superimposed pre-eclampsia).3 Chronic hypertension is most commonly

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‘essential’ in origin, although up to 5% of these patients may have secondary forms (i.e. hypertension with identifiable underlying causes).4 As ‘pure’ pre-eclampsia typically occurs later in pregnancy—often well into the third trimester— a diagnosis of secondary hypertension needs to be considered in women who develop severe forms of pre-eclampsia in the second trimester. Renovascular hypertension is a form of secondary hypertension that occurs as a result of critical narrowing of the renal arteries, most commonly caused by atherosclerotic disease or fibromuscular dysplasia. Narrowing of the renal arteries leads to renal hypoperfusion and activation of the renin–angiotensin–aldosterone system, which has a central role in the development of hypertension. Renal artery stenosis secondary to fibromuscular dysplasia commonly affects women of childbearing age and thus remains an important consideration as a cause of secondary hypertension during pregnancy. The prevalence of renovascular hypertension in women of childbearing age has not been determined, however. Published data are limited to case reports and small series with total numbers of patients not exceeding 30; nevertheless, the data do indicate that among patients with chronic hypertension, those with renovascular hypertension might be at an even higher risk of earlier and more-severe pre-eclampsia than those with essential hypertension.5 The patient in this case presented with severe early pre-eclampsia, but did not have a history of hypertension before pregnancy. Her blood pressure failed to normalize after delivery, leading to the diagnosis of chronic hypertension. The failure of three antihypertensive drugs to control her blood pressure, and the loud abdominal bruit, indicated a possible diagnosis of renovascular hypertension. Clinical features of renovascular hypertension in pregnancy In hemodynamic studies of several hundred hypertensive pregnant patients, a patient with known renal artery stenosis had the highest elevation of peripheral vascular resistance, exceeding even the resistances measured in two patients with pheochromocytoma.6 Conceivably, significant fluid retention in the third trimester, which occurs in the setting of elevated peripheral vascular resistance, might exacerbate hypertension and related complications as the pregnancy approaches full term.

The patient presented here developed severe pre-eclampsia early in pregnancy; the preeclampsia was further complicated by placental abruption and intrauterine fetal demise. The severity of her hypertension and the physical findings indicated renovascular hypertension, prompting further diagnostic studies. Given our patient’s high pre-test probability for renal artery stenosis, we decided to proceed directly to angiography. We reasoned that results of a noninvasive test (such as captopril renography, duplex sonography, magnetic resonance angiography or computed tomographic angiography) would not change our decision, and that we would have pursued an angiogram irrespective of the results of noninvasive testing. An angiogram revealed bilateral renal artery stenosis secondary to fibromuscular dysplasia, with complete occlusion of the right artery, resulting in right kidney atrophy, and a high-grade left renal artery stenosis. Careful review of published case series and case reports and the experience at our institution (Table 1) revealed that those with unrecognized renal artery stenosis typically present with either accelerated hypertension or early and/or severe pre-eclampsia (Table 2). As in previous reports, our case series indicates that women with renovascular hypertension are at particularly high risk of fetal and maternal complications. Two women experienced second-trimester pregnancy losses secondary to intrauterine fetal demise, and one pregnancy was electively terminated because of possible teratogenic fetal effects after exposure to radiation and contrast during a renal angiogram performed early in pregnancy. One woman underwent early induction because of severe pre-eclampsia, and only one carried her pregnancy to full term while on antihypertensive medications. Because of the retrospective character of our study, a selection bias might exist for patients with severe hypertension in whom particularly poor pregnancy outcomes led to further investigations and correct diagnoses. Conceivably, a significant proportion of patients with renovascular hypertension might have their blood pressure controlled effectively using medications and they might do fairly well throughout pregnancy.6 We were unable to identify any prospective studies examining the prevalence, natural course, and prognosis of renal artery stenosis in pregnant patients, however.

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Table 1 Case series of clinical presentations and pregnancy outcomes in patients with renovascular hypertension.a Patient

Presentation

Pregnancy outcome

Renal angiogram

Treatment

Subsequent pregnancies

Index case

Severe pre-eclampsia, placental abruption at gestational week 20

Labor induction for intrauterine fetal demise

Revealed occluded right renal artery, and fibromuscular dysplasia of left renal artery

Nephrectomy of the atrophic right kidney and left renal artery angioplasty

One normotensive, uneventful pregnancy

#1

Hypertensive crisis at gestational week 5; abdominal bruit

Elective abortion after renal angiogram

Revealed bilateral fibromuscular dysplasia at gestational week 6

Bilateral angioplasty resulting in cure of hypertension

Two normal, fullterm pregnancies

#2

Severe hypertension at gestational week 23

Hospitalized at gestational week 23 for blood-pressure control; carried to full term

Performed 4 years after delivery because of resistant hypertension; revealed right fibromuscular dysplasia

Medical therapy

None

#3

Pre-eclampsia with second pregnancy; blood pressure failed to normalize postpartum

Early induction at gestational week 36

Performed 9 years after delivery because of resistant hypertension; revealed right fibromuscular dysplasia

Angioplasty with improved bloodpressure control

None

#4

Chronic hypertension after pre-eclampsia with third pregnancy; presented with hypertensive urgency at gestational week 17 of her fourth pregnancy

Intrauterine fetal demise

Revealed bilateral fibromuscular dysplasia 2 months after delivery

Bilateral angioplasty with cure of hypertension

None

aRetrospective

review of all women of childbearing age diagnosed with hypertension and renal artery stenosis at Mayo Clinic, Rochester from 1986–2005; approved by the Institutional Review Board.

DISCUSSION OF TREATMENT Before conception or after an unsuccessful pregnancy

The introduction of angiotensin-convertingenzyme (ACE) inhibitors and angiotensin II receptor blockers has resulted in marked improvement in blood-pressure control in patients with renovascular hypertension. Special attention should be given to women of childbearing age who have been treated with these antihypertensive medications prior to conception. Both ACE inhibitors and angiotensin II receptor blockers are contraindicated during pregnancy and are therefore commonly discontinued during prepregnancy counseling. Difficulty in controlling blood pressure with alternative regimens should raise suspicion of and prompt evaluation for renovascular causes. Once the diagnosis is confirmed, and if revascularization is considered, conventional percutaneous contrast angiography with angioplasty remains the gold standard for treatment of fibromuscular dysplasia. In young patients with such a diagnosis who typically present with hypertension of a short duration, successful revascularization might be curative.7 In fibromuscular dysplasia, progression to total occlusion might occur, although it is

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relatively uncommon. In our series of 74 patients (43 females, 31 males, mean age 65 years) who underwent nephrectomy of an atrophic kidney for uncontrolled hypertension, 8 patients (11%) had fibromuscular dysplasia.8 Preoperative assessment of the whole cohort indicated a significant decrease in size of the affected kidney (mean length 8.1 cm) and poor function, with an average contribution of only 12% to overall renal function, as assessed by nuclear renogram. After nephrectomy, blood-pressure control improved in 58 of these patients (79%), with improvement defined either as a cure (n = 10) or as a reduction in mean arterial pressure of >10 mmHg while taking fewer antihypertensive medications (n = 48). There was no significant change in glomerular filtration rate from pre-nephrectomy to a 1-year follow-up visit (mean change 0.2 ml/min). Our results indicate that in selected patients with resistant hypertension and renal artery disease, nephrectomy of a small, poorly functioning kidney can improve blood-pressure control without further loss of renal function. In the patient presented in this case, renal-vein renin measurements lateralized to the right kidney, which, not amenable to revascularization because of advanced atrophy, was removed surgically.

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Table 2 Clinical presentations of renovascular hypertension during pregnancy. Clinical presentation

References

Examples of cases (see Table 1)

Severe hypertension and pre-eclampsia early in pregnancy (i.e. during the first or second trimester) in previously normotensive women

Easterling et al. (1991)6 Pollock et al. (1990)14 Cohen et al. (2005)15

Index case and cases #1 and #2

Pre-eclampsia in previously normotensive women with failure of blood pressure to normalize after delivery, especially in patients with clinical signs and symptoms suggestive of renovascular hypertension19

Wylie et al. (1960)18

Case #3

Accelerated hypertension or early and/or severe superimposed pre-eclampsia in women with prior history of chronic hypertension

Hennessy et al. (1997)5 Heyborne et al. (1991)11 Le et al. (1995)12 Landesman et al. (1961)19

Case #4

Recurrent pre-eclampsia

Koskela and Kaski (1971)20



Of note, lateralizing renins, as manifested by a ratio of ≥1.5, are considered diagnostic for hemodynamically significant renal artery stenosis and predictive of surgical curability.1 Initial improvement in blood-pressure control after nephrectomy was followed by successful revascularization of the contralateral kidney and subsequent cure of hypertension. While the literature clearly documents poor pregnancy outcomes in women with renovascular hypertension, only two studies have reported pregnancy outcomes after repair of renal artery stenosis. Sellars et al. reported four patients with renovascular hypertension, two of whom had had unsuccessful pregnancies before intervention for renal artery stenosis. After successful revascularization, the four women had four uncomplicated pregnancies and two pregnancies with mild gestational hypertension between them.9 Another study reported the case of a woman who underwent nephrectomy for advanced fibromuscular dysplasia but had a subsequent pregnancy resulting in stillborn twins; the still births were unrelated to hypertension, however, as she remained normotensive throughout her pregnancy and delivery.10 In the patient presented here, and in patient #1 from our case series (Table 1), normalization of blood pressure after interventions were followed by uncomplicated pregnancies and deliveries of healthy infants. During pregnancy

Medical treatment of hypertension during pregnancy remains a therapeutic challenge. It is frequently suboptimal, as ACE inhibitors and angiotensin II receptor blockers are

contraindicated. Isolated case reports have addressed the use of renal angiograms and revascularization for the diagnosis and treatment of renovascular hypertension during pregnancy, for accelerated hypertension refractory to drug therapy.6,11–15 By limiting the radiation exposure to less than 5 rad (i.e. 50 mGy), the probability of deleterious fetal effects is small16 and outweighed by the benefit of improved bloodpressure control, which allows the pregnancy to be carried closer to term and reduces the morbidity and mortality associated with preterm deliveries. With respect to surgical revascularization, it is important to recognize that bypass techniques that involve cross-clamping of the aorta are contraindicated in pregnancy.11 CONCLUSION

Given the reported severity of complications of renovascular hypertension in pregnancy, it seems justified to exclude renovascular disease in young hypertensive women before conception, especially in those with clinical features suggestive of secondary hypertension.17 This condition should also be considered in patients who present with accelerated hypertension or severe pre-eclampsia, particularly if it occurs early in pregnancy or if there is a history of two or more affected pregnancies. Nephrectomy of a small, poorly functioning kidney and/or revascularization after an unsuccessful pregnancy can improve both maternal and fetal outcomes in subsequent pregnancies. Based on a few published reports, revascularization can be performed safely even during pregnancy, assuming that appropriate shielding is implemented and the dose of radiation is limited to less than 5 rad.

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Competing interests The authors declared they have no competing interests.

References 1 Rudnick MR and Maxwell MH (1984) Limitations of renin assays. In Controversies in Nephrology and Hypertension, 123–160 (Ed. Narins RG) New York: Churchill Livingstone 2 [No authors listed] (2000) Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. Am J Obstet Gynecol 183: S1–S22 3 Sibai BM et al. (1998) Risk factors for preeclampsia, abruptio placentae, and adverse neonatal outcomes among women with chronic hypertension. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Engl J Med 339: 667–671 4 Garg JP et al. (2005) Resistant hypertension revisited: a comparison of two university-based cohorts. Am J Hypertens 18: 619–626 5 Hennessy A et al. (1997) Renovascular hypertension in pregnancy: Increased incidence of severe preeclampsia. J Am Soc Nephrol 8: 316A 6 Easterling TR et al. (1991) Renal vascular hypertension during pregnancy. Obstet Gynecol 78: 921–925 7 Bonelli FS et al. (1995) Renal artery angioplasty: technical results and clinical outcome in 320 patients. Mayo Clin Proc 70: 1041–1052 8 Kane GC et al. (2003) Revisiting the role of nephrectomy for advanced renovascular disease. Am J Med 114: 729–735 9 Sellars L et al. (1985) Prognosis for pregnancy after correction of renovascular hypertension. Nephron 39: 280–281 10 Hotchkiss RL et al. (1971) Renovascular hypertension in pregnancy. South Med J 64: 1256–1258

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11 Heyborne KD et al. (1991) Renal artery stenosis during pregnancy: a review. Obstet Gynecol Surv 46: 509–514 12 Le TT et al. (1995) Endovascular stent placement and magnetic resonance angiography for management of hypertension and renal artery occlusion during pregnancy. Obstet Gynecol 85: 822–825 13 McCarron DA et al. (1982) Transluminal angioplasty for renovascular hypertension complicated by pregnancy. Arch Int Med 142: 1737–1739 14 Pollock CA et al. (1990) Hypertension due to renal artery stenosis in pregnancy—the use of angioplasty. Aust NZ J Obstet Gynaecol 30: 265–268 15 Cohen DL et al. (2005) Renal artery stenosis due to fibromuscular dysplasia in an 18-week pregnant woman. Obstet Gynecol 105: 1232–1235 16 ACOG Committee on Obstetric Practice (2004) ACOG Committee Opinion: guidelines for diagnostic imaging during pregnancy. Number 299, September 2004 (replaces No. 158, September 1995). Obstet Gynecol 104: 647–651 17 Garovic VD et al. (2005) Renovascular hypertension: balancing the controversies in diagnosis and treatment. Cleve Clin J Med 72: 1135–1144 18 Wylie EJ et al. (1960) Hypertension caused by fibromuscular hyperplasia of the renal arteries. Am J Surg 100: 183–193 19 Landesman R et al. (1961) Renal artery lesions associated with the toxemias of pregnancy. Obstet Gynecol 18: 645–652 20 Koskela O and Kaski P (1971) Renal angiography in the follow-up examination of toxaemia of late pregnancy. Acta Obstet Gynecol Scand 50: 41–43

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