This alone is not necessarily an indication for speci \201 c therapy other than increased \202 uid intake and salt restric- tion. The risk of further stone formation in hypercalci u- ric children is low. In those with a signi \201 cantly damaged kidneys, or recur- rent symptoms or stones, consider \201 rstly potassium cit- rate, and then a thiazide diuretic . This page intentionally left blank 285 Chapter 9 Hypertension Chapter Contents Clinical approach to hypertension 286 Renovascular disease 292 Malignant hypertension 300 H ypertensive children 304 Hypertensive disorders in pregnancy 310 A. STANLEY 286 Clinical approach to hypertension Introduction Hypertension (HTN) is one of the most common condi- tions encountered in medic al practice. For the majority of patients, the etiology is unknown and the treatment is str aightforward. This chapter provides an overview of the clinical assessment of a hypertensiv e patient with particu- lar reference to the less common etiologies, its complica- tions an d initial treatment options. Renovascular HTN is a relatively uncommon cause of HTN (<1% of newly diagnosed patients) an d can present as \201 bromuscular dysplasia in the young or atherosclerotic renal artery stenosis in older people. Endocrine disease This is the cause of HTN in 5% of cases. Hyperaldosteronism (e.g. Conn \200\231s syndrome, adrenal hyperplasia) accounts for the majority of cases. The combined o ral contraceptive pill increases BP by an average of 5/3 mmHg; in 1% of women, severe HTN may be seen. De \201 nition British, European and WHO guidelines de \201 ne the catego- ries of HTN ba sed on clinic blood pressure (BP): Blood pressure Other causes Other causes are rare and combined account for 1% of all HTN. Single gene dis orders affecting renal tubular function are very rare and usually present in childhood. Pre gnancy-induced HTN affects 8 \200\22310% of pregnancies and pre-eclampsia affects a further 8% of pregnancies. Blood pressure returns to normal in most women with pregnancy-related H TN after 3 \200\2236 months, but is a risk factor for the development of HTN later in the w oman \200\231s life. Optimum: Normal: High \200\223normal: <120/80 mmHg <130/85 mmHg 130 \200\223139/85 \200\22389 mmHg. Hypertension Mild (grade 1): Moderate (grade 2): Severe (grade 3): 140 \200\223159/90 \200\22399 mmHg 160 \200\223179/100 \200\223109 mmHg >180/110 mmHg. Isolated systolic hypertension Grade 1: Grade 2: 140 \200\223159/<90 mmHg >160/<90 mmHg. Assessment of the patient History Hypertension is often asymptomatic, hence its description as the \200\230silent killer \200\231. The history from a hypertensive patient should: \200 \200 \200 Epidemiology The prevalence of HTN increases with age. Data from the Health Survey for Engl and 1998 revealed 72% of men and 68% of women aged >75 years had HTN (de \201 ned by a BP >140/90 mmHg). This compares to 17% and 4% in men and women aged 16 \200\22324 years respec tively. However, the number of patients prescribed treatment for HTN is much less. Data fro m primary care (Key Health Statistics from General Practice 1998) revealed that <2.5% of pa tients aged under 35 years (men: 1.7%; women: 2.4%) and <30% of patients aged \211 85 year s (men: 20.1%; women: 29.1%) were taking antihypertensive drugs. It is not known whether th ese patients were treated to target BP. attempt to establish an etiology; identify complications/end organ damage; put the HTN into the context of overall cardiovascular risk. Baseline features to assess: \200 \200 \200 duration of HTN and BP values; treatment history and concordance with treatment; any advers e drug reactions. Establishing an etiology A family history of HTN. In women a history of pregnancy-related H TN. A history of any recent \200\230over the counter \200\231 and/or prescribed drug thera py: \200 NSAIDS; \200 combined oral contraceptives; \200 corticosteroids; \200 symp athomimetics. Etiology The cause of HTN in the vast majority of cases, even in young people, is not clear . About 90% of people with newly diagnosed HTN are given the diagnosis \200\230primary \200\231 (or \200\230essential \200\231) HTN and the etiol- ogy is likely to re \202 ect a multifactorial genetic predisposi- tion and/or lifestyle factors such as obesity and poor diet. Secondary HTN accounts for the remaining 10% of cases and the causes are listed in T able 9.1.1. A history of renal or urological disease. A pheochromocytoma might be suggested by: \200 \200 \200 \200 episodic palpitations; sweating; chest pain; paroxysmal HTN. Renal disease This is the cause of HTN in 5% of newly diagnosed hyper- tensive subjects. D iabetic renal disease accounts for the majority of cases and this is increasing both in ter ms of absolute numbers and as a proportion of all CKD. Identifying complications/end-organ damage Common complications to speci \201 cally enquir e about: \200 \200 ischemic heart disease; heart failure; CHAPTER 9.1 Clinical approach to hypertension 287 At the initial assessment, the BP should be measured three times, a minute between each rea ding, and in both arms. The BP for each arm should be recorded as the average of the 2nd an d 3rd readings. A standing BP should be recorded in: \200 \200 \200 \200 Table 9.1.1 Causes of secondary hypertension Renal Diabetic renal disease Chronic pyelonephritis Renovascular hypertension Obstructive n ephropathy Renal parenchymal disease Renin-secreting tumors patients with a history of postural hypotension; the elderly; those at risk of autonomic dy sfunction (e.g. diabetics); those taking multiple antihypertensive drugs. Endocrine Mineralocorticoid hypertension Physical examination A full examination with particular reference to the heart and circulat ory system should always be undertaken. The general appearance of the patient may give clue s towards an endocrine diagnosis such as acromegaly or Cushing \200\231s disease. Signs of tar staining on the hands, obesity or hyperlipidemia (e.g. corneal arcus, xanthelasma) woul d suggest additional cardiovascular risk. Radio-femoral delay or weak peripheral pulses may sug- gest a coarctation of the aorta. A palpable kidney would raise the suspicion of hydro neph- rosis or polycystic kidney disease. Abdominal (renal) bruits are rarely heard in pati ents with renovascular disease, but their presence is highly indicative. Complications of H TN may be evident from signs of heart failure, peripheral vascular disease (femoral or caro tid bruits) or a neurological de \201 cit. Conn \200\231s syndrome Bilateral/(unilateral) adrenal hyperplasia Glucocorticoid-remediabl e aldosteronism Adrenal carcinoma Deoxycorticosterone excess Congenital adrenal hyperplasia 11B-Hydroxylase de \201 ciency 17B-Hydroxylase de \201 cie ncy Glucocorticoid receptor resistance Cortisol excess Cushing \200\231s syndrome 11B-Hydroxysteroid dehydrogenase de \201 ciency Apparent mineralocorticoid excess Glycyrrhetinic acid (licorice) Pheochromocytoma Oral contraceptive and estrogen replacement Hypothyroidism/hyperthyroidism Acromegaly Hyperparathyroidism/hypercalcemia Carcinoid Fundoscopy Fundoscopy is useful in assessing for end-organ damage. Type 2 hypertensive reti nopathy (copper wiring, arteriov- enous nipping) is very common in middle-aged/elderly pati ents with longstanding HTN. Patients with recently elevated severe high BP and type 3 hyper tensive retinopathy (hard exudates, \202 ame-shaped hemorrhages), and all patients with t ype 4 hypertensive retinopathy (type 3 abnormalities and papilloedema) are, by de \201 nit ion, hypertensive urgencies and require immedi- ate treatment. Conversely, normal fundoscop y in a patient with a long- standing history of high BP readings would cast doubt on the di agnosis of severe HTN, suggesting an alternative diagnosis of \200\230white-coat HTN \200 \231. Genetic diseases of renal tubular function Liddle \200\231s syndrome Gordon \200\231s syndr ome Gain of function mutation of the mineralocorticoid receptor Other Coarctation of the aorta Neurologic disorder Psychogenic Sleep apnea Drug-induced (e. g. cocaine) Pregnancy \200 \200 cerebrovascular disease; peripheral vascular disease; renal impairment. Initial investigation Routine investigations in the initial evaluation of a patient will HT N must include: \200 \200 \200 \200 \200 Assessing overall cardiovascular risk: \200 \200 \200 \200 \200 \200 \200 urinalysis for protein and blood; serum electrolytes; serum creatinine providing an estimat ed GFR; fasting blood glucose and lipid pro \201 le; electrocardiogram. obesity; high salt intake; excess alcohol; lack of exercise; diabetes mellitus; hyperlipide mia; smoking. Renal disease may be identi \201 ed by a reduced eGFR and/or abnormal urinalysis. The pres ence of hematuria without other evidence of renal dysfunction should be con \201 rmed by m icroscopy and investigated for disease of the bladder and urinary system. Hypokalemia may b e a pointer towards hyperaldos- teronism (even without hypernatremia). A previous history o f diuretic-induced hypokalemia should not be ignored. Examination Apart from elevated BP readings, the clinical examination may be normal. Measurement of blood pressure BP should be measured after the patient has been seated for 5 min. A. STANLEY 288 Even in the same population, the target BP may be lower than the threshold BP. Thiazide diuretic-induced hypokalemia in patients with hyperaldosteronism can be severe. Hy pokalemia may be seen in renovascular disease. Other investigations such as thyroid and liv er function tests should be taken as clinically indicated. In those patients with ECG evide nce of increased ventricu- lar voltages, echocardiography is advised to con \201 rm (or re fute) the presence of left ventricular hypertrophy. Thresholds for treatment Antihypertensive drug treatment should be initiated in patients wi th: \200 \200 sustained systolic BP \211 160 mmHg; or diastolic BP \211 100 mmHg. A lower threshold exists for patients with: \200 \200 \200 \200 diabetes; an elevated 10 year CVD risk (>20%); end-organ damage; cardiovascular complicatio ns of HTN. Cardiovascular risk assessment Hypertension is one of several factors that can be used to c alculate an individual \200\231s cardiovascular disease (CVD) risk. Risk can be calculated using: \200 \200 \200 \200 For these patients treatment should be initiated for: \200 \200 age; smoking history; pretreatment BP; lipid pro \201 le (total cholesterol:HDL-cholestero l ratio). The Cardiovascular Risk Prediction Charts published in the British National Formu lary provide an easy reference guide. These charts are designed to support clinical decisio ns about the use of antihypertensive, antiplatelet and lipid- lowering therapy in primary p revention. Diabetes mellitus is no longer included in the risk calcula- tion \200\223 all patients with diabetes should be offered primary prevention. sustained systolic BP 140 \200\223159 mmHg; or sustained diastolic BP 90 \200\22399 mmHg. For patients with established CKD and/or proteinuria, the threshold for treatment is identi cal for those with diabetes or target-organ damage. Target blood pressure The usual recommended BP target is \211 140/90 mmHg. For patients wi th established cardiovascular disease and/or diabetes, a lower target of \211 130/80 mmHg is advised. For patients with CKD, a BP target of \211 130/80 mmHg is recommended. For pat ients with proteinuria (>1 g /24 h), a more stringent target of \211 125/75 mmHg is advise d. The concept of a lower BP target than those currently rec- ommended for patients with CK D has yet to be proven in clinical trials. Measurement of BP outside the clinic Investigator-led clinical studies that have generated the evi- dence for BP targets and thresholds have almost exclu- sively used clinic BP readi ngs. About 30% of hypertensive subjects have \200\230white-coat HTN \200\231 or a pronounc ed \200\230white-coat effect \200\231 at the time of BP measurement that prevents a reliab le estimation of BP for these individuals. Home BP monitoring can reduce this \200\230whit e-coat effect \200\231. Ambulatory 24 h BP monitoring allows frequent BP measurements to be made automatically at intervals of 20 \200\22330 min throughout the day and night. The pat ient wears a small device around their waist which is connected to a BP cuff. Self-monitori ng of home BP readings is easy with the use of digital BP monitors. Home BP readings should be taken for a \201 xed period of time (e.g. 5 \200\2237 days) and patients should recor d their BP three times after being seated for 5 min. The average BP is calculated taking th e mean of the 2nd and 3rd readings at each sitting, excluding the \201 rst day \200\231s readings. Patients should be advised to use BP monitors that have been validated by the Bri tish Hypertension Society. Upper arm devices are recommended in preference to wrist monitor s. Treatment The effective management of HTN continues to lag behind guidelines from clinical trial data. Although the \200\230rule of halves \200\231 (half of patients with HTN are di agnosed, of whom half are treated, and of those, half are treated to target) is no longer a pplicable, many patients with HTN remain undertreated. Aged \211 55 years or black patient of any age Aged <55 years Step 1 A C or D Step 2 A + C or D Step 3 A + C + D Blood pressure thresholds and targets The decision to treat high BP with drug therapy is us ually determined when the BP rises above a set threshold. Once treatment is indicated, drug therapy is initiated and escalated until the BP falls below a de \201 ned target. Thresho lds and target BPs differ between different patient populations. Add: -blockers, -blockers, loop diuretics or spironolactone Step 4 Fig. 9.1.1 \200\230ACD rule \200\231 for the treatment of newly diagnosed hypertension. A: angiotensin-converting enzyme inhibitor (or ARB). C: calcium channel blocker. D: thiazide diuretic. (Adapted from the British Hypertension Society and NICE.) CHAPTER 9.1 Clinical approach to hypertension 289 For some patients, there are overriding factors that may in \202 uence the initial prescri ption of antihypertensive therapy. For example, B-blockers are \201 rst-line therapy for patients with angina and there is good clinical evidence for the early prescription of ACEI (or ARB) in patients with diabetes. In many proteinuric renal diseases ACEIs (or ARBs) are considered \201 rst-line therapy as they afford renal protec- tion in addition to BP red uction. A slight fall in GFR should be expected (<15% fall in GFR requires no further inves tigation) on commencement of ACEI and ARB and this is not a reason to stop treatment. Treat ment with ACEI should be up titrated to the maxi- mum tolerated dose and if signi \201 can t proteinuria remains (>1 g/24 h), combination ACEI \200\223ARB therapy should be considere d. BP targets for patients with CKD are lower than other patient groups and additive therap y can be based on the \200\230ACD \200\231 rule. An underlying diagnosis of renovascular d isease is a rela- tive contraindication to ACEI and ARB as these drugs preferentially dilat e the efferent renal arterioles and can cause a profound reduction in glomerular BP and lea d to AKI. Nonpharmacological treatment All patients with raised BP should be advised about appro- pri ate lifestyle regimens that could reduce their BP and/or reduce their cardiovascular risk. There is robust evidence that lifestyle modi \201 cations can signi \201 cantly reduce BP including: \200 \200 \200 \200 \200 maintaining an ideal body weight; dietary salt restriction; a diet high in fruit and vegeta bles; physical exercise; limiting alcohol consumption (if applicable). This advice is particularly pertinent for patients with bor- derline HTN (140/90 to 159/99 mmHg) who do not require drug therapy. Smoking cessation does not reduce BP, but signi \201 cantly reduces cardiovascular risk. Drug treatment Previously, thiazide diuretic and B-blocker drugs were con- sidered the main stay of BP treatment. Newer drug classes, angiotensin-converting enzyme inhibi- tors (ACEIs ), angiotensin receptor blockers (ARBs) and dihydropyridine calcium channel blockers (CCBs) are increasingly prescribed. As a general rule, there is no class of drug more effective t han others in either reducing BP or reducing the risk of cardiovascular events associated w ith HTN. The key determinant of cardiovascular risk reduction appears to be the BP target a ttained rather than the drugs prescribed. There are several caveats. Firstly there are age and ethnicity factors that in \202 uence the initial drug treatment and secondly B-blocker s have recently been shown to be less effective at preventing car- diovascular events despi te similar BP reduction when com- pared to other drug classes. The British Hypertension Soc iety and NICE guidelines propose the \200\230ACD \200\231 rule based on an individual \200 \231s age and ethnicity (Fig. 9.1.1). Younger (<55 years) Caucasian sub- jects have a great er serum renin level compared with older or Black (African/Caribbean) subjects. Therefore t hose drugs (ACEIs or ARBs) which have greater activity against the renin \200\223angiotensi n system (RAS) are likely to provide greater BP reduction in younger patients and thus are more effective \201 rst-line drugs. CCBs and thiazide diuretics have less activity agains t the RAS and are consequently \201 rst-line agents for older or Black patients. If addit ional drug treatment is required, combining a drug that would not have been considered as \201 rst-line therapy with the initial therapy is preferred; for example a young Caucasian patient initially taking an ACEI and requiring further treat- ment would be prescribed a C CB or thiazide diuretic. Further up-titration of therapy to triple therapy would result in all populations taking an ACEI, CCB and thiazide diuretic. If required, fouth-line therapy options include: \200 \200 \200 \200 Primary and secondary prevention Primary prevention is indicated for hypertensive patients with: \200 \200 diabetes; evidence of end-organ damage (i.e. left ventricular hypertrophy, renal impairment ); an estimated 10 year risk of developing cardiovascular disease >20%. Secondary prevention is treatment for any patient with established cardiovascular disease. Antiplatelet therapy Unless contraindicated, antiplatelet therapy with aspirin is indicated for all patients requiring secondary prevention. The evidence for antiplatelet therapy as primary preven- tion only supports treatment of those hypertensive patients with good BP co ntrol (<150/90 mmHg) and aged >50 years. Statin therapy Statin therapy should be considered in all hypertensive patients aged \211 80 years. Based on clinical trial evidence, the Joint British Societies suggest: \200 \200 a total cholesterol target of <4.0 mmol/L and low density lipoprotein (LDL)-cholesterol <2. 0 mmol/L, or \200 \200 a 25% reduction in total cholesterol and 30% reduction in LDL-cholesterol, whichever provid es the lower value. Follow-up It is usual practice to monitor patients monthly after initiat- ing therapy and t o increase drug therapy as required. Patients with severe HTN should be reviewed more frequ ently. B-blockers; A-blockers; loop diuretics; spironolactone. A. STANLEY 290 Once BP is controlled, review of BP should take place every 6 months with an annual assessm ent of renal func- tion and lipid parameters. Those subjects with \200\230high \200\223nor mal \200\231 BP readings should be reassessed annually. All adults with a \200\230normal \200\231 BP should have their BP meas- ured every 5 years. versus atenolol adding bendro \202 umethiazide as required, in the Anglo-Scandinavian Card iac Outcomes Trial \200\223 Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre random ized con- trolled trial. Lancet 2005; 366: 895 \200\223906. Hansson L, et al., for the HOT Study Group. Effects of intensive blood pressure lowering an d low-dose aspirin in patients with hypertension: principal results of the Hypertension Opt imal Treatment (HOT) randomized trial. Lancet 1998; 351: 1755 \200\2231762. Lewis EJ, et al . Renoprotective effect of the angiotensin-receptor antagonist Irbesartan in patients with nephropathy due to type 2 diabetes. New Engl J Med 2001; 345: 851 \200\223860. Prognosis The cardiovascular and renal risks associated with HTN are related directly to th e level of BP. At one extreme, untreated malignant HTN has a life expectancy of <25% at 12 months and <1% at 5 years. Observational studies comparing risk of stroke or ischemic heart disease with diastolic BP show a linear relationship from 75 \200\223105 mmHg, suggesting that a J-shaped relationship between BP and outcome is unlikely to exist. Well-controlled H TN is still associated with a very small increased risk of cardiovascular events. It is imp ortant to remember that BP alone does not deter- mine the overall prognosis, but is one of several key factors that also include smoking status, glycemic control, lipid pro \201 le and age. Sacks FM, et al. Effects on blood pressure of reduced dietary sodium and the Dietary Approa ches to Stop Hypertension (DASH) diet. DASH \200\223 Sodium Collaborative Research Group. N Engl J Med 2001; 344: 3 \200\22310. Internet resources British Hypertension Society: www.bhsoc.org/ NICE CG34 Hypertension guideline: www.nice.org.uk/nicemedia/pdf/Hypertension Guide.pdf Hypertension Education Foundation: http://www.hypertensionfoundation.org/ European Society of Hypertension: Further reading British Hypertension Society. Guidelines for management of hypertension: re port of the fourth working party of the British Hypertension Society, 2004 \200\224BHS IV. J Hum Hypertens 2004; 18: 139 \200\223185. http://www.eshonline.org/ The London Hypertension Society (an excellent link to many of the national guidelines on management of hypertension): Joint British Societies \200\231 Guidelines on Prevention of Cardiovascular http://www.lhs.sgul.ac.uk/links/guidelines.htm Joint British Societies \200\231 Guidelines on prevention of cardio- vascular disease in clinical practice: Disease In Clinical Practice. Heart 2005; 91(Suppl V): v1 \200\223v52: Recent major clinical trials ALLHAT Of \201 cers and Coordinators for the ALLHAT Collabora tive Research Group. Major outcomes in high-risk hypertensive patients randomized to angiot ensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the antihypertens ive and lipid lowering treatment to prevent heart attack trial (ALLHAT). J Am Med Assoc 200 2; 288: 2981 \200\2232997. www.bcs.com/download/651/JBS2final.pdf The British National Formulary: http://bnf.org/bnf/ See also History and clinical examination of renal disease, p. 2 Renovascular disease, p. 2 92 Malignant hypertension, p. 300 Hypertensive children, p. 304 Hypertensive disorders in p regnancy, p. 310 Brenner BM, et al., for the RENAAL Study Investigators. Effects of Losartan on renal and ca rdiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001; 345: 861 \200\223869. Dahlof B, et al. Cardiovascular morbidity and mortality in the Losartan Intervention for en dpoint reduction in hypertension study (LIFE): a randomized trial against atenolol. Lancet 2002; 359: 995 \200\2231003 Dahlof B, et al. Prevention of cardiovascular events with an antihy- pertensive regimen of amlodipine adding perindopril as required This page intentionally left blank P. A. KALRA AND J. E. SCOBLE 292 Renovascular disease Introduction Narrowing of the main renal arteries, renal artery stenosis (RAS), is very com mon and can lead to clinical presenta- tions of hypertension (HTN), mild \200\223severe ren al failure and cardiac failure. The most common condition leading to renovascular narrowing is atheromatous RAS (ARAS) change, which accounts for >90% of the renovascular dis- ease i n the Western world. Fibromuscular disease (FMD) accounts for most of the remaining cases. As the etiology, clinical presentations and responses to treatment of these two conditions can be quite different they are consid- ered separately in this chapter. Takayasu \200\231s arteritis may be responsible for >50% of RAS cases in the Indian subconti- nent and there are other rare causes of RAS such as mid- dle aortic syndrome and antiphospholipid antibody syndrome; these are brie \202 y considered below. Fibromuscular disease of the renal arteries The renal arteries are affected in 60 \200\2237 5% of all cases of FMD but other major arteries can be involved, e.g. the carotids (in 15%) , vertebral, mesenteric, celiac axis, hepatic, iliac and coronary vessels. Epidemiology FMD can be found in 5% of the normotensive population who wish to be a living kidney donor. Just how common it is as a cause of HTN is uncertain, but it is likely to be <1%. Predisposing factors The pathogenesis of FMD is unknown. It has been suggested that female hormones may play an important role and this would explain the female prepon- derance. An a ssociation with A1-antitrypsin de \201 ciency and smoking have also been observed in some cases. De \201 nition and terminology As complete occlusions of the renal artery (renal artery occlusion, RAO) are often seen the term atherosclerotic renovascular disease (ARVD) is preferable to ARAS. Ischemic nephropat hy is the term used when reduced renal function occurs in association with renovascular dis ease. The strict de \201 nition of renovascular HTN requires an improvement or cure (i.e. no further need for antihyper- tensive therapy in the setting of normal BP) of the HTN foll owing interventional treatment of a RAS lesion. Genetics A familial autosomal dominant pattern has been observed in a few cases of FMD. Clinical features The typical presentation is with HTN in young adults, usu- ally female, w ho have well-preserved renal function. FMD should always be considered in young patients wh o present with severe or accelerated phase HTN. Examination may reveal an abdominal bruit. Carotid involvement can be associated with a range of neurological features. Mesenteric ang ina or claudication may be manifestations of extrarenal FMD. Takayasu \200\231s arteritis A disease of large arteries. In some parts of the world such a s Japan and India it is the most important cause of RAS. It has a predominance in female pa tients. Diagnosis is based on the presence of in \202 ammation and disease in a number of vascular territories. Renal presentation is usually with HTN but patients may also have sig ns and symptoms due to arterial narrowing elsewhere in the body (e.g. cerebral or limb isch emia). Treatment depends on suppression of local in \202 ammation followed by improvement in kidney blood \202 ow with sur- gery or angioplasty. Investigations See the section on ARVD below. As some important FMD lesions occur in the di stal renal circulation these may require spiral CT or intrarenal angi- ography for precise evaluation. The value of MRA is more limited to proximal disease. Pathology There are three main subtypes of FMD: Antiphospholipid syndrome Renal artery narrowing is common There is typically coexistent HT N. Individual case studies have shown that anticoagulation can cure the HTN. At present the bene \201 t of any other intervention is unclear. Intimal \201 broplasia Seen in 5 \200\22310% of FMD. There is circumferential deposition of collagen in the intima resulting in smooth tubular stenoses. Medial \201 broplasia This is the commonest form of FMD. It typically affects women in th eir 4th decade. There are areas of arterial wall media thinning leading to aneurysm formati on; these alternate with regions of \201 bro- sis resulting in a \200\230string of beads \200\231 appearance at angiography (Fig. 9.2.2). Middle aorta syndrome This is a rare condition that presents in childhood. It is a non-in \202 ammatory process leading to narrowing of the aorta at the level of the renal arteries at the aortorenal junction (Fig. 9.2.1). Treatment is dif \201 cult and involves percutane ous interven- tions and surgical procedures. The therapeutic approach must take account of the fact that the patients will grow and so any de \201 nitive interven- tion may need to be delayed until growth is completed. Perimedial \201 broplasia 10% of FMD. Fibrous tissue replaces the outer medial muscle lay er lead- ing to severe stenoses. CHAPTER 9.2 Renovascular disease 293 Fig. 9.2.2 Fibromuscular disease. Classical \200\230string of beads \200\231 appearance (a rrowed) within the non-ostial segment of the left renal artery. ARVD is present in >40% of patients aged >75 years, irre- spective of their cause of death. The prevalence of ARVD in an elderly (>65 years) unse- lected general population in the US A was 7%. Large epidemiologic studies report an incidence of 3.9 cases per 1000 patient-ye ars, in patients >65 years. ARVD is frequently found in patients with other atheroma- tous macrovascular disease. ARVD is found in \211 10% of outpatients investigated for CKD and 1 1% of US dialysis patients have a diagnosis of ARVD. However, as will be discussed later, A RVD is likely to be an association and not causative in many of these cases, and this has i mplications for treatment. RAS is found in up to 2% of all cases of HTN but, as with CKD, i t is unlikely to be causal in many of these cases. Fig. 9.2.1 Middle aorta arch syndrome. Treatment Although the correct management of many ARVD cases is still uncertain, this is no t the case for renal FMD. Where there is signi \201 cant HTN associated with a RAS >50%, p ercutaneous renal angioplasty (PTRA) is the inter- vention of choice. RAS lesions in the di stal renal arteries, as well as compli- cated or lengthy lesions, may not be amenable to PT RA and thus require surgery. Follow-up As progressive narrowing of the renal arteries occurs in a third of patients, the majority of stable patients should be seen annually. Repeat imaging would only be indicate d for those with clinical change, such as worsening control of HTN. Predisposing factors Risk factors for development of ARVD, which is an \200\230in \202 am - matory \200\231 disease, are the same as for all atheromatous vascular disease, and inclu de: \200 \200 \200 \200 \200 \200 age hypertension smoking hyperlipidemia diabetes renal failure. Prognosis The overall prognosis is excellent. Unlike atherosclerotic RAS, very few patients develop RAO and renal failure is almost unheard of. The outcomes after PTRA are favorable with a low rate of restenosis (20%); 36% of patients are cured of HTN with most other patie nts having a reduced drug burden and improved BP. The older the age at diagnosis of FMD, th e less likely the possibility of cure. Genetics Currently the only genetic association reported in ARVD is an association with the DD polymorphism of the ACE gene. Clinical features ARVD can present with one or more of several syndromes. Atherosclerotic renovascular disease ARVD is the commonest cause of RAS. It is a disease of aging and may present to many different specialties includ- ing cardiology, vascular surge ry, radiology, elderly care medicine as well as nephrology. Hypertension ARVD may be found in 2% of all cases of HTN and >90% of all patients with ARV D are hypertensive. Despite this frequent association it is often questionable whether a gi ven RAS lesion actually causes the HTN. In many patients the pattern is often that of sever e systolic HTN resistant to medical therapy. Epidemiology Post-mortem studies have found an increased prevalence of incidental ARVD with increasing age. P. A. KALRA AND J. E. SCOBLE 294 More than 35% of elderly patients with congestive cardiac failure (CCF) will have ARVD, and this association is now of growing interest because of the potential for revasculariza- ti on to improve cardiac function and patient survival. It is likely that in many patients essential HTN more often contributes to the development of ARVD, rather than the latter being important in the pathophysiology of the HTN. It is th is hypertensive renal damage which is also thought to be a major contributor to the CKD see n in many patients with ARVD. Non-renal atheromatous macrovascular disease Many patients have asymptomatic, clinically si lent ARVD that is detected incidentally during investigation for other extrarenal atheromat ous conditions. Atherosclerotic RAS can be detected in: \200 \200 \200 Acute kidney injury ARVD may present with AKI for a variety of reasons: \200 severe bilateral RAS or occlusion (an indication for revascularization therapy); accelerate d-phase HTN (an indication for revasculariza- tion therapy); cholesterol atheroembolization (seen in patients with severe aortic atheroma who undergo angiographic pro- cedures or ant icoagulation; Fig. 9.2.3); damage caused by radiocontrast agents during intra- arterial or CT angiography; acute tubular necrosis (ATN) due to a general fall in per- fusion pressure; in association with use of ACEIs or ARBs (see below). There should be a high clinical susp icion of underlying RAS if a signi \201 cant deterioration in renal function occurs after initiation of ACEI or ARB therapy (e.g. >30% increase in serum creatinine). AKI is not unco mmon in patients treated with these drugs and is most often associated with volume depletio n during intercurrent illness rather than the effects of a RAS lesion. Although ACEIs and A RBs can usually be reintroduced safely after stabilization of the patient \200\231s circula tion, renal artery imaging should be considered as a minority of patients will have signi \201 cant RAS that might require a revascularization procedure to allow uncomplicated use o f these bene \201 cial drugs. 30 \200\22350% of patients with peripheral vascular disease; 10 \200\22315% of patients wit h coronary artery disease; 30% of patients undergoing investigation of aortic aneu- rysm; 1 0% of patients with cerebrovascular disease. Physical signs and other suggestive features of ARVD The presence of audible vascular bruit s (epigastric, renal or ilio-femoral) in a patient with unexplained HTN and/or CKD is sugge stive of ARVD. Patients with unilateral signi \201 cant RAS or RAO may have an atrophic ki dney. An unexplained 1.5 cm disparity in bipolar renal length on USS is also an indication to investigate for ARVD. Investigation Random cholesterol need not be elevated. Urinary protein:creatinine ratio (PC R) or albumin creative ratio (ACR) should be assessed. Proteinuria is commonly present in A RVD and is usually re \202 ective of the degree of underlying renal parenchymal damage, as is the case in CKD from other causes. Two-dimensional USS may show renal asymmetry. There are a number of options for imaging of the renal arteries. Chronic kidney disease Many patients with newly identi \201 ed CKD referred to neph- rolog y clinics are found to have ARVD after further investi- gation, and this incidental present ation is by far the commonest. Hypertension is usually also present. A recent report of the US dialysis population showed that 11% had ARVD. In most cases HTN rather than ischemia is thought to be the most important factor in the pathogenesis of CKD and ESRD. ARVD is more often an association of, rather than the cause of, the majority of these cases of CKD and E SRD. The few histopathological studies in ARVD have shown a pattern of intrarenal injury th at is non-speci \201 c and hard to distinguish from hypertensive damage. This has implicat ions for treatment and it is also re \202 ected in the outcomes after renal revascularizat ion procedures. Magnetic resonance angiography (MRA) This is non-invasive. Sensitivity and speci \201 city for detection of RAS are >90% (Fig. 9.2.4). Cardiac failure Signi \201 cant RAS lesions can be detected in patients present- ing with cardiac failure. \200\230Flash pulmonary edema \200\231 refers to a life-threatening pres- entation of acute heart failure with no evidence of signi \201 - cant myocardial ischemia . There is usually severe HTN, and patients have signi \201 cant bilateral RAS. This is co nsidered a de \201 nite indication for revascularization. Fig. 9.2.3 Cholesterol embolization within renal arterioles. Atheromatous material is seen blocking the arteriolar lumen, containing several cholesterol clefts. CHAPTER 9.2 Renovascular disease 295 Fig. 9.2.6 Histopathological changes in ARVD. Non- speci \201 c tubular atrophy, interstit ial \201 brosis and glomer ulosclerosis; features are often indistinguishable from hypert ensive injury. Fig. 9.2.4 Magnetic resonance angiogram showing signi \201 cant right ostial RAS and left renal artery occlusion. The main limitation is the risk of contrast nephropathy in patients with advanced CKD. Duplex ultrasonography Although time-consuming and operator dependent, this technique is no n-invasive and can be very accurate for detection of signi \201 cant RAS. Key measurements are peak velocity of renal arterial blood \202 ow and intrarenal vascular resistive inde x (RI). Renal scintigraphy It is often important to assess the function of each kidney in ARVD. Thi s can be performed accurately by use of DMSA and isotopic GFR techniques in combination. Th e demonstration of a non-functioning/poorly function- ing RAS kidney with scintigraphy can also be useful. Captopril renography is now rarely used to detect func- tionally signi \201 cant RAS as its diagnostic usefulness is limited in CKD. Renal angiography Conventional angiography is now reserved to con \201 rm the presence of RAS at the time of a revascularization pro- cedure, or in diagnosis of more complicated/unc ertain cases. Selective renal angiography provides the best means of de \201 ning distal R AS lesions. Limitations of angiography include: \200 \200 \200 Fig. 9.2.5 CT angiography showing signi \201 cant left ostial RAS. Note the heavily calci \201 ed aorta and left renal artery. provides only 2-D images; no functional information; invasive with a risk of atheroembolism following instru- mentation of aorta and renal artery; associated risk of contrast nephrop athy. It is of limited usefulness for de \201 ning distal disease. Although the contrast agent w as previously thought to be non-toxic there are now concerns over use of gadolinium- enhanc ed MRA in patients with advanced CKD. Over 250 cases of nephrogenic fibrosing dermopathy ha ve accompanied use of certain preparations of gadolin- ium although the majority of cases h ave occurred in dialysis patients. Pathology Atherosclerotic RAS lesions occur most commonly (90%) at the renal ostia, at or w ithin 1 cm of the aortorenal junction. It is likely that sheer stress injury contributes to develop- ment of atheromatous plaques at these sites in predis- posed individuals. Computed tomography angiography or multislice CT This has a similar sensitivity and speci \201 city to MRA for detec- tion of RAS. CT will demonstrate calci \201 cation (Fig. 9.2.5 ) which, if present at the renal ostium, can make assessment of the degree of RAS dif \201 cult. P. A. KALRA AND J. E. SCOBLE 296