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AD_HTT_025_034___APR20_07 13/4/07 8:57 AM Page 27 How to treat Pull-out section w w w. a u s t r a l i a n d o c t o r. c o m . a u Earn CPD points on page 34 Complete How to Treat quizzes online (www.australiandoctor.com.au/cpd) or in every issue. inside Causes Recognising pseudo-resistant hypertension Managing resistant hypertension Detailed case studies The author RESISTANT PROFESSOR DAVID W JOHNSON, director of nephrology and chair of medicine, Princess Alexandra Hospital, Brisbane; professor of medicine, University of Queensland, St Lucia, Brisbane, Queensland. hypertension Background HYPERTENSION is the most commonly managed condition in Australian general practice and contributes about 5.4% to the overall burden of disease in this country. However, the available evidence suggests considerable room for improvement in the recognition, treatment and subsequent control of hypertension in the primary care setting. A recent population-based survey of 11,247 Australian adults found that the overall prevalence of hypertension was 29%. However, only 47% of these people were receiving antihypertensive medications, and less than 20% had adequate blood pressure control 1 (defined as a BP <140/90mmHg). This article primarily focuses on the approach to managing patients with BP that is difficult to control. How often is BP truly difficult to control? Resistant hypertension has generally been defined as an inability to reduce BP to <140/90mmHg despite treatment with a rational combination of at least three antihypertensive medications (including a diuretic) for at least one month. The prevalence of this condition ranges from 3% to 5% in primary health care to 21% in groups of patients referred to tertiary institutions. Studies of higher-risk populations enrolled in large clinical trials suggest an even higher incidence in the general population, ranging from www.australiandoctor.com.au 2 12% (HOT study ) to as high as 3 74% (LIFE study ). In the Antihypertensive and LipidLowering Treatment to Prevent Heart 4 Attack Trial (ALLHAT ), 27.3% of patients required three or more drugs, but 34% of such patients failed to achieve the goal BP of <140/90mmHg. Despite these sobering findings, most patients with resistant hypertension can achieve their BP targets if they are carefully evaluated and appropriate therapy is instituted. 20 April 2007 | Australian Doctor | 27 AD_HTT_025_034___APR20_07 13/4/07 8:57 AM Page 28 How to treat – resistant hypertension Causes of resistant hypertension THE potential causes of resistant hypertension are listed in table 1. The most common is volume overload, which often arises from a combination of excessive salt intake, inadequate diuretic therapy and underlying chronic kidney disease (CKD). Certain antihypertensive medications such as vasodilators (eg, minoxidil) or dihydropyridine calcium-channel blockers also tend to promote avid sodium resorption by the kidneys. The second most common cause of resistant hypertension is non-adherence with treatment. Only 50-60% of patients adhere well to prescribed regimens, 5-10% adhere poorly and 30-40% exhibit an intermediate degree of adherence. More than half of patients with insufficient reductions in BP display suboptimal medication compliance. Prescribing insufficient dosages and numbers of different medications is the next most common cause, accounting for between 43% and 60% of difficult-to-control BP. For example, Berlowitz and colleagues conducted a survey of 800 patients with hypertension over a two-year 5 period. About 40% had BP >160/90mmHg despite an average of more than six hypertension-related consults a year. Even though significantly elevated BP was clearly documented by clinicians, increases in antihypertensive therapy occurred in less than 7% of visits, suggesting that most of the physicians were not sufficiently aggressive with medical therapy. It should also be emphasised that monotherapy achieves an optimal BP response in less than 20% of patients, so multiple antihypertensive agents are usually required (table 3). This is particularly true in the presence of CKD, when the median number of medications required for BP control rises from one in patients with an estimated glomerular filtration rate (eGFR) Table 2: Examples of drug interactions that interfere with hypertension control Table 1: Causes of resistant hypertension Volume overload Excessive salt intake Inadequate diuretic therapy Chronic kidney disease Non-adherence to therapy Lack of consistent and continuous primary care Inconvenient dosing schedules Medication side effects Medication costs Instructions not understood Inadequate patient education Impaired cognition Pseudo-resistance ‘White-coat’ hypertension, or office elevations Pseudo-hypertension Use of inappropriately small sphygmomanometer cuff for arm size Drug-related causes Inadequate dosages Inappropriate combinations (eg, ACE inhibitor and beta blocker) Rapid inactivation (eg, hydralazine, clonidine) Drug interactions (see table 2) Coexisting conditions Smoking Obesity Insulin resistance (metabolic syndrome) Alcohol Anxiety disorders Chronic pain Secondary causes of hypertension Chronic kidney disease (renoparenchymal and renovascular) Primary hyperaldosteronism Cushing’s syndrome Phaeochromocytoma Hyperparathyroidism Myxoedema Acromegaly Obstructive sleep apnoea Coarctation of the aorta Polycythaemia rubra vera Acute intermittent porphyria Pre-eclampsia Neurogenic (dysautonomia, raised intracranial pressure, lead poisoning, GuillainBarré syndrome) NSAIDs (conventional and COX-2 selective) — most common ■ Sympathomimetics (nasal decongestants, appetite suppressants, caffeine, cocaine, amphetamines) ■ Buproprion ■ Oral contraceptives ■ Corticosteroids ■ Antidepressants (monoamine oxidase inhibitors, tricyclic antidepressants) ■ Hepatic enzyme inducers (rifampicin, phenobarbitone) ■ Cholestyramine ■ Cyclosporin, Tacrolimus ■ Erythropoietin, darbepoietin ■ Licorice ■ 2 >90mL/min/1.73m to 3.5 in patients with an eGFR 402 49mL/min/1.73m . Another frequent cause of drug-related resistant hypertension is the concomitant use of pro-hypertensive drugs. The most common of these are conventional and COX-2selective NSAIDs, which promote avid sodium and fluid retention by the kidneys. A recent survey of 601 Australian adults taking BP medications demonstrated that nearly 10% were also taking NSAIDs. This is not only worrying from the point of view of undermining the effectiveness of hypertension control, but most of these patients were additionally at risk of the ‘triple whammy’ (the combination of an NSAID, diuretic and either an ACE inhibitor or angiotensin-II-receptor antagonist) — the most common cause of druginduced acute renal failure in the community. Secondary hypertension, when there is a clearly identifiable (often treatable) cause for BP elevation, is now considered to be more frequent than the previously widely quoted figure of 5%. CKD, defined as GFR 2 <60mL/min/1.73m , was Table 3: Summary of the number of medications required to achieve BP targets in major hypertension clinical trials. a Target BP Average number of BP medications MDRD MAP <92mmHg 3.6 Trial b ABCD DBP <75mmHg 2.7 c HOT DBP <85mmHg 3.3 d UKPDS DBP <85mmHg 2.8 DBP = diastolic BP; MAP = mean arterial pressure a Klahr S, et al. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group. New England Journal of Medicine 1994 330:877-84. b Estacio RO, et al. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension. New England Journal of Medicine 1998; 338:645-52. c Hansson L, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet 1998; 351:1755-62. d UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ 1998; 317:703-13. shown in the recent AusDiab study to be present in about 27% of all Australian adults 6 with hypertension. Most of this disease is renoparenchymal in nature, although renovascular hypertension occurs in about 1-2% of cases. Primary hyperaldosteronism has also been suggested to occur with reasonable frequency in resistant hypertension, based on the reported prevalence of abnormal plasma aldosterone:renin ratios of up to 40% in selected groups. However, this issue is some- what contentious at present, as some authors have raised concerns that extensive use of the test leads to high false-positive rates and unnecessary, costly additional testing. Other rare causes of secondary hypertension are listed in table 1. A final category of resistant hypertension is pseudoresistance. The most common form of this is socalled ‘white-coat’ hypertension, in which clinic BP measurements are elevated, but home or ambulatory BPs are normal. Various case series have reported that up to 40% of patients with resistant hypertension actually have a component of whitecoat hypertension. Other causes of pseudoresistance include pseudohypertension in older patients (due to the presence of calcific arteriosclerosis leading to brachial artery stiffness) and the use of an inappropriately small sphygmomanometer cuff (the cuff bladder length should be at least 80% and the width at least 40% of the circumference of the mid-upper arm). Recognising pseudo-resistant hypertension THE definitive test is confirming the presence of non-elevated BP by either 24-hour ambulatory BP monitoring (daytime average BP <135/85mmHg, night-time average BP <120/70mmHg and 24-hour average <130/80mmHg) or home BP measurements (BP <140/90 mmHg). However, performing such investigations may not always be feasible or practical, particularly in remote practices. Clinical clues to the possible presence of a whitecoat effect in the setting of apparent resistant hypertension include: 28 | Australian Doctor | 20 April 2007 Mild BP elevations (systolic BP <180mmHg). ■ Absence of target-organ damage (eg, retinopathy, proteinuria or left ventricular hypertrophy). ■ Presence of symptoms compatible with hypoperfusion (eg, orthostatic light-headedness) in the absence of excessive reduction of BP. As a general rule of thumb, if the patient has evidence of target-organ damage, one should generally err on the side of augmenting treatment (unless they have hypoperfusion symptoms). ■ www.australiandoctor.com.au When to investigate for secondary causes Given that the prevalence of CKD is high (27%) in the general hypertensive population, the Kidney Check Australia Taskforce recommends screening all hypertensive patients with a serum creatinine test, eGFR and urine dipstick examination for proteinuria on an annual basis. A positive urine dipstick examination or an eGFR <60mL/min/ 2 1.73m warrants further investigation with at least a renal ultrasound scan and formal urinary protein quantification (urine protein:crea- tinine ratio on a random urine sample is recommended). Other forms of secondary hypertension should be investigated in the settings of: ■ Resistant, malignant or accelerated hypertension. ■ An acute rise in BP over a previously stable value. ■ Age of onset of <30 years, with no family history of hypertension and no other risk factors (eg, obesity). ■ Or if any of the clinical or laboratory features listed in table 4 are present. cont’d page 30 AD_HTT_025_034___APR20_07 13/4/07 8:57 AM Page 30 How to treat – resistant hypertension from page 28 Screening for renovascular hypertension is probably best achieved by either renal artery duplex scan or isotope renography (with or without captopril), although other tests are available (eg, magnetic resonance angiography, helical CT, captopril renin stimulation test). A positive screening test warrants proceeding to a renal angiogram with or without determination of renal vein renin level. The preferred initial screening strategy for primary hyperaldosteronism is measurement of a plasma aldosterone:renin ratio. This is best done in the morning and in the upright position. The typical finding in Conn’s syndrome is suppressed plasma renin activity, elevated plasma aldosterone concentration and hence an elevated ratio. This ratio may be modified by several factors, including the use of concomitant medications such as ACE inhibitors and beta blockers, which stimulate renin release. Most BP medications affect the ratio, although verapamil, hydralazine and prazosin generally do not. An elevated plasma ratio is therefore not diagnostic of primary aldosteronism, but warrants further investigation with an aldosterone-suppression test in which Table 4: Clinical or laboratory features suggestive of secondary hypertension and warranting further appropriate investigation Disorder Suggestive clinical or laboratory features Generic (any cause of secondary hypertension) ■ Renoparenchymal disease Renovascular disease Primary hyperaldosteronism Obstructive sleep apnoea Phaeochromocytoma Cushing’s syndrome Coarctation of the aorta Hypothyroidism Primary hyperparathyroidism Polycythaemia rubra vera Resistant hypertension ■ Malignant hypertension (elevated BP + grade 4 hypertensive retinopathy) ■ Accelerated hypertension (elevated BP + grade 3 hypertensive retinopathy) ■ An acute rise in BP over a previously stable value ■ Age of onset <30, with no family history of hypertension and no other risk factors (eg, obesity) 2 ■ eGFR <60mL/min/1.73m ■ Proteinuria/albuminuria ■ Acute elevation in serum creatinine concentration (or fall in eGFR) by 30% or more within one month of starting an ACE inhibitor or angiotensin-II-receptor antagonist ■ Moderate to severe hypertension in a patient with diffuse atherosclerosis or a unilateral small kidney ■ Repeated episodes of flash pulmonary oedema ■ Unexplained hypokalaemia (Note that more than half of Conn’s syndrome patients are normokalaemic) ■ Obese patients who describe a history of witnessed apnoeas, loud snoring, daytime somnolence, early morning headaches, morning confusion or morning sore throat ■ Triad of headache (usually pounding), palpitations and sweating (often episodic) ■ Paroxysmal elevations in BP ■ Cushingoid facies, central obesity, proximal muscle weakness and ecchymoses ■ Hypertension in the arms, with diminished or delayed femoral pulses, and low or unobtainable BPs in the legs ■ Lethargy, cold insensitivity, weight gain, bradycardia or other features of hypothyroidism ■ Elevated serum calcium level ■ Elevated haemoglobin concentration Table 5: Indications for referral of patients with hypertension to a specialist Suspected secondary hypertension ■ Resistant hypertension plus 2 eGFR < 60mL/min/1.73m 2 ■ eGFR <30mL/min/1.73m ■ Proteinuria >1g/day ■ Rapid (>15%) decline in eGFR within three months (not in context of starting an ACE inhibitor) ■ Accelerated hypertension (hypertension with grade 3 retinopathy) (urgent) ■ Malignant hypertension (hypertension with grade 4 retinopathy) (urgent) ■ Multiple drug intolerances or complications ■ levels on at least three separate occasions (phaeochromocytoma). ■ Thyroid function (hypothyroidism). ■ Urinary free cortisol (Cushing’s syndrome). ■ Parathyroid hormone levels (hyperparathyroidism). ■ Polysomnography (obstructive sleep apnoea). When to refer 24-hour urinary aldosterone is measured following salt loading for at least three days. Other screening tests that may be considered for suspected secondary hypertension under appro- priate circumstances include measurements of: ■ 24-hour urinary catecholamine The indications for referral of patients with hypertension to a specialist are listed in table 5. Management Is lifestyle modification important in patients with resistant hypertension? Table 6: Anticipated benefits of lifestyle interventions in hypertensive patients LIFESTYLE modification plays a crucial role in managing patients with resistant hypertension, as they can achieve significant BP reductions on top of those afforded by drugs. Particular attention should be paid to the ‘SNAP’ (smoking, nutrition, alcohol, physical activity) risk factors. Table 6 provides an outline of the magnitude of BP reductions that may be expected as a result of successful lifestyle modification. Intervention Recommendation Weight reduction ■ ■ Dietary salt restriction DASH (dietary approaches to stop hypertension) diet Physical activity Moderate alcohol consumption 30 5-7mmHg 8-14mmHg 2.5-4mmHg 2-4mmHg Table 7: Choice of antihypertensive medications in patients with hypertension and pre-existing conditions. Drug class ACE inhibitor Angiotensin-II-receptor antagonist Diuretic Calcium-channel blocker Potentially favourable effect ■ CKD ■ Diabetic nephropathy ■ Heart failure ■ MI ■ Cerebrovascular accident ■ Diabetic nephropathy ■ Heart failure ■ Heart failure ■ Angina Beta blocker ■ Antihypertensive drug therapy Most antihypertensive agents achieve comparable levels of BP reduction when prescribed as monotherapy (of the order of 12/5mmHg). A metaanalysis of hypertension trials by the Blood Pressure Lowering Treatment Trialist Collaboration demonstrated no major differences between classes of medication with respect to reducing cardiovascular risk, and greater risk reductions occurring with 7 larger reductions in BP. In general terms, the choice of antihypertensive medications in patients with resistant hypertension is dictated by the presence of coexisting conditions (table 7), concomitant medications and how well specific antihypertensive medications are tolerated by the individual patient. Moreover, simple regimens that enhance adherence (eg, once-daily dosing and combination pills) should be tried BMI 18-24.9 Waist circumference ≤94cm (men) or ≤80cm (women) ■ <90mmol/day (low-salt foods + no adding salt to food) ■ Fruit, vegetables, low saturated and total fat ■ Aerobic activity for 30 minutes most days ■ 1-2 standard drinks a day Approximate systolic BP reduction 5-20mmHg/10kg lost Angina Myocardial infarction ■ Heart failure ■ Alpha blocker ■ Prostatism Minoxidil initially. Maximal doses of each agent should be encouraged, whenever they are possible, except for thiazide diuretics, when low doses are often preferred because of a therapeutic ceiling. Because CKD and cardiovascular disease are common in patients with resistant hypertension, ACE inhibitors, angiotensin-II-receptor | Australian Doctor | 20 April 2007 antagonists and diuretics should be among the firstline drugs in the therapeutic armamentarium. One study of patients with resistant hypertension attending a tertiary care clinic demonstrated that good BP control was ultimately achieved in most patients and that the most successful therapeutic strat- Potentially deleterious effect Bilateral renal artery stenosis ■ ■ Bilateral renal artery stenosis Gout Bradycardia ■ Heart block ■ Heart failure ■ Bradycardia ■ Heart block ■ Peripheral vascular disease ■ Asthma ■ Glaucoma ■ Heart failure ■ Angina ■ Heart failure ■ ■ egy was either to add (50% of cases) or modify (24%) 8 diuretic therapy. Thiazide diuretics are effective and preferred because of their longer duration of action in patients with eGFR >50mL/min/ 2 1.73m . For patients with 2 eGFRs <50mL/min/1.73m , loop diuretics are more efficacious. www.australiandoctor.com.au Combining a diuretic with an ACE inhibitor or angiotensin-II-receptor antagonist confers synergistic BP reduction. Spironolactone has also been shown to be effective in resistant hypertension, but patients must be closely monitored for hyperkalaemia (especially when it is used in combination with an ACE inhibitor and/or angiotensin9 II-receptor antagonist). Inappropriate drug combinations, such as a beta blocker with either an ACE inhibitor or centrally acting calcium-channel blocker, are best avoided. If BP treatment remains difficult despite the patient taking three or four different medications, it is often useful to add one or more agents requiring twice- or thrice-daily administration (eg, hydralazine or methyldopa) to attempt to achieve better antihypertensive coverage over a 24-hour period. If all else fails, minoxidil is often effective, although patients have to be monitored closely for signs of fluid retention and pericardial effusion. If minoxidil therapy is instituted, the diuretic dose usually needs to be increased and a beta blocker is also often required to minimise reflex sympathetic activation. Achieving BP targets Reaching BP targets in some patients is sometimes not possible, often because of severe medication intolerances. In the case of therapylimiting symptoms prevent- ing the attainment of BP goals, even a partial reduction of BP may achieve significant cardiovascular and renal benefits. Such patients often benefit from specialist referral. Sometimes, therapy may also be limited in elderly patients because of impaired cerebral or renal autoregulation (leading to cerebral or renal hypoperfusion with even modest reductions in BP) or because of a component of pseudo-hypertension due to the presence of calcific arteriosclerosis. The latter may be suspected if antihypertensive therapy induces symptoms compatible with hypoperfusion (eg, orthostatic lightheadedness) in the absence of an excessive reduction in BP. Nevertheless, the available evidence suggests that a major reason for failure to reach BP targets is a failure or reluctance of physicians to increase antihypertensive therapy because of their focus on relieving symptoms, lack of familiarity or agreement with clinical guidelines, or discomfort in titrating to a goal (particularly when the patient is already taking several BP medications). One of the most effective strategies for dealing with clinical inertia is to institute decision-support systems that prompt clinicians to augment therapy when a goal has not been achieved. In the vast majority of hypertensive patients, it is appropriate to try to reach recommended BP targets. AD_HTT_025_034___APR20_07 13/4/07 8:57 AM Page 31 Summary Resistant hypertension, defined as an inability to reduce BP below 140/90mmHg despite treatment with a rational combination of at least three antihypertensive medications (including a diuretic) for at least one month, occurs in about 5% of patients. ■ The major causes are volume overload, patient non-adherence and reluctance of the clinician to augment treatment. ■ CKD occurs in about one-quarter of all patients with hypertension and should be screened for by annual testing of serum creatinine concentration, eGFR and urine dipstick for protein. ■ Other forms of secondary hypertension should be investigated in the settings of: — Resistant, malignant or accelerated hypertension. — An acute rise in BP over a previously stable value. — Age of onset <30, with no family history of hypertension and no other risk factors (eg, obesity). — Presence of any of the clinical or laboratory features listed in table 4 (page 30). ■ The choice of antihypertensive medications is usually determined by the presence of coexisting conditions (table 7), concomitant medications and how well specific antihypertensive medications are tolerated by the individual patient. ■ Diuretics are particularly useful in managing resistant hypertension. ■ Good BP control is possible in most patients with resistant hypertension. Author’s case studies ■ Case study 1 — Harry HARRY, 56, returns to your clinic for a BP check. He was last seen by you two weeks ago for an URTI and was noted at the time to have a BP of 175/105mmHg. He now feels perfectly well. His seated BP today is 170/105mmHg (large cuff). Harry has a past history of “borderline” hypertension diagnosed during an insurance medical 10 years ago, but has not received antihypertensive therapy or subsequent BP checks. His mother and father were diagnosed with hypertension in their 60s and his father died at 68 from a heart attack. Harry has been overweight for most of his adult life but has no symptoms suggestive of obstructive sleep apnoea. There is no other past medical history. Harry is on no regular medications. He smokes 10 cigarettes a day, drinks 20-30g of alcohol (2-3 standard drinks) on most nights and does very little exercise. He works as an administrative officer. Physical examination reveals obesity (waist circumference 102cm, BMI 30.2). His pulse is 72bpm and regular. Cardiorespiratory and abdominal examinations are normal. There are no audible carotid or renal bruits. His peripheral pulses are normal. Fundoscopic examination reveals grade 2 hypertensive retinopathy (figure 1). His investigations reveal: ■ Urine dipstick 1+ protein, no blood. ■ FBC normal. ■ Biochemistry: urea 7.0mmol/L, creatinine 120µmol/L, eGFR 2 58mL/min/1.73m , urate 0.45mmol/L, fasting blood glucose 6.2mmol/L. ■ Cholesterol: total 6.3 mmol/L, HDL 0.8mmol/L, LDL 4.2mmol/L. ■ Triglycerides: 2.2mmol/L. ■ ECG voltage criteria of left ventricular hypertrophy. ■ Echocardiograph: left ventricular hypertrophy. ■ Urine protein:creatinine ratio: 40g/mol (normal <15) Question 1: What would you do now? a. Recommend lifestyle modification. b. See Harry in two weeks to recheck his BP before considering antihypertensive medication. c. Start antihypertensive medication this visit. d. Start drug therapy other than antihypertensive medication. e. Order 24-hour ambulatory BP monitoring. f. Order a renal ultrasound scan. g. Refer to a nephrologist. (My answer: a, c, d and f) Harry has moderate hypertension, with target-organ damage (retinopathy, CKD, Figure 1: Grade 2 hypertensive retinopathy (silver wiring and arteriovenous nipping). Therapeutic modifications often required in resistant hypertension (after exclusion of secondary causes) Often 4-5 antihypertensive medications (occasionally more) ■ Maximal doses (except thiazide diuretics) ■ Must include a diuretic ■ Use a loop diuretic if eGFR is 2 <50mL/min/1.73m ■ Consider spironolactone (beware of the risk of hyperkalaemia, especially if the patient is also taking an ACE inhibitor and/or an angiotensin-II-receptor antagonist) ■ Consider adding medications with twice- or thrice-daily dosing (eg, hydralazine, methyldopa) ■ Minoxidil is useful in severe refractory cases ■ Allow at least 3-4 weeks after medication change to assess full impact ■ Follow patients at least monthly while BP remains uncontrolled ■ left ventricular hypertrophy). Under these circumstances the Hypertension Management 10 Guide for Doctors 2004 recommends instituting lifestyle modification (table 6) and drug treatment; 24-hour ambulatory monitoring is unlikely to contribute to management. Based on his many risk factors (hypertension, obesity, smoking, hypercholesterolaemia, sedentary lifestyle, positive family history of ischaemic heart disease, impaired fasting glycaemia, low eGFR, proteinuria) and his high risk (>30%) of a cardiovascular event in the next five years, the Guide recommends instituting low-dose aspirin and a statin, in addition to antihypertensive therapy. Given that Harry has stage 3 CKD, as evidenced by an 2 eGFR of 58mL/min/1.73m and mild proteinuria, it would be reasonable to start therapy with either an ACE inhibitor or angiotensin-II-receptor antagonist. Ultimately he is likely to require combination antihypertensive therapy (including a diuretic) to adequately control his BP. A renal ultrasound scan is appropriate in the setting of stage 3 CKD to assess for evidence of kidney damage (scarring, stones, obstruction or neoplasms). Despite his moderate hypertension and CKD, Harry does not meet the Kidney Check Australia Taskforce guidelines for referral to a nephrologist. Question 2: What should Harry’s target BP be? a. 145/95mmHg b. 140/90mmHg c. 130/80mmHg d. 125/75mmHg (My answer: c) The Caring for Australians with Renal Impairment (CARI) guidelines (see Online resources, page 32) recommend a target BP of <130/80mmHg in patients with hypertension and CKD. The lower target of 125/75mmHg is only recommended in those with hypertension and diabetes if their proteinuria exceeds 1g/day (approximately equivalent to a urine protein:creatinine ratio of 120g/mol). The higher target of 140/90mmHg is recommended for patients with hypertension without diabetes or evidence of CKD. Three weeks later After giving Harry appropriate lifestyle advice and starting him on perindopril 5mg in the morning, aspirin 100mg daily and atorvastatin 10mg daily, you ask him to return for a clinical review. His BP is 160/100mmHg. Repeat blood tests demonstrate a serum potassium concentration of 5.3mmol/L and his serum creatinine concentration has risen to 136µmol/L 2 (eGFR 50mL/min/1.73m ). His renal ultrasound scan demonstrated normal-sized kidneys with a normal appearance. Question 3: What would you do now? a. Stop the perindopril and www.australiandoctor.com.au start an alternative antihypertensive agent. b. Reduce the dose of perindopril. c. Refer to a nephrologist. d. Start a diuretic. e. Order a renal artery duplex scan. (My answer: d) Current national and international guidelines recommend clinicians tolerate up to a 30% rise in serum creatinine concentration and/or a 30% fall in eGFR within the first month of starting an ACE inhibitor or angiotensin-IIreceptor antagonist. An initial rise in serum creatinine concentration, which then stabilises and is <30% above baseline value, is predictive of a renoprotective benefit, compared with patients who experience no alteration in kidney function at all. It is therefore important NOT to stop an ACE inhibitor or angiotensin-IIreceptor antagonist because of a modest rise in serum creatinine concentration or fall in eGFR. If a patient experiences a progressive rise in serum creatinine concentration or an absolute rise of >30% above baseline in the first month of ACE inhibitor or angiotensinII-receptor antagonist therapy, the agent should be stopped and consideration given to investigating for the possibility of bilateral renal artery stenosis (eg, with a renal artery duplex scan). Elevation of serum potassium concentration to >6mmol/L, which is not controlled by diuretic therapy, also warrants cessation of ACE inhibitor therapy. Because Harry’s BP is still poorly controlled, it is reasonable to start a diuretic (which may be in the form of a combination pill with perindopril). Six months later Harry has lost 6kg after adopting a healthier diet and regular exercise program. He has reduced his alcohol consumption but continues to smoke 10 cigarettes a day. His current medications include perindopril/indapamide 4/1.25 mg daily, irbesartan 300mg daily and ibuprofen for knee osteoarthritis. His office BP is 140/90mmHg and his serum creatinine concentration is 160µmol/L (eGFR 41mL/ 2 min/1.73m ). Question 4: What would you do now? a. Assess drug compliance. b. Stop the ibuprofen. c. Change indapamide to a loop diuretic. d. Add another antihypertensive medication. e. Screen for renal artery stenosis. f. Refer to a nephrologist. (My answer: a, b and c) Harry has resistant hypertension, given that he has not reached his BP target despite treatment with three agents (including a diuretic). This is most likely due to progression of his underlying CKD, which in turn has been aggravated by a ‘triple whammy’ (ACE inhibitor or angiotensin-IIreceptor antagonist, diuretic and NSAID). It is therefore critically important to stop his NSAID. Harry’s indapamide should also be changed to a loop diuretic in view of his low eGFR. Options d, e and f would be reasonable if the above measures did not result in substantial improvement in Harry’s BP control. Follow-up Harry ’s partner confirmed he was taking his medications religiously. After changing his diuretic from indapamide to frusemide 40mg in the morning and discontinuing the ibuprofen, Harry’s BP improved to 135/80mmHg and his serum creatinine concentration improved to 140µmol/L. Doppler examination of the renal arteries was within normal limits. Harry was referred to a nephrologist who started amlodipine 10mg daily. Harry’s BP is now well controlled and he sees his GP and specialist alternately every three months. Case study 2 — Jane Jane, 42, presents with a oneweek history of constant, generalised headache. She was diagnosed with white-coat hypertension at 27 but started antihypertensive medications at 35, after elevated BP was confirmed by 24-hour ambulatory monitoring. She has numerous medication intolerances, including enalapril (cough), verapamil (flushing), hydralazine (palipitations) and prazosin (nausea). Her current medications include candesartan 16mg daily, clonidine 100µg qid and salbutamol (for asthma). There is no family history of hypertension. Her office BP is 210/110mmHg (confirmed on repeat testing). Previous measurements at your clinic have consistently been in the range of 120-30/70-80mmHg. Her physical examination is unremarkable apart from grade 2 hypertensive retinopathy and 1+ protein on urine dipstick. Her serum biochemistry reveals normal renal function (serum creatinine concentration 60µmol/L, 2 eGFR >60mL/min/1.73m ) and an ECG demonstrates voltage criteria of left ventricular hypertrophy. Question 1: How would you manage Jane now? a. See her again in the next few days to recheck BP before considering additional antihypertensive therapy. cont’d next page 20 April 2007 | Australian Doctor | 31 AD_HTT_025_034___APR20_07 13/4/07 8:57 AM Page 32 How to treat – resistant hypertension from previous page b. Start a diuretic. c. Order a renal artery duplex scan. d. Order tests for 24-hour urinary catecholamines, plasma aldosterone:renin ratio, thyroid function and urinary free cortisol. e. Refer to a specialist. (My answer: b, c, d and e) Jane has developed recentonset, symptomatic grade 3 BP elevation with documented target-organ damage in the setting of longstanding adequately controlled hypertension, which developed at a young age in the absence of a family history or other risk factors. She is at risk of accelerated or malignant hypertension and has a high probability of secondary hypertension. Her BP requires prompt treatment to reduce it towards a target level of <140/90mmHg over the next few weeks. It is appropriate to start an additional antihypertensive medication immediately (a diuretic seems reasonable). All the listed investigations Figure 2: Renal angiogram demonstrating the classic ‘beaded’ appearance of the left renal artery, characteristic of fibromuscular dysplasia. Her blood tests were normal apart from: ■ Plasma renin activity 2.8ng/mL/hour (normal range <2ng/mL/hour). ■ Aldosterone 810pmol/L (NR 30-450pmol/L). ■ Aldosterone:renin ratio 289 (NR 80-530). A renal artery duplex found elevated flow velocities in the mid-to-distal sections of both renal arteries, with elevation of renal artery resistances, suggesting 6099% stenoses. Question 2: What should be done now? are justified and she should be reviewed within a week. Specialist referral is warranted, particularly if a secondary cause is identified. Follow-up Jane was started on candesartan/hydrochlorothiazide 16/12.5mg daily. On review five days later her BP was still elevated at 180/100mmHg. a. Arrange for a CT scan of the abdomen (focusing on the adrenal glands). b. Order an isotope renogram. c. Start an additional antihypertensive medication. d. Order a renal angiogram. e. Measure 24-hour urinary aldosterone after oral salt loading. (My answer: c and d) The investigations suggest that Jane has bilateral renal artery stenosis (probably due Hypertensive emergency and hypertensive urgency Hypertensive emergency is defined as severe hypertension with acute impairment of an organ system (eg, the central nervous, cardiovascular or renal systems). In these conditions, the BP should be lowered aggressively over minutes to hours. Typical examples would include: ■ Hypertensive intracranial haemorrhage. ■ Severe hypertension with an aortic dissection. ■ Severe pre-eclampsia. ■ Severe hypertension resulting in acute renal failure. Hypertensive urgency is defined as a severe elevation of BP without evidence of progressive target-organ damage. These patients require BP control over several days to weeks. In these patients, dropping the blood pressure acutely may be problematic because of impaired autoregulation (for example, it is possible to precipitate ischaemic strokes or acute renal failure under such circumstances). The clinical distinction between hypertensive emergencies and hypertensive urgencies depends on the presence of acutely worsening targetorgan damage and not on the absolute level of the BP. to fibromuscular dysplasia) complicated by secondary hyperaldosteronism (both renin and aldosterone concentrations elevated). She should be referred to a nephrologist or other specialist and have renal angiography. In the meantime, her BP is still significantly elevated and warrants augmentation of therapy. Follow-up Jane was started on methyldopa 500mg tds with good effect. Her angiogram confirmed the presence of bilateral renal artery stenosis due to fibromuscular dysplasia (figure 2). After bilateral renal angioplasty with stenting, her BP remains well controlled on candesartan alone. GP’s contribution DR DIANNE CHAMBERS Leichhardt, NSW Case study MJ, 61, had longstanding hypertension over the past 20 years. When she first came under my care she was taking a beta blocker and diuretic. She has a positive family history of cardiovascular disease, with her mother and father dying of infarct and stroke, respectively. She also has an uncle and three brothers who all died of MI in their 40s. Marie is overweight at 75kg (BMI 30) and has coexisting gastrooesophageal reflux disease and fatty liver (persistently mild elevation of liver enzyme levels). She is not a smoker but had LDL-cholesterol recorded at 6.8mmol/L in 1993. Initially, the thrust of treatment was to encourage weight loss and increase exercise. With this advice she managed to lose 8kg and her cholesterol level dropped. However, her BP slowly climbed and with the advent of ACE inhibitors I switched her to Coversyl (BP was 170/100mmHg before this change). Marie’s BP was not controlled so I switched her to Coversyl Plus, but this needed to be stopped because she developed ACE inhibitor cough. I switched her to Atacand Plus 150/12.5mg. Her BP was 150/95 mmHg and I increased the dose to 300/12.5mg. During 2003 she had an episode of back pain (osteoarthritis after an old back injury) and I prescribed pulse Celebrex and maintenance paracetamol. She developed a severe rash (possibly from the Celebrex) and her BP 32 | Australian Doctor | 20 April 2007 climbed to 210/110mmHg. She was sent for urgent physician review. Amlodipine was added and the COX-2 inhibitor stopped (serum creatinine concentration was 64µmol/L). BP fell but Marie developed mild pitting oedema secondary to the calciumchannel blocker. Her other medications at this time included tibolone, aspirin and Xenical. Full hypertension investigations were started. Marie had a aldosterone-renin test, a vasculitic screen, 24-hour catecholamines, a renal ultrasound and urine examination for proteinuria and haematuria. Her renal ultrasound showed kidney disproportion so she was sent for renal angiogram, which was normal, as were other investigations for renal disease. The aldosterone:renin ratio was elevated, which was said to be consistent with her prescribed angiotensin-IIreceptor blocker. Later in 2003, Marie had her first episode of angina, and an angiogram confirmed widespread coronary artery disease. She had a drug-eluting stent inserted in April 2003 but in 2004 she had an in-stent thrombosis with a moderate rise in creatine kinase level, and required further stenting. Because of her abnormal LFTs she had not previously been prescribed a statin, but Lipitor was cautiously introduced at this time. A beta blocker was recommended also, as coronary protection. Marie’s recovery was complicated by recurring pericarditis, which required prednisone (rheumatology review did not reveal any autoimmune cause). While taking steroids her BP rose to 160/90mmHg. Medication options were limited because of previous reactions to calcium-channel blockers, so the dose of her beta blocker was increased and she was started on Minipress. Initially this was 1mg bd but, as a 24-hour BP chart showed significant hypertension during the day, it was increased to tds, with some improve- ment in control. Daytime readings on the home monitor were up to 160/100mmHg, so the Minipress dose was increased to 1.5mg at lunch. Interestingly, recent cessation of vitamin E supplements also resulted in improvement in BP control. Current medications are: ■ Avapro 300mg, one tablet in the morning. ■ Cartia 100mg, one tablet daily. ■ Clopidogrel 75mg, one tablet daily. ■ Endep 25, 25mg, two tablets before bed. ■ Lasix M 20mg one tablet in the morning. ■ Lipitor 20mg, one tablet daily. ■ Metoprolol 100mg, one tablet tds. ■ Minipress 1mg, one tablet tds. Currently Marie is normotensive and the thrust of her therapy is to assist with weight loss, as her BMI is 29 despite extensive assistance from the metabolism and obesity unit. Questions for the author Primary hyperaldosteronism is listed as one of the more common causes of resistant hypertension. You suggested that abnormal plasma aldosterone:renin ratios may not be a reliwww.australiandoctor.com.au able investigation. Marie’s ratio was raised but it was considered that her medications caused elevation. As both ACE inhibitors and angiotensin-IIreceptor antagonists make interpretation difficult, can you elaborate on the investigation of Conn’s syndrome? Most antihypertensive medications (except verapamil, hydralazine and prazosin) can affect the plasma aldosterone:renin ratio (ARR). In this particular patient’s case, the elevated ARR is not consistent with her prescribed angiotensin-II-receptor antagonist, as such agents generally suppress plasma aldosterone concentrations and increase plasma renin levels, thereby decreasing ARR. Most antihypertensive agents decrease the ARR, although examples of medications that increase the ARR include beta blockers, clonidine, methyldopa and NSAIDs. To investigate the possibility of Conn’s syndrome, the recommended practice is to convert patients to reninneutral medications, such as verapamil slow release, hydralazine or prazosin, alone or in combination. In cases in which a potentially interfering medication cannot be withdrawn (eg, because of severe hypertension), useful information can still be obtained by taking into account the known effects of that medication. For example, an elevated ARR in someone who is taking a diuretic, ACE inhibitor, angiotensin-II-receptor antagonist and/or a dihydropyridine calciumchannel blocker would suggest Conn’s syndrome (as these medications ordinarily suppress the ARR). Marie required 24-hour BP monitoring. Although her resting BP was generally satisfactory, she had significant daytime elevation and needed Minipress tds. Can you comment on the usefulness of 24-hour BP monitoring and on tds regimens? Twenty-four-hour BP monitoring is a well-validated method of BP measurecont’d page 34 References Available on request from julian.mcallan@ reedbusiness.com.au Further reading 1. Rudd P. Clinicians and patients with hypertension: unsettled issues about compliance. American Heart Journal 1995; 130:572-79. 2. Yakovlevitch M, Black HR. Resistant hypertension in a tertiary care clinic. Archives of Internal Medicine 1991; 151:1786-92. Online resources For GPs Caring for Australians with Renal Impairment (CARI): www.cari.org.au ■ The seventh Joint National Committee on the Prevention, Detection, Evaluation and Treatment of High Blood Pressure: www.nhlbi.nih.gov/ guidelines/hypertension/ express.pdf ■ National Heart Foundation Hypertension Management Guide for Doctors 2004. www.heartfoundation. com.au/downloads/ hypertension_management_ guide_2004.pdf ■ National Heart Foundation patient information guide to blood pressure, selfmeasurement and dietary salt intake: www.heartfoundation.com. au/index.cfm?page=141 ■ For GPs and patients ■ National High Blood Pressure Education Program: www.nhlbi.nih.gov/ guidelines/hypertension AD_HTT_025_034___APR20_07 13/4/07 8:57 AM Page 34 How to treat – resistant hypertension from page 32 ment that correlates closely with vascular risk and outcomes, and with surrogate markers of target-organ damage (eg, left ventricular hypertrophy and albuminuria). The main indications for this investigation include: ■ Possible white-coat hypertension in patients with newly discovered hypertension and no target-organ injury. ■ Borderline/labile hypertension. ■ Poor BP control or loss of BP control despite appropriate therapy and patient compliance (as in this case). ■ Satisfactory clinic BP but progressive target-organ damage. Adding medications with twice- or thrice-daily dosing (eg, hydralazine, methyldopa) is a useful strategy that should be considered in patients with resistant hypertension, to obtain better 24-hour BP control. Prazosin (Minipress) can sion. How common is it for a treatable cause to be found? Treatable causes have been reported to occur in up to 40% of cases of therapy-resistant hypertension, although in my own (albeit skewed) experience, the figure is probably closer to 5-10%. certainly be administered tds, but medication intolerance (eg, postural lightheadedness and nasal stuffiness) is often limiting with this regimen. Stopping vitamin E resulted in improved BP control. Can you comment on herbal and vitamin contribution to BP? A recently published randomised, double-blind placebocontrolled trial has demonstrated that vitamin E can raise both systolic and diastolic BP by average values of 7 and 11 5mmHg, respectively. Many herbal products contain considerable amounts of glycyrrhizic acid, which can cause aldosterone-like effects, including hypertension and hypokalaemia. Examples include herbal cough mixtures, licorice tea, licorice root, gancao and Boui-ougi-tou (a mixture of Chinese drugs intended to cure obesity). Glycyrrhiza glabra and Glycyrrhiza radix have the same effect and can be found General questions for the author in most Chinese herbal teas. Ma huang, used to treat asthma, colds and flus, contains about 1% ephedrine and has the potential to induce hypertension. It is also noteworthy that this patient was receiving tibolone, which is associated with hypertension in 2-3% of cases and can raise the plasma ARR. Despite extensive investigation, Marie has not been found to have a cause for treatment-resistant hyperten- How to Treat Quiz 2. Which TWO statements about the taking of BP readings are correct? ❏ a) Using a BP cuff size that is too small for the patient’s arm can result in a falsely low reading ❏ b) The cuff bladder length should be at least 80% of the circumference of the upper arm ❏ c) Recent cigarette smoking has no effect on BP readings ❏ d) Older patients may have a falsely high BP reading due to a hardened brachial artery 3. Con, 62, presents as a new patient for a BP check and repeat prescription of his antihypertensive medication. He has been taking atenolol 50mg daily for six months and has been adherent with therapy. His BP is 165/98mmHg. Which THREE reasons could explain why Con’s BP is inadequately controlled? ❏ a) He is one of the 30% of patients who need more than one antihypertensive medication ❏ b) He has taken some celecoxib daily for the past few weeks for arthritis ❏ c) He has been eating liquorice recently ❏ d) He eats a diet high in salt 4. You arrange a serum creatinine test, eGFR and dipstick urinalysis for Con. His eGFR is 2 46mL/min/1.73m and his urine protein reading is 1+. He takes no other medications regularly and has no significant past history. Physical examination reveals no renal bruits or masses. Which TWO statements about Con’s further management are correct? ❏ a) He should have a renal ultrasound scan and a protein:creatinine ratio test ❏ b) He should have a non-dihydropyridine calcium-channel blocker (such as diltiazem) added to his treatment regimen ❏ c) The best diuretic choice for Con is a thiazide diuretic ❏ d) Con has stage 3 chronic kidney disease and should be prescribed an ACE inhibitor or angiotensin-II-receptor antagonist 5. In choosing appropriate antihypertensive medication for patients with resistant hypertension which TWO statements are correct? ❏ a) It is better to combine several medications at low doses than to increase a single agent to its maximal dose ❏ b) All treatment regimens in patients with resistant hypertension should ideally include a diuretic ❏ c) A potential side effect of minoxidil is fluid retention and heart failure ❏ d) Calcium-channel blockers can potentiate glaucoma 6. Melinda, 24, presents for contraceptive advice. She has been previously well, takes no medication and has not seen a doctor for several years. Her BP at this visit is 180/100mmHg, checked twice. The remainder of her physical examination is unremark- Can you explain the advantage of renal imaging with and without captopril? When should you definitely use captopril and when should you definitely not? Isotope renography without captopril has a false-negative rate of 20-25%. Administering oral captopril (25-50mg) one hour before the isotope is injected increases the positive and negative predictive values of radioisotope scanning by often augmenting the differential uptake of isotope between the left and right kidneys in the setting of unilateral renal artery stenosis. This effect is based upon the typical ACE-inhibitorinduced decline in GFR in the stenotic kidney, often accompanied by an equivalent increase in GFR in the contralateral kidney due to removal of angiotensin IImediated vasoconstriction. In the setting of bilateral renal artery stenosis this test remains relatively insensitive (although may be detected by a delay in the peak uptake of isotope to more than 10-11 minutes) and the ACE inhibitor may be potentially harmful to kidney function. The 2005 American College of Cardiology and American Heart Association guidelines recommend that the captopril renogram not be used as a screening test for the diagnosis of renal artery stenosis. I prefer renal artery duplex or isotope renography without captopril. INSTRUCTIONS Complete this quiz to earn 2 CPD points and/or 1 PDP point by marking the correct answer(s) with an X on this form. Fill in your contact details and return to us by fax or free post. FAX BACK Photocopy form and fax to (02) 9422 2844 Resistant hypertension — 20 April 2007 1. Which TWO statements about hypertension in general practice are correct? ❏ a) 29% of Australian adults have hypertension ❏ b) Blood pressure is adequately controlled in about half of people with hypertension ❏ c) Resistant hypertension is defined as an inability to reduce BP to <140/90mmHg using three antihypertensive medications ❏ d) In general practice about one-quarter of patients with hypertension have resistant hypertension In cases of white-coat hypertension I have often asked for a home BP record. How reliable are home BP machines? Most semi-automated upper-limb home BP measuring devices are generally quite reliable, provided an appropriate cuff size is used. However, wrist and finger devices are not recommended. Home BP measurements are often more reproducible than office pressure measurements and demonstrate a superior correlation with cardiovascular risk and prognosis. Their accuracy approaches that of 24-hour BP monitoring (awake average pressure), although there is a group of patients (especially elderly women) whose white-coat effect persists with self measurement. Home BP machines may also aid in compliance by involving patients in their own management. It is worth remembering that an office BP of 140/90mmHg is probably equivalent to a home BP of about 135/85mmHg. FREE POST How to Treat quiz Reply Paid 60416 Chatswood DC NSW 2067 able. She has no personal or family history of hypertension. You think Melinda may have secondary hypertension. Which THREE conditions could be causing this? ❏ a) Phaeochromocytoma ❏ b) Renal artery stenosis ❏ c) Addison’s disease ❏ d) Conn’s syndrome ONLINE www.australiandoctor.com.au/cpd/ for immediate feedback ❏ b) Alcohol consumption at any level tends to increase blood pressure ❏ c) Restricting salt to <90mmol/L/day can result in a 5-7mmHg drop in systolic blood pressure ❏ d) Roger should aim to achieve a waist circumference of ≤94cm 7. Melinda returns in a week and her BP is still at the same level. Which TWO statements about further investigation of Melinda’s hypertension are correct? ❏ a) A normal serum potassium result effectively excludes primary hyperaldosteronism ❏ b) An elevated plasma aldosterone:renin ratio is diagnostic of primary hyperaldosteronism ❏ c) Melinda should have a renal artery duplex or isotope renography to check for renovascular hypertension ❏ d) Melinda’s blood tests should include thyroid function tests and serum calcium level 9. After three months Roger returns for review. He has lost 2kg in weight but had not been able to significantly change his diet and exercise habits. His BP is 155/95mmHg and you decide to start him on an ACE inhibitor. After two weeks on this medication his repeat blood test shows his creatinine has increased to 110µmol/L, from a baseline level of 95µmol/L. Which ONE action would you now take? ❏ a) Stop Roger’s ACE inhibitor ❏ b) Arrange a renal angiogram ❏ c) Continue the ACE inhibitor and repeat the serum creatinine test in a few more weeks ❏ d) Switch from the ACE inhibitor to an angiotensin-II-receptor antagonist 8. Roger, 48, has recently been diagnosed with hypertension, with BP readings of about 160/95mmHg. He smokes 15 cigarettes daily, has a BMI of 29, with total cholesterol 5.4mmol/L and LDL-C 3.0mmol/L. He has no family history of cardiovascular disease, takes no medications and has a normal blood sugar level, electrolytes, serum creatinine and eGFR. Roger is keen to avoid taking medications and you discuss lifestyle modifications with him. Which THREE statements about lifestyle interventions for Roger are correct? ❏ a) If Roger lost 10kg in weight, this could result in up to a 20mmHg drop in his systolic blood pressure 10. Which TWO statements about managing resistant hypertension are correct? ❏ a) Patients with renal impairment need fewer medications to control their blood pressure than patients with normal renal function ❏ b) The combination of an ACE inhibitor, diuretic and NSAID should be avoided, as it can result in acute renal failure ❏ c) Patients taking spironolactone should be monitored for hypokalaemia ❏ d) A secondary cause for hypertension should be suspected when there is an acute rise in blood pressure over a previously stable value CONTACT DETAILS Dr: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 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NEXT WEEK Both macroscopic and microscopic haematuria may be a sign of serious underlying disease. The next How to Treat focuses on microscopic haematuria, which is usually asymptomatic. The author is Associate Professor Timothy Mathew, nephrologist, department of medicine, Queen Elizabeth Hospital, Adelaide; and national medical director, Kidney Health Australia. 34 | Australian Doctor | 20 April 2007 www.australiandoctor.com.au