Microalbuminuria in Essential Hypertension

G Crippa Hypertension Unit, Department of Internal Medicine, Civil Hospital, Via Taverna 49, 29100 Piacenza, Italy

Microalbuminuria (urinary albumin excretion equal to to blood pressure reduction, but angiotensin-converting 30–300 mg/24 h) is a reliable indicator of premature enzyme inhibitors and angiotensin-II-receptor antagon- cardiovascular mortality in diabetic patients and in the ists show an additional beneficial effect on urinary general population. In insulin-dependent and non-insu- albumin excretion. Whether the reduction of micro- lin-dependent diabetes mellitus microalbuminuria is a albuminuria obtained through pharmacological inter- marker of initial diabetic nephropathy and predicts the vention has favourable prognostic implications remain evolution toward renal insufficiency. In essential to be demonstrated. However, screening for micro- hypertension the clinical and prognostic role of microalbuminuria is a relatively easy and inexpensive pro- albuminuria is more controversial. While it is a recog- cedure and reveals a potentially treatable abnormality. nised marker of cardiovascular complications and a Thus, considering that microalbuminuria identifies reliable predictor of ischaemic heart disease, its prog- hypertensive subjects at higher risk than standard, uri- nostic value on the risk of progressive renal alterations nary albumin excretion should be routinely measured in is still uncertain because no prospective studies, taking hypertensive patients and, in the presence of micro- microalbuminuria as a selection criterion and renal albuminuria, antihypertensive treatment should be insufficiency as an end point, are available. Blood intensified in order to obtain an optimal blood press- pressure control with antihypertensive drugs is ure control. accompanied by a reduction in urinary albumin Journal of Human Hypertension (2002) 16 (Suppl 1), S74– excretion. The favourable effects of antihypertensive S77. DOI: 10.1038/sj/jhh/1001348 agents on microalbuminuria appear to be proportional

Keywords: cardiovascular risk; essential hypertension; microalbuminuria; renal disease

Introduction microalbuminuria as a predictor of impaired renal function remains controversial among hypertensive Microalbuminuria (urinary albumin excretion subjects because no prospective studies taking ␮ (UAE) of 20–200 g/min, corresponding to 30– microalbuminuria as a selection criterion and renal 300 mg/24 h) has been regarded as an important insufﬁciency as an end point are available. prognostic indicator since, in various clinical conditions, has shown to be related with higher cardiovascular risk and progressive renal damage. Signiﬁcance of microalbuminuria In insulin-dependent and non-insulin-dependent Experimental and clinical studies recognise two diabetes mellitus microalbuminuria is also a reliable major causes for the increased UAE in essential marker of initial diabetic nephropathy, predicts the hypertension: appearance of overt proteinuria and the evolution toward chronic renal failure.1–3 • haemodynamic changes leading to elevation in In maturity onset diabetes and in elderly subjects, intraglomerular pressure; microalbuminuria predicts premature cardiovascu- • generalised angiopathy, perhaps related to endo- lar mortality3,4 and in men of the general population thelial dysfunction, characterised by renal and aged Ͼ40 years is an independent risk factor for cor- systemic transvascular albumin leakage. 5 onary artery disease. Among hypertensive patients the prevalence of In essential hypertension, microalbuminuria is a microalbuminuria is about 25% and is higher than recognised marker of cardiovascular complications that observed in diabetic patients (20%).7 and a reliable predictor of ischaemic heart disease.6 Conversely, the prognostic value of increased UAE Microalbuminuria and cardiovascular risk

Correspondence: G Crippa, MD, Hypertension Unit, Civil Hosp- Microalbuminuria is related to a number of clinical tial, Via Taverna 49, 29100 Piacenza, Italy variables such as age, gender, race, hyperglycaemia, E-mail: crippagȰaltrimedia.it hyperlipaemia, hyperinsulinaemia, hypertension, Microalbuminuria in essential hypertension G Crippa S75 obesity, left ventricular hypertrophy, smoking hab- hypertensive subjects with enhanced UAE show a its, diet etc. Practically, all recognised cardiovascu- loss of nocturnal blood pressure decline (non- lar risk factors are related to microalbuminuria. dipping pattern)22 as it happens in more severe However, they do not account for the whole vari- degrees of essential hypertension and in patients ance in UAE8 as if other and still unknown determi- with hypertension due to renal disease. Whether nants could be more important in the pathogenesis microalbuminuria indicates an underlying renal dis- of microalbuminuria and its relationship with car- ease or an early renal damage due to hypertension diovascular diseases. remains to be elucidated. Microalbuminuria has a definitely higher preva- Thus, if there are no unequivocal evidence that lence in hypertensive subjects than in the general microalbuminuria is a marker for developing renal population7,9 and there is convincing evidence of insufficiency there are at least strong hints that sup- independent relationships between its presence and port this conclusion. Increased UAE seems to ident- diastolic blood pressure levels,10 pulse pressure, and ify a subgroup of hypertensive patients at higher risk isolated systolic hypertension.11 of developing renal (and cardiovascular) compli- These relationships become even closer when cation. It has been found that macroalbuminuria blood pressure levels are evaluated through ambu- (UAE Ͼ300 mg/24 h, detectable with reactive strips) latory blood pressure monitoring12–14 which pro- is related with a progressive decline in renal func- vides a more precise estimation of the real blood tion17 and it is difficult to postulate that renal dis- pressure status. ease with overt proteinuria does not pass through Microalbuminuria (as well as the other major car- a microalbuminuric stage. Assessing the prognostic diovascular risk factors) could simply reflect an aug- value of microalbuminuria in monitoring the pro- mented susceptibility to atherosclerosis linked to gression of hypertensive renal alteration is very dif- common pathogenetic factors (for instance endo- ficult since end-stage renal disease takes a long time thelial dysfunction). to become established.23 However, considering that The relationship between microalbuminuria and either glomerular filtration rate decline or pro- atherosclerotic processes seems very tight and teinuria are not sensitive end points in the mildest increased UAE has been considered a marker of forms of renal disease (such as the one related to prevalent subclinical atherosclerosis.15–17 essential hypertension) it emerges that micro- Clinical studies have clearly shown that among albuminuria can be considered the best surrogate hypertensive patients with microalbuminuria an end point to evaluate hypertensive patients at risk increased cardiovascular risk exists compared to of developing renal failure. normoalbuminuric patients with similar blood pressure levels.10 This correlation is particularly evident for coron- Antihypertensive drugs and ary artery disease: it has been pointed out that microalbuminuria microalbuminuria is the strongest independent determinant of ischaemic heart disease since confers Blood pressure control with antihypertensive medi- a four-fold increased risk for this illness among cations is accompanied by a reduction (but not a hypertensive or borderline hypertensive subjects.6 normalisation) in UAE. Redon has performed a com- prehensive review of the most recent studies (1990– 1998) to assess whether antihypertensive agents differ Microalbuminuria and renal disease with respect to their action on microalbuminuria.24 Among hypertensive patients the relationship Although some data are discordant, all of these between increased UAE and impaired renal function studies showed that reduction of blood pressure is still uncertain. with ACE-inhibitors, some calcium channel block- Microalbuminuria might be an expression of renal ers, beta-blockers, diuretics, alpha-1-blockers and damage induced by hypertension but also the sign angiotensin-II receptor antagonists also reduce UAE. of a generalised vascular alteration.18 The role of Furthermore, the majority of the studies report bet- microalbuminuria as a prognostic indicator of future ter outcomes for ACE-inhibitors when compared renal damage has only been demonstrated in dia- with other drugs, except for the angiotensin-II recep- betics1 while in essential hypertension no such data tor antagonist losartan, which results at least as are available yet. effective as enalapril. What is certain, in essential hypertension, is that The favourable effects of antihypertensive agents microalbuminuria is associated with other con- on microalbuminuria appear to be proportional to ditions characterised by high risk profile and poorer blood pressure reduction, but angiotensin-con- renal prognosis. In fact, increased UAE is more verting enzyme (ACE)-inhibitors and angiotensin-II prevalent in salt-sensitive, high-renin, obese and receptor antagonists show an additional beneficial African-American hypertensives,19–21 conditions effect on UAE which is independent of blood press- that are known to be related with a higher preva- ure reduction. lence of renal insufficiency than the rest of the In different studies and models, treatment with hypertensive population. Furthermore, essential nifedipine has shown controversial effects on uri-

Journal of Human Hypertension Microalbuminuria in essential hypertension G Crippa S76 Table 1 Changes in systolic and diastolic blood pressure (BP) (mm Hg, mean ± s.d.) and urinary albumin excretion (␮g/min, mean ± s.d.) in microalbuminuric hypertensive patients before and after medication with various antihypertensive drugs

Medication No. Systolic BP Diastolic BP Albumin

Before After Before After Before After

Nifedipine 10 mg 16 161 ± 9 145 ± 8** 94 ± 584± 4** 67.8 ± 32 98.3 ± 36* t.i.d. Captopril 25 mg t.i.d 16 160 ± 8 142 ± 6** 94 ± 382± 3** 64.5 ± 31 38.5 ± 27** Nifedipine GITS 16 158 ± 10 140 ± 8** 93 ± 380± 3** 61.8 ± 38 45.0 ± 32* 30 mg o.d. Enalapril 20 mg o.d. 16 160 ± 11 141 ± 9** 95 ± 382± 2** 62.4 ± 23 35.7 ± 17**

No., number of patients; t.i.d., thrice daily; o.d. once daily. **P Ͻ 0.01, *P Ͻ 0.05 before vs after treatment (Student’s t-test for paired data, ␣ level Ͻ0.05).

nary protein excretion with some data indicating a In hypertensive patients, screening for micro- decrease, and others an increase in albuminuria.25–28 albuminuria is a relatively easy and inexpensive pro- These conflicting results could be due to the dif- cedure and reveals a potentially treatable abnormality. ferent actions of the short-acting and the long-acting Thus, in the presence of increased UAE, indepen- (GITS) formulation of this drug. In a first investig- dently from its intrinsic significance (renal damage ative series we evaluated the effect of short-acting secondary to hypertension or underlying renal and nifedipine and captopril fixed doses on UAE.29 systemic endothelial dysfunction) antihypertensive Thirty-two patients with untreated mild-to-moder- treatment should be intensified and blood pressure ate essential hypertension and microalbuminuria, control optimised, since microalbuminuria identifies after a 4-week period of low-sodium fixed-protein hypertensive subjects at higher risk than standard. diet, were randomly treated with nifedipine (10 mg thrice daily) or captopril (25 mg thrice daily). UAE (average of two 24-h collections) at baseline was References compared with that observed after 12 weeks of phar- 1 Mogensen CE et al. Microalbuminuria an early marker macological treatment. The same protocol was later of renal involvement in diabetes. Uremia Invest 1985– carried out in a group of other 32 mild-to-moderate 86; 9:85–95. hypertensives to investigate the effect of long-acting 2 Deckert T et al. Microalbuminuria. Implications for (GITS) nifedipine 30 mg vs enalapril 20 mg.30 micro- and macrovascular disease. Diabetes Care 1992; The results of the two studies are summarised in 15: 1181–1191. Table 1. As expected, both ACE-inhibitors reduced 3 Mogensen CE. Microalbuminuria predicts clinical proteinuria and early mortality in maturity onset diabetes. UAE at the same extent. The two different formu- N Engl J Med 1984; 310: 356–360. lations of nifedipine showed opposite effects on 4 Damsgaard EM et al. Microalbuminuria is a predictor microalbuminuria: short-acting nifedipine signifi- of increased mortality in elderly people. Br Med J cantly increased while nifedipine GITS significantly 1990; 300: 297–300. decreased UAE, despite very similar effects on 5 Yudkin JS, Jackson CA. Microalbuminuria as predictor blood pressure. of vascular disease in non-diabetic subjects. Lancet These data indicate that the particular pharmaco- 1988; ii: 530–533. dynamics and pharmacokinetics of short-acting 6 Jensen JS et al. Arterial hypertension, microalbumin- nifedipine (characterised by rapid absorption, uria, and risk of ischemic heart disease. Hypertension abrupt onset and short duration of action), determin- 2000; 35: 898–903. 7 Parving HH. Microalbuminuria in essential hyperten- ing quick vasodilatation and reflex vasoconstriction sion and diabetes mellitus. J Hypertens 1996; 14 due to neurohumoral activation, may play an (Suppl 2): S89-S93. important role in this apparent discrepancy on UAE. 8 Marre M, Bouhanick B, Berrut G. Microalbuminuria. In fact the rapid fluctuation of systemic blood In: Brenner D (ed). Current Opinion in Nephrology and pressure, caused by short-acting nifedipine, could Hypertension. Current Science: Philadelphia, 1994, ‘catch’ the preglomerular and afferent arteriole still pp 558–5638. dilated when systemic blood pressure is increasing 9Ho¨mer D, Fliser D, Klimm HP, Ritz E. Albuminuria in due to sympathetic and hormonal activation, normotensive and hypertensive individuals attending allowing a greater transmission of systemic blood office of general practitioners. J Hypertens 1996; 14: pressure to the glomerular capillaries and thus aug- 655–660. 10 Redon J et al. Factors related to the presence of micro- menting albuminuria. albuminuria in essential hypertension. Am J Hypert- Whether the reduction of UAE determined by dif- ens 1994; 7: 801–807. ferent pharmacological interventions has favourable 11 Cirillo M et al. Pulse pressure and isolated systolic prognostic implications remains to be demonstrated hypertension: association with albuminuria. Kidney through ad hoc designed studies. Int 2000; 58: 1211–1218.

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