From the Haemostasis, Thrombosis & Vascular Biology Unit, University Department ofMedicine, City Hospital, Birmingham, UK The term ‘microalbuminuria’ has been introduced thelial damage or dysfunction, such as von to describe a measurable increase in urine albumin Willebrand factor, suggests the possibility that excretion, which is still within normal total urine microalbuminuria may be a simple, cheap and easy protein excretion levels. Many data suggest that index of endothelial abnormalities in cardiovascular microalbuminuria is of value as an index of vascular disease. Nevertheless, further information on the damage, especially in hypertension and diabetes, value of microalbuminuria in other atherosclerotic and there is increasing information on its associ- vascular complications, such as ischaemic heart ations with traditional cardiovascular risk factors disease, stroke and peripheral artery disease is still and its prognostic value. The association between microalbuminuria and peripheral markers of endo- The various components of urinary protein excretion protein excretion in the urine. The usual screening are useful indicators of renal function. The biggest method for the detection of proteinuria is the fraction of protein excreted in normal urine consists dipstick (for example, ‘Albustix’) which has a of Tamm-Horsfall protein, which originates from sensitivity of 150–300 mg/l. However, even with afive-fold increase of albumin excretion, the total renal tubular cells. Low-molecular-mass plasma urine protein (as detected by Albustix) may remain within normal range, and so increased levels of albuminuria may be undetected.3 Nevertheless, such through the glomerular basement membrane and changes may have pathological significance. For reabsorbed by tubular cells,1 and thus an increase example, Viberti et al.4 showed in 1982 that in their urinary excretion indicates tubular damage.
increased albumin levels, even within the ‘normal’ On the other hand, medium-size (40–150 kDa) proteinuric range, may herald the onset of nephro- plasma proteins are precluded almost completely pathy in insulin-dependent diabetes mellitus (IDDM) from glomerular ultrafiltrate and therefore any patients, whilst Parving et al.5 reported in 1974 that detection in urine of these proteins indicates increased urine albumin excretion (UAE) can be alteration of the glomerular barrier. Proteins such found in poorly-controlled hypertensives. The term albumin, transferrin, immunoglobulin G, caerulo- ‘microalbuminuria’ was therefore introduced to plasmin, a1-acid glycoprotein and the HDL particles describe such an increase in urine albumin are typical examples of the latter category.2 excretion, which was still within normal total urine Albumin is the major constituent of abnormal Address correspondence to Dr C. Lydakis, University Department of Medicine, City Hospital, Birmingham B18 7QH.
e-mail: greg@chtmedicine.demon.co.uk
cardiovascular risk in Black subjects, even with mild increases of blood pressure, when compared with The term ‘microalbuminuria’ was introduced by Viberti et al.4 to refer to a subclinical rise in UAE Age correlates positively with UAE in both normo- >30 mg/24 h in patients with IDDM. The definition and hypertensives, perhaps due to a degree of has also been applied to patients with essential nephrosclerosis that accompanies age (which is hypertension; although the same as that used in greater in hypertensives).21 By contrast, a negative diabetes, this definition may not be necessarily correlation was noted between UAE and age in the correct. It would be more relevant to study UAE in population study from New Zealand, which was a large background population with exactly the same attributed to the progressive reduction of glomerular techniques and procedures as in essential hypertens- ive patients, and to define abnormal albuminuria as increased UAE rate has been reported in the erect the level above (say) the 95th percentile.6 For position22 and during exercise23 in both normo- and example, in a study from the general population with 5670 subjects (using random urine samples) inNew Zealand, the 97.5th percentile concentrationof UAE was 28 mg/l for men and 29 mg/l for women.7 The UAE rate can vary highly from day to day, by up to 40%.8 Early-morning urine specimens have been reported to have smaller variations,9 but large Several methods are used for measuring UAE, such variations in morning and night specimens have as nephelometry,12 immunoturbidimetry,24 immuno- previously been noted.10,11 Measurement of the 24-h assay with latex bodies,25 radial immunodiffusion,26 urine collection has probably the lowest variability.
fluroimmunoassay,27 and enzyme immunoassay.28 In one study, for example, the coefficients of variation Urine albumin is stable at room temperature, so in daily, overnight and 24 h urine collections were urine specimens can even be sent by post.29 Urine 50%, 58% and 44%, respectively.12 Due to this wide specimens can be stored in the fridge at −4 °C for variation, more than one urine collection has been 8 weeks, although for periods longer than 2 weeks advocated as necessary before convincingly labelling the addition of preservative (sodium azide) is a patient as ‘microalbuminuric’.
Other factors should also be taken in account An important issue in measuring urine albumin is when evaluating patients for microalbuminuria the high variability in the measurements within and (MAL). For example, normal variations in UAE can between laboratories. In a study which was designed occur with exercise,13 with increased diuresis14 and to estimate existing variability, aliquots with albumin within 24 h, being higher during day than night.15 concentrations at or near the normal range were sent The latter diurnal variation could be the result of to five laboratories; the assays used were immunotur- greater activity during the day or higher blood bidimetry, enzyme immunoassay, fluoroimmuno- pressure values throughout day time, or could simply assay, and zone immunoelectrophoresis.30 Variability be due to a true circadian rhythm in excretion rates.
was equally attributable to differences in precision Furthermore, gender and obesity are also factors of individual immunoassays and to variation within which play a role. In a large population study from each laboratory; however, total variance between New Zealand, body mass index (BMI) was found to laboratories ranged between 43.8% to 51.4%, while correlate positively with UAE, but only for subjects that due to within-laboratory variance ranged of European ethnicity, and only for BMI values between 48.6% to 56.2%, with the immunoturbidi- >25.9 kg/m2 for men and >28.9 kg/m2 for women, metric method having the greater variability.
with no differences between sexes.16 By contrast, astudy of 1046 non-diabetic subjects found slightlyhigher UAE values in men compared with women,and also an inverse correlation between UAE and height.17 On the other hand, no significant correlation between BMI and UAE was found in an Americanstudy of 1298 non-diabetics.18 Ethnicity may be The glomerular transmembrane transport of albumin another important factor in UAE rates. For example, depends upon several factors: the electric charge subjects of Asian origin (Maori and Pacific natives) and size of the molecule, membrane status and have been found to have greater UAE values than specific renal haemodynamics.31 The fractional clear- those of European origin.16 In addition, the correla- ance of albumin, which is defined as the fraction of tion of UAE and blood pressure is greater in Black albumin clearance to filtration rate, is normally very than in White subjects,19,20 consistent with the greater low (<0.1%) due to the negative charge and to the comparatively large molecular size of albumin (with intrarenal vascular dysfunction exists in hyper- a molecular mass of 69 kDa). However, albumin excretion is altered in many physiological and patho- Hyperfiltration may also be present in 10–15% of newly hypertensive patients.43 In some studies ‘renalfunctional reserve’, that is, the ability of the kidneyto increase RPF and GFR through renal vasodilatationafter a protein meal, has been used to assess the hyperfiltration status. It has been reported that renal In hypertension, specific haemodynamic conditions functional reserve was reduced in hypertensives with may lead to increased albumin transmembrane normal renal function44 and in offsprings of hyper- escape. For example, the basic findings in hypertens- tensive subjects.45 These observations suggest that ives are low renal plasma flow (RPF) and increased hyperfiltration was already present even before a renal vascular resistance, with maintenance of the protein meal intake, resulting in the kidney being glomerular filtration rate (GFR), suggesting an unable to increase the GFR further after the protein increase in the filtration fraction (FF).32,33 This can meal. On the other hand, other studies do not seem be attributed either to the unimpeded transmission of systemic blood pressure within the glomerulus, or Indeed, blood pressure levels correlate signific- to increased post-glomerular vasoconstriction (of the antly with UAE in hypertensives and probably in efferent arteriole).32 However, Hollenberg et al.34 normotensives. Both office systolic47–49 and dia- showed that the reduction in RPF is at least a partly stolic,49,50 as well as 24-h systolic and diastolic48,50,51 functional phenomenon, since dopamine, phentol- blood pressure levels, have been shown to correlate amine and acetylcholine can reverse it.
with UAE in hypertensives. Although some studies In addition, pharmacological inhibition of the have shown a correlation with UAE, this relationship action of angiotensin II causes renal vasodilatation is only with 24-h blood pressure measurements and in hypertensives.35 Small doses of angiotensin II not with single office values,52,53 with a regression normally causes renal vasoconstriction in hypertens- coefficient for this association ranging from 0.32 to ives, but this does not appear to be the case in 0.62. The strongest correlations are seen when 24-h normotensives.36 This might mean however that blood pressure measurements were used, suggesting sensitivity to angiotensin II infusion is higher in that the 24-h ambulatory blood pressure monitoring hypertensives than normotensives. Increased sensit- is more reliable than casual measurements in evalu- ivity to angiotensin II has also been documented in ating early target-organ damage.54 Hypertensive normotensive subjects with positive family history subjects without the normal night time fall in blood of hypertension, since a reduction of RPF and GFR pressure (‘non dippers’) have higher UAE values after infusion of this peptide was greater than in the when compared to hypertensives with dipping control group.37 Angiotensin II is considered to maintain GFR (although RPF is reduced) through Several studies in general (unselected) popula- selective constriction of the efferent arterioles,38 thus tions55,56 or in non-diabetic populations57,58,60 have increasing the intraglomerular hydraulic pressure shown either positive correlations between UAE and and leading to increased membrane permeability to systolic57–59 or diastolic blood pressures,55,58,59 or a protein. In two studies, infusion of angiotensin lack of any correlation.56,60 However, these studies II increased proteinuria in rats,39,40 and either collection methods, including morning or casual or increase of membrane permeability, perhaps due to overnight or 24-h urine collections. In the largest an increase of membrane pore size, are the population study from New Zealand involving 5349 subjects, using morning specimen collections, a These pathophysiological mechanisms are closely positive correlation was noted only with diastolic correlated with clinical observations. Higher GFR values have been documented in a microalbuminuricgroup of hypertensive patients when compared witha normoalbuminuric group.41 Another study in hypertensive subjects showed that microalbuminuricsubjects had higher plasma renin activity levels after MAL has been established as a major risk factor for being given captopril, when compared to normo- the evolution of overt nephropathy and other micro- albuminurics.42 Renal vasodilatation was also less and macroangiopathic complications in patients with prominent in hypertensive microalbuminurics after both insulin-dependent62 and non-insulin-dependent captopril, compared with hypertensive normoalbumi- diabetes.63,64 High intraglomerular pressure, hyper- nurics.15 The latter findings indicate that a state of filtration and increased GFR have been documented in the early stages of nephropathy secondary MAL in pregnant women during the third trimester may be an early predictor of pre-eclamptic complica- It is also well recognized that a significant associ- tions.74 Finally, other conditions, such as exacerba- ation exists between UAE and peripheral insulin tions of psoriasis have been reported to correlate resistance. In the diabetic Munich Wistar rat model, with UAE independently of sex, age and blood administration of insulin normalized glomerular capillary pressure, suggesting that glomerular hyper-tension (and subsequent increased UAE) in diabetesmay be related to insulin deficiency rather than glomerular hypertrophy.66 Insulin resistance has alsobeen associated with increased renal sodium reab- sorption.67 These observations suggest that hyper- insulinemia may be one causal factor for thedevelopment of MAL.
The association between MAL and cardiovascular In a study of 333 treated hypertensives, UAE was risk has been closely studied in hypertensives.
found to correlate with BMI, waist-to-hip ratio, fasting However, the prevalence of MAL in hypertension insulin levels and sum of insulin levels at times varies in different studies from 11%47 to 40%76 or 0, 30, 60, 90 and 120 min during an oral glucose greater, depending upon the number of patients tolerance test (OGTT).68 In another study of 25 studied, severity of hypertension, age, race and hypertensives and 20 controls undergoing an OGTT, microalbuminuric hypertensives had higher values Correlations between UAE and several cardiovas- of insulin area-under-the-curve values, when com- cular risk factors have been observed in hypertensive pared to 15 normoalbuminuric hypertensives.47 patients. For example, hypertensives with MAL have The above studies suggest that there is an higher left ventricular mass than normoalbuminur- association between MAL and hyperinsulinaemia, ics.50,52 In a further study with 74 patients with and presumably insulin resistance in hypertensive untreated hypertension, there was a positive correla- tion between left ventricular mass and UAE, but only between MAL and hyperinsulinemia per se is, how- in men and not in women.77 Hypertensives with ever, obscure. It is possible that both these phen- other risk factors such as smoking or hyperlipidemia omena are genetically determined and co-segregate show greater target organ damage in patients in the same patient, or that hyperinsulinaemia may with MAL, with cardiovascular disease being 50% cause hypertension and MAL, perhaps by altering higher in microalbuminurics.68 The levels of UAE membrane permeability and causing renal damage; were also significantly correlated with body mass alternatively, they may both be a consequence of index and waist to hip ratio, which have recognised the same (as yet unknown) pathogenetic factor.69 The thickness of the intima and media layers of the carotid artery is higher in microalbuminuric hypertensives in comparison to normoalbuminuric Several other diseases or pathological situations are hypertensives and normotensive controls.78 In the associated with MAL. In cases of patients suffering same study, other cardiovascular risk factors, such from burns, trauma,70 muscle ischaemia or pancreat- as total cholesterol, triglycerides, lipoprotein (a), itis high values of UAE have been reported during insulin area-under-the-curve and glucose area-under- the acute phase, which remain high especially if the-curve, were significantly more prevalent among septic or respiratory complications occur.71 MAL has been reported during exacerbations of inflammatory In a large study of 11 343 non-diabetic hypertens- bowel disease72 and rheumatoid arthritis,73 and ives from a general population sample, the preval- remissions of these conditions are often followed by ence of MAL was 30%.79 The analysis showed that normalization of UAE. These observations suggest microalbuminurics (compared to normoalbuminur- that UAE may perhaps behave like an acute-phase ics) had a higher prevalence of hyperlipidemia reactant. The postulated mechanism of albumin leak- (57.4% vs. 52.2%), coronary artery disease (31% age through the kidney in such diseases is that there vs. 22.4%), peripheral vascular disease (7.3% vs.
is increased microvascular permeability secondary 4.9%), myocardial infarction (7% vs. 4%) and stroke to increased circulating inflammatory mediators, such (5.8% vs. 4.2%). In addition, MAL was a risk factor as the cytokines.72 MAL may thus reflect either the which was independent of age, duration of hyper- direct effect of cytokines on the renal matrix or tension and degree of blood pressure elevation.
indirect effects mediated through an inflammatory MAL has also been regarded as a marker of cell infiltrate into the affected kidney.72 generalized endothelial damage. The latter is the basis of the Steno hypothesis, where that the hypertensive complications, not all the questions transmembrane passage of albumin (which is nega- tively charged) is facilitated when the production ofheparan sulphate (the main negatively chargedmolecule in the glomerular basement membrane) is reduced; poor glycaemic control inhibits the Some studies, particularly in hypertensives, imply enzyme N-deacetylase (which is responsible for that MAL is accompanied by higher levels of blood heparan sulphate production).80 Transcapillary albu- lipids.88,89 For example, UAE has been significantly min leakage is not confined only to the glomerulus correlated with serum triglyceride levels (even on a but may occur also in the retina and other vascular multivariate analysis),88 and VLDL, triglycerides and beds.80 In support of this, increased transcapillary lipoprotein (a).89 A large study of 11 343 non-diabetic escape of albumin has been observed in hypertens- hypertensives also reported that the microalbumin- ives, contributing to the development of MAL,81,82 uric subgroup had a higher prevalence of hyperlipid- and hypertensives with MAL have increased levels aemia in comparison to normoalbuminurics (57.4 of von Willebrand factor, an established marker of vs. 52.2%).70 Another report of 12 patients with endothelial dysfunction, when compared to hyper- tensives with normal UAE and with normotensive of UAE, HDL, LDL and lipoprotein (a) when com- controls.83 Furthermore, in a Japanese study where pared with patients with salt-resistant hypertension.90 several markers of endothelial dysfunction were By contrast, another study of 313 hypertensives investigated in a group of 61 elderly hypertensives, found no relationship between various lipid compon- the microalbuminuric subgroup showed significant elevations of activated Factor VII (FVIIa), vonWillebrand factor and thrombomodulin, comparedwith a normoalbuminuric group and a group of patients with ‘white coat’ hypertension.84 The Obesity is considered to be a well-recognized risk increased levels of such markers might account for factor for increased morbidity and mortality, usually the higher cardiovascular risk in hypertensive from cardiovascular complications.90–92 It has been patients with MAL. A further assumption of the postulated that high intake of food, including protein, hypothesis that MAL is an index of endothelial can lead to renal hyperfiltration and renal impair- dysfunction is that a widespread transcapillary ment.93 Consistent with this hypothesis, proteinuria94 escape of albumin and other plasma proteins not and focal glomerulosclerosis have been reported in only occurs at the capillary level but also in other obese patients,95 with strong correlations between parts of the vascular tree (such as the coronary vessels) thus triggering or contributing to the volume.96 A correlation of UAE with waist-to-hip ratio and insulin levels has also been noted in However, not all the evidence is fully supportive hypertensive men68 and in obese healthy subjects.97 of generalized vascular or target-organ damage in These findings imply that MAL may be one of the microalbuminuric patients. For example, where metabolic abnormalities that accompany central-type direct vasodilatation of the forearm vascular tree obesity; these have been included together as part after infusion of acetylcholine and nitroprusside was of the insulin resistance syndrome (‘syndrome X’).
measured in hypertensives and normotensives, therewere no significant differences in the type and degreeof vascular response between micro- and normoalbu- minuric hypertensives.85 Furthermore, in a prospect-ive follow-up of 345 non-diabetic hypertensive men In hypertensive subjects, an increased prevalence of with several risk factors, it was observed that the hypertensive retinopathy has been reported in mic- increased risk for cardiovascular events occurred roalbuminuric patients.50,98 In another study of 84 only in patients with UAE above 100 mg/12 h, corres- poorly-controlled hypertensives, the prevalences of ponding to macroalbuminuria rather than MAL.86 retinopathy in patients with irreversible MAL (n= Results from the HARVEST study in 870 young 12), patients with reversible MAL (n=27) and hypertensives (up to 45 years old) reported that no patients with normoalbuminuria (n=45) were 85%, significant correlation existed between left ventricular 33% and 31%, respectively.89 The significantly mass and UAE,87 suggesting that in the initial phase higher prevalence of retinopathy in patients with of hypertension, renal and cardiac involvement do irreversible (after short intensive therapy) MAL was considered to be compatible with the hypothesis Overall, although it is generally accepted that the that MAL is a marker of widespread diabetic presence of raised UAE levels increases the risk for demonstrated in smokers irrespective of their blood Smoking correlates positively with UAE in patientswith IDDM on univariate analysis,99,100 but not onmultivariate analysis.101 This suggests that smoking probably plays a minor role in the evolution ofdiabetic nephropathy.
MAL can be altered by therapeutic interventions, In the general population, however, a positive particularly in hypertensive subjects. Indeed, the correlation between smoking and UAE was found in positive correlation between blood pressure levels the New Zealand study.55 By contrast, other studies and MAL implies that lowering of blood pressure in hypertensive populations did not find any signific- could reduce UAE levels as well.43 This has been ant relationship between UAE and smoking.68,89,102 substantiated by several studies, using different anti- Smoking status also did not appear to contribute hypertensive drugs. An unanswered issue, however, to UAE variation in three groups of hypertensives is whether different classes of antihypertensive drugs (one microalbuminuric, one normoalbuminuric and exert different and specific actions in the kidney.
one healthy controls), once von Willebrand factor Bianchi et al.106 studied hypertensives with four different classes of drugs (chlorthalidone, atenolol, nitrendipine and enalapril) given in random order between MAL and endothelial damage or dysfunction but despite a similar effect on blood pressure in diabetics.103,105 Increased von Willebrand factor lowering, only enalapril significantly reduced UAE.
levels, an index of endothelial damage, have been Similar decreases in UAE following treatment withquinapril or captopril have been noted.107 By con- trast, some reports suggest that the calcium antagon-ists, such as isdradipine had no significant influence on UAE.108 These studies suggest that angiotensin- converting-enzyme (ACE) inhibitors had a morespecific capacity to reduce UAE compared to other antihypertensive drugs. This favourable effect may be a consequence of the decrease in intraglomerular pressure, and glomerular permeability or selectivity.43 By contrast, in another study mild hypertensives were treated with 12-week courses of doxazosin, felodipine, metoprolol and ramipril, and all four drugs reduced both blood pressure and UAE to the same extent. The reduction of blood pressure per se had beneficial effects on UAE levels, irrespective of specific drug actions.109 The authors therefore suggest that in patients with mild hypertension but without elevation of the filtration fraction (as is usually the Microalbuminuria in various cardiovascular disorders complications.
Established significanceof reversibility case with younger hypertensives), no special and insulin levels during OGTT when compared to expensive antihypertensive treatment (such as ACE normoalbuminurics.60 A recent Finnish study in 1069 inhibitors) is required, in contrast to diabetic patients non-diabetic subjects also found that high UAE values correlated with coronary morbidity and mor- Overall, it seems that antihypertensive therapy can tality (with OR of 5.93 and 3.39, respectively) and reduce high levels of UAE (to a larger or lesser the coexistence of MAL and hyperinsulinaemia was extent with different antihypertensive drugs). Long- an even stronger cardiovascular risk factor.114 Finally, term treatment would be expected to cause perman- an British study of 1046 White non-diabetics reported ent reduction of albuminuria and to have a beneficial a positive correlation between UAE with blood effect on renal haemodynamics. Hartford et al.110 pressure (in men) age, impaired glucose tolerance showed that even 7 years of effective treatment of and a negative correlation with height.18 hypertensive patients eventually resulted in normal- ization of initial increased UAE levels and a decrease normotensive non-diabetic microalbuminuric sub- in renal vascular resistance, with no change in GFR jects have a more atherogenic profile and tend to compared with control subjects. Large prospective be more insulin-resistant than normoalbuminurics.
randomized trials are needed to investigate whether Measurement of UAE in the general population can reduction of MAL reduces the long-term cardiovas- thus be helpful in the evaluation of patients with Changes in MAL in various cardiovascular disordersare likely to be more than an epiphenomenon. Data Yudkin et al.111 in 1988 were the first to report that, suggest that it is of value as an index of vascular in non-diabetic subjects, UAE significantly correlated damage, especially in hypertension and diabetes, with prevalence of atherosclerotic arterial disease and increasing information on its associations with with odds ratio (OR) of 6.38, especially the risk of traditional cardiovascular risk factors and its pro- peripheral vascular disease (with OR of 7.72).
gnostic value is becoming available. The association Damsgaard et al.112 also reported a decreased sur- between MAL and peripheral markers of endothelial vival rate in 216 microalbuminuric nondiabetics damage or dysfunction suggests the possibility when compared to normoalbuminuric subjects. In that MAL may be a simple, cheap and easy measure the large population study from New Zealand, the of endothelial abnormalities in cardiovascular dis- parameters that correlated positively with UAE in a ease. This opens the possibility of assessing various multivariate regression model) were BMI, diastolic treatment modalities, for example, antihypertensive pressure, smoking, sex and ethnicity, with Asians drugs, and their effects in reversing MAL. Never- having greater risk than subjects of European theless, further information of the value of MAL in origin.55,113 The strongest risk factor found for the investigation of other atherosclerotic vascular developing MAL was in fact the existence of hyper- complications, such as ischaemic heart disease, glycaemia and impaired glucose tolerance.
stroke and peripheral artery disease is still necessary.
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