Is microalbuminuria a predictor of cardiovascular and renal disease in patients with essential hypertension?

Introduction The term microalbuminuria refers to urinary albumin excretion (UAE) that is above the 95% confidence interval of the normal population, but that is below amounts detectable by semiquantitative methods (30-300 mg/24 h or 20-200 μg/min). In patients with insulin-dependent diabetes mellitus (IDDM), several studies 1-3 have indicated that microalbuminuria is a marker of glomerular damage, and strongly predicts the development of overt proteinuria and progressive renal failure. The predictive value of microalbuminuria for the development of renal damage in noninsulin-dependent diabetes mellitus (NIDDM) is less well established 4. Increasing evidence also supports the notion that microalbuminuria predicts cardiovascular morbidity and mortality in both IDDM and NIDDM patients 5,6. Recently, a large body of evidence has been published that suggests that the predictive value of microalbuminuria may extend to patients with essential hypertension. The present review discusses the incidence of microalbuminuria in patients with essential hypertension, its relationship with blood pressure levels and other cardiovascular risk factors, and the evidence supporting its role in predicting cardiovascular as well as renal complications. Prevalence of microalbuminuria and its relationship with blood pressure levels The prevalence of microalbuminuria in patients with essential hypertension varies enormously among different studies, with rates ranging between 5 and 37% 7-11. In a study of 11 343 nondiabetic hypertensive patients with a mean age of 57 years 12, microalbuminuria was present in 32% of men and 28% of women (P < 0.05) and increased with age, severity and duration of hypertension. Most studies have shown a significant but weak correlation between UAE and office blood pressure, whereas a stronger correlation usually exists between average 24 h blood pressure measured using continuous ambulatory monitoring and UAE 13-15. We have observed a blunted or absent nocturnal dipping of blood pressure in hypertensive patients with microalbuminuria compared with those with normal UAE and with normotensive healthy individuals 16. This observation is relevant in light of evidence that nocturnal blood pressure correlates better than office blood pressure with cardiovascular complications 17-19 and silent cerebrovascular disease 20. Pathogenesis of microalbuminuria in essential hypertension The pathogenesis of microalbuminuria in patients with essential hypertension has not been established, and there are no studies available regarding the renal pathological findings associated with this abnormality. Most studies have focused on the role of increased glomerular hydrostatic pressure or increased permselectivity of the glomerular basement membrane. Glomerular hydrostatic pressure is regulated by the relative vasoconstriction-vasodilatation of the afferent and efferent glomerular arterioles. Normally, an elevation in systemic arterial pressure is associated with vasoconstriction of the glomerular afferent arterioles, which prevents transmission of the elevated hydrostatic pressure to the glomerulus and maintains the glomerular hydrostatic pressure unaltered 21. A large body of experimental and clinical evidence supports the notion that a derangement in these adaptive mechanisms may increase susceptibility to renal injury. Renal function deteriorates faster in salt-sensitive than in salt-resistant models of hypertension. In spontaneously hypertensive rats, a model of salt-resistant hypertension, the superficial nephrons adapt to the rise in blood pressure with an increase in renal afferent arteriolar resistance, which protects the kidneys from the adverse effects of arterial hypertension 22. Dahl salt-sensitive rats, on the other hand, adapt to a rise in blood pressure with no change in the afferent arteriolar resistance, which results in increased glomerular capillary pressure, glomerulosclerosis and proteinuria 23. In salt-sensitive patients with essential hypertension, we have observed renal haemodynamic derangements that are similar to those observed in the Dahl salt-sensitive rat. Renal blood flow decreased, and filtration fraction and intraglomerular pressure increased in salt-sensitive patients during high salt intake, whereas renal blood flow increased and filtration fraction and intraglomerular pressure decreased in salt-resistant individuals 24. UAE was greater in salt-sensitive than in salt-resistant patients, and it was aggravated by a high salt intake 25. In all, these studies suggest that microalbuminuria in essential hypertension could be the result of increased intraglomerular hydrostatic pressure, and high salt intake may aggravate this abnormality. Microalbuminuria in patients with essential hypertension could also be due to alterations of the permselectivity of the glomerular basement membrane. Impaired glomerular charge selectivity has been observed even in healthy individuals with microalbuminuria 26. The increased permeability of the glomerular basement membrane for albumin could be due to increased production by mesangial or endothelial cells of factors such as the vascular endothelial growth factor and the vascular permeability factor 27,28. Vascular permeability factor is implicated in the pathogenesis of microalbuminuria and proteinuria in diabetic patients 29, and in patients with glomerulonephritis 30. A good estimate of vascular permeability to albumin can be obtained from the measurement of the albumin transcapillary escape rate (TER). Patients with IDDM 31 and NIDDM microalbuminuria 32,33 manifest greater albumin TER than patients without microalbuminuria. An increase in albumin TER has been described in normotensive healthy individuals with microalbuminuria 34. In patients with essential hypertension and microalbuminuria, Pedrinelli et al. 35 observed higher serum levels of von Willebrand factor, a marker of endothelial dysfunction, than in patients with normal UAE. In all, this evidence suggests that alterations in the permeability of endothelial cells can contribute to microalbuminuria in individuals with essential hypertension. Microalbuminuria and serum lipids In patients with essential hypertension, microalbuminuria is frequently associated with dislipidaemia, which is characterized by higher serum levels of low-density lipoprotein (LDL), triglycerides, apolipoprotein B, lipoprotein(a) and lower serum levels of high-density lipoprotein cholesterol 36-39. On one hand, hyperlipidaemia could be secondary to increased urinary loss of protein. This is supported by the evidence that urinary losses of large amounts of proteins may lead to increased serum levels of total cholesterol and LDL-cholesterol 40,41 as well as lipoprotein (a) 42,43, and that microalbuminuria may be present in normotensive individuals with a genetic risk for diabetes 44 and hypertension 45. On the other hand, microalbuminuria could be a consequence of renal damage caused by hyperlipidaemia. Evidence is mounting that lipid abnormalities may contribute to renal damage by accelerating atherosclerosis as well as intrarenal microvascular and macrovascular disease, thus contributing to the progression of renal disease 46,47. Cholesterol-enriched diets may cause albuminuria and glomerulosclerosis in different animal species, particularly when combined with hypertension 48,49. In addition, pharmacological agents that lower serum lipids ameliorate renal injury in several experimental models of renal disease 50. The mechanism(s) responsible for the deleterious effects of lipids on glomerular injury are not well established. The resemblance between glomerular mesangial cells and vascular smooth muscle cells and the important role played by the latter cells in the process of atherosclerosis suggest that accumulation of lipids in the mesangial cells may cause or accelerate glomerulosclerosis 51. Klahr et al. 52 have suggested that mesangial cells exposed to increased amounts of lipoproteins may incorporate lipids which, in turn, may stimulate their proliferation and results in the deposition of excessive glomerular basement membrane and progressive glomerulosclerosis. LDL can promote adherence of monocytes to endothelial cells, a potentially important factor in the progression of inflammatory glomerular diseases 53,54. Microalbuminuria, insulin resistance and hyperinsulinaemia in essential hypertension Several investigators have described the presence of insulin resistance and hyperinsulinaemia in a substantial number of patients with essential hypertension 55,56. Some have suggested that hyperinsulinaemia may be associated with a greater risk of cardiovascular 57-59 and coronary artery diseases 60,61. Several lines of evidence also suggest that hypertensive patients with hyperinsulinaemia excrete greater amounts of urinary albumin. We measured the plasma insulin response to an oral glucose load in patients with or without microalbuminuria and normotensive control individuals. In the hypertensive patients, the plasma insulin response to a glucose load (evaluated as the insulin area under the curve) was significantly enhanced compared with that in control individuals. Microalbuminuric patients had significantly higher insulin area under the curve values than patients with normal UAE 62. Using the euglycaemic clamp technique, we have also observed a 35% reduction in the peripheral glucose uptake stimulated by insulin in patients with essential hypertension and microalbuminuria compared with in patients with normal UAE 63. This appeared to be secondary to a reduction in glycogen synthesis, because the glucose oxidation was not altered. The significance of the association between insulin resistance and microalbuminuria is uncertain. Because microalbuminuria and insulin resistance 64-67 occur in nondiabetic normotensive individuals with a genetic predisposition for hypertension, and hyperinsulinaemia and insulin resistance are genetically transmitted, microalbuminuria and enhanced plasma insulin response to glucose could both be genetically determined and cosegregate with the hypertensive status. Alternatively, insulin resistance and hyperinsulinaemia, or both, could be causally related to microalbuminuria. For example, insulin may alter glomerular haemodynamics directly or in association with other factors such as catecholamines, angiotensin II, glucagone and sodium 68. Insulin could also increase UAE by altering glomerular membrane permeability, because the infusion of insulin increases UAE both in normal individuals and in patients with IDDM 69,70. Microalbuminuria and cardiovascular disease The increasing interest in the significance of microalbuminuria in essential hypertension derives, in large part, from the recognition that a rise in UAE is associated with an increased incidence of cardiovascular complications and morbid events, such as left ventricular hypertrophy 71-73, coronary heart disease 74-76, carotid artery thickness 77 and hypertensive retinopathy. After a follow-up of 62-83 months, Damsgaard et al. 78 reported a greater incidence of strokes and other cardiovascular events in elderly nondiabetic individuals with increased UAE than in those with normal UAE. Other risk factors identified in this analysis were male sex and hypertension. The predictive value of microalbuminuria faded after the initial 5 years of follow-up. Kuusisto et al. 79 studied the impact of hyperinsulinaemia and microalbuminuria, alone or in combination, on the incidence of cardiovascular events in 1069 elderly individuals followed for an average of 3.5 years. Of males 48% and of females 60.8% had hypertension. The incidence of fatal and nonfatal cardiovascular events was significantly greater in patients with microalbuminuria than in those without. By contrast, the incidence of cardiovascular events was only slightly, but not significantly increased in patients with higher serum insulin levels. The combined presence of microalbuminuria and hyperinsulinaemia increased the probability of fatal and nonfatal cardiovascular events, even after adjusting for other risk factors, such as male sex, cigarette smoking, hypertension and serum cholesterol levels. In a study of 11 343 nondiabetic hypertensive patients, among patients with microalbuminuria 31% had coronary artery disease, 24% had left ventricular hypertrophy, 6% had had a stroke and 7% had peripheral vascular disease. In patients without microalbuminuria, these rates were 22, 14, 4 and 5%, respectively (P < 0.001). Furthermore, in patients with coronary artery disease, left ventricular hypertrophy, stroke and peripheral vascular disease, microalbuminuria was significantly greater than in patients who did not have these complications (P < 0.001) 12. In a retrospective cohort analysis of 141 hypertensive individuals, after an average follow up of 7 years, we observed 12 cardiovascular events among the 54 patients with microalbuminuria and only two events among the 87 patients with normal UAE 80. In a prospective cohort study of 631 individuals aged 50-75 years (54% of these patients had impaired glucose tolerance or NIDDM), Jager et al. 81 observed that microalbuminuria and peripheral arterial disease were both independent predictors of cardiovascular and all-cause mortality, especially among hypertensive individuals. In a prospective study of 2085 nondiabetic individuals 82, the relative risk of ischaemic heart disease associated with microalbuminuria was 2.3, and was independent of other conventional atherosclerotic risk factors. Microalbuminuria and nephroangiosclerosis One important question is whether microalbuminuria can predict the risk of progressive renal disease in patients with essential hypertension. There are no sufficient data to support this notion. After a follow-up of 5 years, Ruilope et al. 83 reported a decline of 11 ml/min in creatinine clearance among 24 hypertensive patients with microalbuminuria, as opposed to a decrease of only 2 ml/min in 49 hypertensive patients with normal UAE. In a retrospective cohort analysis of 141 hypertensive individuals followed for approximately 7 years 80, we observed that creatinine clearance decreased significantly more in patients with microalbuminuria than in those with normal UAE (−12.1 ± 2.77 versus −7.1 ± 0.88 ml/min, P < 0.05). Larger prospective studies are necessary to determine whether microalbuminuria does predict the risk of end-stage renal disease in patients with essential hypertension.