Microalbuminuria: Prognostic and Therapeutic Implications in Diabetes Mellitus

Thirty years following the development of the first radioimmunoassay for albumin, microalbuminuria is widely acknowledged as an important predictor of overt nephropathy in patients with Type 1 diabetes and of cardiovascular mortality in Type 2 diabetes. In addition, there is accumulating evidence to suggest that diabetic patients with microalbuminuria may have more advanced retinopathy, higher blood pressure, and worse dyslipidaemia than patients with normal albumin excretion rates. Recent studies have focused on the role of intervention, principally with antihypertensive therapy and intensive glycaemic control, in reducing microalbuminuria. While successful in reducing urinary albumin excretion it remains to be established whether such therapies will be translated into a reduction in renal failure and decreased cardiovascular mobidity and mortality.     

Banting Memorial Lecture 2016 Reducing lifetime risk of complications in adolescents with Type 1 diabetes

Adolescence is a challenging period of life for any young person, and for those with Type 1 diabetes, physiological and psychological factors can result in a deterioration in glycaemic control. In young people with Type 1 diabetes, puberty may be an additional risk factor impacting on the lifetime risk for renal and cardiovascular complications. Our longitudinal studies have identified that increases in urinary albumin excretion through childhood are associated with the development of microalbuminuria and a generalized endotheliopathy linked to cardiovascular risk. Screening of participants recruited to the Adolescent type 1 Diabetes cardio‐renal Intervention Trial (AdDIT) confirms that these early changes in albumin excretion are related to both diabetic nephropathy and cardiovascular risk; in part, independent of glycaemic control. Thus, as well as current attempts to improve glycaemic control through enhanced targeted insulin delivery, pumps, sensors and closed loop, we have explored the role of angiotensin‐converting enzyme inhibitors and statins in providing cardio‐renal protection during adolescence.     

Treatment of Microalbuminuria in Patients with Type 2 Diabetes Mellitus

The incidence of type 2 diabetes mellitus is increasing world-wide, and is now one of the leading causes of end-stage renal disease in Western countries. Type 2 diabetes mellitus is also a major risk factor for cardiovascular events. Therefore, the early identification of patients at greatest risk, and the subsequent initiation of renal and cardiovascular protective treatments, are of the utmost importance. Microalbuminuria refers to a subclinical increase in urinary albumin excretion. By definition it corresponds to an albumin excretion rate of 20 to 200 microg/min (30 to 300 mg/day) or an albumin to creatinine ratio (mg/mmol) of 2.5 to 25 in males and 3.5 to 35 in females. Microalbuminuria is an important clinical finding because it is not only associated with an increased risk of progression to overt proteinuria (macroalbuminuria) and renal failure, but also cardiovascular events. In patients who progress to overt nephropathy, microalbuminuria usually precedes macroalbuminuria by an interval of 5 to 10 years. In patients with type 1 diabetes mellitus, blood pressure increases and renal function declines after the onset of macroalbuminuria. However, in patients with type 2 diabetes mellitus, hypertension and a decline in renal function may occur when albumin excretion is still in the microalbuminuric range. Large clinical trials have demonstrated that achieving tight glycemic (i.e. glycosylated hemoglobin < 7.0%) and blood pressure (i.e. < 130/85mm Hg) control retards the progression of renal disease. There is accumulating evidence to suggest that the use of antihypertensive agents which target the renin-angiotensin system (RAS) can slow the progression of renal disease and provide cardioprotection in patients with type 2 diabetes mellitus and microalbuminuria. Antihypertensive agents which target the RAS also appear to have advantages over and above reductions in systemic blood pressure. In summary, the annual screening of patients with type 2 diabetes mellitus for microalbuminuria, and the initiation of measures to retard the progression of renal and cardiovascular disease, are now considered part of routine clinical practice. In particular, the finding of microalbuminuria should provoke an intensified modification of the common risk factors for renal and cardiovascular disease, that is hyperglycemia, hypertension, dyslipidemia and smoking. Antihypertensive therapy in patients with microalbuminuria and type 2 diabetes mellitus should be initiated with angiotensin converting enzyme (ACE) inhibitors or angiotensin-II type 1 receptor antagonists.     

The importance of microalbuminuria as a cardiovascular risk indicator: A review

The present review describes the knowledge of microalbuminuria as a cardiovascular risk indicator. Microalbuminuria is usually defined as a urinary albumin excretion rate of 30 to 300 mg in a 24 h urine collection, or as a urinary albumin excretion rate of 20 to 200 mg/min in a timed overnight urine collection, although microalbuminuria was demonstrated to be a predictor for cardiovascular events at levels below these conventional cut-off values. More than one consecutive urine collection is preferred given the high day to day variability of urinary albumin excretion. Microalbuminuria is frequently present and a known cardiovascular risk indicator in diabetic populations. Also, in hypertensive and general populations, microalbuminuria is common and has been associated with an adverse atherogenic risk profile and a higher prevalence of cardiovascular disease. Moreover, evidence strongly suggests that microalbuminuria is also an independent predictor of cardiovascular disease in these populations. However, more prospective studies are needed to elucidate fully the value of microalbuminuria as a cardiovascular risk indicator in hypertensive and general populations. Generalized endothelial dysfunction has been hypothesized to be the underlying factor for microalbuminuria on one hand and the underlying factor for increased cardiovascular risk on the other. In this respect, the loss of the glycosaminoglycan heparin sulphate might be an important pathophysiological mechanism. This hypothesis needs further clarification, especially in nondiabetic populations.     

Microalbuminuria in essential hypertension

Microalbuminuria (urinary albumin excretion equal to 30-300 mg/24 h) is a reliable indicator of premature cardiovascular mortality in diabetic patients and in the general population. In insulin-dependent and non-insulin-dependent diabetes mellitus microalbuminuria is a marker of initial diabetic nephropathy and predicts the evolution toward renal insufficiency. In essential hypertension the clinical and prognostic role of microalbuminuria is more controversial. While it is a recognised marker of cardiovascular complications and a reliable predictor of ischaemic heart disease, its prognostic value on the risk of progressive renal alterations is still uncertain because no prospective studies, taking microalbuminuria as a selection criterion and renal insufficiency as an end point, are available. Blood pressure control with antihypertensive drugs is accompanied by a reduction in urinary albumin excretion. The favourable effects of antihypertensive agents on microalbuminuria appear to be proportional to blood pressure reduction, but angiotensin-converting enzyme inhibitors and angiotensin-II-receptor antagonists show an additional beneficial effect on urinary albumin excretion. Whether the reduction of microalbuminuria obtained through pharmacological intervention has favourable prognostic implications remain to be demonstrated. However, screening for microalbuminuria is a relatively easy and inexpensive procedure and reveals a potentially treatable abnormality. Thus, considering that microalbuminuria identifies hypertensive subjects at higher risk than standard, urinary albumin excretion should be routinely measured in hypertensive patients and, in the presence of microalbuminuria, antihypertensive treatment should be intensified in order to obtain an optimal blood pressure control.     

Preventing microalbuminuria in patients with type 2 diabetes

The public health burden of type 2 diabetes mellitus has been dramatically increasing world-wide. The chronic complications of type 2 diabetes play an important role in decreasing life expectancy and adversely affecting quality of life. Diabetic nephropathy, which is originally microvascular in nature, is widely considered an important complication of diabetes. In prospective clinical investigations, increased urinary albumin excretion proved to be associated not only with subsequent renal outcomes but also with cardiovascular morbidity/mortality independently of other risk factors. Therefore, microalbuminuria as an early sign of increased urinary albumin excretion should be considered important for both treatment and even for prevention. Preventing microalbuminuria might diminish progression to overt nephropathy and, hopefully, might limit cardiovascular events. Regarding primary prevention of diabetic nephropathy, therapeutic intervention should optimally be initiated at the stage of normoalbuminuria. Although additional factors such as smoking cessation, reduction of protein intake, and treatment of lipid abnormalities are important, providing optimal diabetic control as well as targeting optimal blood pressure are the key elements of a prevention strategy in diabetic patients. Recently, the Bergamo Nephrologic Diabetes Complications Trial (BENEDICT) documented that a significant decrease of the development of persistent microalbuminuria could be achieved by using an ACE-inhibitor, trandolapril alone or in combination with verapamil SR, a non-dihydropyridine calcium-channel blocker in hypertensive type 2 diabetic patients with normoalbuminuria. The results of this primary-prevention strategy should be corroborated by further investigations to determine whether these beneficial changes could later result in improvement of renal clinical outcomes, macrovascular complications, or both.     

Pathogenesis and Treatment of Microalbuminuria in Patients With Diabetes: The Road Ahead

The incidence of type 2 diabetes is increasing in the United States, which is expected to result in an increased prevalence of microalbuminuria and higher cardiovascular risk. Microalbuminuria is an indication that a low-level inflammatory process is ongoing. In patients with hypertension, with or without diabetes, increasing urinary albumin excretion (UAE) is associated with elevated levels of inflammatory markers, endothelial dysfunction, and platelet activation. Microalbuminuria is associated with an increased incidence of cardiovascular disease (CVD) morbidity and mortality in patients with hypertension and in those with diabetes with or without hypertension. Antihypertensive agents that modulate the renin-angiotensin-aldosterone system (RAAS) can delay the onset and reduce progression of microalbuminuria and decrease CVD morbidity and mortality in patients with diabetes. Clinical trials provide a spectrum of results regarding the protective effects of RAAS-blocking agents. Consideration of baseline blood pressure (BP), UAE and CVD risk, and the extent of BP lowering with treatment is necessary when interpreting clinical trial results in patients with microalbuminuria. It remains to be determined whether targeting the underlying inflammatory process can retard or prevent microalbuminuria progression or whether treatment of microalbuminuria can prevent end-stage renal disease or death.     

+Microalbuminuria in hypertension

A body of evidence indicates that microalbuminuria is a well-recognized marker of cardiovascular complications and increased cardiovascular risk in hypertension. However, the prognostic significance of microalbuminuria remains controversial because only the results of a few prospective studies performed in small groups of hypertensive subjects without diabetes mellitus are available. Several factors can affect the prevalence of microalbuminuria in hypertension including age, sex, race, severity of the disease, and concomitant risk factors. This accounts for the large differences in the prevalence of microalbuminuria that can be found in the literature, with prevalence rates going from a low of 4.7% to a high of 46%. The main determinant of albumin excretion rate in subjects with mild hypertension and no cardiovascular complications seems to be the hemodynamic load, whereas in subjects with more severe hypertension and associated target organ damage, the augmented urinary albumin leak is probably the consequence of glomerular damage. Inhibition of the reninangiotensin system with angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists is particularly effective at reducing the albumin excretion rate, but whether these classes of drugs are more beneficial in patients with microalbuminuria remains to be determined. There is general consensus that evaluation of microalbuminuria is useful for the assessment of overall cardiovascular risk in hypertension, since albumin excretion rate appears to be a cost-effective way to identify patients at higher risk for whom additional preventive and therapeutic measures are advisable.     

Mild renal dysfunction and subclinical cardiovascular damage in primary hypertension

The presence of mild renal dysfunction is associated with high cardiovascular morbidity and mortality rates in patients with primary hypertension. The pathophysiological mechanisms underlying this association are currently unknown. We investigated the relation between mild renal dysfunction and subclinical cardiovascular organ damage in 358 never previously treated patients with primary hypertension. Mild renal dysfunction was defined as a creatinine clearance <60 mL/min and/or the presence of microalbuminuria. Left ventricular mass index and carotid intima-media thickness were assessed by ultrasound scan. The prevalence of mild renal dysfunction, left ventricular hypertrophy, and carotid plaque was 18%, 48%, and 28%, respectively. Mild renal dysfunction was related to the presence of several risk factors, such as older age, higher blood pressure levels and lipid status, and smoking habits. Patients with the highest left ventricular mass and carotid intima-media thickness (upper quartiles) showed a higher prevalence of mild renal dysfunction (P<0.0001). After adjusting for duration of hypertension, mean blood pressure, smoking habits, and age, we found that the risk of left ventricular hypertrophy and/or carotid atherosclerosis increased by 43% with each SD reduction in creatinine clearance, and by 89% with each SD increase in albuminuria. Mild renal dysfunction is associated with preclinical end-organ damage in patients with primary hypertension. These data may help explain the high cardiovascular mortality rates reported in patients with low glomerular filtration rate or with increased albuminuria. The evaluation of creatinine clearance and urinary albumin excretion could be useful for identifying subjects at higher cardiovascular risk.     

Renal disease: a common and a silent killer

Cardiovascular risk profiling and therapy have traditionally been based on established risk factors, such as age, smoking, sex, hypertension, dyslipidemia, body weight, and diabetes mellitus. Despite optimum therapy, cardiovascular mortality and morbidity remain high. Attention is being devoted, therefore, to identifying new risk factors that can also be used as therapeutic targets. Renal dysfunction manifesting as low glomerular filtration rate, albuminuria, or anemia is a strong risk factor for cardiovascular disease and is prevalent in the general population and among patients with cardiovascular disease. Epidemiological data suggest that 10-11% of the general population have low glomerular filtration rates, 5-7% have increased urinary albumin excretion, and 5-10% have anemia. Each of these features represents an independent but additive cardiovascular risk. Treatments for all these indications can reduce cardiovascular mortality and morbidity as well as renal risk. Such findings suggest that treatment should be directed towards improving renal function in order to achieve optimum cardiovascular benefit. Such a strategy would offer the possibility of multiorgan therapy in diseases characterized by multiorgan impairment, such as type 2 diabetes. I present the evidence that renal dysfunction is a common and powerful cardiovascular risk factor and that treatment strategies intervening in the renin-angiotensin-aldosterone system can be used to target albuminuria and reduce cardiovascular and renal risk.     

Autonomic nerve function in adolescents with Type 1 diabetes mellitus: relationship to microalbuminuria.

AIMS: Thirty adolescent patients with Type 1 diabetes mellitus and microalbuminuria were studied for evidence of early autonomic neuropathy. METHODS: Using tests involving cardiovascular and pupillary reflexes, the adolescents were compared with a normoalbuminuric group of patients with diabetes, who were matched for age, sex, puberty and duration of diabetes. RESULTS: There was an increased prevalence of autonomic nerve dysfunction in the patients with microalbuminuria. These patients had higher resting heart rates (86 beats/min in the microalbuminuric group vs. 77 beats/min in normoalbuminuric controls, P = 0.002), and impaired pupillary dilatation in darkness (pupillary diameter % 56.5% vs. 62.5%, P = 0.003). Patients with microalbuminuria also had poorer long term glycaemic control (mean HbA1C 8.7% vs. 7.8%, P = 0.002) and higher blood pressures (systolic 125 vs. 116 mmHg, P = 0.001; diastolic 69 vs. 62 mmHg, P = 0.0001; mean arterial pressure 90 vs. 83 mmHg, P = 0.002) than those with normal urinary albumin excretion. CONCLUSIONS: Microalbuminuria and autonomic nerve dysfunction co-exist in patients with Type 1 DM. Longitudinal studies will determine whether these findings have implications for the identification of patients at higher risk of progression of early renal complications.     

Microalbuminuria: cardiovascular and renal risk factors underestimated in clinical practice

Determination of microalbuminuria has been shown to be useful to identify patients with type 2 diabetes (DM2) at high risk of renal and cardiovascular (CV) diseases. The determination of the albumin/creatinine (Cr) ratio in an isolate sample of urine has been shown to be sufficient for the diagnosis as well as for the evaluation of the efficacy of the therapy employed to reduce microalbuminuria. Values of urinary albumin >30 mg/g of Cr or 3,4 mg/mmol of Cr are evidence of microalbuminuria. This condition is frequently associated with high blood pressure levels, which increases dramatically not only the progression of renal disease but also de risk of a CV event. Epidemiologic studies have demonstrated that the presence of microalbuminuria is predictive of higher morbi-mortality independent of the presence of other CV risk factors. It appears to reflect a generalized vascular lesion not confined to the glomeruli. The capacity of reducing blood pressure, intraglomerular pressure and the permeability of the glomerular membrane, which are important factors in the progression of renal disease, may explain the renoprotective effects of the angiotensin converting enzyme inhibitors (ACEIs) and the angiotensin II receptors blockers (ARBs). In the treatment of diabetic nephropathy, the control of blood pressure, which has to be maintained near or below 130/80 mmHg associated to the blockade of the renin-angiotensin system with ACEIs or BRAs are the best strategies to promote renal and CV protection.     

Microabluminuria in arterial hypertension. Measurement, variables, interpretation, recommendations

Permanent hypertension is frequently associated with increased glomerular permeability to albumin at an early stage, indicating renal involvement and endothelial dysfunction. The definition of microalbuminuria is an urinary albumin excretion of 30-300 mg/24 hrs, confirmed on two occasions over a 3 month period. It may also be expressed in microgram/min, m/l or mg/mmol of creatinine. Radio-immunological, immunonephelometric methods and Elisa are specific and the most sensitive methods of measurement. There is a large intra-individual variability (25-60%) making it essential to repeat measurements always by the same technique. The prevalence of microalbuminuria is 5-8% in the general population and 6-24% in hypertensive patients. When present, it is a marker of increased cardiovascular risk. Clinical recommendations suggest adaptation of urinary collection according to the context: screening, diagnosis or clinical research. It is always necessary to start by dip-stick detection of proteinuria, haematuria or urinary infection. Clinical research requires repeated measurement of 24 hour microalbuminuria, sometimes divided into two periods of day and night, often associated with ambulatory blood pressure recordings and renal function tests. Studies of the effects of anti-hypertensive drugs on microalbuminuria could provide better evaluation. In conclusion, measurement of microalbuminuria remains a tool of clinical research allowing an assessment of cardiovascular and renal risk of hypertensive patients.     

Development of microalbuminuria in essential hypertension

During the past few years, microalbuminuria has become a prognostic marker for cardiovascular and/or renal risk in diabetic and nondiabetic subjects. In essential hypertensives, an increased transglomerular passage of albumin may result from several mechanisms—hyperfiltration, glomerular basal membrane abnormalities, endothelial dysfunction, and nephrosclerosis. Cross-sectional studies have demonstrated that the main factors related to microalbuminuria are blood pressure (BP) values and hyperinsulinemia, as an expression of insulin resistance. Genetics, obesity, and smoking, however, have also been implicated as determinants of microalbuminuria in some of the studies. Follow-up studies support the role of BP values and subtle alterations in glucose metabolism, although contributing roles need to be assessed in further studies. It seems that the significance of microalbuminuria in essential hypertension is much broader than expected, and several factors may influence the presence of microalbuminuria. Thus, to reverse microalbuminuria, and to reduce urine albumin excretion and cardiovascular and renal risk, a strategy of multiple approaches may be needed. Whether or not the multiple approaches need to be implemented from the beginning or step by step in an individual approach should be established in the near future.     

Rationale and design of a study to evaluate management of proteinuria in patients at high risk for vascular events: the IMPROVE trial

Declining kidney function predicts increasing cardiovascular risk in people with hypertension. Microalbuminuria is a marker for cardiovascular risk and declining kidney function. Agents that block the renin-angiotensin-aldosterone system (RAAS), notably angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), reduce proteinuria and microalbuminuria, lower blood pressure and slow the progression of proteinuric kidney disease. Evidence is accumulating that the combination of an ACE inhibitor and an ARB is the optimal means of RAAS blockade in this setting, slowing the progression of nephropathy independently of blood pressure lowering to a greater degree than can be achieved using maximum approved doses of either agent alone. However, the emerging therapeutic potential of ACE inhibitor/ARB combination therapy in hypertensive kidney disease requires further characterization. The Irbesartan in the Management of PROteinuric patients at high risk for Vascular Events trial aims to determine definitively whether the combination therapy of an ARB, irbesartan and an ACE inhibitor, ramipril, is more effective than ramipril alone in reducing the urinary albumin excretion rate in patients at high cardiovascular risk with hypertension and proteinuria or microalbuminuria.     

Microalbuminuria is more frequent in South Asian than in European origin populations: a comparative study in Newcastle, UK.

AIMS: We aimed to compare levels of urinary albumin excretion and the prevalence of microalbuminuria in UK South Asians and Europeans. Microalbuminuria predicts cardiovascular disease in European origin populations, but evidence from the general population of South Asians is lacking. Coronary heart disease (CHD) mortality is 40-50% higher in UK South Asians compared with the whole population, for reasons that are incompletely understood. METHODS: Microalbuminuria was measured using the albumin-creatinine ratio in an age- and sex-stratified random sample of 1509 adults from European (n = 825), Indian (n = 259), Pakistani (n = 305) and Bangladeshi (n = 120) ethnic groups. RESULTS: Levels of urinary albumin excretion were substantially higher in South Asians (geometric mean albumin creatinine ratio (95% confidence interval) 0.83 (0.75, 0.91)) than in Europeans (0.55 (0.51, 0.60)). Microalbuminuria was associated with older age, hypertension and diabetes, but independently of these risk factors urinary albumin excretion was higher in South Asians than Europeans. CONCLUSIONS: Urinary albumin excretion is higher and microalbuminuria more frequent in UK South Asians compared with the majority ethnic population. Microalbuminuria may be relevant to the causal pathways leading to the excess of cardiovascular mortality and possibly renal failure in UK South Asians.     

Microalbuminuria as Surrogate Endpoint in Therapeutic Trials

A surrogate endpoint is a measure of the effect of a certain treatment that may correlate with a real clinical endpoint but does not necessarily have a guaranteed relationship. The concept is particularly useful in cardiovascular and renal disease. We review evidence regarding microalbuminuria as one potential surrogate endpoint. In diabetes, hypertension and high cardiovascular risk, recent studies have demonstrated the prognostic value of significant changes in urinary albumin excretion for cardiovascular and renal outcomes. The most appropriate timing with which to repeat microalbuminuria and whether or not changes should be targeted during the antihypertensive treatment remain unanswered.     

Diabetic nephropathy and cardiac disease

Patients in different stages of diabetic nephropathy (DN) frequently present cardiac disease expressed by myocardial ischemia and/or diabetic cardiomyopathy. These changes are already present at early stages of DN, probably even before urinary albumin excretion (UAE) reaches the traditionally diagnostic levels of microalbuminuria. The cardiac changes are responsible for a significant proportion of the increased death rates in patients with DN and can be reduced through multiple intervention on the several risk factors present in these patients. Cardiac disease assessment should ideally be performed in every patient, irrespective of renal status, through specific methods to detect ischemia and myocardial dysfunction, besides routinely performing 24-h ambulatory blood pressure monitoring. In patients with advanced atherosclerosis, other arteries (aorta, carotid, renal) should be evaluated as well. Intensive treatment of arterial hypertension, and use of cardioprotective drugs, correction of the associated dyslipidemia and anemia, and use of antiplatelet agents can reduce the elevated cardiovascular mortality in patients with DN.     

Primary renal disease as a cardiovascular risk factor

Cardiovascular disease (CVD) is the No. 1 cause of death in patients with end-stage renal disease (ESRD) and is approximately 3 to 5 times that of non-uremic control subjects. Moreover, higher rates of CVD are seen in patients with moderate and even mild renal dysfunction, particularly if the patient has hypertension or diabetes. Recent studies have indicated that even modest elevations in serum creatinine and urinary albumin excretion are associated with increased CVD risk, not only in persons with diabetes or hypertension but also in the general population. In addition, recent studies have suggested that targeting the kidney and/or kidney specific endpoints (via the renin-angiotensin-aldosterone-kinin system) in the treatment of hypertension, diabetes, and heart failure slows progression of renal disease and reduces the risk of extra-renal micro- and macrovascular complications. We conclude that it is important to screen for renal disease in those with hypertension, diabetes, and other CVD risk factors because it predicts those who are at high risk for major CVD events.     

Rationale and design of a study comparing two fixed-dose combination regimens to reduce albuminuria in patients with type II diabetes and hypertension

Diabetic nephropathy is the leading cause of end-stage renal disease (ESRD). The early stage of nephropathy is manifested by the presence of low levels of urinary albumin (microalbuminuria or urinary albumin excretion >or=30 and <299 mg/day). Albuminuria is a marker for development of nephropathy in type II diabetes and for increased cardiovascular morbidity and mortality. Recent studies have demonstrated the importance of antihypertensive agents that inhibit the renin-angiotensin-aldosterone (RAA) system to reduce the risk and slow down the progression of renal disease. A new clinical trial, GUARD (Gauging Albuminuria Reduction With Lotrel in Diabetic Patients With Hypertension), is designed to compare the change in urinary albumin to creatinine ratio after 1 year of initial treatment with either amlodipine besylate/benazepril HCl or benazepril HCl/hydrochlorothiazide. Other objectives include a comparison of the proportion of patients who progress to overt diabetic nephropathy and the safety of these two combination therapies in these high-risk patients.