Is microalbuminuria a marker for microangiopathy or macroangiopathy?



1. M. Burnier, Switzerland
2. P. Fioretto, Italy
3. J. Gumprecht, Poland
4. G. Halaby, Lebanon
5. R. Unnikrishnan and V. Mohan, India
6. F. Puchulu, Argentina
7. R. Roussel, France
8. G. Schernthaner, Austria
9. M. Shestakova, Russia
10. J.-G. Wang, Y. Li, and C.-S. Sheng, China


1. M. Burnier, Switzerland

Michel BURNIER, MD
Professor, Department of Nephrology
CHUV, University Hospital
17 Rue du Bugnon, CH 1011 Lausanne
SWITZERLAND
(e-mail: michel.burnier@chuv.ch)

The presence of a low concentration of albumin in the urine (microalbuminuria) was originally considered a marker of renal microangiopathy, thus confining its clinical usefulness mainly to the early detection of patients at higher risk of diabetic nephropathy. In the last 10 years, this concept has been challenged in several respects. Microalbuminuria was found in nondiabetic patients and in the general population, where the risk of nephropathy is extremely low. Several large epidemiological studies, eg, the Prevention of REnal and Vascular ENdstage Disease (PREVEND) and European Prospective Investigation of Cancer-Norfolk (EPICNorfolk) studies, showed that microalbuminuria was associated with a higher risk of cardiovascular complications, such as coronary artery disease or death from a cardiovascular event, in unselected populations. As such, microalbuminuria probably reflects an alternative mechanism of cardiovascular pathogenicity. It is now generally considered a surrogate marker of endothelial dysfunction present in most patients with cardiovascular complications.

Large clinical studies, such as the Heart Outcomes Prevention Evaluation (HOPE) and the Losartan Intervention For Endpoint reduction in hypertension (LIFE), provided further confirmation of the association between microalbuminuria and macroangiopathy. The prevalence of cardiovascular problems, such as coronary artery disease, peripheral vascular disease, and cerebrovascular disease, was significantly and dose-dependently associated with the intensity of proteinuria, as was the risk of cardiovascular death. Most interestingly, post-hoc analysis showed that the ability to lower microalbuminuria using a renin-angiotensin system blocker in LIFE and HOPE lowered the risk of an adverse cardiovascular end point. This was further evidence that intervention against microalbuminuria could delay disease progression.

However, in the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET), coadministration of an angiotensin-converting enzyme (ACE) inhibitor with an angiotensin receptor blocker failed to impact the cardiovascular event rate, despite having a greater proteinuria- lowering effect than ACE inhibition alone. This is a surprising discrepancy that still needs explanation.

In the recently published Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation (ADVANCE) trial, the risk of end-stage renal disease or renal disease progression was again significantly associated with the level of proteinuria. Hazard ratios for a renal event were around 12 in patients with macroalbuminuria and 5-6 in type 2 diabetics with microalbuminuria. In this study, microalbuminuria was clearly associated with the development of microangiopathy and was reduced by the administration of perindopril and indapamide. Interestingly, however, both before and during treatment in this population, microalbuminuria was, in addition, directly and significantly associated with the risk of cardiovascular death, suggesting that proteinuria is also marker of macroangiopathy.

This new evidence suggests that microalbuminuria is probably an indicator of both micro- and macroangiopathy, rather than a preferential or exclusive indicator of either. However, a major outstanding issue is whether pharmacological targeting of microalbuminuria will lower the incidence of cardiovascular complications independently of any effect on blood pressure. This remains a major challenge for future studies.

2. P. Fioretto, Italy

Paola FIORETTO, MD, PhD
Professor, Department of Medical and
Surgical Sciences, University of Padova
Via Giustiniani, 2 – 35128 Padova, ITALY
(e-mail: paola.fioretto@unipd.it)

The term microalbuminuria was introduced in 1982 to describe concentrations of urinary albumin, undetected by standard dipsticks, that predicted the development of overt proteinuria in diabetics. Given that diabetic nephropathy is a common manifestation of microangiopathy, microalbuminuria is naturally associated with other microangiopathic complications, especially diabetic retinopathy. Shortly after the first reports, it became evident that microalbuminuria also predicted mortality, largely from cardiovascular disease, in diabetics and nondiabetics. In the last decade, microalbuminuria has become recognized as an independent predictor of cardiovascular and renal events in diabetes and hypertension, with the result that most guidelines now recommend screening.

Meta-analysis showed that microalbuminuria doubles cardiovascular morbidity and mortality and all-cause mortality in type 2 diabetics, after correction for traditional risk factors. Similar findings were reported in hypertensives and the general population. Yet the values associated with increased cardiovascular risk are consistently lower than the cut-offs currently used to define microalbuminuria. Although lower cut-offs have been proposed, no consensus has been reached. Thus, albumin excretion rate (AER) should be considered a continuous, rather than categorical, variable. The pathophysiology of the association with cardiovascular disease remains unelucidated, but microalbuminuria is a marker of generalized vascular dysfunction, as borne out by its associations with hypertension, lipid abnormalities, insulin resistance, endothelial dysfunction, low-grade chronic inflammation, peripheral vascular disease, and prothrombotic status.

Retrospective studies in the early 1980s reported that 80% of type 1 diabetics with microalbuminuria progressed to proteinuria over 6-14 years. Although microalbuminuria remains the best available marker for nephropathy risk, prospective studies suggest that the percentage of patients with microalbuminuria progressing to proteinuria over a decade is much lower (30%); this may be due to initial overestimation, improved treatments, or both. Many microalbuminuric patients spontaneously revert to normoalbuminuria. In type 2 diabetes, the progression rate from microalbuminuria to proteinuria is similar (30% in 10 years): in the Steno 2 study, 31% progressed to proteinuria over 7.8 years, 31% reverted to normoalbuminuria, and 38% remained microalbuminuric. Decline in glomerular filtration rate (GFR) was much slower in patients reverting to normoalbuminuria than in those progressing to proteinuria, suggesting that reversion is associated with preserved renal function. Overall, AER remains the strongest indicator of nephropathy risk in diabetics, but is a weaker predictor of proteinuria than first thought. Its accuracy can be improved by combining it with other parameters, eg, GFR, blood pressure, glycemia, lipid levels, retinopathy, family history, and smoking. Diabetics with microalbuminuria are 2-3 times more likely to progress to proteinuria than those with a normal AER.

In hypertensives, in contrast, a relationship between microalbuminuria and subsequent nephropathy has yet to be established. The available data are conflicting and, in the absence of large well-performed prospective studies, the predictive value of microalbuminuria for hypertensive renal damage remains a tempting, but speculative, hypothesis. Most general population studies have detected no correlation between microalbuminuria and GFR. Thus, it remains to be documented whether microalbuminuria predicts renal dysfunction in hypertensive and general populations as in diabetics. An increased AER may be due to increased intracapillary glomerular pressure (in hypertension), structural damage to the capillary barrier (in diabetes), or tubular dysfunction (in a subset of diabetic patients). These differing pathogenetic mechanisms probably carry different renal risk, accounting for the imprecise predictive value of microalbuminuria for renal disease.

In conclusion, microalbuminuria predicts micro- and macroangiopathy in diabetics and cardiovascular risk in hypertensive patients and the general population. Its accuracy in predicting nephropathy risk is less than originally believed. In nondiabetics, there is no clear evidence that microalbuminuria predicts renal disease, but it is widely accepted as a strong and powerful predictor of cardiovascular disease in diabetics and nondiabetics alike.

3. J. Gumprecht, Poland

Janusz GUMPRECHT, MD, PhD
Professor, Department and Clinic of Internal
Medicine, Diabetology, and Nephrology
Medical University of Silesia
Zabrze, POLAND
(e-mail: jgumprecht@sum.edu.pl)

Viberti et al introduced the term “microalbuminuria” in 1982 to denote a subclinical rise in urinary albumin excretion (UAE) >30 mg/24 hours in type 1 diabetics. It is typically defined as a UAE of 20-200 ìg/min in an overnight collection or 30-300 mg in a 24-hour collection.1 We now know that 5% to 10% of nondiabetic, normotensive individuals have UAE values within the microalbuminuric range and that hypertension is the major risk factor for microalbuminuria in the general population. Microalbuminuria occurs in 53% to 71% patients with essential hypertension, and is highest in uncontrolled disease, increasing with age, disease severity, and disease duration.

The prevalence of microalbuminuria in type 1 diabetes increases gradually from disease onset to over 50% after 20 years and is a strong risk factor for overt nephropathy. In type 2 diabetes, it is an accurate predictor of cardiovascular events and has a prevalence of 20% to 25%, regardless of disease stage.2 The most probable reasons for the difference between types 1 and 2 diabetes in this regard are greater disease heterogeneity, association with risk factors (eg, insulin resistance, metabolic control, dyslipidemia, central obesity, and the absence of a nocturnal drop in both systolic and diastolic blood pressure), and premature cardiovascular death.

Population studies suggest that UAE starting in the submicroalbuminuric range is an independent predictor of renal and cardiovascular events. It is also recognized as a significant risk factor for cardiovascular and noncardiovascular mortality in diabetics and the general population.3

Cardiovascular mortality is higher in type 2 diabetics with microalbuminuria than in those without, especially in the presence of retinopathy or raised von Willebrand factor (vWf). Persistence of microalbuminuria in type 1 diabetes is a marker not only of renal and cardiac risk, but also of severe and predominantly proliferative retinopathy. In type 2 diabetes, on the other hand, there is no prognostic relationship between microalbuminuria and retinopathy progression.Vascular risk is not distributed equally in diabetics. Although most type 1 diabetics develop vascular complications, some never experience severe angiopathy, presumably because of genetic or environmental factors. The pathophysiological mechanism underlying the association between UAE and angiopathy remains unelucidated. In 1989, in an attempt to explain why the development of microalbuminuria foreshadows serious multiple organ failure, Deckert et al presented the “Steno hypothesis,” viewing elevated UAE as an indicator of more generalized vascular dysfunction simultaneously involving not only the glomeruli and retina, but also the macrovascular intima via increased endothelial permeability. Microalbuminuria was described as a renal marker of generalized endothelial dysfunction, predisposing to vascular complications (retinopathy, nephropathy, and atherosclerosis) in diabetes types 1 and 2.4

UAE indeed correlates with endothelial dysfunction in type 1 and type 2 diabetics as well as in nondiabetics and is related not only to symptomatic vascular disease, but also to incipient atherosclerosis.5 Data suggest a link between microalbuminuria and cardiovascular disease via coagulation and fibrinolytic dysfunction. Microalbuminuria itself is associated with increased levels of fibrinogen, vWf, plasminogen activator inhibitor 1, and thrombomodulin as well as with impaired fibrinolysis. It may thus serve as a marker of a prothrombotic state.

Microalbuminuria is a frequent finding in renal and cardiovascular organ damage in diabetics, hypertensives, and the general population. Regardless of the pathogenesis of the vascular injury, it identifies incipient micro- and macrovascular disease. UAE is thus a useful parameter in assessing risk, in identifying patients needing more intensive management (stricter blood pressure, glucose, and lipid control), and in tailoring vasculoprotective treatment before glomerular filtration rate declines.6 Reduction or reversal of microalbuminuria indicates correction of generalized endothelial dysfunction and a potential reduction in overall cardiovascular risk.

References

1. Viberti GC, Hill RD, Jarret RJ, et al. Microalbuminuria as a predictor of clinical nephropathy in insulin-dependent diabetes mellitus. Lancet. 1982;1:1430-1432.
2. Mattock MB, Morrish NJ, Viberti GC, et al. Prospective study of microalbuminuria as predictor of mortality in type 2 diabetes. Diabetes. 1992;41:736-741.
3. Mogensen CE. Microalbuminuria predicts clinical proteinuria and early mortality in maturity-onset diabetes. N Engl J Med. 1984;310:356-360.
4. Deckert T, Feldt-Rasmussen B, Borch-Johnsen K, et al. Albuminuria reflects widespread vascular damage. The Steno hypothesis. Diabetologia. 1989;32:219-226.
5. Furtner M, Kiechl S, Mair A, et al. Urinary albumin excretion is independently associated with carotid and femoral artery atherosclerosis in the general population. Eur Heart J. 2005;26:279-287.
6. Weir MR. CME microalbuminuria in type 2 diabetics: an important, overlooked cardiovascular risk factor. J Clin Hypertens. 2004;6:134-143.



4. G. Halaby,Lebanon

Georges HALABY, MD
Professor of Endocrinology
Saint Joseph University
Rue de Damas, BP 17-5208 Mar Mikhaël
Beirut 1104-2020, LEBANON
(e-mail: mjhalaby@sodetel.net.lb)

Albumin measurement is useful in various clinical settings, in particular to identify and monitor glomerular disease and assess cardiovascular risk. The preferred parameter of urinary albumin excretion (UAE) is the total albumin- to-creatinine ratio, preferably in an early morning urine sample.1 Microalbuminuria is considered positive between 20 and 200 ìg/mg creatinine. Above this level it becomes macroalbuminuria. Even when it remains within the normal range an elevated UAE probably reflects abnormal glomerular hemodynamics and permselectivity, which may predispose to diabetic glomerulopathy.2 The most significant modifiable predictor for microalbuminuria is hemoglobin A1c.

Microalbuminuria has a prevalence of 28% and a mean duration of 15 years in type 1 and 2 diabetics, 33% of whom proceed to macroalbuminuria. Microalbuminuria is often present at diagnosis. In the United Kingdom Prospective Diabetes Study (UKPDS), the yearly rates of progression from diagnosis of diabetes to microalbuminuria, microalbuminuria to macroalbuminuria, and macroalbuminuria to an elevated plasma creatinine or renal replacement therapy were 2.0%, 2.8%, and 2.3%.3

Microalbuminuria is not only an indicator of incipient renal damage, but also associated with essential hypertension and glucose intolerance, suggesting its involvement in early vascular damage and its utility in predicting the onset and progression of cardiovascular disease. In the European Prospective Investigation of Cancer-Norfolk (EPIC-Norfolk) and Losartan Intervention For Endpoint reduction in hypertension (LIFE) studies, microalbuminuria predicted the incidence of stroke. For every 10-fold increase in UAE, the hazard ratio for stroke increased by 51% in nondiabetics and by 37% in diabetics.

Microalbuminuria is an important cardiovascular and mortality risk factor, irrespective of diabetes or hypertension. It increases the relative risk of major cardiovascular events, even after adjustment for other cardiovascular risk factors. Risk increases with the albumin-to-creatinine ratio, starting well below the microalbuminuria cutoff. Multivariate analysis has shown that left ventricular (LV) hypertrophy is associated with a 1.6-fold higher prevalence of microalbuminuria, independent of age, systolic or diastolic blood pressure (BP), diabetes, gender, race, serum creatinine, or smoking status.

The Framingham Heart Study revealed the relationship between low-grade microalbuminuria, hypertension, and BP progression in normotensive nondiabetics. Microalbuminuria appears to correlate with the severity and duration of hypertension. Although it has been shown to correlate with another inflammatory biomarker of cardiovascular risk, C-reactive protein (CRP), little is known about the relative effectiveness of either indicator or of any other indicator, alone or in combination, in predicting cardiovascular risk.

In addition to being linked to hypertension and diabetes, microalbuminuria is independently associated with several modifiable cardiovascular risk factors and markers of cardiovascular disease, including obesity, smoking, insulin resistance syndrome, LV hypertrophy, LV dysfunction, and elevated CRP. It is also a reliable indicator of endothelial dysfunction, itself associated with the transendothelial albumin escape rate and plasma von Willebrand factor levels. Microalbuminuria correlates with endothelial dysfunction in the brachial artery. Such dysfunction is an early step in atherosclerosis and represents an increased risk for cardiovascular events.4

Lowering systolic BP lowers microalbuminuria. So does reninangiotensin system blockade, irrespective of lowering BP. Most effective of all are intensive antihypertensive regimens that effectively block the renin-angiotensin system. Microalbuminuria screening and antihypertensive therapy that lowers microalbuminuria in high-risk patients should improve cardiovascular and renal outcomes. Treatment with a fixed combination of perindopril and indapamide significantly reduced all renal events.5 Many trials have confirmed the long-term benefits of glycemic control in reducing new-onset microalbuminuria, nephropathy, and, perhaps, in reducing cardiovascular events.6 Intensive intervention with multiple drug combinations and behavior modification is associated with a sustained reduction in vascular complications and in cardiovascular and allcause mortality in type 2 diabetics with microalbuminuria.

References

1. National Kidney Foundation: K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification and stratification. Am J Kidney Dis. 2002;39 (2 suppl 1):S1-S266.
2. Hostetter TH, Rennke HG, Brenner BM. The case for intrarenal hypertension in the initiation and progression of diabetic and other glomerulopathies. Am J Med. 1982;72:375-380.
3. Adler AI, Stevens RJ, Manley SE, Bilous RW, Cull CA, Holman RR. Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int. 2003;63:225-232.
4. Quyyumi AA. Prognostic value of endothelial function. Am J Cardiol. 2003;91: 19-24.
5. Patel A, MacMahon S, Chalmers J, et al; ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomized controlled trial. Lancet. 2007;370:829-840.
6. ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560-2572.



5. R. Unnikrishnan and V. Mohan, India

Ranjit UNNIKRISHNAN, I, MD – Viswanthan MOHAN, MD, FRCP, PhD, DSc
Corresponding author:
Viswanthan Mohan, Doctor
Chairman and Chief of Diabetology
Madras Diabetes Research Foundation
Dr Mohan’s Diabetes Specialities Centre
& WHO Collaborating Centre for Noncommunicable
Diseases, Prevention and Control
4, Conran Smith Road, Gopalapuram
Chennai, 600 086, INDIA
(e-mail: drmohans@vsnl.net)

The term microalbuminuria refers to a level of urinary albumin excretion, commonly defined as being between 30 and 299 mg albumin per day and below the sensitivity threshold of conventional dipsticks. It is usually detected by measuring the albumin-creatinine ratio, either in a spot urine sample or in a timed urine collection.

Microalbuminuria is considered the earliest detectable stage of diabetic nephropathy. This stage is potentially reversible: prompt intervention with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) is extremely effective in slowing the progression to overt nephropathy.

Microalbuminuria is considered to result from a defect in the glomerular filtration barrier, which consists of the glomerular capillary endothelium, basement membrane, and visceral epithelium. The endothelial defect responsible for microalbuminuria may be a marker for a more widespread pathological process, involving blood vessels in several organs and sharing the common etiological factor of prolonged uncontrolled hypoglycemia. The mechanisms of endothelial dysfunction in diabetes may involve the polyol pathway, aldose reductase pathway, and/or the formation of advanced glycation end products. The finding of microalbuminuria should alert the clinician to signs of vascular disease at other sites in the body in addition to the kidney.

Diabetic nephropathy and retinopathy, the two major microvascular complications of diabetes, share many risk factors. Hence, it is not surprising that many studies have shown a strong correlation between microalbuminuria and diabetic retinopathy.1 The association persists after adjustment for age, duration of diabetes, and quality of glycemic control. Moreover, retinopathy increases in severity with increase in albuminuria.2

The association of microalbuminuria with macrovascular disease, such as coronary artery disease, stroke, and peripheral arterial disease, has been well established.3,4 In type 2 diabetic subjects, the albumin excretion rate is a significant predictor of coronary morbidity, even after adjustment for potential confounders, such as hypertension and other cardiovascular risk factors.4 It is of interest to note that the association between elevated albumin excretion and coronary artery disease is also largely valid in nondiabetics.5 Microalbuminuria is associated with increased mortality not only in diabetic subjects, but also in the general elderly population.3,5

Thus, microalbuminuria is not only a marker of diabetic nephropathy, of which it is the earliest detectable stage, but also of other complications, both microvascular, such as diabetic retinopathy, and macrovascular. Its presence in a diabetic subject therefore warrants a careful search for such complications. In addition to ACE inhibitors and ARBs, patients found to have microalbuminuria should receive treatment to minimize their known cardiovascular risk factors. This should include cessation of smoking and, possibly, the addition of aspirin or hydroxymethylglutaryl coenzyme A inhibitors (ie, statins). In the Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation (ADVANCE) trial, the ACE inhibitor perindopril in combination with indapamide reduced the risk of major vascular events and death in type 2 diabetics, irrespective of the use of other antihypertensive agents and initial blood pressure levels.6 Such an approach will help to reduce morbidity and mortality from both micro- and macroangiopathy.

References

1. Klein R, Klein BE, Linton KL, Moss SE. Microalbuminuria in a population-based study of diabetes. Arch Intern Med. 1992;152:153-158.
2. Gall MA, Rossing P, Skøtt P, et al. Prevalence of micro- and macroalbuminuria, arterial hypertension, retinopathy and large vessel disease in European type 2 (non-insulin-dependent) diabetic patients. Diabetologia. 1991;34:655-661.
3. Yudkin JS, Forrest RD, Jackson CA. Microalbuminuria as predictor of vascular disease in non-diabetic subjects. Islington Diabetes Survey. Lancet. 1988;2:530- 533.
4. Mattock MB, Keen H, Viberti GC, et al. Coronary heart disease and urinary albumin excretion rate in type 2 (non-insulin-dependent) diabetic patients. Diabetologia. 1988;31:82-87.
5. Damsgaard EM, Frøland A, Jørgensen OD, Mogensen CE. Microalbuminuria as predictor of increased mortality in elderly people. BMJ. 1990;300:297-300.
6. Patel A, MacMahon S, Chalmers J, et al; ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet. 2007;370:829-840.


6. F. Puchulu, Argentina

Felix PUCHULU, MD
Doctor, Juncal 1177 5º B (1021)
Capital Federal, Buenos Aires
ARGENTINA
(e-mail: fpuchulu@gmail.com)em>

Microalbuminuria is an early marker of nephropathy, a chronic microangiopathic complication of diabetes. It also represents an increased risk of retinopathy and an independent cardiovascular risk factor in diabetes types 1 and 2. Additionally, it is a cardiovascular risk factor in nondiabetics and a component of the metabolic syndrome. Its prevalence in nondiabetic essential hypertension is around 25%.

Two main factors in the shared underlying pathogenesis are generalized endothelial dysfunction and chronic low-grade inflammation. The pathophysiology of the transcapillary escape rate of albumin is poorly understood, but probably involves hemodynamic changes and damage to the structure and/or function of the vascular wall. The permeability of the glomerular filtration barrier depends on a three-layer structure: endothelium (with fenestrae filled by glycocalyx), glomerular basement membrane, and podocytes (glomerular epithelial cells). The glycocalyx is a dynamic layer of glycoproteins and proteoglycans with adsorbed plasma proteins. In diabetics and nondiabetics, microalbuminuria is related to changes in the size and charge selectivity of the glomerular filtration barrier. Defects in charge selectivity occur earlier than loss of size selectivity,1 probably due to damage to the negatively charged glycocalyx. Removing the glycocalyx increases vascular protein permeability, ie, the presence of significant endothelial glycocalyx implies that glomerular endothelium has a key role in retaining macromolecules.2

Reactive oxygen species (ROS) disrupt the glycocalyx, causing proteinuria with no structural changes in the glomerular filtration barrier identifiable on electron microscopy. Hyperglycemia increases the production of ROS, increasing nuclear factor-ê B, interfering with nitric oxide bioavailability, directly disrupting the endothelial glycocalyx,3 and decreasing heparan sulfate proteoglycan production. Podocytes also produce ROS during hyperglycemia. Since glomerular endothelium is exposed to the same diabetic disorders as endothelium elsewhere, it is presumably also dysfunctional.

Several markers of endothelial cell dysfunction are increased in microalbuminuria. Brachial artery bloodflow is decreased during reactive hyperemia in type 1 diabetics with microalbuminuria. Impaired endothelial nitric oxide synthesis may link microalbuminuria with cardiovascular risk, regardless of diabetes: endothelial dysfunction precedes and predicts microalbuminuria onset in both diabetics and nondiabetics.4 Microalbuminuria represents increased albumin leakage through the glomerular capillary wall due to an increase in wall permeability, intraglomerular pressure, or both. Hyperglycemia and hypertension are both risk factors for microalbuminuria and can increase intraglomerular pressure. Hyperglycemia also alters the charge selectivity of the glomerular capillary wall, thereby increasing its permeability.

Endothelial dysfunction increases glomerular pressure and glomerular barrier permeability. The endothelium appears to be directly involved in determining permeability to albumin. Abnormalities in endothelial glycocalyx are also implicated in the pathogenesis of atherosclerosis, thus providing a potential common pathogenesis for albuminuria and cardiovascular disease.5 Chronic low-grade inflammation, also common in diabetes, is the other major factor in shared pathogenesis. It is reflected in the plasma levels of C-reactive protein and cytokines, such as interleukin 6 and tumor necrosis factor á. These markers have shown that, irrespective of diabetes, low-grade inflammation is associated with the occurrence and progression of microalbuminuria and atherothrombotic risk.6

A major aspect of microalbuminuria is disruption of the endothelial glycocalyx by the direct or indirect actions of mediators related to hyperglycemia. Glycocalyx dysfunction reflects the generalized endothelial dysfunction that may link microalbuminuria to vascular disease. Microalbuminuria is probably more a marker of generalized endothelial dysfunction than of micro- or macroangiopathy, and should always extend the clinician’s concern from the kidney to other territories, such as the retina and heart.

References

1. Deckert T, Kofoe-Enevoldsen A, Vidal P, Norgaard K, Andreasen HB, Feldt-Rasmussen B. Size and charge selectivity of glomerular filtration in type 1 (insulin dependent) diabetic patients with and without albuminuria. Diabetologia. 1993;36: 244-251.
2. Satchell SC, Tooke JE. What is the mechanism of microalbuminuria in diabetes: a role for the glomerular endothelium? Diabetologia. 2008;51:714-725.
3. Vink H, Duling BR. Identification of distinct luminal domains for macromolecules, erythrocytes, and leukocytes within mammalian capillaries. Circ Res. 1996;79: 581-589.
4. Stehouwer CDA. Endothelial dysfunction in diabetic nephropathy: state of the art and potential significance for nondiabetic renal disease. Nephrol Dial Transplant. 2004;19:778-781. Editorial.
5. Nieuwdorp M, Meuwese MC, Vink H, Hoekstra JB, Kastelein JJP, Stroes ES. The endothelial glycocalix: a potential barrier between health and vascular disease. Curr Opin Lipidol. 2005;16:507-511.
6. Schram MT, Chaturvedi N, Schalkwijk CG, Fuller JH, Stehouwer CDA; EURODIAB Prospective Complications Study Group. Markers of inflammation are cross-sectionally associated with microvascular complications and cardiovascular disease in type 1 diabetes: the EURODIAB Prospective Complications Study. Diabetologia. 2005;48:370-378.



7. R. Roussel,France

Ronan ROUSSEL,MD, PhD
Doctor, Assistance Publique-Hôpitaux
de Paris, Hôpital Bichat, Département
d’Endocrinologie, Diabétologie et Nutrition
46 rue Huchard, 75018 Paris, FRANCE
(e-mail: ronan.roussel@bch.aphp.fr)

Microalbuminuria is the persistently increased urinary excretion of albumin above 30 mg/24 hours (or 20 mg/L, or 20 mg/g creatinine), but below 300 mg/ 24 hours (200 ìg/L, or 200 mg/g). The National Health And Nutrition Examination Survey showed a prevalence of 8.8% in US adults.1 Prevalence increases markedly in diabetes and hypertension, reflecting disease duration: it reached 25% in controls in the United Kingdom Prospective Diabetes Study.2

Microalbuminuria as a marker of micro- and macroangiopathic outcome

The relationship with adverse clinical outcome is continuous and positive. In the Heart Outcomes Prevention Evaluation (HOPE), microalbuminuria was associated with myocardial infarction, stroke, cardiovascular death, all-cause mortality, and hospitalization for congestive heart failure, not only in all patients, but also in the diabetic and nondiabetic subgroups.3 It has been associated with mortality in other populations, including those at lower cardiovascular risk than in HOPE,4 and even in the general population (Prevention of REnal and Vascular ENdstage Disease [PREVEND] study). Risk is also increased in high-normal albuminuria. The Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation (ADVANCE) study found an impressively positive linear relationship between log albumin excretion rate and endstage renal disease or cardiovascular death.4 Microalbuminuria also correlated with stroke risk in the European Prospective Investigation of Cancer-Norfolk (EPIC-Norfolk). PREVEND reported a matching trend in peripheral arterial disease.

Microalbuminuria is strongly associated with microangiopathy in type 1 diabetes, especially with progression to severe diabetic nephropathy,5 proliferative retinopathy, and neuropathy.

Is microalbuminuria a useful marker of micro- and macroangiopathy?

Undoubtedly yes, ever since pioneering evidence from the Danish groups and others prompted the American Diabetes Association to recommend screening for incipient nephropathy: “Perform an annual test to assess urine albumin excretion in type 1 diabetic patients with diabetes duration of _5 years and in all type 2 diabetic patients, starting at diagnosis.” As for macroangiopathy, especially coronary heart disease and stroke, microalbuminuria is both practical to measure, using an early morning or random spot urine sample, and independent of other validated risk factors. The epidemiological data show that it remains associated with future cardiovascular events after adjustment for such validated common risk factors as age, smoking, gender, weight, waist circumference, blood pressure, glycated hemoglobin, and lipids.6 The HOPE study found that relative risks for major cardiovascular events were similar in diabetics and nondiabetics, again after adjusting for cardiovascular risk factors. Thus, microalbuminuria provides added value in cardiovascular prognosis.

Microalbuminuria and cardiovascular risk reduction

The Losartan Intervention For Endpoint reduction in hypertension (LIFE) found that although changes in albuminuria during antihypertensive treatment over time translated into reduction in cardiovascular risk, this was not explained by the in-treatment blood pressure level, suggesting the benefit of repeated albuminuria assessment during treatment. However, only 13% of the participants were diabetic. In type 2 diabetes, reduced proteinuria is undoubtedly associated with improved renal outcome (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan [RENAAL] study and Irbesartan in Diabetic Nephropathy Trial [IDNT]). Of course, with nephropathy being defined by urinary albumin level, decreasing microalbuminuria, by definition, decreases the risk of overt nephropathy. However, data in type 2 diabetes are lacking to test for a relationship between reduced microalbuminuria and reduced cardiovascular events. Extrapolated evidence from nondiabetics (hypertensive LIFE patients) suggests that diabetologists should measure albuminuria in every diabetic and be as aggressive in reducing this modifiable risk factor as they are in reducing blood pressure, lipids, or glycemia in the early stages of diabetes.

References

1. Coresh J, Byrd-Holt D, Astor BC, et al. Chronic kidney disease awareness, prevalence, and trends among U.S. adults, 1999 to 2000. J Am Soc Nephrol. 2005;16:180-188.
2. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ. 1998;317:703-713.
3. Gerstein HC, Mann JF, Yi Q, et al; HOPE Study Investigators. Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals. JAMA. 2001;286:421-426.
4. Patel A, MacMahon S, Chalmers J, et al; ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet. 2007;370:829-840.
5. Mogensen C, Christensen CK, Vittinghus E. The stages in diabetic renal disease. With emphasis on the stage of incipient diabetic nephropathy. Diabetes. 1983;32 (suppl 2):64-78.
6. Brantsma AH, Bakker SJ, Hillege HL, de Zeeuw D, de Jong PE, Gansevoort RT; PREVEND Study Group. Urinary albumin excretion and its relation with C-reactive protein and the metabolic syndrome in the prediction of type 2 diabetes. Diabetes Care. 2005;28:2525-2530.



8. G. Schernthaner, Austria

Guntram SCHERNTHANER,MD
Professor, Head of the Department of
Medicine I, Rudolfstiftung Hospital
Juchgasse 25, A-1030 Vienna
AUSTRIA
(e-mail: guntram.schernthaner@
meduniwien.ac.at)

In the past three decades, urinary albumin excretion has played a central role in the diagnosis and management of nephropathy in type 1 and type 2 diabetics. Microalbuminuria was found to predict overt albuminuria (>300 mg/24 hours), which in turn predicted loss of kidney function. More recent data indicate that glomerular filtration rate and albuminuria are twin manifestations of nephropathy in diabetes.

In 1984, Mogensen demonstrated that microalbuminuria predicts increased mortality in type 2 diabetes.1 The United Kingdom Prospective Diabetes Study showed that cardiovascular mortality increased significantly with increasing nephropathy (P<0.0001), with annual mortality rates of 0.7% for subjects without nephropathy, 2.0% for those with microalbuminuria, 3.5% for those with macroalbuminuria, and 12.1% for those with elevated plasma creatinine or renal replacement therapy.

During the last 20 years, many prospective and epidemiologic studies have found that microalbuminuria is predictive, independently of traditional risk factors, of all-cause and cardiovascular mortality and cardiovascular disease events within groups of patients with diabetes or hypertension and in the general population. In 1989, Deckert et al had already postulated that albuminuria reflects widespread vascular damage.2 The pathophysiological mechanism underlying the association between albumin excretion and cardiovascular disease has, to this day, not been fully elucidated. One hypothesis is that microalbuminuria may be a marker of cardiovascular risk because it reflects subclinical vascular damage in the kidneys and other vascular beds. It may also signify systemic endothelial dysfunction that predisposes to future cardiovascular events.

A positive test for urinary albumin excretion should be taken as a clarion call to initiate an intensive multifactorial intervention strategy, including behavior modification and targeted pharmacotherapy aimed at preventing further renal deterioration and improving the overall cardiovascular risk factor profile.3 Data from intervention studies suggest that treatment with angiotensin- converting enzyme inhibitors or angiotensin II receptor blockers, statins, and/or strict glycemic control (in diabetics) offer significant reductions in cardiovascular and/or renal morbidity in patients with albuminuria. Use of the microalbuminuria marker may allow improved use of medications and strategies for secondary prevention.

There has been good news from the Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation (ADVANCE) study. Its results indicate that both routine blood pressure lowering4 and intensive glucose control5 significantly decrease new or worsening nephropathy by 18% and 19%, respectively, attaining a relative risk reduction of 33% for the joint effect of both interventions.6 Since microalbuminuria and, in particular, macroalbuminuria are strong predictors of end-stage renal disease, cardiovascular morbidity, and cardiovascular mortality, the routine use of the intervention strategies deployed in ADVANCE will help to improve the persistently poor overall prognosis of large numbers of type 2 diabetic patients worldwide.

References

1. Mogensen CE. Microalbuminuria predicts clinical proteinuria and early mortality in maturity-onset diabetes. N Engl J Med. 1984;310:356-360.
2. Deckert T, Feldt-Rasmussen B, Borch-Johnsen K, Jensen T, Kofoed-Enevoldsen A. Albuminuria reflects widespread vascular damage. The Steno hypothesis. Diabetologia. 1989;32:219-226.
3. Schernthaner G. Kidney disease in diabetology: lessons from 2007. Nephrol Dial Transplant. 2008;23:1112-1115.
4. Patel A, MacMahon S, Chalmers J, et al; ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet. 2007;370:829-840.
5. ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560-2572.
6. Chalmers J et al. Joint effects of routine blood pressure lowering with Coversyl Plus and intensive glucose control with a gliclazide MR-based regimen. In: The 44th Annual Meeting of the European Association for the Study of Diabetes; September 7-11, 2008; Rome, Italy.



9. M. Shestakova,Russia

Marina SHESTAKOVA,MD, PhD
Professor, Director, Diabetes Institute
Endocrinology Research Center, 117036
Dm Ulyanov str 11, Moscow, RUSSIA
(e-mail: nephro@endocrincentr.ru)

Diabetic nephropathy has long laid the largest single claim on dialysis services in developed countries, accounting for 44% of dialysis facilities in the USA. The rates of progression to proteinuria 15 years after diagnosis are 15% and 20% in diabetes types 1 and 2.1 The Datamonitor multiclient study in type 2 diabetes suggests that the overall prevalence of nephropathy (microalbuminuria, proteinuria, and end-stage renal disease [ESRD]) is 48% across the seven countries, representing 18.6 million patients.

However, the markers of diabetic nephropathy—micro- and macroalbuminuria—are not only predictors of progression, but also independent cardiovascular risk factors. This association constitutes the cardiorenal syndrome. In the current setting of timely nephrological care, diabetics no longer die from uremia, but from cardiovascular disorders (myocardial infarction, stroke, and large artery thrombosis). ESRD is responsible for 30% of deaths in type 1 diabetes and 5% in type 2, with cardiovascular accidents still accountable for the majority.2

In the Wisconsin Epidemiological Study of Diabetic Retinopathy in type 2 diabetics, micro- and macroalbuminuria (or proteinuria) increased cardiovascular mortality 2.2-fold and 3.7- fold in comparison with patients without renal disease, even after adjusting for traditional coronary risk factors (age, gender, blood glucose, blood pressure [BP], and family history).

In the Heart Outcomes Prevention Evaluation (HOPE) in over- 55s with coronary risk factors, microalbuminuria also doubled cardiovascular mortality in patients without renal disease, in both type 2 diabetics and nondiabetics. Every 0.4 mg/mmol increase in albumin/creatinine ratio increased major cardiovascular events by 5.9%, all-cause mortality by 6.8%, and heart failure–related hospitalization by 10.6%.3

Two large trials, Losartan Intervention For Endpoint reduction in hypertension (LIFE) and Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL), provided robust evidence linking urinary albumin excretion to cardiovascular mortality. Both showed parallel decreases in urinary albumin excretion in response to long-term antihypertensive treatment, on the one hand, and in cardiovascular mortality, stroke, and myocardial infarction, on the other. The atherogenicity of microalbuminuria remains unexplained. Microalbuminuria may reflect systemic endothelial dysfunction and increased plasma membrane permeability throughout the vascular tree; there is also an association with inflammatory markers. In diabetes, it reflects endothelial dysfunction, resulting in increased permeability to blood corpuscles, proteins, lipids, and other plasma components.4

The Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation (ADVANCE) trial, the largest ever in diabetes (>11 000 type 2 diabetics, mean age 66 years, 10% and 32% with micro- and macrovascular complications), has shed light on the clinical relationship between nephropathy markers and cardiovascular events.5 Nephropathy markers were equally sensitive to intensive blood glucose control (using Diamicron MR) and intensive BP control (using Preterax Forte): total renal events decreased significantly by 21% in both arms. Joint intensive control achieved the greatest decrease in renal events (33%),6 and in total and cardiovascular mortality (18% and 24%).

The parallel between renoprotection and decrease in cardiovascular mortality confirms the hypothesis of a relationship between the markers of renal and cardiovascular disorders. ADVANCE provides convincing evidence that even in elderly longstanding type 2 diabetics at high cardiovascular risk, treatments such as Diamicron MR and Preterax Forte are a safe and effective strategy for decreasing the development and progression of cardiorenal syndrome and cardiovascular mortality.

References

1. Hovind P, Tarnow L, Rossing P, et al. Predictors for the development of microalbuminuria and macroalbuminuria in patients with type 1 diabetes: inception cohort study. BMJ. 2004;328:1105-1116.
2. Allen KV, Walker JD. Microalbuminuria and mortality in long-duration type 1 diabetes. Diabetes Care. 2003;26:2389-2391.
3. Gerstein HC, Mann JFE, Yi Q, et al. Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and non-diabetic individuals. JAMA. 2001;286: 421-426.
4. Shestakova MV, Jarek-Martynowa IR, Ivanishiva NS, et al. Role of endothelial dysfunction in the development of cardiorenal syndrome in patients with type 1 diabetes mellitus. Diab Res Clin Pract. 2005;68(suppl 1):S65-S72.
5. ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560-2572.
6. www.advance-trial.com.



10. J.-G. Wang, Y. Li, and C.-S. Sheng,China

Ji-Guang WANG, MD, PhD
Yan LI, MD, PhD
Chang-Sheng SHENG,Corresponding author:
Ji-Guang Wang, Professor
Shanghai Institute of Hypertension
Ruijin 2nd Road 197
Shanghai 200025, CHINA
(e-mail: jiguangw@gmail.com)

Microalbuminuria is a biological indicator or marker of structural and/or functional lesions in small arteries. Given the difficulties in imaging arteriolar structure and function, microalbuminuria is probably the best available measure of microangiopathy. Numerous studies in various populations have demonstrated that it predicts not only endstage renal disease, but also major cardiovascular disease, such as myocardial infarction and stroke.1 There is also abundant evidence that contemporary cardiovascular treatments, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), reduce urinary albumin excretion in addition to lowering blood pressure.2

There is no doubt that microalbuminuria is a predictor of cardiovascular mortality and morbidity. However, the main controversial issue is whether pharmacologically reducing urinary albumin excretion using ACE inhibitors or ARBs is clinically relevant in preventing cardiovascular events. The Irbesartan in Diabetic Nephropathy Trial (IDNT) compared an ARB, irbesartan (titrated from 75 mg to 300 mg/day), with a calcium channel blocker, amlodipine (titrated from 2.5 mg to 10 mg/day), in type 2 diabetics with proteinuria (at least 900 mg/day) and blood pressure _135/85 mm Hg or receiving antihypertensive therapy.3 During follow-up (mean 2.6 years), irbesartan significantly reduced the risks of serum creatinine doubling (–37%, P<0.001), end-stage renal disease (–23%, P=0.07),3 and congestive heart failure (–35%,P=0.004) versus amlodipine.4 However, the risks of myocardial infarction (+54%, P=0.07), stroke (+55%, P=0.16), and cardiovascular mortality (+36%, P=0.15) were higher in the irbesartan group.4

The recently published ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) observed the same paradoxical results in three parallel groups of patients receiving an ACE inhibitor, ramipril (10 mg/day), alone, an ARB, telmisartan (80 mg/day), alone, and the combination of ramipril and telmisartan (10 mg & 80 mg/day).5 There was a significant difference in urinary albumin excretion at 2 years and at the end of the trial, the most pronounced effect being in the combination therapy group of ramipril and telmisartan (2-year urinary albumin/creatinine ratio to baseline, 1.05; P<0.0001 vs ramipril), with an intermediate effect in the telmisartan group (1.08, P=0.001 vs ramipril), and the least effect in the ramipril group (1.17).6 However, the risk of the primary outcome (cardiovascular death, myocardial infarction, stroke, and hospitalization for congestive heart failure) was similar in the three groups (16.3% vs 16.7% vs 16.5%).5

The IDNT and ONTARGET results suggest that the reduction of urinary albumin excretion cannot be translated into hard cardiovascular outcome benefit in patients at high cardiovascular or renal risk. However, the contradictory effects of treatment on albuminuria and cardiovascular outcome do not entirely exclude the possibility that the long-term amelioration of microalbuminuria is protective against cardiovascular disease because, in both these trials, patients were at high risk and follow-up duration was short (2.6 to 4.8 years). Future studies should focus on patients with microalbuminuria, but without preexisting cardiovascular disease or evidence of large arterial lesions in order to investigate the influence of ACE inhibitors and ARBs (potentially beneficial because of their dilating effect on the microcirculation, including arterioles and venules).

References

1. Diercks GF, van Boven AJ, Hillege JL, de Jong PE, Rouleau JL, van Gilst WH. The importance of microalbuminuria as a cardiovascular risk indicator: a review. Can J Cardiol. 2002;18:525-535.
2. de Zeeuw D, Parving HH, Henning RH. Microalbuminuria as an early marker for cardiovascular disease. J Am Soc Nephrol. 2006;17:2100-2105.
3. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin- receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851-860.
4. Berl T, Hunsicker LG, Lewis JB, et al. Cardiovascular outcomes in the Irbesartan Diabetic Nephropathy Trial of patients with type 2 diabetes and overt nephropathy. Ann Intern Med. 2003;138:542-549.
5. ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358:1547-1559.
6. Mann JF, Schmieder RE, McQueen M, et al. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet. 2008;372:547-553.