Microalbuminuria: target for renoprotective therapy PRO
2014; Elsevier BV; Volume: 86; Issue: 1 Linguagem: Inglês
10.1038/ki.2013.490
ISSN1523-1755
AutoresSara S. Roscioni, Hiddo J.L. Heerspink, Dick de Zeeuw,
Tópico(s)Dialysis and Renal Disease Management
ResumoDrug efficacy is ascertained using clinically meaningful outcomes that directly affect the well-being of patients. However, in studies of chronic kidney disease progression, clinically meaningful outcomes like end-stage renal disease take a long time to occur. The use of surrogate end points/markers as replacement for clinical outcomes is tempting as it may reduce sample size requirements, shorten follow-up time, facilitate trial conduct, and allow the performance of intervention trials in earlier stages of kidney disease to be carried out. We here reviewed recent data supporting the use of microalbuminuria as a valid surrogate end point in clinical trials of chronic kidney disease. We provide data that albuminuria is associated with worse renal prognosis and that pharmacological treatment aimed to reduce albuminuria levels delays the progression of renal disease and the occurrence of clinical outcomes. Furthermore, we review new studies showing that albumin is not only an inert molecule but also directly affects the function of several cell types in the kidney and may have a pathogenic role in renal disease. Accepting microalbuminuria as a surrogate marker for renal outcomes will lead to less resource-consuming hard outcome trials, will accelerate the development of drugs for chronic kidney disease, and enable earlier access of these drugs to individual patients. Drug efficacy is ascertained using clinically meaningful outcomes that directly affect the well-being of patients. However, in studies of chronic kidney disease progression, clinically meaningful outcomes like end-stage renal disease take a long time to occur. The use of surrogate end points/markers as replacement for clinical outcomes is tempting as it may reduce sample size requirements, shorten follow-up time, facilitate trial conduct, and allow the performance of intervention trials in earlier stages of kidney disease to be carried out. We here reviewed recent data supporting the use of microalbuminuria as a valid surrogate end point in clinical trials of chronic kidney disease. We provide data that albuminuria is associated with worse renal prognosis and that pharmacological treatment aimed to reduce albuminuria levels delays the progression of renal disease and the occurrence of clinical outcomes. Furthermore, we review new studies showing that albumin is not only an inert molecule but also directly affects the function of several cell types in the kidney and may have a pathogenic role in renal disease. Accepting microalbuminuria as a surrogate marker for renal outcomes will lead to less resource-consuming hard outcome trials, will accelerate the development of drugs for chronic kidney disease, and enable earlier access of these drugs to individual patients. Despite the availability of effective treatments to delay the progression of renal function loss, the prevalence of end-stage renal disease (ESRD) continues to rise.1.van Dijk P.C. Jager K.J. de Charro F. et al.Renal replacement therapy in Europe: the results of a collaborative effort by the ERA-EDTA registry and six national or regional registries.Nephrol Dial Transplant. 2001; 16: 1120-1129Crossref PubMed Scopus (277) Google Scholar Novel strategies are needed to lessen the burden of this devastating condition. Health campaigns have focused on early detection of chronic kidney disease on the basis of the rationale that early intervention and appropriate treatment has a greater impact in delaying the progression of renal function loss compared with late intervention. To study the efficacy of new drugs, clinically meaningful outcomes that directly affect the well-being of patients are needed. ESRD is a commonly used hard clinical end point in drug trials in nephrology. However, the progression of kidney disease to ESRD takes many years if not decades. Clinical trials enrolling patients at early stages of disease would therefore require a long follow-up and/or an impractical large sample size to establish drug efficacy toward ESRD. The use of a surrogate end point may be a solution to this problem. A surrogate end point of a clinical trial is a laboratory measurement or a physical sign that measures the effect of a certain treatment and is intended to substitute for the clinical end point.2.Cohn J.N. Introduction to surrogate markers.Circulation. 2004; 109: IV20-IV21Crossref PubMed Google Scholar Although such a surrogate end point does not directly measure how a patient feels, functions, or survives, it is associated with clinically meaningful outcomes so that changes in the marker level are expected to predict benefit or harm. The use of surrogate end points in clinical trials is tempting as it may reduce sample size requirements, shorten the follow-up time of clinical trials, and allow the performance of early intervention trials to be carried out. The presence of microalbuminuria is an early sign of renal damage and predicts an accelerated loss of renal function.3.Lambers Heerspink H.J. Brinkman J.W. Bakker S.J. et al.Update on microalbuminuria as a biomarker in renal and cardiovascular disease.Curr Opin Nephrol Hypertens. 2006; 15: 631-636Crossref PubMed Scopus (65) Google Scholar Clinicians currently use microalbuminuria to diagnose renal damage and establish the prognosis of an individual. Moreover, the change in albuminuria after treatment initiation with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers is frequently used to monitor renal and/or cardiovascular -protective response to therapy. Microalbuminuria could therefore be used as target for treatment and as a surrogate end point in clinical trials. However, there is growing awareness that surrogate end points should be used in clinical trials only after they have been sufficiently validated and reflect a true clinical end point. In the past, a number of promising potentially valid surrogate end points (e.g., hemoglobin) have failed to reflect a true clinical end point.4.Singh A.K. Szczech L. Tang K.L. et al.Correction of anemia with epoietin alfa in chronic kidney disease.N Engl J Med. 2006; 355: 2085-2098Crossref PubMed Scopus (2273) Google Scholar,5.Pfeffer M.A. Burdmann E.A. Chen C.Y. et al.A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease.N Engl J Med. 2009; 361: 2019-2032Crossref PubMed Scopus (1641) Google Scholar Therefore, rigorous validation of a surrogate end point is necessary before it can be implemented in clinical practice. The criteria for validation of surrogacy have been described in the 'statistical principles for clinical trials' of the International Conference on Harmonization.6.ICH Harmonised Tripartite Guideline Statistical principles for clinical trials. International Conference on Harmonisation E9 Expert Working Group.Stat Med. 1999; 18: 1905-1942PubMed Google Scholar First, prognostic evidence of the surrogate end point with patient outcome must be available. Second, a biologically plausible relationship between the surrogate and outcome should exist, and third, clinical trial data must demonstrate that the effect of interventions that change the surrogate end point is directly associated with the same change in clinical outcomes. Herein, we provide new updates that support the concept that microalbuminuria is a valid surrogate renal end point and a target for treatment in renal disease. Twenty-four-hour urine collection represents the gold standard method for determining the presence of microalbuminuria. However, as 24-hour urine collection is an inconvenient procedure for patients, more practical alternatives have been proposed, such as measurement of the albumin:creatinine ratio (UACR) derived from a first morning void or a spot urine sample. Of these, the measurement of UACR in a first morning void appears to be the most reliable alternative to the 24-hour urinary albumin excretion (UAE) in determining the presence of microalbuminuria and also in predicting the progression of disease.7.Lambers Heerspink H.J. Gansevoort R.T. Brenner B.M. et al.Comparison of different measures of urinary protein excretion for prediction of renal events.J Am Soc Nephrol. 2010; 21: 1355-1360Crossref PubMed Scopus (126) Google Scholar,8.Witte E.C. Lambers Heerspink H.J. de Zeeuw D. et al.First morning voids are more reliable than spot urine samples to assess microalbuminuria.J Am Soc Nephrol. 2009; 20: 436-443Crossref PubMed Scopus (178) Google Scholar For practical purposes albuminuria is categorized into different classes—namely, normoalbuminuria ( 300mg albumin/day or per g creatinine). The changes between these albuminuria states represent a hallmark of the progression or regression of disease.9.Ninomiya T. Perkovic V. de Galan B.E. et al.Albuminuria and kidney function independently predict cardiovascular and renal outcomes in diabetes.J Am Soc Nephrol. 2009; 20: 1813-1821Crossref PubMed Scopus (689) Google Scholar Emerging evidence shows that individuals with high grades of albuminuria are at increased risk of accelerated loss of renal function.10.Gansevoort R.T. Matsushita K. van der Velde M. et al.Lower estimated GFR and higher albuminuria are associated with adverse kidney outcomes. A collaborative meta-analysis of general and high-risk population cohorts.Kidney Int. 2011; 80: 93-104Abstract Full Text Full Text PDF PubMed Scopus (549) Google Scholar Whereas the association between the severity of albuminuria and renal disease progression was initially described in individuals with high albuminuria (>1.0g per day),11.Peterson J.C. Adler S. Burkart J.M. et al.Blood pressure control, proteinuria, and the progression of renal disease. The Modification of Diet in Renal Disease Study.Ann Intern Med. 1995; 123: 754-762Crossref PubMed Scopus (1228) Google Scholar more recent studies show that an increase in albuminuria, even within the range that is currently considered normal, indicates higher renal risk.10.Gansevoort R.T. Matsushita K. van der Velde M. et al.Lower estimated GFR and higher albuminuria are associated with adverse kidney outcomes. A collaborative meta-analysis of general and high-risk population cohorts.Kidney Int. 2011; 80: 93-104Abstract Full Text Full Text PDF PubMed Scopus (549) Google Scholar This is a consistent finding that has been shown in different populations. In patients with type 2 diabetes followed up for at least 5 years, higher UACR at baseline was associated with a faster decline in renal function. Importantly, although within the normal range, a UACR of ≥10mg/g in women or ≥5mg/g in men was associated with a significantly greater rate of renal function decline.12.Babazono T. Nyumura I. Toya K. et al.Higher levels of urinary albumin excretion within the normal range predict faster decline in glomerular filtration rate in diabetic patients.Diabetes Care. 2009; 32: 1518-1520Crossref PubMed Scopus (55) Google Scholar Similar data were found in patients with type 2 diabetes and microalbuminuria participating in the Irbesartan Microalbuminuria-2 (IRMA-2) trial. Subjects in the highest quintile of baseline albuminuria excretion (between 102 and 300μg/min, which equals a UACR of ~150 and 450mg/g) had approximately 2.5-fold greater rate of renal function decline compared with subjects with urinary albumin excretion between 20 and 30μg/min13.Hellemons M.E. Persson F. Bakker S.J. et al.Initial angiotensin receptor blockade-induced decrease in albuminuria is associated with long-term renal outcome in type 2 diabetic patients with microalbuminuria: a post hoc analysis of the IRMA-2 trial.Diabetes Care. 2011; 34: 2078-2083Crossref PubMed Scopus (53) Google Scholar (which equals a UACR of ~30 and 45mg/g) (Figure 1a). The association between the increases in albuminuria and hard renal outcomes in type 2 diabetes was established in the ADVANCE trial.9.Ninomiya T. Perkovic V. de Galan B.E. et al.Albuminuria and kidney function independently predict cardiovascular and renal outcomes in diabetes.J Am Soc Nephrol. 2009; 20: 1813-1821Crossref PubMed Scopus (689) Google Scholar Although the majority of patients (69%) enrolled in this trial had albuminuria in the normal range, baseline albuminuria was an independent determinant of the progression to renal outcomes, and even subtle changes in albuminuria in the normal range were strongly associated with disease progression. Similar associations between albuminuria and renal function decline have been described in the non-diabetic hypertensive population. In 1998, Bigazzi et al.14.Bigazzi R. Bianchi S. Baldari D. et al.Microalbuminuria predicts cardiovascular events and renal insufficiency in patients with essential hypertension.J Hypertens. 1998; 16: 1325-1333Crossref PubMed Scopus (323) Google Scholar showed that subjects with essential hypertension and microalbuminuria had a faster rate of renal function decline (assessed by creatinine clearance) compared with subjects with normoalbuminuria (Figure 1b). These data were confirmed in a larger cohort of patients with essential hypertension, of whom the majority had normoalbuminuria (92%). Subjects who developed a renal event had higher baseline albumin-to-creatinine ratio (ACR) compared with subjects who did not develop a renal event (5.12 vs. 4.42mg/g; P<0.001). Moreover, a regression analysis revealed that the ACR level at baseline predicted renal events independent of other renal risk markers.15.Viazzi F. Leoncini G. Conti N. et al.Microalbuminuria is a predictor of chronic renal insufficiency in patients without diabetes and with hypertension: the MAGIC study.Clin J Am Soc Nephrol. 2010; 5: 1099-1106Crossref PubMed Scopus (48) Google Scholar Finally, studies from the community cohorts Prevention of Renal and Vascular End-stage Disease (PREVEND) and the Nord-Trøndelag Health (HUNT 2) provide further insight into the relationship between levels of albuminuria and renal disease in the general population.16.van der Velde M. Halbesma N. de Charro F.T. et al.Screening for albuminuria identifies individuals at increased renal risk.J Am Soc Nephrol. 2009; 20: 852-862Crossref PubMed Scopus (118) Google Scholar, 17.Verhave J.C. Gansevoort R.T. Hillege H.L. et al.An elevated urinary albumin excretion predicts de novo development of renal function impairment in the general population.Kidney Int Suppl. 2004; 92: S18-S21Abstract Full Text Full Text PDF PubMed Google Scholar, 18.Hallan S.I. Ritz E. Lydersen S. et al.Combining GFR and albuminuria to classify CKD improves prediction of ESRD.J Am Soc Nephrol. 2009; 20: 1069-1077Crossref PubMed Scopus (344) Google Scholar In the PREVEND cohort, higher UACR levels were associated with a faster rate of estimated glomerular filtration rate (eGFR) decline and an increased risk for ESRD (Figure 1c).16.van der Velde M. Halbesma N. de Charro F.T. et al.Screening for albuminuria identifies individuals at increased renal risk.J Am Soc Nephrol. 2009; 20: 852-862Crossref PubMed Scopus (118) Google Scholar As observed in individuals with diabetes or hypertension, the relation between albuminuria and renal disease progression persists even within the normoalbuminuric and microalbuminuric range. Similar association between subtle increases in albuminuria and progression to ESRD was found in the HUNT 2 study.18.Hallan S.I. Ritz E. Lydersen S. et al.Combining GFR and albuminuria to classify CKD improves prediction of ESRD.J Am Soc Nephrol. 2009; 20: 1069-1077Crossref PubMed Scopus (344) Google Scholar Of note, in the HUNT 2 study the risk prediction of albuminuria alone performed significantly better than a clinical risk prediction score consisting of multiple risk factors including age, gender, physical activity, diabetes, systolic blood pressure, antihypertensive medication, and high-density lipoprotein cholesterol.18.Hallan S.I. Ritz E. Lydersen S. et al.Combining GFR and albuminuria to classify CKD improves prediction of ESRD.J Am Soc Nephrol. 2009; 20: 1069-1077Crossref PubMed Scopus (344) Google Scholar This last aspect may be of great clinical relevance considering that albuminuria can be easily collected (and in big amounts) by the patients themselves. Because the progression from microalbuminuria to ESRD takes many years to manifest, few ESRD outcomes are observed in observational studies. Consequently, many studies were underpowered to investigate the association between microalbuminuria and ESRD. A collaborative meta-analysis was therefore performed to assess whether the severity of albuminuria associates with ESRD and whether albuminuria provides additional prognostic information beyond eGFR.19.Astor B.C. Matsushita K. Gansevoort R.T. et al.Lower estimated glomerular filtration rate and higher albuminuria are associated with mortality and end-stage renal disease. A collaborative meta-analysis of kidney disease population cohorts.Kidney Int. 2011; 79: 1331-1340Abstract Full Text Full Text PDF PubMed Scopus (518) Google Scholar In this meta-analysis involving 13 cohorts and 21,688 individuals, it was shown that albuminuria was independently associated with a higher risk for ESRD. In particular, compared with subjects with normoalbuminuria, those with microalbuminuria had a threefold higher risk for ESRD. The risk further increased with more severe albuminuria (Figure 2). Subsequent analyses from this collaborative initiative showed that the association between albuminuria and ESRD is similar in non-hypertensive versus hypertensive individuals and in non-diabetic versus diabetic individuals.20.Fox C.S. Matsushita K. Woodward M. et al.Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without diabetes: a meta-analysis.Lancet. 2012; 380: 1662-1673Abstract Full Text Full Text PDF PubMed Scopus (737) Google Scholar,21.Mahmoodi B.K. Matsushita K. Woodward M. et al.Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without hypertension: a meta-analysis.Lancet. 2012; 380: 1649-1661Abstract Full Text Full Text PDF PubMed Scopus (329) Google Scholar These data indicate that, in the absence of comorbid conditions such as hypertension or diabetes, the association between albuminuria and ESRD persists. Hence, albuminuria is not a consequence of hypertension or diabetes but is a valid independent marker of progressive renal function loss. This notion is supported by another study comparing the rate of renal function decline in diabetic versus non-diabetic individuals.22.Lorenzo V. Saracho R. Zamora J. et al.Similar renal decline in diabetic and non-diabetic patients with comparable levels of albuminuria.Nephrol Dial Transplant. 2010; 25: 835-841Crossref PubMed Scopus (48) Google Scholar Subjects with diabetes had a higher risk of progressing to ESRD than did non-diabetic subjects. However, subjects with diabetes also had a fourfold higher UACR level (~2000mg/g) compared with non-diabetic subjects (~500mg/g). When the difference in UACR was taken into account, the difference in progression of renal function decline in diabetic and non-diabetic subjects disappeared, indicating that the higher rate of renal function decline in diabetic subjects is explained by the generally higher albuminuria level. Not only the albuminuria level itself but also changes in albuminuria (within the microalbuminuric range) over time predict renal or cardiovascular risk changes. The regression or progression of albuminuria frequently occurs in different populations. In patients with type 2 diabetes and microalbuminuria, it has been shown that those subjects in whom albuminuria declined by more than 50% over 2 years' follow-up had a subsequent renal function decline of -1.8ml/min per year. In contrast, in subjects without a 50% reduction in albuminuria long-term renal function decline was significantly larger, being -3.1ml/min per year.23.Araki S. Haneda M. Koya D. et al.Reduction in microalbuminuria as an integrated indicator for renal and cardiovascular risk reduction in patients with type 2 diabetes.Diabetes. 2007; 56: 1727-1730Crossref PubMed Scopus (133) Google Scholar These data imply that reduction in albuminuria is an integrated renal risk indicator. In summary, data from multiple studies in a broad range of patients show that subtle increases in albuminuria (even within the normo- or microalbuminuric range) are a determinant of renal outcome: higher exposure of albumin to renal tissue increases the chances of losing renal function over time, independent of the underlying renal disease or other comorbidities. It is important to note that the strong and consistent association between albuminuria and renal outcome does not mean that albuminuria is the sole factor associated with renal progression. Studies showing that subjects without microalbuminuria progress to ESRD demonstrate that other renal risk factors are involved as well.24.Thomas M.C. Macisaac R.J. Jerums G. et al.Nonalbuminuric renal impairment in type 2 diabetic patients and in the general population (national evaluation of the frequency of renal impairment cO-existing with NIDDM [NEFRON] 11).Diabetes Care. 2009; 32: 1497-1502Crossref PubMed Scopus (148) Google Scholar More important is the fact that, whenever albuminuria is increased for a certain period of time, it inevitably leads to progressive renal function decline. Thus, despite the fact that the susceptibility of progressive renal function decline may be dictated by multiple factors including environmental factors, concurrent diseases, or genetic variability, albuminuria predicts renal function loss in most circumstances,16.van der Velde M. Halbesma N. de Charro F.T. et al.Screening for albuminuria identifies individuals at increased renal risk.J Am Soc Nephrol. 2009; 20: 852-862Crossref PubMed Scopus (118) Google Scholar,17.Verhave J.C. Gansevoort R.T. 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Weil E.J. Knowler W.C. et al.Albuminuria and estimated glomerular filtration rate as predictors of diabetic end-stage renal disease and death.Clin J Am Soc Nephrol. 2011; 6: 2444-2451Crossref PubMed Scopus (112) Google Scholar indicating that close monitoring of albuminuria and its change over time will help identify subjects at increased renal risk. Given its size and charge characteristics, it is believed that under physiological circumstances albumin is only minimally filtered in the glomeruli. The increased leakage of albumin should therefore be the result of glomerular damage.29.Haraldsson B. Nystrom J. Deen W.M. Properties of the glomerular barrier and mechanisms of proteinuria.Physiol Rev. 2008; 88: 451-487Crossref PubMed Scopus (608) Google Scholar,30.Mathieson P.W. The cellular basis of albuminuria.Clin Sci (Lond). 2004; 107: 533-538Crossref PubMed Scopus (33) Google Scholar Glomerular (micro) albuminuria can be physiological—owing to an increase in hydrostatic pressure or an altered glomerular filtration coefficient, as in stress, exercise, and inflammation—or it can be pathological—for example, due to hypertension or renal disease. The integrity of the glomerulus depends on the function and interaction of at least three distinct layers—namely, the inner glomerular endothelial cell layer, the outer layer of glomerular epithelial cells or podocytes, and, between them, the glomerular basement membrane.29.Haraldsson B. Nystrom J. Deen W.M. Properties of the glomerular barrier and mechanisms of proteinuria.Physiol Rev. 2008; 88: 451-487Crossref PubMed Scopus (608) Google Scholar, 30.Mathieson P.W. The cellular basis of albuminuria.Clin Sci (Lond). 2004; 107: 533-538Crossref PubMed Scopus (33) Google Scholar, 31.Thomas M.C. Pathogenesis and progression of proteinuria.Contrib Nephrol. 2011; 170: 48-56Crossref PubMed Scopus (22) Google Scholar Furthermore, mesangial cells and extracellular matrix surround the nephrons and help in maintaining the structure and function of the glomerular barrier.29.Haraldsson B. Nystrom J. Deen W.M. Properties of the glomerular barrier and mechanisms of proteinuria.Physiol Rev. 2008; 88: 451-487Crossref PubMed Scopus (608) Google Scholar, 30.Mathieson P.W. The cellular basis of albuminuria.Clin Sci (Lond). 2004; 107: 533-538Crossref PubMed Scopus (33) Google Scholar, 31.Thomas M.C. Pathogenesis and progression of proteinuria.Contrib Nephrol. 2011; 170: 48-56Crossref PubMed Scopus (22) Google Scholar, 32.Tryggvason K. Patrakka J. Wartiovaara J. Hereditary proteinuria syndromes and mechanisms of proteinuria.N Engl J Med. 2006; 354: 1387-1401Crossref PubMed Scopus (444) Google Scholar Damage to each individual component affects the excretion of albumin and may compromise the function of the other components and ultimately affect the whole nephron.31.Thomas M.C. Pathogenesis and progression of proteinuria.Contrib Nephrol. 2011; 170: 48-56Crossref PubMed Scopus (22) Google Scholar Emerging recent data provided renewed interest in the importance of another component of the glomerular barrier—namely, the glycocalyx. The glycocalyx is a thin layer of proteoglycans with their associated glycosaminoglycans that covers the outer endothelial layer and its fenestrae in a gel-like diaphragm and excludes (charged) macromolecules from the ultrafiltrate. Thus, glycocalyx damage may affect the charge selectivity of the glomerular filtration barrier, leading to increased leakage of albumin in the ultrafiltrate. The glycocalyx layer is not restricted to the kidney but is present in all capillary beds. Indeed, alterations in the endothelial glycocalyx, for example, due to hyperglycemia,33.Singh A. Friden V. Dasgupta I. et al.High glucose causes dysfunction of the human glomerular endothelial glycocalyx.Am J Physiol Renal Physiol. 2011; 300: F40-F48Crossref PubMed Scopus (97) Google Scholar are implicated in the pathogenesis of atherosclerosis and have been associated with the onset of microalbuminuria in diabetes.34.Nieuwdorp M. Mooij H.L. Kroon J. et al.Endothelial glycocalyx damage coincides with microalbuminuria in type 1 diabetes.Diabetes. 2006; 55: 1127-1132Crossref PubMed Scopus (307) Google Scholar Moreover, changes in urine albumin excretion have been associated with general albumin leakage throughout the body.35.Nannipieri M. Rizzo L. 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Burford J.L. et al.Loss of the endothelial glycocalyx links albuminuria and vascular dysfunction.J Am Soc Nephrol. 2012; 23: 1339-1350Crossref PubMed Scopus (173) Google Scholar recently demonstrated that loss of endothelial glycocalyx links albuminuria to vascular dysfunction, supporting the concept that microalbuminuria is not only a marker of renal damage but also a more generalized marker of endothelial damage.39.Deckert T. Feldt-Rasmussen B. Borch-Johnsen K. et al.Albuminuria reflects widespread vascular damage. The Steno hypothesis.Diabetologia. 1989; 32: 219-226Crossref PubMed Scopus (1306) Google Scholar A new technique was recently validated to measure the endothelial glycocalyx dimension in humans using imaging of the sublingual microcirculation by orthogonal polarization spectroscopy.40.Nieuwdorp M. Meuwese M.C. 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Within the past few decades, the classical assumption of albuminuria as merely a reflection of disease has been challenged by consistent evidence that albumin is not an inert molecu
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