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Microalbuminuria, renal disease, metabolic syndrome and risks in diabetes
Diabetes & Metabolic Syndrome: Clinical Research & Reviews (2007) 1, 127—133
http://diabetesindia.com/
REVIEW
Microalbuminuria, renal disease, metabolic syndrome and risks in diabetes C.E. Mogensen * Med. Department M, Aarhus Sygehus, NBG, Aarhus University Hospital, DK-8000 Aarhus, Denmark Accepted 15 November 2006
KEYWORDS Microalbuminuria; Diabetic nephropathy; Metabolic syndrome; Blood pressure; Antihypertensive treatment
Abstract Microalbuminuria was identified as an important predictor of renal disease as well as of cardiovascular disease about 20 years ago. This concept has been confirmed in many studies, and it has been shown that microalbuminuria is associated to the metabolic syndrome. Microalbuminuria is an important risk marker along with a series of other markers and factors. It is associated to a structural damage in the kidney, and a loss of auto-regulation and inflammation. It is a predictor of proteinuria, low GFR and cardiovascular events as well as of endstage renal disease and mortality, including cardiovascular mortality. Microalbuminuria is an important goal for intervention. Several studies have shown that reduction of microalbuminuria indicates a better prognosis. The reason is not clear but may be associated to less structural damage in patients that show regression in microalbuminuria. It is recommended to screen for microalbuminuria in diabetic patients with hypertension and may be in the population, although this is less clarified. # 2006 Diabetes India. Published by Elsevier Ltd. All rights reserved.
Contents Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Microalbuminuria/proteinuria: screening, pathophysiology and predictive studies . Estimated GFR and risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Metabolic syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Advanced renal and cardiovascular disease . . . . . . . . . . . . . . . . . . . . . . . . . Final remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Background Diabetic patients are at considerable risk of either having or developing renal disease and/or related * Tel.: +45 89492011; fax: +45 89492010. E-mail address: [email protected].
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127 128 129 130 130 130 131
cardiovascular diseases, usually starting with microalbuminuria often related to insulin resistance (or metabolic syndrome) [1—3]. In most cases, glomerular filtration rate (GFR) is well preserved in such patients, but according to recent reports GFR may also be decreased even in patients with normoalbuminuria, especially in type 2 dia-
1871-4021/$ — see front matter # 2006 Diabetes India. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.dsx.2006.11.011
128 betes microalbuminuria remains, however, an important risk factor and a signal for intervention, which is not documented for patients with isolated reduced GFR in diabetes [4]. Yuyun et al. [2] reviewed and confirmed the evidence that microalbuminuria is a predictor of cardiovascular disease and mortality. It may be proposed that in the future, risk factor prediction charts for heart disease and cardiovascular events should include microalbuminuria as a risk factor being modifiable by intensive multifactorial intervention, also related to metabolic syndrome. This means that the department of diabetes, internal medicine, and cardiology should screen for microalbuminuria [4,5]. In addition, however, the suggestion has been put forward recently that future screening for renal disease in diabetes should also include screening for reduced GFR. From a practical point of view, large-scale screening is only possible by screening for serum creatinine and derived parameters, and intervention strategies are not by any means established.
Table 1
C.E. Mogensen Clearly, antiglycemic treatment is essential, since hyperglycaemia is a key factor in the genesis of complication. As shown in the DIGAMI 2 study [6] in high-risk patients (with myocardial infarction), it is BG-lowering that is of importance; e.g. patients treated with SU seemed to have a lower risk than patients on insulin.
Microalbuminuria/proteinuria: screening, pathophysiology and predictive studies Adler et al. recently confirmed that microalbuminuria strongly predicts early mortality in diabetes, and proteinuria is clearly associated with even greater risk very much in agreement with my original observation from 1984 [4,7]. Microalbuminuria is as well associated with abnormalities and risk factors connected to the metabolic syn-
Microalbuminuria, renal disease, metabolic syndrome and risks in diabetes Table 2 Definitions of urinary albumin excretion categories
Table 3 Predicts
129
Significance of microalbuminuria Development of nephropathy Development of cardiovascular disease
Parameter influencing AER
Effect on AER
Erect position
Increased (children affected more than adults) Increased Increased (transient) Increased during day Higher in Afro-Caribbean and Asian population Uncertain may increase with increasing BMI Uncertain, possible increase in AER with age Uncertain, males possibly higher AER AER reduced
Associated with Diabetic microvascular complication Glomerular structural damage and injury Left ventricular hypertrophy and dysfunction Endothelial dysfunction Elevated CRP Abnormal lipid profile Hypertension and absent nocturnal drop in blood pressure Insulin resistance Abnormal coagulation/fibrinolytic profile, raised PAI-1 Salt sensitivity Central obesity Smoking
AER increased
CRP, C-reactive protein; PAI-1, plasminogen activator inhibitor-1.
Exercise Increase diuresis Time of day Ethnicity Body mass index Age
Sex Drug–—ACE inhibitors, NSAID Congestive cardiac failure Fever Urinary tract infection Vaginal discharge Acute poor metabolic control
AER AER AER AER
increased may be increased increased increased
AER, Albumin excretion rate; BMI, body mass index; ACE, angiotensin converting enzyme; NSAID, non-steroidal antiinflammatory drug.
drome, and multifactorial intervention is warranted. This includes glycemic control, blood pressure lowering, statins, as well as dietary advice, including sodium limitation [5]. Thus, it may be of interest to screen for microalbuminuria, also within cardiology units, as microalbuminuria predicts early mortality and cardiovascular disease [7,8], Studies, such as the HOPE study, and the more recent HOPE study extension [9,10], indicated that intervention with angiotensin-converting-enzyme-inhibitors (ACE inhibitors), used in many intervention studies, is also beneficial in patients with risk factors. Indeed, microalbuminuria was a strong risk factor in the HOPE study for predefined end-points, and treatment with ramipril was effective in long-term follow-up. Screening is most easily performed by measuring the urine albumin creatinine ratio [4,11]. The mechanism(s) how albuminuria predicts mortality is (are) still unclear. Possibly, it is a surrogate marker for most other cardiovascular risk factors [2,4]. Interestingly, microalbuminuria predicts mortality also after myocardial infarction [12—14]. Table 1 provides a review of microalbuminuria and cardiovascular renal risk. Microalbuminuria is common in
patients with metabolic syndrome and basis for intervention [5]. New studies document that reduction in microalbuminuria is an important marker for better outcome [15]. I suggest that microalbuminuria is not a ‘‘maker’’ but a ‘‘marker’’ summarizing risk factors [4]. Tables 2 and 3 provide information on the confounding factors and on the significance of microalbuminuria [11].
Estimated GFR and risks It is well established that there is an increasing risk of renal disease and cardiovascular disease as well as mortality according to the level of microalbuminuria, starting with normo- to micro- to macroalbuminuria [1,3,4,7,8] (Table 3). Recent studies suggest, however, that there may be reduced renal function even in the presence of normoalbuminuria, which is partly explained by the use ACE inhibitors that may reduce albuminuria and stabilize GFR within the lower level [16]. New guidelines from the National Kidney Foundation [6,17] focus on the level of GFR as estimated from prediction equations taking into account serum creatinine concentration as well as some other variables, such as age, gender, race and body size. In adults, the MDRD and the Cockcroft—Gault equation may be used, but figures are not very correct with common over- and especially understimulation of GFR, so the concept is often misleading [18,19], and further studies are needed.
130
C.E. Mogensen
Metabolic syndrome Regarding the metabolic syndrome, it is clear that this is a risk factor for the development both of renal and cardiovascular disease. It has also been observed in such subjects that reduced renal function, as estimated by serum creatinine, is a risk factor, which again may underscore the need for estimation of GFR. Moreover, it was also confirmed that microalbuminuria is quite prevalent in patients suffering from the metabolic syndrome as it is common in patients with chronic renal diseases [19]. Accordingly, microalbuminuria may be a part of the metabolic syndrome, and both microalbuminuria and metabolic syndrome are associated with increased risk [20]. Microalbuminuria and proteinuria are as well as parameters of the metabolic syndrome and should therefore be used when evaluating the risk for patients. Regarding intervention strategies, this approach is evident and well established in patients with microalbuminuria and proteinuria. This is not the case for patients with estimated reduced GFR. Statin-treatment seems not to be beneficial in type 2 diabetic patients undergoing haemodialysis [21]. The treatment should rather be started earlier, i.e. in the stage of microalbuminuria and the metabolic syndrome [22]. Diuretics might have a slight BG-increasing effect, but this is out-weighed by the important BP-lowering effect, especially in combination with ACE inhibitors [5,10].
Advanced renal and cardiovascular disease Some patients admitted to the cardiac unit may have advanced renal disease, and the RENAAL study and IDNT study for type 2 diabetes, showed that treatment with angiotensin-receptor-blockers (ARBs) is useful in this situation, so this may be standard treatment [23—25]. However, there
was no comparison with ACE inhibitors in these studies. The landmark Captopril study [26] in type 1 diabetes showed that such patients with advanced renal disease should be treated with an ACE inhibitor. ACE inhibitors may, however, as shown by Barnett et al. [27], also be useful in renal disease of patients with type 2 diabetes. In patients with advanced renal disease and also in patients with left ventricular hypertrophy, studies argue for the use of ARBs, but, on the other hand, ACE inhibitors may also be of value before such an advanced disease state. In patients with advanced renal disease and left ventricular hypertrophy, we are still missing strict comparative studies. A review on studies on inhibition of ACE inhibitors and ARBs is presented in Table 4. The IRMA 2 study [25] focused on the use of ARBs in patients with microalbuminuria, but new studies suggest that also ACE inhibitors can be used [27]. Dual blockade is as well a possibility in patients, where blood pressure cannot be effectively controlled with single blockade [28]. Recent results from the proactive study indicated no significant effect of pioglitazone on primary end-points including cardiac revascularisation and peripheral bypass surgery, but on so called principal secondary endpoints (all cause mortality, non-fatal myocardial infarction and stroke) [29]. Blood pressure, lipids and glycemia were better controlled in the active arm. Importantly, statin-treatment was associated with a better prognosis and there was little additional effect of pioglitazone in the patients treated with statins. Notably, there was no effect in the proactive study on microalbuminuria. This should, however, be expected when considering the effect of decreased blood pressure (BP: 3 mmHg) and HbA1c (0.5%). Lowering of HA1c is thus by any means essential [29].
Final remarks Patients with diabetes admitted to departments of internal medicine, endocrinology and cardiology
Table 4 Inhibition of the RA(A)S in diabetes Prevention of T2 DM
Prevention of micro
Treating micro
Treating macro
ACEi ++ (Mancia et al. [33])
+++ (Benedict [34])
T1+++, T2+++ (Detail [27]a)
T1+++ [26], T2+ [27] a
ARBs ++ (Mancia et al. [33])
Roadmap study [37] (in progress)
T1 , T2+++ (Detail [27])
T1 , T2+++ [27] (RENAAL), IDNT [23,21]
a
Combination with diuretics is of importance.
LVH
T2+++ (LIFE) [35]
Heart failure
Stroke
+++ a
T2++ [4] a
+
T2++ [35]
Microalbuminuria, renal disease, metabolic syndrome and risks in diabetes need intensified multifactorial intervention, as suggested in the Steno 2 study in which Diamicron was used [5]. This approach is protective both against cardiovascular disease and nephropathy [30]. As far as the metabolic target for HbA1c is concerned, the situation is still controversial. Many diabetologists would be pleased with an A1c less than 7%, but in cardiology guidelines 6.0—6.5% has been proposed. The issue here is the increased risk of severe hypoglycaemia with improving glucose control, which may be quite common in patients with advanced cardiovascular disease, who may suffer also from hypoglycaemic unawareness. As far as BP-lowering is concerned, normalisation of BP, i.e. <125/80 should be considered in all patients with early signs of nephropathy by use of ACE inhibitors or ARBs, plus Beta-Blockers and diuretics (or other antihypertension drugs) if necessary (Fig. 1). The b-blocker, Carvedilol, has less metabolic side-effects than, e.g. Metopolol [31], but long-term effects are not clarified. Most patients would qualify for treatment with ACE inhibitors, but in the presence of the sideeffects of ACE inhibitors and in patients with advanced renal disease and in patients with left ventricular hypertrophy, ARBs can be proposed along with other antihypertensive agents, including dual blockade. Diuretic treatment is practically always essential [4,5]. Most patients should be treated with statins, as proposed in several studies [5]. Reference should also be made to K/DOQI E-Newsletter [32] and the American diabetes guidelines for nephropathy [36] and to new proposals on hypertension management in T2 Diabetes [37,38] with the following conclusion:
131
(1) Patients with type 2 diabetes should be aggressively treated for hypertension when BP is above 140 and/or 90 mmHg aiming at BP < 130/ 80 mmHg. (2) These patients usually need two or more drugs/ combination therapy to reach the BP target, especially for systolic BP. (3) Though ACE inhibitors have been proven CV protective and some angiotensin-II-receptor blockers nephroprotective, there is no consensus on the ‘‘drug of choice’’ for all hypertensive type 2 diabetic patients [38,39]. (4) Most studies support the notion that BP reduction per se is more important than individual properties of specific drugs in most cases. (5) Blockade of the renin-angiotensin system seems to be an appropriate choice for being one of the partner drugs in offering combination therapy to hypertensive patients with diabetes or glucose intolerance [42]. (6) It is recommended to follow trends in the quality of health care for patients with hypertension and diabetes, for example by local, regional or national registers with input based on data on BP control in representative samples. (7) Antidiabetic treatment, including with SU-preparations in combination with ACE inhibitors (e.g. Perindopril) has a useful perspective, as in the ADVANCE study [42,43]. (8) Regression of abnormal albuminuria remains an important goal in the treatment strategy [30,35] as well in non-diabetics [44]. The last word: lifestyle intervention remains important in reducing BP and risk factors [40]. Especially, BP-reducing treatment is of key importance in preventing progression of renal disease [41].
References
Fig. 1 The BP-lowering hexagone in diabetes (ABCDEF). (+) Indicate the level of evidence. The number indicate sequence of treatment (l—7) (vary from patients to patients). Remember sufficient doses, clinical and laboratory control.
[1] Baumelou A, Bruckert E, Bagnis C, Deray G. Renal disease in cardiovascular disorders: an underrecognized problem. Am J Nephrol 2005;25:95—105. [2] Yuyun MF, Adler AI, Wareham NJ. What is the evidence that microalbuminuria is a predictor of cardiovascular disease events? Curr Opin Nephrol Hypertens 2005;14: 271—6. [3] Park HY, Schumock GT, Pickard S, Akhras K. A structured review of the relationship between microalbuminuria and cardiovascular events in patients with diabetes mellitus and hypertension. Pharmacotherapy 2003;23: 1611—6. [4] Mogensen CE. Microalbumnuria and hypertension with focus on type 1 and type 2 diabetes. J Intern Med 2003; 254:45—66.
132 [5] Gaede P, Vedel P, Larsen J, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003;348:383— 93. [6] Malmberg K, Ryden L, Wedel H, Birkeland K, Bootsma A, Dickstein K, et al. Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity. Eur Heart J 2005;26(April (7)):650— 61. [7] Adler AI, Stevens RJ, Manley SE, Bilous RW, Cull CA, Holman RR. On behalf of the UKPDS GROUP. Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (64). Kidney Int 2003;63:225—32. [8] Arnlov J, Evans JC, Meigs JB. Low-grade albuminuria and incidence of cardiovascular disease events in nonhypertensive and nondiabetic individuals. The Framingham Heart Study. Circulation 2005;112:969—75. [9] Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet 2000;355: 253—9. [10] HOPE/HOPE-TOO Study Investigators. Long-term effects of ramipril on cardiovascular events and on diabetes. Results of the HOPE Study Extension. Circulation 2005;112:1339— 46. [11] Karalliedde JL, Viberti GC. Microalbuminuria: concepts, definition and monitoring. In: Mogensen CE, editor. Microalbuminuria: a marker for end organ damage.. London: Science Press; 2004. p. 1—10. [12] Koulouris S, Lekatsas I, Karabinos I, Ioannidis G, Katostaras T, Kranidis A, et al. Microalbuminuria: a strong predictor of 3year adverse prognosis in nondiabetic patients with acute myocardial infarction. Am Heart J 2005;149:840—5. [13] Agewall S, Berglund, Henareh L. Reduced quality of life after myocardial infarction in women compared with men. Clin Cardiol 2004;27(5):271—4. [14] Berton G, Cordiano R, Palmieri R, De Toni R, Guarnieri GL, Palatini P. Albumin excretion in diabetic patients in the setting of acute myocardial infarction: association with 3year mortality. Diabetologia 2004;47:1511—8. [15] Ibsen H, Olsen MH, Wachtell K, Borch-Johnsen K, Lindholm LH, Mogensen CE, et al. Does albuminuria predict cardiovascular outcomes on treatment with losartan versus atenolol in patients with diabetes, hypertension, and left ventricular hypertrophy? The LIFE Study. Diabetes Care 2006;29(3):595—600. [16] 2003 European Society of Hypertension–—European Society of Cardiology guidelines for the management of arterial hypertension. J Hypertens 2003;21:1011—53. [17] K/DOQI Clinical Pracice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification. Part 5: evaluation of laboratory measurements for clinical assessment of kidney disease. Am J Kidney Dis 2002;39(2, Suppl. 1):S76—110. [18] Adler A, Shine BS, Edwards O. Validity of Cockcroft—Gault and MDRD equations in diabetes. Diabetes 2005;54(Suppl. 1):A550. [19] Froissart M, Rossert J, Jacquot C, Paillard M, Houillier P. Predictive performance of the modification of diet in renal disease and Cockcroft-Gault equations for estimating renal function. J Am Soc Nephrol 2005;16:763—73. [20] Chen J, Muntner P, Hamm LL, Jones DW, Batuman V, Fonseca V, et al. The metabolic syndrome and chronic kidney disease in U.S. adults. Ann Intern Med 2004;140:167—74.
C.E. Mogensen [21] Wanner C, Krane V, Marz W, Olschewski M, Mann JR, Ruf G, et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005;353: 238—48. [22] Geluk CA, Asselbergs FW, Hillege HL, Bakker SJ, De Jong PE, Zijlstra F, et al. Impact of statins in microalbuminuric subjects with the metabolic syndrome: a substudy of the PREVEND Intervention Trial. Eur Heart J 2005;26:1314— 20. [23] Lewis EJ, Hunsicker LG, Clarke RW, Berl T, Pohl MA, Lewis JB, et al. Renoprotective effect of the angiotensinreceptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345:851— 60. [24] Brenner CM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:861—9. [25] Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen S, Amer P, et al. The effect of ibesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001;345:870—8. [26] Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med 1993;329(20):1456—62. [27] Barnett AH, Bain SC, Bouter P, Karlberg B, Madsbad S, Jervell J, et al. Angiotensin-receptor blockade versus convertingenzyme inhibition in type 2 diabetes and nephropathy. N Engl J Med 2004;351:1952—61. [28] Mogensen CE, Neldam S, Tikkanen I, Oren S, Viskoper R, Watts RW, et al. Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: the candesartan and lisinopril microalbuminuria (CALM) study. BMJ 2000;321:1440—4. [29] Freemantle N. How well does the evidence on pioglitazone back up researcher’s claims for a reduction in macrovascular events. Br Med J 2005;331:836—40. [30] Gaede P, Tarnow L, Vedel P, Parving HH, Pedersen O. Remission to normoalbuminuria during multifactorial treatment preserves kidney function in patients with Type 2 diabetes and microalbuminuria. Nephrol Dial Transplant 2004; 19:2784—8. [31] Bakris GL, Fonseca V, Katholi RE, McGill JB, Messerli FH, Phillips RA, et al. Metabolic effects of carvedilos vs metoprolol in patients with type 2 diabetes mellitus and hypertension. A randomized controlled trial. JAMA 2005; 292(18):2227—36. [32] K/DOQI E-Newsletter. www.kidney.org/professionals/ kdoqi/index.cfm. [33] Mancia G, Grassi G, Zanchetti A. New-onset diabetes and antihypertensive drugs. J Hypertens 2006;24:3—10. [34] Ruggenenti P, Fassi A, Ilieva AP, Bruno S, Iliev IP, Brusegan V, et al. Preventing microalbuminuria in type 2 diabetes. N Engl J Med 2004;351(19):1941—51. [35] Ibsen H, Olsen MH, Wachtell K, Borch-Johnsen, Lindholm LH, Mogensen CE, et al. Reduction in albuminuria translates to reduction in cardiovascular events in hypertensive patients. Losartan intervention for endpoint reduction in hypertension study. Hypertension 2005;45:198—202. [36] American Diabetes Association: nephropathy in diabetes (position statement). Diabetes Care 2004;27(Suppl.):S79— 83. [37] Haller H, Viberti GC, Mimran A, Remuzzi G, Rabelink AJ, Ritz E, et al. Preventing microalbuminuria in patients with diabetes—rationale and design of the Randomised Olmesartan
Microalbuminuria, renal disease, metabolic syndrome and risks in diabetes and Diabetes Microalbuminuria Prevention Study. J Hypertens 2006;24(2):403—8. [38] Nilsson PM, Cifkova R, Kjeldsen SE. Update on hypertension management: treatment of hypertension on patients with type 2 diabetes mellitus. J Hypertens 2006;24(1):208—10. [39] Burnier M, Zanchi A. Blockade of the renin-angiotensinaldosterone system: a key therapeutic strategy to reduce renal and cardiovascular events in patients with diabetes. J Hypertens 2006;24:11—25. [40] Casas JP, Chua W, Loukogeorgakis S, Vallance P, Smeeth L, Hingorani AD, et al. Effect of inhibitors of the renin-angiotensin system and other antihypertensive drugs on renal outcomes: systematic review and meta-analysis. Lancet 2005;366(9502):2026—33.
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[41] Dickinson HO, Mason JM, Nicolson DJ. Lifestyle interventions to reduce raised blood pressure: a systematic review of randomized controlled trials. J Hypertens 2006;24(2): 215—33. [42] Mogensen CE, Viberti GC, Halimi S, Ritz E, Ruilope L, Jermendy G, et al. Effect of low-dose perindopril/indapamide on albuminuria in diabetes. Preterax in albuminuria regression: PREMIER. Hypertension 2003;41:1063—71. [43] ADVANCE Collaborative Group. ADVANCE–—action in diabetes and vascular disease: patient recruitment and characteristics of the study at baseline. Diabetic Med 2005;22: 882—8. [44] Pascual JM, Rodilla E, Miralles Amparo, Gonzalez C, Redon J. J Hypertens 2006;24:2277—84.
http://diabetesindia.com/
REVIEW
Microalbuminuria, renal disease, metabolic syndrome and risks in diabetes C.E. Mogensen * Med. Department M, Aarhus Sygehus, NBG, Aarhus University Hospital, DK-8000 Aarhus, Denmark Accepted 15 November 2006
KEYWORDS Microalbuminuria; Diabetic nephropathy; Metabolic syndrome; Blood pressure; Antihypertensive treatment
Abstract Microalbuminuria was identified as an important predictor of renal disease as well as of cardiovascular disease about 20 years ago. This concept has been confirmed in many studies, and it has been shown that microalbuminuria is associated to the metabolic syndrome. Microalbuminuria is an important risk marker along with a series of other markers and factors. It is associated to a structural damage in the kidney, and a loss of auto-regulation and inflammation. It is a predictor of proteinuria, low GFR and cardiovascular events as well as of endstage renal disease and mortality, including cardiovascular mortality. Microalbuminuria is an important goal for intervention. Several studies have shown that reduction of microalbuminuria indicates a better prognosis. The reason is not clear but may be associated to less structural damage in patients that show regression in microalbuminuria. It is recommended to screen for microalbuminuria in diabetic patients with hypertension and may be in the population, although this is less clarified. # 2006 Diabetes India. Published by Elsevier Ltd. All rights reserved.
Contents Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Microalbuminuria/proteinuria: screening, pathophysiology and predictive studies . Estimated GFR and risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Metabolic syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Advanced renal and cardiovascular disease . . . . . . . . . . . . . . . . . . . . . . . . . Final remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Background Diabetic patients are at considerable risk of either having or developing renal disease and/or related * Tel.: +45 89492011; fax: +45 89492010. E-mail address: [email protected].
. . . . . . .
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127 128 129 130 130 130 131
cardiovascular diseases, usually starting with microalbuminuria often related to insulin resistance (or metabolic syndrome) [1—3]. In most cases, glomerular filtration rate (GFR) is well preserved in such patients, but according to recent reports GFR may also be decreased even in patients with normoalbuminuria, especially in type 2 dia-
1871-4021/$ — see front matter # 2006 Diabetes India. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.dsx.2006.11.011
128 betes microalbuminuria remains, however, an important risk factor and a signal for intervention, which is not documented for patients with isolated reduced GFR in diabetes [4]. Yuyun et al. [2] reviewed and confirmed the evidence that microalbuminuria is a predictor of cardiovascular disease and mortality. It may be proposed that in the future, risk factor prediction charts for heart disease and cardiovascular events should include microalbuminuria as a risk factor being modifiable by intensive multifactorial intervention, also related to metabolic syndrome. This means that the department of diabetes, internal medicine, and cardiology should screen for microalbuminuria [4,5]. In addition, however, the suggestion has been put forward recently that future screening for renal disease in diabetes should also include screening for reduced GFR. From a practical point of view, large-scale screening is only possible by screening for serum creatinine and derived parameters, and intervention strategies are not by any means established.
Table 1
C.E. Mogensen Clearly, antiglycemic treatment is essential, since hyperglycaemia is a key factor in the genesis of complication. As shown in the DIGAMI 2 study [6] in high-risk patients (with myocardial infarction), it is BG-lowering that is of importance; e.g. patients treated with SU seemed to have a lower risk than patients on insulin.
Microalbuminuria/proteinuria: screening, pathophysiology and predictive studies Adler et al. recently confirmed that microalbuminuria strongly predicts early mortality in diabetes, and proteinuria is clearly associated with even greater risk very much in agreement with my original observation from 1984 [4,7]. Microalbuminuria is as well associated with abnormalities and risk factors connected to the metabolic syn-
Microalbuminuria, renal disease, metabolic syndrome and risks in diabetes Table 2 Definitions of urinary albumin excretion categories
Table 3 Predicts
129
Significance of microalbuminuria Development of nephropathy Development of cardiovascular disease
Parameter influencing AER
Effect on AER
Erect position
Increased (children affected more than adults) Increased Increased (transient) Increased during day Higher in Afro-Caribbean and Asian population Uncertain may increase with increasing BMI Uncertain, possible increase in AER with age Uncertain, males possibly higher AER AER reduced
Associated with Diabetic microvascular complication Glomerular structural damage and injury Left ventricular hypertrophy and dysfunction Endothelial dysfunction Elevated CRP Abnormal lipid profile Hypertension and absent nocturnal drop in blood pressure Insulin resistance Abnormal coagulation/fibrinolytic profile, raised PAI-1 Salt sensitivity Central obesity Smoking
AER increased
CRP, C-reactive protein; PAI-1, plasminogen activator inhibitor-1.
Exercise Increase diuresis Time of day Ethnicity Body mass index Age
Sex Drug–—ACE inhibitors, NSAID Congestive cardiac failure Fever Urinary tract infection Vaginal discharge Acute poor metabolic control
AER AER AER AER
increased may be increased increased increased
AER, Albumin excretion rate; BMI, body mass index; ACE, angiotensin converting enzyme; NSAID, non-steroidal antiinflammatory drug.
drome, and multifactorial intervention is warranted. This includes glycemic control, blood pressure lowering, statins, as well as dietary advice, including sodium limitation [5]. Thus, it may be of interest to screen for microalbuminuria, also within cardiology units, as microalbuminuria predicts early mortality and cardiovascular disease [7,8], Studies, such as the HOPE study, and the more recent HOPE study extension [9,10], indicated that intervention with angiotensin-converting-enzyme-inhibitors (ACE inhibitors), used in many intervention studies, is also beneficial in patients with risk factors. Indeed, microalbuminuria was a strong risk factor in the HOPE study for predefined end-points, and treatment with ramipril was effective in long-term follow-up. Screening is most easily performed by measuring the urine albumin creatinine ratio [4,11]. The mechanism(s) how albuminuria predicts mortality is (are) still unclear. Possibly, it is a surrogate marker for most other cardiovascular risk factors [2,4]. Interestingly, microalbuminuria predicts mortality also after myocardial infarction [12—14]. Table 1 provides a review of microalbuminuria and cardiovascular renal risk. Microalbuminuria is common in
patients with metabolic syndrome and basis for intervention [5]. New studies document that reduction in microalbuminuria is an important marker for better outcome [15]. I suggest that microalbuminuria is not a ‘‘maker’’ but a ‘‘marker’’ summarizing risk factors [4]. Tables 2 and 3 provide information on the confounding factors and on the significance of microalbuminuria [11].
Estimated GFR and risks It is well established that there is an increasing risk of renal disease and cardiovascular disease as well as mortality according to the level of microalbuminuria, starting with normo- to micro- to macroalbuminuria [1,3,4,7,8] (Table 3). Recent studies suggest, however, that there may be reduced renal function even in the presence of normoalbuminuria, which is partly explained by the use ACE inhibitors that may reduce albuminuria and stabilize GFR within the lower level [16]. New guidelines from the National Kidney Foundation [6,17] focus on the level of GFR as estimated from prediction equations taking into account serum creatinine concentration as well as some other variables, such as age, gender, race and body size. In adults, the MDRD and the Cockcroft—Gault equation may be used, but figures are not very correct with common over- and especially understimulation of GFR, so the concept is often misleading [18,19], and further studies are needed.
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C.E. Mogensen
Metabolic syndrome Regarding the metabolic syndrome, it is clear that this is a risk factor for the development both of renal and cardiovascular disease. It has also been observed in such subjects that reduced renal function, as estimated by serum creatinine, is a risk factor, which again may underscore the need for estimation of GFR. Moreover, it was also confirmed that microalbuminuria is quite prevalent in patients suffering from the metabolic syndrome as it is common in patients with chronic renal diseases [19]. Accordingly, microalbuminuria may be a part of the metabolic syndrome, and both microalbuminuria and metabolic syndrome are associated with increased risk [20]. Microalbuminuria and proteinuria are as well as parameters of the metabolic syndrome and should therefore be used when evaluating the risk for patients. Regarding intervention strategies, this approach is evident and well established in patients with microalbuminuria and proteinuria. This is not the case for patients with estimated reduced GFR. Statin-treatment seems not to be beneficial in type 2 diabetic patients undergoing haemodialysis [21]. The treatment should rather be started earlier, i.e. in the stage of microalbuminuria and the metabolic syndrome [22]. Diuretics might have a slight BG-increasing effect, but this is out-weighed by the important BP-lowering effect, especially in combination with ACE inhibitors [5,10].
Advanced renal and cardiovascular disease Some patients admitted to the cardiac unit may have advanced renal disease, and the RENAAL study and IDNT study for type 2 diabetes, showed that treatment with angiotensin-receptor-blockers (ARBs) is useful in this situation, so this may be standard treatment [23—25]. However, there
was no comparison with ACE inhibitors in these studies. The landmark Captopril study [26] in type 1 diabetes showed that such patients with advanced renal disease should be treated with an ACE inhibitor. ACE inhibitors may, however, as shown by Barnett et al. [27], also be useful in renal disease of patients with type 2 diabetes. In patients with advanced renal disease and also in patients with left ventricular hypertrophy, studies argue for the use of ARBs, but, on the other hand, ACE inhibitors may also be of value before such an advanced disease state. In patients with advanced renal disease and left ventricular hypertrophy, we are still missing strict comparative studies. A review on studies on inhibition of ACE inhibitors and ARBs is presented in Table 4. The IRMA 2 study [25] focused on the use of ARBs in patients with microalbuminuria, but new studies suggest that also ACE inhibitors can be used [27]. Dual blockade is as well a possibility in patients, where blood pressure cannot be effectively controlled with single blockade [28]. Recent results from the proactive study indicated no significant effect of pioglitazone on primary end-points including cardiac revascularisation and peripheral bypass surgery, but on so called principal secondary endpoints (all cause mortality, non-fatal myocardial infarction and stroke) [29]. Blood pressure, lipids and glycemia were better controlled in the active arm. Importantly, statin-treatment was associated with a better prognosis and there was little additional effect of pioglitazone in the patients treated with statins. Notably, there was no effect in the proactive study on microalbuminuria. This should, however, be expected when considering the effect of decreased blood pressure (BP: 3 mmHg) and HbA1c (0.5%). Lowering of HA1c is thus by any means essential [29].
Final remarks Patients with diabetes admitted to departments of internal medicine, endocrinology and cardiology
Table 4 Inhibition of the RA(A)S in diabetes Prevention of T2 DM
Prevention of micro
Treating micro
Treating macro
ACEi ++ (Mancia et al. [33])
+++ (Benedict [34])
T1+++, T2+++ (Detail [27]a)
T1+++ [26], T2+ [27] a
ARBs ++ (Mancia et al. [33])
Roadmap study [37] (in progress)
T1 , T2+++ (Detail [27])
T1 , T2+++ [27] (RENAAL), IDNT [23,21]
a
Combination with diuretics is of importance.
LVH
T2+++ (LIFE) [35]
Heart failure
Stroke
+++ a
T2++ [4] a
+
T2++ [35]
Microalbuminuria, renal disease, metabolic syndrome and risks in diabetes need intensified multifactorial intervention, as suggested in the Steno 2 study in which Diamicron was used [5]. This approach is protective both against cardiovascular disease and nephropathy [30]. As far as the metabolic target for HbA1c is concerned, the situation is still controversial. Many diabetologists would be pleased with an A1c less than 7%, but in cardiology guidelines 6.0—6.5% has been proposed. The issue here is the increased risk of severe hypoglycaemia with improving glucose control, which may be quite common in patients with advanced cardiovascular disease, who may suffer also from hypoglycaemic unawareness. As far as BP-lowering is concerned, normalisation of BP, i.e. <125/80 should be considered in all patients with early signs of nephropathy by use of ACE inhibitors or ARBs, plus Beta-Blockers and diuretics (or other antihypertension drugs) if necessary (Fig. 1). The b-blocker, Carvedilol, has less metabolic side-effects than, e.g. Metopolol [31], but long-term effects are not clarified. Most patients would qualify for treatment with ACE inhibitors, but in the presence of the sideeffects of ACE inhibitors and in patients with advanced renal disease and in patients with left ventricular hypertrophy, ARBs can be proposed along with other antihypertensive agents, including dual blockade. Diuretic treatment is practically always essential [4,5]. Most patients should be treated with statins, as proposed in several studies [5]. Reference should also be made to K/DOQI E-Newsletter [32] and the American diabetes guidelines for nephropathy [36] and to new proposals on hypertension management in T2 Diabetes [37,38] with the following conclusion:
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(1) Patients with type 2 diabetes should be aggressively treated for hypertension when BP is above 140 and/or 90 mmHg aiming at BP < 130/ 80 mmHg. (2) These patients usually need two or more drugs/ combination therapy to reach the BP target, especially for systolic BP. (3) Though ACE inhibitors have been proven CV protective and some angiotensin-II-receptor blockers nephroprotective, there is no consensus on the ‘‘drug of choice’’ for all hypertensive type 2 diabetic patients [38,39]. (4) Most studies support the notion that BP reduction per se is more important than individual properties of specific drugs in most cases. (5) Blockade of the renin-angiotensin system seems to be an appropriate choice for being one of the partner drugs in offering combination therapy to hypertensive patients with diabetes or glucose intolerance [42]. (6) It is recommended to follow trends in the quality of health care for patients with hypertension and diabetes, for example by local, regional or national registers with input based on data on BP control in representative samples. (7) Antidiabetic treatment, including with SU-preparations in combination with ACE inhibitors (e.g. Perindopril) has a useful perspective, as in the ADVANCE study [42,43]. (8) Regression of abnormal albuminuria remains an important goal in the treatment strategy [30,35] as well in non-diabetics [44]. The last word: lifestyle intervention remains important in reducing BP and risk factors [40]. Especially, BP-reducing treatment is of key importance in preventing progression of renal disease [41].
References
Fig. 1 The BP-lowering hexagone in diabetes (ABCDEF). (+) Indicate the level of evidence. The number indicate sequence of treatment (l—7) (vary from patients to patients). Remember sufficient doses, clinical and laboratory control.
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