doi: 10.1161/01.CIR.0000156440.91081.EE
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(Circulation. 2005;111:e110-e111.)
© 2005 American Heart Association, Inc.
Correspondence |
Letter Regarding Article by Klausen et al, "Very Low Levels of Microalbuminuria Are Associated With Increased Risk of Coronary Heart Disease and Death Independently of Renal Function, Hypertension, and Diabetes"
Kidney Center, University Medical Center Groningen, Groningen, The Netherlands
Trial Coordination Center, University Medical Center Groningen, Groningen, The Netherlands
Klausen et al1 suggest changing the cutoff point for the definition of microalbuminuria to lower levels than are presently used (30 to 300 mg/24 h, or 20 to 200 µg/min). On the basis of their findings, they argue that urinary albumin excretion (UAE) of >5 µg/min in nocturnal collections should be defined as abnormal. We believe that the data provided in their study do not support this argument for the following reasons.
First, their study is not designed to reach such a conclusion. The authors found their cutoff point after arbitrarily dividing their population in quartiles of UAE. This is not the appropriate technique to determine a cutoff level because the achieved cutoff value is dependent on the distribution of the parameter within the population under study. Levels of UAE are not normally distributed, so the quartile with the highest values of UAE will comprise individuals with both a relatively low and a clearly elevated level of UAE. Because the increased risk is calculated for the whole quartile, the individuals with a still-normal level of UAE will be erroneously considered to be at risk.
Second, it would have been more appropriate for Klausen et al to perform continuous modeling of albuminuria versus cardiovascular risk because the relation between levels of UAE and cardiovascular disease and death has been shown to be continuous and log-linear.2–4 This becomes especially clear in our study,4 in which we investigate the relationship between UAE and cardiovascular death. We found a continuous increased risk for cardiovascular death that started far below the levels of urinary albumin concentration currently considered normal, with no apparent minimal cutoff value.
Third, why define cutoff values? It not only implies that we want to define a value as abnormal or as normal; it also should be used as a value above which, when microalbuminuria is diagnosed, treatment should be provided to lower the risk associated with that value. In that regard, our recent finding that an angiotensin-converting enzyme inhibitor given to subjects with an albuminuria of 15 to 50 mg/d lowered the number of cardiovascular events by 29%, whereas the risk reduction amounted to 60% in patients with an albuminuria of 50 to 300 mg/d, is of interest.5 It shows that subjects with a higher UAE benefit more from intervention with an angiotensin-converting enzyme inhibitor. Cost-effectiveness will also be taken into account when defining the value above which treatment is warranted. Until these issues are resolved, the current definition for microalbuminuria should continue to be used.
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 Top References References |
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1. Klausen K, Borch-Johnsen K, Feldt-Rasmussen B, Jensen G, Clausen P, Scharling H, et al. Very low levels of microalbuminuria are associated with increased risk of coronary heart disease and death independently of renal function, hypertension, and diabetes. Circulation. 2004; 110: 32–35.
2. Gerstein HC, Mann JF, Yi Q, Zinman B, Dinneen SF, Hoogwerf B, et al. Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals. JAMA. 2001; 286: 421–426.
3. Yuyun MF, Khaw KT, Luben R, Welch A, Bingham S, Day NE, et al. A prospective study of microalbuminuria and incident coronary heart disease and its prognostic significance in a British population: the EPIC-Norfolk study. Am J Epidemiol. 2004; 159: 284–293.
4. Hillege HL, Fidler V, Diercks GF, van Gilst WH, de Zeeuw D, van Veldhuisen DJ, et al. Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population. Circulation. 2002; 106: 1777–1782.
5. Asselbergs FW, Diercks GFH, Hillege HL, van Boven AJ, Janssen WMT, Voors AA, et al. Effects of fosinopril and pravastatin on cardiovascular events in subjects with microalbuminuria. Circulation. 2004; 110: 2809–2816.
Response
Copenhagen City Heart Study, Epidemiological Research Unit, Bispebjerg University Hospital, Copenhagen, Denmark, jsje{at}c.dk
We agree with Brantsma et al that the risk of coronary heart disease and death is increased at urinary albumin excretion levels that were previously considered normal. This has been clearly documented in several well-conducted population studies.1–5 Therefore, the definition of microalbuminuria must be revised. The original definition of microalbuminuria was based on the risk of chronic renal failure among patients with diabetes6,7 and not on cardiovascular risk in the general population.
From a clinical point of view, a lower cutoff level must be defined. We have in 2 independent Danish population studies identified an increased risk only if the urinary albumin:creatinine ratio exceeds 0.6 mg/mmol or urinary albumin excretion exceeds 4.8 µg/min.1,5 In the latter study,5 the relative risk of coronary heart disease was 2.3, 2.1, and 2.8 for urinary albumin excretion >4.8 µg/min, 4.8 to 15 µg/min, and >15 µg/min, respectively, with 
4.8 µg/min as the reference level. If the level was <4.8 µg/min, then the relative risk did not increase with increasing urinary albumin excretion (see Figure in reference 5).
Urinary albumin excretion >15 µg/min is rare unless diabetes or renal disease is present and is thus of limited clinical relevance as a cardiovascular risk factor in the general population. Perhaps 15 µg/min is the optimal lower cutoff level for the prediction of diabetic nephropathy, a condition that is rare in comparison with coronary heart disease.
Although this was not the case for urinary albumin excretion in our studies,1,5 some risk functions exhibit statistically increasing dose responses from rather low levels (eg, blood pressure). In spite of this, antihypertensive drugs are not instituted unless blood pressure exceeds a certain level. It is also typical that individuals with high risk factor levels of, for example, blood pressure or lipoproteins benefit more from intervention than do individuals with low risk factor levels.
On the basis of the results of our recent study5 and the arguments given above, we recommend redefining microalbuminuria as urinary albumin excretion >5 µg/min (or 5 mg/L).
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1. Borch-Johnsen K, Feldt-Rasmussen B, Strandgaard S, Schroll M, Jensen JS. Urinary albumin excretion. An independent predictor of ischemic heart disease. Arterioscler Thromb Vasc Biol. 1999; 19: 1992–1997.
2. Gerstein HC, Mann JF, Yi Q, Zinman B, Dinneen SF, Hoogwerf B, Halle JP, Young J, Rashkow A, Joyce C, Nawaz S, Yusuf S; HOPE Study Investigators. Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals. JAMA. 2001; 286: 421–426.
3. Hillege HL, Fidler V, Diercks GF, van Gilst WH, de Zeeuw D, van Veldhuisen DJ, Gans RO, Janssen WM, Grobbee DE, de Jong PE; Prevention of Renal and Vascular End Stage Disease (PREVEND) Study Group. Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population. Circulation. 2002; 106: 1777–1782.
4. Romundstad S, Holmen J, Kvenild K, Hallan H, Ellekjær H. Microalbuminuria and all-cause mortality in 2,089 apparently healthy individuals: a 4.4-year follow-up study. The Nord-Trøndelag Health Study (HUNT), Norway. Am J Kidney Dis. 2003; 42: 466–473.[CrossRef][Medline] [Order article via Infotrieve]
5. Klausen K, Borch-Johnsen K, Feldt-Rasmussen B, Jensen G, Clausen P, Scharling H, Appleyard M, Jensen JS. Very low levels of microalbuminuria are associated with increased risk of coronary heart disease and death independently of renal function, hypertension, and diabetes. Circulation. 2004; 110: 32–35.
6. Mogensen CE. Microalbuminuria predicts clinical proteinuria and early mortality in maturity-onset diabetes. N Engl J Med. 1984; 310: 356–360.[Abstract]
7. Viberti GC, Hill RD, Jarrett RJ, Argyropoulos A, Mahmud U, Keen H. Microalbuminuria as a predictor of clinical nephropathy in insulin-dependent diabetes mellitus. Lancet. 1982; 1: 1430–1432.[CrossRef][Medline] [Order article via Infotrieve]
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