Correspondence
Regression of Microalbuminuria in Type 1 Diabetes
N Engl J Med 2003; 349:906-908August 28, 2003
- Article
To the Editor:
In their meticulous study of type 1 diabetes (June 5 issue), Perkins et al.1 overlook dietary protein intake as a potentially important determinant of fluctuations in urinary albumin excretion over time. Dietary protein intake has been positively associated with increased urinary albumin excretion in diabetic2 and nondiabetic3 populations. Consistent with these observations is the finding that a protein load induces an increase in urinary albumin excretion in healthy persons with a single kidney.4 The mechanism by which this process occurs is not well understood, but it may be related to alterations in the permeability of the glomerular capillaries as a result of increased glomerular filtration (i.e., hyperfiltration),5 which is itself caused by dietary protein ingestion. Since persons with diabetes frequently have glomerular hyperfiltration early in the course of their disease, they may be particularly susceptible to the renal effects of protein intake. Interestingly, the finding that plasma lipids are inversely associated with regression of albuminuria is consistent with this hypothesis. Americans tend to obtain much of their dietary protein from fat-rich animal tissues — a diet that may, in turn, predispose them toward elevated cholesterol and triglyceride levels.
5 ReferencesAllon N. Friedman, M.D.
Indiana University School of Medicine, Indianapolis, IN 46202
allfried@iupui.edu 1
Perkins BA ,Ficociello LH ,Silva KH ,Finkelstein DM ,Warram JH ,Krolewski AS . Regression of microalbuminuria in type 1 diabetes. N Engl J Med 2003;348:2285-2293
Full Text | Web of Science | Medline2
Toeller M ,Buyken A ,Heitkamp G , et al. Protein intake and urinary albumin excretion rates in the EURODIAB IDDM Complications Study. Diabetologia 1997;40:1219-1226
CrossRef | Web of Science | Medline3
Hoogeveen EK ,Kostense PJ ,Jager A , et al. Serum homocysteine level and protein intake are related to risk of microalbuminuria: the Hoorn Study. Kidney Int 1998;54:203-209
CrossRef | Web of Science | Medline4
Coppo R ,Amore A ,Roccatello D , et al. Microalbuminuria in single kidney patients: relationship with protein intake. Clin Nephrol 1988;29:219-228
Web of Science | Medline5
Johnsson E ,Rippe B ,Haraldsson B . Reduced permselectivity in isolated perfused rat kidneys following small elevations of glomerular capillary pressure. Acta Physiol Scand 1994;150:201-209
CrossRef | Medline
To the Editor:
Perkins et al. report that microalbuminuria in patients with type 1 diabetes is three times more likely to disappear than to progress to overt proteinuria. Although these findings compel us to rethink the natural course and clinical evaluation of diabetic nephropathy, we believe that two important issues regarding this study should be considered.
First, Perkins et al. did not measure the glomerular filtration rate during the study; they report only base-line plasma creatinine levels. Glomerular hyperfiltration occurs at the earliest stages of diabetic nephropathy both in humans1 and in animal models2 and is a leading factor in the progression of glomerular damage.3
Second, the authors do not explain why regression of microalbuminuria occurs almost exclusively during the first follow-up period, whereas it remains stable thereafter. Was there any temporary beneficial effect that waned during the study?
3 ReferencesCristiana Catena, M.D.
Marileda Novello, M.D.
Leonardo A. Sechi, M.D.
University of Udine, 33100 Udine, Italy1
Mathiesen ER ,Feldt-Rasmussen B ,Hommel E ,Deckert T ,Parving HH . Stable glomerular filtration rate in normotensive IDDM patients with stable microalbuminuria: a 5-year prospective study. Diabetes Care 1997;20:286-289
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Hostetter TH ,Troy JL ,Brenner BM . Glomerular hemodynamics in experimental diabetes mellitus. Kidney Int 1981;19:410-415
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Remuzzi G ,Ruggenenti P ,Benigni A . Understanding the nature of renal disease progression. Kidney Int 1997;51:2-15
CrossRef | Web of Science | Medline
To the Editor:
Perkins et al. describe the regression of microalbuminuria in 58 percent of patients who had had type 1 diabetes for a mean of 18 years. They propose a revised model of early diabetic nephropathy in which microalbuminuria has a reduced role in the prediction of diabetic nephropathy. However, the authors do not discuss the effect of the duration of diabetes in their study population. In only one third of all patients with type 1 diabetes does diabetic nephropathy ever develop1 and that incidence peaks early during the second decade of diabetes.2,3 In the patients studied by Perkins et al., the duration of diabetes exceeded the period of susceptibility to diabetic nephropathy.4 For reasons to be determined, the study population, in which microalbuminuria was relatively transient, may therefore differ from populations in which the role of microalbuminuria as a predictor of diabetic nephropathy has been established. We wonder why the study did not include patients with a duration of diabetes that left them still at risk for the development of proteinuria.
4 ReferencesDaniela Hohenadel, M.D.
Hinrich Bode, M.D.
Fokko J. van der Woude, M.D., Ph.D.
University Clinic Mannheim, 68169 Mannheim, Germany
daniela.hohenadel@med5. uni-heidelberg. de 1
Krolewski AS ,Canessa M ,Warram JH , et al. Predisposition to hypertension and susceptibility to renal disease in insulin-dependent diabetes mellitus. N Engl J Med 1988;318:140-145
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Krolewski AS ,Warram JH ,Christlieb AR ,Busick EJ ,Kahn CR . The changing natural history of nephropathy in type 1 diabetes. Am J Med 1985;78:785-794
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Andersen AR ,Christiansen JS ,Andersen JK ,Kreiner S ,Deckert T . Diabetic nephropathy in Type 1 (insulin-dependent) diabetes: an epidemiologic study. Diabetologia 1983;25:496-501
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Krolewski AS ,Warram JH ,Rand LI ,Christlieb AR ,Busick EJ ,Kahn CR . Risk of proliferative diabetic retinopathy in juvenile-onset type I diabetes: a 40-yr follow-up study. Diabetes Care 1986;9:443-452
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To the Editor:
Perkins et al. report that, in patients with type 1 diabetes and microalbuminuria, regression of microalbuminuria reached a six-year cumulative incidence of 58 percent. The study, initiated in January 1991, lasted for the next eight years. Interestingly enough, in September 1993, the initial results of the Diabetes Control and Complications Trial (DCCT) went public. These results showed that intensive therapy delays the onset and slows the progression of diabetic nephropathy (not to mention other complications) in patients with type 1 diabetes.1 Because this finding substantially revolutionized the clinical management of diabetes all over the world, it is reasonable to assume that most of the patients included in the Joslin Study of the Natural History of Microalbuminuria might have had substantial changes in their treatment protocols — changes that possibly affected their renal prognosis. How did Perkins et al. account for the impact of the “DCCT effect”? Were the levels of glycosylated hemoglobin measured before the publication of the DCCT results related to the levels measured afterward?
1 ReferencesGianpaolo Zerbini, M.D., Ph.D.
Istituto Scientifico San Raffaele, I-20132 Milan, Italy
g.zerbini@hsr. it 1
The Diabetes Control and Complications Trial Research Group
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Author/Editor Response
Our colleagues seek further explanation for the unexpectedly high six-year cumulative incidence of regression of microalbuminuria (58 percent). Friedman and Zerbini hypothesize that temporal trends in exposure (dietary protein intake and the severity of hyperglycemia, respectively) account for the inconsistency between our study, conducted in the 1990s, and earlier studies, in which microalbuminuria marked the beginning of progressive renal disease. The chief problem with both hypotheses is that there is no evidence of a temporal trend in either time period. With respect to the severity of hyperglycemia, there was only a trivial change in the mean glycosylated hemoglobin values over the course of the decade (Table 1Table 1
Characteristics of the 386 Participants According to Study Period.). Dietary protein cannot be measured easily and was not recorded in this study. The short-term changes in protein intake and albumin excretion cited by Friedman would not be consistent enough to affect the geometric mean of the several measurements we took at two-year intervals. Moreover, even if 50 percent reductions in albumin excretion are feasible with a persistent dietary change, the adoption of such a rigorous diet by more than half the patients is not plausible and is not reflected in the temporal trends in lipid variables (Table 1).We agree with Hohenadel et al. about the importance of the duration of diabetes on the susceptibility to nephropathy and point out that nearly three quarters of the study group had had diabetes for less than two decades. The risks of regression of microalbuminuria according to quartiles of the duration of diabetes (quartile cutoff points, 9, 16, and 22 years) were 63 percent, 52 percent, 53 percent, and 54 percent, respectively (P=0.38 by the chi-square test). Thus, the duration of diabetes did not affect the risk of regression of microalbuminuria.
With respect to regression of microalbuminuria, Catena and colleagues appear to have been misled by the presentation in Table 1 of our article of four cross-sectional slices of follow-up time. The proportion of patients with normal albumin excretion appears static because remissions are offset by the recurrent onset of microalbuminuria in other patients. For patients with microalbuminuria of short duration (the incidence cohort), remission occurred in 45 percent during each follow-up period; for patients with microalbuminuria of longer duration (the prevalence cohort), remission occurred in 31 percent, 27 percent, and 21 percent during the first, second, and third intervals, respectively.
Regarding Catena and colleagues' other point, we agree that the presentation of only base-line creatinine levels does not adequately address the course of renal function over time in patients with microalbuminuria. We are currently investigating this important question, which also was raised by Ritz in his editorial.2
2 ReferencesBruce A. Perkins, M.D., M.P.H.
James H. Warram, M.D., Sc.D.
Andrzej S. Krolewski, M.D., Ph.D.
Joslin Diabetes Center, Boston, MA 02215
andrzej.krolewski@joslin. harvard. edu 1
The Diabetes Control and Complications Trial Research Group
Full Text | Web of Science | Medline2
Ritz E . Albuminuria and vascular damage -- the vicious twins. N Engl J Med 2003;348:2349-2352
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