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Original Investigation |

Long-term Renal Outcomes of Patients With Type 1 Diabetes Mellitus and Microalbuminuria:  An Analysis of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Cohort FREE

Ian H. de Boer, MD, MS; Tessa C. Rue, MS; Patricia A. Cleary, MS; John M. Lachin, ScD; Mark E. Molitch, MD; Michael W. Steffes, MD, PhD; Wanjie Sun, MS; Bernard Zinman, MDCM; John D. Brunzell, MD; Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study Research Group
[+] Author Affiliations

Author Affiliations: Kidney Research Institute and Division of Nephrology, Department of Medicine (Dr de Boer), Department of Biostatistics (Ms Rue), and the Division of Metabolism, Endocrinology, and Metabolism, Department of Medicine (Dr Brunzell), University of Washington, Seattle; The Biostatistics Center, George Washington University, Rockville, Maryland (Ms Cleary, Dr Lachin, and Ms Sun); Department of Medicine, Northwestern University, Chicago, Illinois (Dr Molitch); Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis (Dr Steffes); and Department of Medicine, University of Toronto, Toronto, Ontario, Canada (Dr Zinman).Group Information: A list of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study Research Group members was published in Arch Ophthalmol. 2008;126(12):1713.


Arch Intern Med. 2011;171(5):412-420. doi:10.1001/archinternmed.2011.16.
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Published online

Background  Microalbuminuria is a common diagnosis in the clinical care of patients with type 1 diabetes mellitus. Long-term outcomes after the development of microalbuminuria are variable.

Methods  We quantified the incidence of and risk factors for long-term renal outcomes after the development of microalbuminuria in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study. The DCCT randomly assigned 1441 persons with type 1 diabetes to intensive or conventional diabetes therapy, and participants were subsequently followed up during the observational EDIC study. During the DCCT/EDIC study, 325 participants developed incident persistent microalbuminuria (albumin excretion rate, ≥30 mg/24 h at 2 consecutive study visits). We assessed their subsequent renal outcomes, including progression to macroalbuminuria (albumin excretion rate, ≥300 mg/24 h at 2 consecutive visits), impaired glomerular filtration rate (estimated glomerular filtration rate, <60 mL/min/1.73 m2 at 2 consecutive study visits), end-stage renal disease, and regression to normoalbuminuria (albumin excretion rate, <30 mg/24 h at 2 consecutive visits).

Results  The median follow-up period after persistent microalbuminuria diagnosis was 13 years (maximum, 23 years). Ten-year cumulative incidences of progression to macroalbuminuria, impaired glomerular filtration rate, end-stage renal disease, and regression to normoalbuminuria were 28%, 15%, 4%, and 40%, respectively. Albuminuria outcomes were more favorable with intensive diabetes therapy, lower glycated hemoglobin level, absence of retinopathy, female sex, lower blood pressure, and lower concentrations of low-density lipoprotein cholesterol and triglycerides. Lower glycated hemoglobin level, absence of retinopathy, and lower blood pressure were also associated with decreased risk of impaired glomerular filtration rate.

Conclusions  After the development of persistent microalbuminuria, progression and regression of kidney disease each commonly occur. Intensive glycemic control, lower blood pressure, and a more favorable lipid profile are associated with improved outcomes.

Figures in this Article

Microalbuminuria (urine albumin excretion rate [AER], 30-300 mg/24 h) is a common diagnosis in the clinical care of patients with type 1 diabetes mellitus, with a lifetime cumulative incidence of 20% to 40%.14 Clinical guidelines recommend regular screening for microalbuminuria because it is common, is known to be associated with adverse renal and cardiovascular outcomes, and can be treated with antagonists of the renin-angiotensin-aldosterone system (RAAS).4

The Diabetes Control and Complications Trial (DCCT) demonstrated that hyperglycemia is a risk factor for developing microalbuminuria and that intensive diabetes therapy can prevent or delay the development of microalbuminuria.5,6 Additional risk factors for microalbuminuria have been well described and include older age, male sex, long duration of diabetes, smoking, obesity, elevated blood pressure, and genetic predisposition.713

Less is known about long-term renal outcomes of individuals with type 1 diabetes after microalbuminuria develops, in part because few studies are able to accurately ascertain the time at which microalbuminuria occurs and to perform detailed follow-up among participants for long subsequent periods. Accurate characterization of long-term renal outcomes is critically important to provide prognosis for patients with type 1 diabetes and to identify opportunities for therapeutic intervention.

The DCCT and its observational extension, the Epidemiology of Diabetes Interventions and Complications (EDIC) study, offer a unique opportunity to assess long-term clinical renal outcomes after the development of microalbuminuria because the time of albuminuria onset can be precisely defined using extensive longitudinal measurements and because participants have been followed up for more than 2 decades using standardized methods.5,6 In this study, we describe long-term renal outcomes of persistent microalbuminuria (PMA) in the DCCT/EDIC cohort and assess risk factors for progression and regression of kidney disease. We focus on the potential effect of glycemia because the DCCT was a randomized trial of intensive diabetes therapy and because detailed longitudinal glycated hemoglobin data were collected during the DCCT/EDIC study.

THE DCCT/EDIC STUDY

The DCCT was a multicenter clinical trial among patients with type 1 diabetes mellitus examining the effects of intensive diabetes therapy that was aimed at lowering glycemia as close as safely possible to the nondiabetic range compared with conventional therapy.5,6 The trial included 2 cohorts, a primary prevention cohort (1-5 years' duration of diabetes, AER of <40 mg/24 h, and no retinopathy by fundus photography) and a secondary intervention cohort (1-15 years' duration of diabetes, AER of ≤200 mg/24 h, and ≥1 microaneurysm in either eye but no more than moderate nonproliferative retinopathy). Between August 23, 1983, through June 30, 1989, a total of 1441 persons aged 13 to 39 years were enrolled and randomly assigned to intensive or conventional diabetes therapy. Intensive therapy included 3 or more insulin injections daily or the use of an insulin pump, with the aim of achieving glycated hemoglobin levels of less than 6.05% (to convert glycated hemoglobin level to proportion of total hemoglobin, multiply by 0.01). The goal of conventional therapy was the prevention of hyperglycemic and hypoglycemic symptoms using 1 or 2 daily injections of insulin. Participants were followed up for a mean of 6.5 years until the DCCT closeout in 1993.

At the end of the DCCT, all former conventional treatment participants were offered instruction in intensive therapy, and all participants returned to their personal health care providers for ongoing diabetes care. All DCCT participants were invited to join the EDIC study, an observational extension of the DCCT, and 1375 of 1428 (96.3% of the surviving cohort) agreed to participate. During the EDIC study, the mean glycated hemoglobin levels, which had been separated by approximately 2% between the conventional and intensive therapy groups during the DCCT, converged between the former treatment groups.6 The DCCT/EDIC study procedures were approved by the institutional review boards of participating centers, and all participants provided written informed consent. The study described herein includes data from the DCCT baseline through year 14 of the EDIC study (ending May 30, 2008).

COHORT WITH PMA

This analysis focuses on 325 DCCT/EDIC study participants who developed incident PMA during the course of the DCCT/EDIC study observation. For this and other epidemiological studies of the DCCT/EDIC cohort,1315 PMA is defined as an AER of at least 30 mg/24 h at 2 consecutive study visits. This definition of PMA differs from the original DCCT definition of microalbuminuria used for the assessment of treatment effect (AER, ≥40 mg/24 h at a single visit) to reflect current American Diabetes Association4 and National Kidney Foundation16 recommendations, which include a threshold of 30 mg/24 h and persistence, and to reduce the effect of measurement error on the diagnosis of microalbuminuria. The AER was measured yearly during the DCCT and every 2 years during the EDIC study. Urine was collected for 4 hours during a water diuresis, and albumin was measured by fluoroimmunoassay (coefficient of variation, 9.4%).5 A diagnosis of PMA was based on 2 consecutive DCCT AER measurements, the last DCCT and first EDIC study AER measurements, or 2 consecutive EDIC study measurements. The cohort of 325 participants with incident PMA did not include 68 separate participants with an AER of at least 30 mg/24 h at their first 2 DCCT visits (prevalent microalbuminuria).

DEFINITIONS OF LONG-TERM RENAL OUTCOMES

Among the PMA cohort, we assessed progression to macroalbuminuria, development of impaired glomerular filtration rate (GFR), development of end-stage renal disease (ESRD), and regression to normoalbuminuria. Progression to macroalbuminuria was defined as an AER of at least 300 mg/24 h at 2 consecutive study visits. Impaired GFR was defined as an estimated GFR of less than 60 mL/min/1.73 m2 at 2 consecutive study visits.4,16 Regression to normoalbuminuria was defined as an AER of less than 30 mg/24 h at 2 consecutive study visits. Serum creatinine level was measured yearly during the DCCT/EDIC study using the modified Jaffe reaction, and the estimated GFR was calculated using the Modification of Diet in Renal Disease formula.17 End-stage renal disease was defined as the initiation of maintenance dialysis (n = 13) or kidney transplantation (n = 8), assessed yearly by questionnaire. Renal outcomes were not mutually exclusive.

COVARIATES

Demographic data and smoking were assessed by self-report. Body mass index was calculated as weight in kilograms divided by height in meters squared. Blood pressure was measured by trained personnel.18 All laboratory measurements were completed at the DCCT/EDIC study central biochemistry laboratory. Glycated hemoglobin level was measured using high-performance ion-exchange liquid chromatography (coefficient of variation, <4%).19 Plasma lipids were measured using conventional enzymatic methods, with low-density lipoprotein cholesterol concentration calculated using the Friedewald formula. Prevalence of any retinopathy (≥1 microaneurysm in either eye) was assessed using 7-field stereofundus photography.

Medication use was assessed yearly by self-report only during the EDIC study. The use of angiotensin-converting enzyme inhibitors was discouraged during the DCCT, and only 6.2% reported angiotensin-converting enzyme inhibitor use at their first EDIC study visit. Angiotensin receptor blockers were available for clinical use only during the EDIC study. RAAS inhibitors (angiotensin-converting enzyme inhibitors and angiotensin receptor blockers) were combined and analyzed as a class. Hydroxymethylglutaryl coenzyme A reductase inhibitors became available at the end of the DCCT (beginning in 1989), and the use of a lipid-lowering agent was reported by only 2.2% of participants at their first EDIC study visit.

STATISTICAL ANALYSIS

To describe the development of PMA over the clinical course of type 1 diabetes in our population, we first graphed the cumulative incidence of PMA by duration of diabetes in the full DCCT/EDIC cohort. We used an estimator by Turnbull20 for interval-censored observations to allow for left censoring of participants with prevalent PMA and right censoring of participants who did not develop PMA during the DCCT/EDIC observation period.

Among 325 participants who developed incident PMA, long-term renal outcomes were evaluated separately. Time at risk began at PMA diagnosis and extended to diagnosis of the renal outcome being analyzed or to each participant's penultimate AER measurement (for progression and regression of microalbuminuria), penultimate estimated GFR (for impaired GFR), or last study visit (for ESRD). Incidence rates were expressed in person-years. In prevalence analyses only, normoalbuminuria, microalbuminuria, and macroalbuminuria were assessed at 2-year intervals, and the mean AER was used if 2 AER measurements were available.

Risk factors for long-term renal outcomes after diagnosis of PMA were assessed using cumulative incidence plots and discrete Cox proportional hazards regression models.21 We repeated all analyses using a Weibull model for interval censoring, with no substantial differences in results. Cox proportional hazards regression models assessed as exposures (1) characteristics at the time of PMA diagnosis and (2) characteristics at the time of follow-up examination (time-updated variables) and adjusted for age, sex, and duration of diabetes at the time of PMA diagnosis. Analyses were performed using commercially available statistical software (SAS version 9.1; SAS Institute, Cary, North Carolina).

INCIDENCE OF PMA

Among participants randomly assigned to DCCT conventional therapy, PMA developed most frequently during the second decade after diagnosis of diabetes (Figure 1). Cumulative incidences of PMA were 14%, 33%, and 38% at 10, 20, and 30 years' duration of diabetes, respectively, and the cumulative incidence seemed to plateau below 40%. Among participants assigned to intensive therapy, the cumulative incidence of PMA was reduced, and the development of PMA during the second decade after diagnosis of diabetes was particularly blunted. Cumulative incidences of PMA were 10%, 21%, and 25% at 10, 20, and 30 years' duration of diabetes, respectively, and the cumulative incidence seemed to plateau near 25%.

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Figure 1.

Cumulative incidence of persistent microalbuminuria in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study by duration of type 1 diabetes and by Diabetes Control and Complications Trial treatment assignment.

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CLINICAL CHARACTERISTICS

Of 325 participants who developed incident PMA, 40.6% were women, and 35.4% had been assigned to intensive diabetes therapy (Table 1). At the time of PMA diagnosis, the mean age was 33.3 years, the mean duration of diabetes was 14 years, 71.1% of participants had retinopathy, and 47.7% were in the EDIC phase of the study. The median AER was 48 mg/24 h, and the mean estimated GFR was 114 mL/min/1.73 m2. Compared with participants assigned to DCCT conventional therapy who developed PMA, participants assigned to intensive therapy who developed PMA did so at a slightly later duration of diabetes (15 vs 13 years), were slightly heavier (mean body mass index, 26.6 vs 25.0), had lower glycated hemoglobin levels (mean, 8.9% vs 9.6%), and were more likely to report the use of RAAS inhibitors (10.4% vs 5.7%) and lipid-lowering agents (7.8% vs 3.3%); other characteristics did not differ.

Table Graphic Jump LocationTable 1. Characteristics of 325 Participants in the DCCT/EDIC Study at the Time of Incident Persistent Microalbuminuria Diagnosis
LONG-TERM RENAL OUTCOMES

The mean and median follow-up periods after diagnosis of PMA were 13 years, with a maximum follow-up period of 23 years (Table 2). Follow-up data for the AER and the estimated GFR were complete for 95.4% and 93.3% of study visits, respectively. Twenty-six of 325 participants (8.0%) with incident PMA died during the follow-up period. Ninety-eight participants progressed to macroalbuminuria, 60 developed impaired GFRs, 21 developed ESRD, and 117 regressed to normoalbuminuria; 26, 4, 0, and 44 of these events, respectively, occurred during the DCCT, with the remainder occurring during the EDIC follow-up period. Ten-year cumulative incidences of progression to macroalbuminuria, impaired GFR, ESRD, and regression to normoalbuminuria were 28%, 15%, 4%, and 40%, respectively (Table 2 and Figure 2). At the time of progression or regression, RAAS inhibitor use was reported by 36.7% of participants who progressed to macroalbuminuria, 70.7% of participants who developed impaired GFRs, and 24.6% of participants who regressed to normoalbuminuria.

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Figure 2.

Cumulative incidence of long-term renal outcomes after the development of persistent microalbuminuria (time 0) among 325 participants in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study. ESRD indicates end-stage renal disease; GFR, glomerular filtration rate.

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Table Graphic Jump LocationTable 2. Incidence of Long-term Renal Outcomes After Diagnosis of Persistent Microalbuminuria Among 325 Participants in the DCCT/EDIC Study

Seventeen participants regressed to normoalbuminuria more than 10 years after the initial PMA diagnosis. At the time of regression to normoalbuminuria, the mean glycated hemoglobin level was 7.7%, and the mean blood pressure was 121/77 mm Hg. Prevalences of RAAS inhibitor and lipid-lowering medication use were 47.1% and 11.8%, respectively. Three of these late regressors developed sustained macroalbuminuria before regressing to normoalbuminuria, but none developed sustained impaired GFR before regressing.

Macroalbuminuria prevalence increased over the first 4 years following PMA diagnosis and then stabilized near 20% (Figure 3). Further increases in macroalbuminuria may have been obscured by increasing prevalence of RAAS inhibitor use among participants with an AER measured in the microalbuminuria range (>50% at 7-8 years after PMA diagnosis). Normoalbuminuria became increasingly prevalent over the full follow-up period, exceeding 50% after 13 to 14 years. Fewer than 50% of participants who regressed to prevalent normoalbuminuria during the first 14 years after PMA diagnosis were using RAAS inhibitors.

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Figure 3.

Prevalence of normoalbuminuria, microalbuminuria, and macroalbuminuria by time following the diagnosis of incident persistent microalbuminuria (time 0) among 325 participants in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study. Ellipsis indicates not applicable; RAAS, renin-angiotensin-aldosterone system.

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INTENSIVE DIABETES THERAPY, GLYCEMIA, AND LONG-TERM RENAL OUTCOMES

Participants who were assigned to intensive diabetes therapy during the DCCT and developed PMA experienced more favorable long-term renal outcomes than those who were assigned to conventional diabetes therapy and developed PMA (Figure 4). Adjusting for age, sex, and duration of diabetes, the hazard ratios associated with intensive diabetes therapy were 0.64 (95% confidence interval [CI], 0.40-1.02) for progression to macroalbuminuria, 0.65 (95% CI, 0.36-1.16) for impaired GFR, and 1.92 (95% CI, 1.28-2.86) for regression to normoalbuminuria (P < .05 for regression to normoalbuminuria only) (Table 3). Further adjusting for body mass index and the use of RAAS inhibitors and lipid-lowering medications, the hazard ratios associated with intensive diabetes therapy were 0.61 (95% CI, 0.38-0.98) for progression to macroalbuminuria, 0.64 (95% CI, 0.35-1.17) for impaired GFR, and 2.16 (95% CI, 1.43-3.26) for regression to normoalbuminuria. Associations of intensive diabetes therapy with renal outcomes were stronger for participants diagnosed as having PMA during the DCCT compared with participants diagnosed as having PMA during the EDIC follow-up period, although these interactions were not statistically significant (data not shown). Lower glycated hemoglobin levels measured at PMA diagnosis or after PMA diagnosis were associated with decreased risk of progression to macroalbuminuria and of impaired GFR and with increased probability of regression to normoalbuminuria (P < .05 for all) (Table 3).

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Figure 4.

Cumulative incidence of long-term renal outcomes after the development of persistent microalbuminuria (time 0) among 325 participants in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study by Diabetes Control and Complications Trial treatment assignment. A, Regression to normoalbuminuria. B, Progression to macroalbuminuria. C, Impaired glomerular filtration rate (GFR). D, End-stage renal disease (ESRD).

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Table Graphic Jump LocationTable 3. Risk Factors for Long-term Renal Outcomes After Diagnosis of Persistent Microalbuminuria (PMA) Among 325 Participants in the DCCT/EDIC Study
OTHER RISK FACTORS

Albuminuria outcomes were also more favorable (decreased risk of progression to macroalbuminuria and increased probability of regression to normoalbuminuria) with absence of retinopathy, female sex, lower blood pressure (at diagnosis or during the follow-up period), and lower concentrations of low-density lipoprotein cholesterol and triglycerides (Table 3). Younger age, absence of retinopathy, and lower blood pressure (the latter during the follow-up period) were also associated with decreased risk of impaired GFR. RAAS inhibitor use was not associated with improved albuminuria or GFR outcomes, with or without adjustment for blood pressure. The AER at PMA diagnosis was strongly associated with progression to macroalbuminuria and development of impaired GFR but was only weakly associated with regression to normoalbuminuria.

This study characterizes long-term renal outcomes from the time of development of PMA in type 1 diabetes. Progression to macroalbuminuria, impaired GFR, and ESRD occurred at clinically important frequencies (cumulative incidences of 28%, 15%, and 4% at 10 years, respectively). However, regression to normoalbuminuria was the most common renal outcome, with a 10-year cumulative incidence of 40%. Therefore, the development of PMA does not necessarily represent the start of an inexorable downhill course for diabetic nephropathy. Among persons who develop microalbuminuria, lower levels of glycemia and the use of intensive insulin therapy remain associated with more favorable long-term renal outcomes, providing provocative evidence that glycemic control may help prevent progression of existing kidney disease in addition to the development of microalbuminuria. Other modifiable risk factors associated with long-term renal outcomes included blood pressure (for albuminuria and GFR outcomes) and lipid concentrations (for albuminuria outcomes only).

Progression of PMA to macroalbuminuria and impaired GFR was common in our study. This progression carries important implications, as it portends substantially increased risk of cardiovascular events and mortality.7,22 Although progression to ESRD has been uncommon in the DCCT/EDIC cohort,6 this study reinforces the adverse prognostic renal implications of microalbuminuria by noting substantial cumulative incidences of ESRD of 4% and 7% at 10 and 15 years after the development of PMA, respectively. Furthermore, ESRD incidence rates will likely increase with further EDIC follow-up.

Microalbuminuria was once viewed as the first step in a committed course of progressive diabetic kidney disease in type 1 diabetes, but it is now widely recognized that microalbuminuria may commonly regress to normoalbuminuria.23 Although RAAS inhibitors reduce urine albumin excretion and can induce regression, most regression to normoalbuminuria in our study was spontaneous, as previously observed in other studies.23,24 Our results also document regression to normoalbuminuria after more than a decade of PMA, mostly without RAAS inhibitor use and generally in the setting of excellent control of glycemia and blood pressure.

We observed an incidence of regression to normoalbuminuria higher than that in some studies11,12,23 and comparable to that in other studies.2527 Our high incidence rate is likely owing to our unique study design. Participants were longitudinally screened for the onset of PMA, as recommended for clinical care.4 This approach yields a representative mix of persons with incident PMA, which is less likely to be selected for persistent and severe disease compared with populations having prevalent microalbuminuria. Rates of regression may also vary with the frequency of AER ascertainment. More frequent AER sampling is likely to detect microalbuminuria of shorter duration, which is more susceptible to regression, and more frequent AER sampling after microalbuminuria diagnosis is likely to increase the observed rate of regression, each contributing to higher observed rates of disease “regression.” Our sampling interval (every 1-2 years) is consistent with current screening recommendations and actual clinical care.

The DCCT5,6 and the United Kingdom Prospective Diabetes Study28 demonstrated an important role for glycemic control in the prevention of early diabetic kidney disease. However, the role of glycemic control in preventing progression of established kidney disease remains controversial.12 In particular, it has been suggested that glycemic control may improve metabolic and endothelial abnormalities that lead to microalbuminuria but not necessarily fibrotic processes that lead to macroalbuminuria, impaired GFR, and ESRD. In the DCCT, intensive diabetes therapy significantly reduced the incidence of macroalbuminuria, but it has been difficult to determine whether this was owing to the large effect of intensive diabetes therapy on preventing the development of microalbuminuria or to effects on progression of microalbuminuria to macroalbuminuria per se.5 The present study identifies hyperglycemia as an important risk factor for progression of established microalbuminuria to macroalbuminuria and impaired GFR. Furthermore, our results suggest that intensive diabetes therapy may help prevent this progression, whether applied before, at, or after the time of PMA diagnosis. The latter results are not definitive because participants were not randomized to diabetes therapy at the time of PMA diagnosis. The direction and magnitude of resulting bias cannot be determined, but it is reasonable to speculate that the benefits of intensive diabetes therapy were underestimated in our study, as the outcomes of participants who developed PMA with conventional therapy were compared with the outcomes of participants who developed PMA despite intensive therapy. Therefore, our findings suggest that glycemic control remains important for preventing renal progression in type 1 diabetes even after microalbuminuria has developed.

Our results highlight the known importance of blood pressure control in the prevention of diabetic kidney disease and again note the associations of lipid concentrations with renal outcomes.11,27,29,30 We confirm that men with type 1 diabetes have less favorable albuminuria outcomes.7,11,13 Sex was not associated with the development of impaired GFR in our analyses, although this relationship may be biased by the inclusion of sex in the formula used to estimate GFR.17 Our data cannot be validly used to assess the effect of RAAS inhibitors or lipid-lowering medications on disease progression, as the use of these medications in this observational study is subject to confounding by indication.31 As a result, and given rigorous randomized clinical trials demonstrating that RAAS inhibitors prevent progression of kidney disease in patients with type 1 and type 2 diabetes,3235 our data should not discourage the use of RAAS inhibitors in the setting of microalbuminuria.

Although our study population is not an inception cohort, our observed PMA cumulative incidence (25%-40% at 30 years' duration of diabetes) and timing (largely during the second decade of diabetes duration) are similar to those in prior studies.7,11 This concordance reinforces the prior observation that complication rates among the DCCT participants assigned to conventional diabetes therapy are similar to historical rates in a community-based cohort.36

The main strengths of this study derive from the careful longitudinal characterization of the DCCT/EDIC participants over a long duration of follow-up, allowing identification of PMA at or near its time of onset and accurate diagnosis of subsequent outcomes. By requiring persistence of microalbuminuria at diagnosis and persistence of normoalbuminuria, macroalbuminuria, and impaired GFR during the follow-up period, we are able to report changes in disease status with confidence. As a result, our findings offer relevant guidance to clinicians and patients who are newly diagnosed as having PMA.

This study also has limitations. We evaluated GFR only as a dichotomous outcome, although early renal function decline is also likely to have important clinical implications.37 Few ESRD cases were observed. The incidence and outcomes of PMA may be changing over time with innovations in clinical care, including increased RAAS inhibitor use. We did not assess cardiovascular and mortality outcomes; however, because death has been uncommon in the DCCT/EDIC study relative to renal outcomes,38 it is unlikely that the incidence of renal outcomes was substantially biased because of informative censoring.

In conclusion, progression and regression of kidney disease commonly occur after the development of PMA in type 1 diabetes, suggesting that PMA diagnosis represents a valuable occasion to assess and target renal interventions. In particular, intensive diabetes therapy seems to improve renal outcomes after the development of PMA in addition to preventing progression to microalbuminuria.

Correspondence: Ian H. de Boer, MD, MS, Kidney Research Institute and Division of Nephrology, University of Washington, Campus Box 359606, 325 Ninth Ave, Seattle, WA 98104 (deboer@u.washington.edu).

Accepted for Publication: August 2, 2010.

Author Contributions:Study concept and design: de Boer, Lachin, Molitch, Steffes, Zinman, and Brunzell. Acquisition of data: Cleary, Lachin, Steffes, and Zinman. Analysis and interpretation of data: de Boer, Rue, Cleary, Lachin, Molitch, Sun, and Brunzell. Drafting of the manuscript: de Boer, Lachin, and Brunzell. Critical revision of the manuscript for important intellectual content: de Boer, Rue, Cleary, Lachin, Molitch, Steffes, Zinman, and Brunzell. Statistical analysis: de Boer, Rue, Cleary, Lachin, and Sun. Obtained funding: de Boer, Lachin, Zinman, and Brunzell. Administrative, technical, and material support: Cleary, Steffes, Zinman, and Brunzell. Study supervision: Zinman and Brunzell.

Financial Disclosure: None reported.

Funding/Support: The DCCT/EDIC project is supported by contracts with the Division of Diabetes, Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases, the National Eye Institute, the National Institute of Neurological Disorders and Stroke, the General Clinical Research Centers Program and the Clinical and Translational Science Awards Program, and the National Center for Research Resources and by Genentech through a Cooperative Research and Development Agreement with the National Institute of Diabetes and Digestive and Kidney Diseases. Additional funding for this study was provided by grant UL1 RR 025014 from the National Center for Research Resources. Contributors of free or discounted supplies or equipment include Lifescan, Roche, Aventis, Eli Lilly, OmniPod, Can-Am, B-D, Animas, Medtronic, Medtronic Minimed, Bayer (a single donation in 2008), and Omron.

Previous Presentation: This study was presented as an abstract during Renal Week at the 43rd Annual Meeting and Scientific Exposition of the American Society of Nephrology; November 19, 2010; Denver, Colorado.

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de Boer  IHSibley  SDKestenbaum  B  et al. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study Research Group, Central obesity, incident microalbuminuria, and change in creatinine clearance in the Epidemiology of Diabetes Interventions and Complications study. J Am Soc Nephrol 2007;18 (1) 235- 243
PubMed Link to Article
Boright  APPaterson  ADMirea  L  et al. DCCT/EDIC Research Group, Genetic variation at the ACE gene is associated with persistent microalbuminuria and severe nephropathy in type 1 diabetes: the DCCT/EDIC Genetics Study. Diabetes 2005;54 (4) 1238- 1244
PubMed Link to Article
Al-Kateb  HBoright  APMirea  L  et al. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group, Multiple superoxide dismutase 1/splicing factor serine alanine 15 variants are associated with the development and progression of diabetic nephropathy: the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Genetics study. Diabetes 2008;57 (1) 218- 228
PubMed Link to Article
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
PubMed Link to Article
Levey  ASGreene  TKusek  JWBeck  GJ A simplified equation to predict glomerular filtration rate from serum creatinine [abstract]. J Am Soc Nephrol 2000;11A0828
de Boer  IHKestenbaum  BRue  TC  et al. Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) Study Research Group, Insulin therapy, hyperglycemia, and hypertension in type 1 diabetes mellitus. Arch Intern Med 2008;168 (17) 1867- 1873
PubMed Link to Article
Steffes  MCleary  PGoldstein  D  et al.  Hemoglobin A1c measurements over nearly two decades: sustaining comparable values throughout the Diabetes Control and Complications Trial and the Epidemiology of Diabetes Interventions and Complications study. Clin Chem 2005;51 (4) 753- 758
PubMed Link to Article
Turnbull  BW The empirical distribution function with arbitrarily grouped, censored and truncated data. J R Stat Soc B 1976;38290- 295
Lachin  JM Introduction to sample size determination and power analysis for clinical trials. Control Clin Trials 1981;2 (2) 93- 113
PubMed Link to Article
Borch-Johnsen  KKreiner  S Proteinuria: value as predictor of cardiovascular mortality in insulin dependent diabetes mellitus. Br Med J (Clin Res Ed) 1987;294 (6588) 1651- 1654
PubMed Link to Article
Perkins  BAFicociello  LHSilva  KHFinkelstein  DMWarram  JHKrolewski  AS Regression of microalbuminuria in type 1 diabetes. N Engl J Med 2003;348 (23) 2285- 2293
PubMed Link to Article
Steinke  JMSinaiko  ARKramer  MSSuissa  SChavers  BMMauer  MInternational Diabetic Nephopathy Study Group, The early natural history of nephropathy in type 1 diabetes, III: predictors of 5-year urinary albumin excretion rate patterns in initially normoalbuminuric patients. Diabetes 2005;54 (7) 2164- 2171
PubMed Link to Article
Dahlquist  GStattin  ELRudberg  S Urinary albumin excretion rate and glomerular filtration rate in the prediction of diabetic nephropathy; a long-term follow-up study of childhood onset type-1 diabetic patients. Nephrol Dial Transplant 2001;16 (7) 1382- 1386
PubMed Link to Article
Bojestig  MArnqvist  HJKarlberg  BELudvigsson  J Glycemic control and prognosis in type I diabetic patients with microalbuminuria. Diabetes Care 1996;19 (4) 313- 317
PubMed Link to Article
Giorgino  FLaviola  LCavallo Perin  PSolnica  BFuller  JChaturvedi  N Factors associated with progression to macroalbuminuria in microalbuminuric type 1 diabetic patients: the EURODIAB Prospective Complications Study. Diabetologia 2004;47 (6) 1020- 1028
PubMed Link to Article
Adler  AIStevens  RJManley  SEBilous  RWCull  CAHolman  RRUKPDS GROUP, Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int 2003;63 (1) 225- 232
PubMed Link to Article
Orchard  TJChang  YFFerrell  REPetro  NEllis  DE Nephropathy in type 1 diabetes: a manifestation of insulin resistance and multiple genetic susceptibilities? Further evidence from the Pittsburgh Epidemiology of Diabetes Complication Study. Kidney Int 2002;62 (3) 963- 970
PubMed Link to Article
Molitch  MERupp  DCarnethon  M Higher levels of HDL cholesterol are associated with a decreased likelihood of albuminuria in patients with long-standing type 1 diabetes. Diabetes Care 2006;29 (1) 78- 82
PubMed Link to Article
Avorn  J In defense of pharmacoepidemiology—embracing the yin and yang of drug research. N Engl J Med 2007;357 (22) 2219- 2221
PubMed Link to Article
Lewis  EJHunsicker  LGBain  RPRohde  RDThe Collaborative Study Group, The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy [published correction appears in N Engl J Med. 1993;330(2):152]. N Engl J Med 1993;329 (20) 1456- 1462
PubMed Link to Article
Parving  HHLehnert  HBröchner-Mortensen  JGomis  RAndersen  SArner  PIrbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group, The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001;345 (12) 870- 878
PubMed Link to Article
Brenner  BMCooper  MEde Zeeuw  D  et al. RENAAL Study Investigators, Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345 (12) 861- 869
PubMed Link to Article
Lewis  EJHunsicker  LGClarke  WR  et al. Collaborative Study Group, Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345 (12) 851- 860
PubMed Link to Article
Nathan  DMZinman  BCleary  PA  et al. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Research Group, Modern-day clinical course of type 1 diabetes mellitus after 30 years' duration: the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications and Pittsburgh epidemiology of diabetes complications experience (1983-2005). Arch Intern Med 2009;169 (14) 1307- 1316
PubMed Link to Article
Perkins  BAFicociello  LHOstrander  BE  et al.  Microalbuminuria and the risk for early progressive renal function decline in type 1 diabetes. J Am Soc Nephrol 2007;18 (4) 1353- 1361
PubMed Link to Article
Nathan  DMCleary  PABacklund  JY  et al. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group, Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005;353 (25) 2643- 2653
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Cumulative incidence of persistent microalbuminuria in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study by duration of type 1 diabetes and by Diabetes Control and Complications Trial treatment assignment.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Cumulative incidence of long-term renal outcomes after the development of persistent microalbuminuria (time 0) among 325 participants in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study. ESRD indicates end-stage renal disease; GFR, glomerular filtration rate.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Prevalence of normoalbuminuria, microalbuminuria, and macroalbuminuria by time following the diagnosis of incident persistent microalbuminuria (time 0) among 325 participants in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study. Ellipsis indicates not applicable; RAAS, renin-angiotensin-aldosterone system.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Cumulative incidence of long-term renal outcomes after the development of persistent microalbuminuria (time 0) among 325 participants in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study by Diabetes Control and Complications Trial treatment assignment. A, Regression to normoalbuminuria. B, Progression to macroalbuminuria. C, Impaired glomerular filtration rate (GFR). D, End-stage renal disease (ESRD).

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Characteristics of 325 Participants in the DCCT/EDIC Study at the Time of Incident Persistent Microalbuminuria Diagnosis
Table Graphic Jump LocationTable 2. Incidence of Long-term Renal Outcomes After Diagnosis of Persistent Microalbuminuria Among 325 Participants in the DCCT/EDIC Study
Table Graphic Jump LocationTable 3. Risk Factors for Long-term Renal Outcomes After Diagnosis of Persistent Microalbuminuria (PMA) Among 325 Participants in the DCCT/EDIC Study

References

Parving  HHOxenbøll  BSvendsen  PAChristiansen  JSAndersen  AR Early detection of patients at risk of developing diabetic nephropathy. A longitudinal study of urinary albumin excretion. Acta Endocrinol (Copenh) 1982;100 (4) 550- 555
PubMed
Viberti  GCHill  RDJarrett  RJArgyropoulos  AMahmud  UKeen  H Microalbuminuria as a predictor of clinical nephropathy in insulin-dependent diabetes mellitus. Lancet 1982;1 (8287) 1430- 1432
PubMed Link to Article
Mogensen  CE Microalbuminuria predicts clinical proteinuria and early mortality in maturity-onset diabetes. N Engl J Med 1984;310 (6) 356- 360
PubMed Link to Article
American Diabetes Association, Standards of medical care in diabetes−2009. Diabetes Care 2009;32 ((suppl 1)) S13- S61
PubMed Link to Article
The Diabetes Control and Complications (DCCT) Research Group, Effect of intensive therapy on the development and progression of diabetic nephropathy in the Diabetes Control and Complications Trial. Kidney Int 1995;47 (6) 1703- 1720
PubMed Link to Article
Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group, Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy: the Epidemiology of Diabetes Interventions and Complications (EDIC) study. JAMA 2003;290 (16) 2159- 2167
PubMed Link to Article
Andersen  ARChristiansen  JSAndersen  JKKreiner  SDeckert  T Diabetic nephropathy in type 1 (insulin-dependent) diabetes: an epidemiological study. Diabetologia 1983;25 (6) 496- 501
PubMed Link to Article
Seaquist  ERGoetz  FCRich  SBarbosa  J Familial clustering of diabetic kidney disease. Evidence for genetic susceptibility to diabetic nephropathy. N Engl J Med 1989;320 (18) 1161- 1165
PubMed Link to Article
Coonrod  BAEllis  DBecker  DJ  et al. Pittsburgh Epidemiology of Diabetes Complications Study, Predictors of microalbuminuria in individuals with IDDM. Diabetes Care 1993;16 (10) 1376- 1383
PubMed Link to Article
Chaturvedi  NBandinelli  SMangili  RPenno  GRottiers  REFuller  JH Microalbuminuria in type 1 diabetes: rates, risk factors and glycemic threshold. Kidney Int 2001;60 (1) 219- 227
PubMed Link to Article
Hovind  PTarnow  LRossing  P  et al.  Predictors for the development of microalbuminuria and macroalbuminuria in patients with type 1 diabetes: inception cohort study. BMJ 2004;328 (7448) 1105http://www.ncbi.nlm.nih.gov/pmc/articles/PMC406322/?tool=pubmed. Accessed December 15, 2010
PubMed Link to Article
Rossing  PHougaard  PParving  HH Progression of microalbuminuria in type 1 diabetes: ten-year prospective observational study. Kidney Int 2005;68 (4) 1446- 1450
PubMed Link to Article
de Boer  IHSibley  SDKestenbaum  B  et al. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study Research Group, Central obesity, incident microalbuminuria, and change in creatinine clearance in the Epidemiology of Diabetes Interventions and Complications study. J Am Soc Nephrol 2007;18 (1) 235- 243
PubMed Link to Article
Boright  APPaterson  ADMirea  L  et al. DCCT/EDIC Research Group, Genetic variation at the ACE gene is associated with persistent microalbuminuria and severe nephropathy in type 1 diabetes: the DCCT/EDIC Genetics Study. Diabetes 2005;54 (4) 1238- 1244
PubMed Link to Article
Al-Kateb  HBoright  APMirea  L  et al. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group, Multiple superoxide dismutase 1/splicing factor serine alanine 15 variants are associated with the development and progression of diabetic nephropathy: the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Genetics study. Diabetes 2008;57 (1) 218- 228
PubMed Link to Article
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
PubMed Link to Article
Levey  ASGreene  TKusek  JWBeck  GJ A simplified equation to predict glomerular filtration rate from serum creatinine [abstract]. J Am Soc Nephrol 2000;11A0828
de Boer  IHKestenbaum  BRue  TC  et al. Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) Study Research Group, Insulin therapy, hyperglycemia, and hypertension in type 1 diabetes mellitus. Arch Intern Med 2008;168 (17) 1867- 1873
PubMed Link to Article
Steffes  MCleary  PGoldstein  D  et al.  Hemoglobin A1c measurements over nearly two decades: sustaining comparable values throughout the Diabetes Control and Complications Trial and the Epidemiology of Diabetes Interventions and Complications study. Clin Chem 2005;51 (4) 753- 758
PubMed Link to Article
Turnbull  BW The empirical distribution function with arbitrarily grouped, censored and truncated data. J R Stat Soc B 1976;38290- 295
Lachin  JM Introduction to sample size determination and power analysis for clinical trials. Control Clin Trials 1981;2 (2) 93- 113
PubMed Link to Article
Borch-Johnsen  KKreiner  S Proteinuria: value as predictor of cardiovascular mortality in insulin dependent diabetes mellitus. Br Med J (Clin Res Ed) 1987;294 (6588) 1651- 1654
PubMed Link to Article
Perkins  BAFicociello  LHSilva  KHFinkelstein  DMWarram  JHKrolewski  AS Regression of microalbuminuria in type 1 diabetes. N Engl J Med 2003;348 (23) 2285- 2293
PubMed Link to Article
Steinke  JMSinaiko  ARKramer  MSSuissa  SChavers  BMMauer  MInternational Diabetic Nephopathy Study Group, The early natural history of nephropathy in type 1 diabetes, III: predictors of 5-year urinary albumin excretion rate patterns in initially normoalbuminuric patients. Diabetes 2005;54 (7) 2164- 2171
PubMed Link to Article
Dahlquist  GStattin  ELRudberg  S Urinary albumin excretion rate and glomerular filtration rate in the prediction of diabetic nephropathy; a long-term follow-up study of childhood onset type-1 diabetic patients. Nephrol Dial Transplant 2001;16 (7) 1382- 1386
PubMed Link to Article
Bojestig  MArnqvist  HJKarlberg  BELudvigsson  J Glycemic control and prognosis in type I diabetic patients with microalbuminuria. Diabetes Care 1996;19 (4) 313- 317
PubMed Link to Article
Giorgino  FLaviola  LCavallo Perin  PSolnica  BFuller  JChaturvedi  N Factors associated with progression to macroalbuminuria in microalbuminuric type 1 diabetic patients: the EURODIAB Prospective Complications Study. Diabetologia 2004;47 (6) 1020- 1028
PubMed Link to Article
Adler  AIStevens  RJManley  SEBilous  RWCull  CAHolman  RRUKPDS GROUP, Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int 2003;63 (1) 225- 232
PubMed Link to Article
Orchard  TJChang  YFFerrell  REPetro  NEllis  DE Nephropathy in type 1 diabetes: a manifestation of insulin resistance and multiple genetic susceptibilities? Further evidence from the Pittsburgh Epidemiology of Diabetes Complication Study. Kidney Int 2002;62 (3) 963- 970
PubMed Link to Article
Molitch  MERupp  DCarnethon  M Higher levels of HDL cholesterol are associated with a decreased likelihood of albuminuria in patients with long-standing type 1 diabetes. Diabetes Care 2006;29 (1) 78- 82
PubMed Link to Article
Avorn  J In defense of pharmacoepidemiology—embracing the yin and yang of drug research. N Engl J Med 2007;357 (22) 2219- 2221
PubMed Link to Article
Lewis  EJHunsicker  LGBain  RPRohde  RDThe Collaborative Study Group, The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy [published correction appears in N Engl J Med. 1993;330(2):152]. N Engl J Med 1993;329 (20) 1456- 1462
PubMed Link to Article
Parving  HHLehnert  HBröchner-Mortensen  JGomis  RAndersen  SArner  PIrbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group, The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001;345 (12) 870- 878
PubMed Link to Article
Brenner  BMCooper  MEde Zeeuw  D  et al. RENAAL Study Investigators, Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345 (12) 861- 869
PubMed Link to Article
Lewis  EJHunsicker  LGClarke  WR  et al. Collaborative Study Group, Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345 (12) 851- 860
PubMed Link to Article
Nathan  DMZinman  BCleary  PA  et al. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Research Group, Modern-day clinical course of type 1 diabetes mellitus after 30 years' duration: the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications and Pittsburgh epidemiology of diabetes complications experience (1983-2005). Arch Intern Med 2009;169 (14) 1307- 1316
PubMed Link to Article
Perkins  BAFicociello  LHOstrander  BE  et al.  Microalbuminuria and the risk for early progressive renal function decline in type 1 diabetes. J Am Soc Nephrol 2007;18 (4) 1353- 1361
PubMed Link to Article
Nathan  DMCleary  PABacklund  JY  et al. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group, Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005;353 (25) 2643- 2653
PubMed Link to Article

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