Development and progression of renal insufficiency with and without albuminuria in adults with type 1 diabetes in the diabetes control and complications trial and the epidemiology of diabetes interventions and complications study

Abstract

Objective: This multicenter study examined the impact of albumin excretion rate (AER) on the course of estimated glomerular filtration rate (eGFR) and the incidence of sustained eGFR <60 ml/min/1.73 m(2) in type 1 diabetes up to year 14 of the Epidemiology of Diabetes Interventions and Complications (EDIC) study (mean duration of 19 years in the Diabetes Control and Complications Trial [DCCT]/EDIC).

Research design and methods: Urinary albumin measurements from 4-h urine collections were obtained from participants annually during the DCCT and every other year during the EDIC study, and serum creatinine was measured annually in both the DCCT and EDIC study. GFR was estimated from serum creatinine using the abbreviated Modification of Diet in Renal Disease equation.

Results: A total of 89 of 1,439 subjects developed an eGFR <60 ml/min/1.73 m(2) (stage 3 chronic kidney disease on two or more successive occasions (sustained) during the DCCT/EDIC study (cumulative incidence 11.4%). Of these, 20 (24%) had AER <30 mg/24 h at all prior evaluations, 14 (16%) had developed microalbuminuria (AER 30-300 mg/24 h) before they reached stage 3 chronic kidney disease, and 54 (61%) had macroalbuminuria (AER >300 mg/24 h) before they reached stage 3 chronic kidney disease. Macroalbuminuria is associated with a markedly increased rate of fall in eGFR (5.7%/year vs. 1.2%/year with AER <30 mg/24 h, P < 0.0001) and risk of eGFR <60 ml/min/1.73 m(2) (adjusted hazard ratio 15.3, P < 0.0001), whereas microalbuminuria had weaker and less consistent effects on eGFR.

Conclusions: Macroalbuminuria was a strong predictor of eGFR loss and risk of developing sustained eGFR <60 ml/min/1.73 m(2). However, screening with AER alone would have missed 24% of cases of sustained impaired eGFR.

Trial registration: ClinicalTrials.gov NCT00360815.

Figures

Figure 1

A: The proportions of subjects with a history of normal AER (AER ≤30 mg/24 h), microalbuminuria (AER >30 and ≤300 mg/24 h), and macroalbuminuria (AER >300 mg/24 h or ESRD) among subjects who never developed a sustained eGFR <60 ml/min/1.73 m2 by the time of their final visit, or at the visit where a subject first presents with a sustained eGFR <60 ml/min/1.73 m2. B: Cumulative incidence of sustained eGFR <60 ml/min/1.73 m2 during the DCCT/EDIC follow-up among the 1,439 DCCT/EDIC participants.

Figure 2

A: Estimates of the mean levels of eGFR at each DCCT-EDIC follow-up year among subjects currently with normal AER, or microalbuminuria or macroalbuminuria at that time, obtained from the general linear mixed model in Table 2. Subjects may switch from one AER category to another depending on their current AER levels at each visit. For each AER category, the estimated mean levels of eGFR are shown for intervals during which at least 20 subjects had a visit. B: Smoothed estimates of the distribution of percent change in eGFR per year while subjects were in each current AER category. The y-axis is the probability density or the derivative of the probability distribution such that the integrated area under each curve equals 1. Each patient's rate of change in eGFR while currently in each AER category is estimated from the general linear mixed model in Table 2 (the current albuminuria model). Note the range of substantially increased rates of decline in eGFR while subjects had macroalbuminuria relative to those while having normal albuminuria or microalbuminuria.