Elevated baseline glomerular filtration rate (GFR) is independently associated with a more rapid decline in renal function of patients with type 1 diabetes

https://doi.org/10.1016/j.jdiacomp.2015.11.003Get rights and content

Abstract

Aims

Renal hyperfiltration is observed prior to the development of diabetic kidney disease (DKD) in patients with type 1 diabetes (T1DM); however its significance remains uncertain. Longitudinal data were used to investigate the association between measured baseline glomerular filtration rate (GFR) and renal function decline in patients with T1DM.

Methods

This study included 142 adult patients with T1DM and ≥ 2 measurements of glomerular filtration rate (mGFR; determined by diethylene-triamine-penta-acetic acid plasma clearance). Median follow up was 19 years. Patients were stratified by baseline mGFR quartile. The relationship between baseline mGFR and rate of renal function decline was assessed using random-effect generalized least squares regression, adjusted for age, duration of diabetes, HbA1c, blood pressure, renin-angiotensin-aldosterone system inhibitor therapy, LDL and BMI.

Results

The average rates of decline in renal function for the 2nd (baseline mGFR: 96.4–112.6 ml min− 1 1.73 m− 2), 3rd (baseline mGFR: 112.6–125.5 ml min− 1 1.73 m− 2) and 4th quartiles (baseline mGFR >125.5 ml min− 1 1.73 m− 2) were significantly faster than the first quartile (baseline mGFR: 60.9–96.4 ml min− 1 1.73 m− 2). In further detail, the average rates of decline in the 2nd (rate of decline 1.25 ml min− 1 1.73 m− 2 per year, 95% CI: 0.97; 1.52, p=0.008), 3rd (rate of decline 1.35 ml min− 1 1.73 m− 2 per year, 95% CI: 1.08; 1.62, p= 0.001) and 4th quartiles (rate of decline 1.6 ml min− 1 1.73 m− 2 per year, 95% CI: 1.34, 1.88, <0.0001) were significantly faster when compared to the first quartile (rate of decline 0.67 ml min− 1 1.73 m− 2 per year, 95% CI: 0.37; 0.96). Sub-analysis of quartile 4 revealed higher HbA1c measurements throughout follow-up in those with rapid mGFR decline (> 3.0 ml min 1 1.73 m 2/year).

Conclusions

In patients with T1DM, higher baseline mGFR is associated with more rapid mGFR decline. Patients with high baseline mGFR who developed rapid mGFR decline had higher HbA1c measurements throughout the study. These findings are consistent with the concept that poor glycaemic control over time may be a determining factor for the rapid renal function decline observed in some hyperfiltering patients.

Introduction

Renal hyperfiltration is observed in patients with early, uncomplicated type 1 diabetes prior to the development of diabetic kidney disease (DKD) (Premaratne et al., 2015). Renal hyperfiltration is typically defined as a glomerular filtration rate (GFR) greater than two standard deviations above the mean in the population studied (Jerums, Premaratne, Panagiotopoulos, & MacIsaac, 2010). Previous studies have used cut offs ranging from 90.7 to 175 ml min 1 1.73 m 2 (median 135 ml min 1 1.73 m 2), however, a consensus for the exact definition of hyperfiltration has yet to be reached (Cachat, Combescure, Cauderay, Girardin, & Chehade, 2015).

The significance of hyperfiltration in terms of its causative or predictive role in progressive DKD remains uncertain. Conclusive evidence that hyperfiltration has a pathological impact on renal function has mostly been garnered from animal studies (Luippold, Beilharz, & Muhlbauer, 2004). Previous studies, including a meta-analysis, have concluded that early hyperfiltration is a risk factor for subsequent development of DKD and a faster rate of renal function decline in patients with type 1 diabetes (Caramori, Gross, Pecis, & de Azevedo, 1999). This would suggest that early hyperfiltration could potentially be used to identify those patients with type 1 diabetes at greater risk of developing DKD. However, this finding has not been universal. Methodological challenges for existing studies have included small sample size and difficulty controlling for confounding variables such as glycaemic control, blood pressure (BP) and duration of diabetes (Jerums et al., 2010). A consistent limitation has been lack of long term follow up, making it difficult to accurately monitor the development and progression of hyperfiltration and its relationship to DKD over time. Further studies are required to assess the potential contribution of hyperfiltration to the risk of DKD development in humans.

We hypothesized that in patients with type 1 diabetes, an increase in baseline GFR is associated with a faster rate of renal function decline. Utilising longitudinal data, we aimed to investigate whether baseline GFR is independently associated with the rate of decline in renal function of patients with type 1 diabetes, while taking into account known risk factors for progression of DKD.

Section snippets

Methods

The study group comprised of adult patients with type 1 diabetes (n = 142) attending Austin Health Diabetes Clinics (a tertiary referral centre), who had at least two measured GFR (mGFR) measurements over a minimum of 4 years. Patients attending diabetes clinics at Austin Health routinely have mGFR measurements every two to three years to accurately assess their renal function, as part of complications surveillance. 142 patients with type 1 diabetes had at least 2 mGFR readings between 1986 and

Statistical analysis

Statistical software used for data analysis was Stata v13. All models were run adjusting for baseline age and baseline mGFR as a marker of the patient’s baseline condition. The data were not adjusted for duration of diabetes as this was strongly associated with baseline mGFR.

The relationship between time from baseline in (in years; independent variable) and mGFR (dependent variable) was investigated using random effect generalized least squares regression, using the subject as a grouping

Results

Patients with type 1 diabetes with at least two mGFR readings (n = 142) were included in the study. Individual mGFR readings over time are presented in Fig. 1, stratified by baseline mGFR quartile. Baseline patient characteristics are presented in Table 1. Median (IQR; min-max) patient follow up was 19 years (13.5–25.5; 4.9–34.6). Median (IQR) number of mGFR readings per patient over time in the overall group was 5.5 (4–8). For baseline mGFR quartiles 1–4, respectively, median (IQR) number of mGFR

Discussion

The contribution of early hyperfiltration in the development and progression of diabetic kidney disease (DKD) in type 1 diabetes is widely disputed. We demonstrated that, as compared to the lowest quartile (60.9–96.4 ml min 1 1.73 m 2), patients whose baseline mGFR was in the 2nd, 3rd and 4th quartiles (96.5–112.6, 112.7–125.5 and > 125.5 ml min 1 1.73 m 2, respectively) had a significantly greater rate of decline in mGFR. The 4th quartile group approximately equates to the 125 ml min 1 1.73 m 2 threshold

Acknowledgements

Author Contributions: H. J. Thomson collected data and wrote the initial draft of the manuscript. E. I. Ekinci planned the study, collected data, reviewed and edited the manuscript and contributed to discussion. N. Radcliffe assisted in subsequent drafting and data analysis/presentation. E. Ekinci, G. Jerums, R. MacIsaac, E. Premaratne & J. Seah planned the study, assisted in the collection of data, reviewed and edited the manuscript and contributed to discussion.

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    Conflicts of Interest: None.

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