Association of Estimated Glomerular Filtration Rate With Progression of Albuminuria in People With Type 2 Diabetes

   OBJECTIVE: To elucidate the association of glomerular filtration rate (GFR) at baseline with subsequent albuminuria development and progression in people with type 2 diabetes. RESEARCH DESIGN AND METHODS: This was a single-center, retrospective cohort study of 6,618 Japanese adults with type 2 diabetes and urinary albumin-to-creatinine ratio of RESULTS: During the median follow-up period of 6.3 years, 1,190 reached the outcome. When people with a baseline eGFR of 75-90 mL/min/1.73m2 were considered the reference group, the hazard ratios (95% CI) for the outcome in those with a baseline eGFR of ≥90, 60-75, 45-60 and CONCLUSIONS: This study of Japanese adults with type 2 diabetes suggests that both a high and low GFR are implicated in the pathogenesis of albuminuria development and progression.   </p

The Influence of a Single Nucleotide Polymorphism within <em>CNDP1</em> on Susceptibility to Diabetic Nephropathy in Japanese Women with Type 2 Diabetes

<div><h3>Background</h3><p>Several linkage analyses have mapped a susceptibility locus for diabetic nephropathy to chromosome 18q22–23, and polymorphisms within the carnosine dipeptidase 1 gene (<em>CNDP1)</em>, located on 18q22.3, have been shown to be associated with diabetic nephropathy in European subjects with type 2 diabetes. However, the association of this locus with diabetic nephropathy has not been evaluated in the Japanese population. In this study, we examined the association of polymorphisms within the <em>CNDP1/CNDP 2</em> locus with diabetic nephropathy in Japanese subjects with type 2 diabetes.</p> <h3>Methodology/Principal Findings</h3><p>We genotyped a leucine repeat polymorphism (D18S880) that is within <em>CNDP1</em> along with 29 single nucleotide polymorphisms (SNPs) in the <em>CNDP1</em>/<em>CNDP2</em> locus for 2,740 Japanese subjects with type 2 diabetes (1,205 nephropathy cases with overt nephropathy or with end-stage renal disease [ESRD], and 1,535 controls with normoalbuminuria). The association of each polymorphism with diabetic nephropathy was analysed by performing logistic regression analysis. We did not observe any association between D18S880 and diabetic nephropathy in Japanese subjects with type 2 diabetes. None of the 29 SNPs within the <em>CNDP1/CNDP2</em> locus were associated with diabetic nephropathy, but a subsequent sex-stratified analysis revealed that 1 SNP in <em>CNDP1</em> was nominally associated with diabetic nephropathy in women (rs12604675-A; <em>p</em> = 0.005, odds ratio [OR] = 1.76, 95% confidence interval [CI], 1.19−2.61). Rs12604675 was associated with overt proteinuria (<em>p</em> = 0.002, OR = 2.18, 95% CI, 1.32−3.60), but not with ESRD in Japanese women with type 2 diabetes.</p> <h3>Conclusions/Significance</h3><p>Rs12604675-A in <em>CNDP1</em> may confer susceptibility to overt proteinuria in Japanese women with type 2 diabetes.</p> </div

Clinical characteristics of the participants.

<p>Abbreviations: BMI, body mass index; HbA1c, hemoglobin A1c; SBP, systolic blood pressure; DBP, diastolic blood pressure.</p>a<p>4 unknown,</p>b<p>14 unknown.</p>#<p>Mean ± SD, HbA1c; NGSP.</p

Association of single nucleotide polymorphisms (SNPs) within <i>CNDP1/CNDP2</i> locus with diabetic nephropathy.

<p>Results of association studies are shown using: A) men and women, B) men only, or C) women only. The x-axis represents the position in chromosome 18, and the y-axis shows the absolute values of log₁₀-transformed association <i>p</i> values. Open squares represent unadjusted values, and black squares represent values adjusted for age, log-transformed body mass index, and duration of diabetes. Thresholds for nominal (<i>p</i> = 0.05) or statistical (<i>p</i> = 0.0004) significance are shown as broken lines.</p

Association of rs12604675-A with diabetic nephropathy.

<p>OR represents the odds ratio per copy of risk allele (A). P-values were calculated using a logistic regression analysis with additive model (adjusted for sex, age, log-transformed body mass index and duration of diabetes).</p

Estimated glomerular filtration rate decline and risk of end-stage renal disease in type 2 diabetes - Fig 4

<p>Percent population attributable risk (%PAR) of end-stage renal disease associated with percent changes in eGFR during the (a) 2-year or (b) 3-year baseline period.</p

Estimated glomerular filtration rate decline and risk of end-stage renal disease in type 2 diabetes - Fig 2

<p><b>Adjusted hazard ratios of end-stage renal disease according to percent changes in eGFR during the (a) 2-year or (b) 3-year baseline period.</b> The model was adjusted for gender, age, systolic blood pressure, baseline eGFR, baseline urinary albumin, and history of cardiovascular disease. Knots were placed at −53%, −25%, −10%, and 10%. A reference point was set at 0% change in eGFR. Value trimmed at less than −70% and >10% change in eGFR.</p

Estimated glomerular filtration rate decline and risk of end-stage renal disease in type 2 diabetes - Fig 3

<p><b>Adjusted hazard ratios of end-stage renal disease according to percent changes in eGFR during the (a) 2-year or (b) 3-year baseline period in subgroup analysis based on baseline urinary albumin levels.</b> The model was adjusted with gender, age, systolic blood pressure, baseline eGFR, baseline urinary albumin, and history of cardiovascular disease. Knots were placed at −53%, −25%, −10%, and 10%. A reference point was set at 0% change in eGFR. Value trimmed at less than −70% and >10% change in eGFR.</p

Estimated glomerular filtration rate decline and risk of end-stage renal disease in type 2 diabetes - Fig 1

<p><b>Distribution of percent changes in eGFR during the (a) 2-year or (b) 3-year baseline period.</b> Percent change in eGFR was calculated as (last eGFR at baseline period–first available eGFR) / (first available eGFR) * 100.</p

Positive predictive value (PPV) with 95% confidence interval for end-stage renal disease according to percent changes in eGFR during the 2-year and 3-year baseline periods.

<p>Positive predictive value (PPV) with 95% confidence interval for end-stage renal disease according to percent changes in eGFR during the 2-year and 3-year baseline periods.</p