High fractional excretion of glycation adducts is associated with subsequent early decline in renal function in type 1 diabetes

Increased protein glycation, oxidation and nitration is linked to the development of diabetic nephropathy. We reported levels of serum protein glycation, oxidation and nitration and related hydrolysis products, glycation, oxidation and nitration free adducts in patients with type 1 diabetes (T1DM) during onset of microalbuminuria (MA) from the First Joslin Kidney Study, a prospective case–control study of patients with T1DM with and without early decline in GFR. Herein we report urinary excretion of the latter analytes and related fractional excretion values, exploring the link to MA and early decline in GFR. We recruited patients with T1DM and normoalbuminuria (NA) (n = 30) or new onset MA with and without early GFR decline (n = 22 and 33, respectively) for this study. We determined urinary protein glycation, oxidation and nitration free adducts by stable isotopic dilution analysis liquid chromatography-tandem mass spectrometry (LC–MS/MS) and deduced fractional excretion using reported plasma levels and urinary and plasma creatinine estimates. We found urinary excretion of pentosidine was increased ca. twofold in patients with MA, compared to normoalbuminuria (0.0442 vs 0.0103 nmol/mg creatinine, P < 0.0001), and increased ca. threefold in patients with early decline in GFR, compared to patients with stable GFR (0.0561 vs 0.0176 nmol/mg creatinine, P < 0.01). Urinary excretion of all other analytes was unchanged between the study groups. Remarkably, fractional excretions of 6 lysine and arginine-derived glycation free adducts were higher in patients with early decline in GFR, compared to those with stable GFR. Impaired tubular reuptake of glycation free adducts by lysine and arginine transporter proteins in patients with early GFR decline is likely involved. We conclude that higher fractional excretions of glycation adducts are potential biomarkers for early GFR decline in T1DM and MA. Measurement of these analytes could provide the basis for identifying patients at risk of early decline in renal function to target and intensify renoprotective treatment

Validity of a point-of-care nerve conduction device for polyneuropathy identification in older adults with diabetes: Results from the Canadian Study of Longevity in Type 1 Diabetes

<div><p>Objective</p><p>Point-of-care nerve conduction devices (POCD) have been studied in younger patients and may facilitate screening for polyneuropathy in non-specialized clinical settings. However, performance may be impaired with advanced age owing to age-related changes in nerve conduction. We aimed to evaluate the validity of a POCD as a proxy for standard nerve conduction studies (NCS) in older adults with type 1 diabetes (T1D).</p><p>Methods</p><p>Sural nerve amplitude potential (AMP) and sural nerve conduction velocity (CV) was measured in 68 participants with ≥ 50 years T1D duration and 71 controls (from age/sex-matched subgroups) using POCD and NCS protocols. Agreement was determined by the Bland-Altman method, and validity was determined by receiver operating characteristic curves.</p><p>Results</p><p>T1D were 53% female, aged 66±8yr and had diabetes duration 54yr[52,58]. Controls were 56%(p = 0.69) female and aged 65±8yr(p = 0.36). Mean AMP_POCD and CV_POCD for the 139 participants was 7.4±5.8μV and 45.7±11.2m/s and mean AMP_NCS and CV_NCS was 7.2±6.1μV and 43.3±8.3m/s. Mean difference of AMP_POCD−AMP_NCS was 0.3±3.8μV and was 2.3±8.5m/s for CV_POCD−CV_NCS. A AMP_POCD of ≤6μV had 80% sensitivity and 80% specificity for identifying abnormal AMP_NCS, while a CV_POCD of ≤44m/s had 81% sensitivity and 82% specificity to identify abnormal CV_NCS. Abnormality in AMP_POCD or CV_POCD was associated with 87% sensitivity, while abnormality in both measures was associated with 97% specificity for polyneuropathy identification.</p><p>Conclusions</p><p>The POCD has strong agreement and diagnostic accuracy for identification of polyneuropathy in a high-risk subgroup and thus may represent a sufficiently accurate and rapid test for routinely detecting those with electrophysiological dysfunction.</p></div

Quantification of AMP and CV using standard NCS and the POCD.

<p>Quantification of AMP and CV using standard NCS and the POCD.</p

Baseline characteristics for the 139 participants.

<p>Baseline characteristics for the 139 participants.</p

Flow of study participants.

<p>Of the 150 study participants in the Canadian Study of Longevity in Type 1 Diabetes, 1 refused the POCD procedure (index test) and 6 refused the NCS procedure (reference standard). Four study participants were excluded due to device errors using the POCD, resulting in 139 participants for analysis.</p

Validity of a point-of-care nerve conduction device for polyneuropathy identification in older adults with diabetes: Results from the Canadian Study of Longevity in Type 1 Diabetes - Fig 2

<p>Scatterplots (A, B) and Bland-Altman plots (C, D) for comparison of AMP and CV as determined by POCD and standard NCS. Panels A and B display the scatterplot of AMP (A) and CV (B) obtained by the two methods, r_s refers to Spearman’s rank correlation coefficient, and the solid diagonal line represents the line of unity (x = y). Panels C and D display the Bland-Altman plots demonstrating the difference between AMP_POCD−AMP_NCS (C) and CV_POCD−CV_NCS (D); points above or below zero on the y-axis represent overestimation and underestimation by the POCD, respectively. The dotted lines (C, D) correspond to, from top to bottom, the 97.5^th percentile of differences, the mean difference, and the 2.5^th percentile of differences.</p