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

Abstract

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. Diabetic nephropathy is the leading cause of end-stage renal disease (ESRD) and severely decreases likelihood of long-term survival of patients with diabetes 1. It has high occurrence linked to a high global prevalence of diabetes, 5% type 1 diabetes mellitus (T1DM) and 95% type 2 diabetes mellitus (T2DM), with ca. 40% of patients with diabetes developing diabetic nephropathy 2,3. Approximately half of patients with diabetic nephropathy progress to diabetic kidney disease and ESRD with increased risk of potentially fatal cardiovascular disease. Current treatment guidelines address modifiable risk factors through intensification of control of glycemic status, blood

Protein glycation – biomarkers of metabolic dysfunction and early-stage decline in health in the era of precision medicine

“… [ 87 ] CVD (Risk predictor) Plasma protein (MG-H1) Increased mortality in nondiabetic women [ 90 ] Glycation endproduct free adducts Chronic kidney disease (Risk predictor) Fractional excretion of free adducts (FL, CML, CEL MG-H1, CMA and Pentosidine) Fractional excretion of glycation free adduct is increased in patients with diabetes at high risk of EDRF, supporting a precision medicine approach. [ 8 ] Plasma free adducts (CML, CEL and MG-H1) Logistic regression model for progression of diabetic kidney disease [ 106 ] …”

“…Reproduced from Refs. [ 8 , 48 ] with permission. Abbreviations: GRF, glomerular filtration rate; TER, transcapillary escape rate.…”

“…Protein glycation biomarkers in CKD were recently reviewed elsewhere [ 86 ]. Total plasma pentosidine (protein-bound + free adduct), was a risk predictor of mortality in CKD after adjusting for all confounders [ 87 ] and may be reporting increased pentosephosphate pathway activity in response to oxidative stress induced by rapid decline in renal function and associated increased mortality [ 8 ]. CML residue contents of plasma protein was investigated as a biomarker of mortality risk in renal failure in patients receiving hemodialysis therapy in two studies with contrary outcomes [ 88 , 89 ].…”

“…2 b). Increased fractional excretions of glycation adducts are potential risk predictors for EDRF in diabetes and possibly progression of non-diabetic CKD [ 8 ]. In an alternative approach, a logistic regression model indicated that plasma concentrations of CML, CEL and MG-H1 free adducts, but not A1C, were linked to progression of diabetic kidney disease in patients with T1DM, assessed by thickening of the renal glomerular basement membrane [ 106 ] ( Table 3 ).…”

“…The major route of excretion of glycation adducts is as free adducts in urine, with minor excretion in urinary albumin, other proteins and peptides. Glycation free adducts with molecular mass <500 Da pass readily through the glomerular filter into glomerular filtrate and are reabsorbed and secreted in the renal proximal tubules, likely by amino acid transporters, producing usually high and characteristic fractional excretions [ 7 , 8 ].

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