Advanced Glycation End Products Predict Loss of Renal Function and Correlate With Lesions of Diabetic Kidney Disease in American Indians With Type 2 Diabetes.
We examined associations of advanced glycation end products (AGEs) with renal function loss (RFL) and its structural determinants in American Indians with type 2 diabetes. Data were from a 6-year clinical trial that assessed renoprotective efficacy of losartan. Participants remained under observation after the trial concluded. Glomerular filtration rate (GFR) was measured annually. Kidney biopsies were performed at the end of the trial. Five AGEs were measured in serum collected at enrollment and at kidney biopsy. RFL was defined as ≥40% decline of measured GFR from baseline. Of 168 participants (mean baseline age 41 years, HbA1c9.2%, GFR 164 mL/min, and albumin-to-creatinine ratio 31 mg/g), 104 reached the RFL end point during median follow-up of 8.0 years. After multivariable adjustment, each doubling of carboxyethyl lysine (hazard ratio [HR] 1.60 [95% CI 1.08-2.37]) or methylglyoxal hydroimidazolone (HR 1.30 [95% CI 1.02-1.65]) concentration was associated with RFL. Carboxyethyl lysine, carboxymethyl lysine, and methylglyoxal hydroimidazolone correlated positively with cortical interstitial fractional volume (partial r = 0.23, P = 0.03; partial r = 0.25, P = 0.02; and partial r = 0.31, P = 0.003, respectively). Glyoxyl hydroimidazolone and methylglyoxal hydroimidazolone correlated negatively with total filtration surface per glomerulus (partial r = -0.26, P = 0.01; and partial r = -0.21, P = 0.046, respectively). AGEs improve prediction of RFL and its major structural correlates.
Phoenix Epidemiology and Clinical Research Branch, Phoenix, AZ.|CHU Poitiers, University of Poitiers, Clinical Investigation Center, INSERM CIC1402, Poitiers, France.
Pierre-Jean
PJ
Saulnier
Phoenix Epidemiology and Clinical Research Branch, Phoenix, AZ.
Kevin M
KM
Wheelock
PreventAGE Health Care, Lebanon, NH.
Scott
S
Howell
Phoenix Epidemiology and Clinical Research Branch, Phoenix, AZ.
E Jennifer
EJ
Weil
Phoenix Epidemiology and Clinical Research Branch, Phoenix, AZ.
Stephanie K
SK
Tanamas
Phoenix Epidemiology and Clinical Research Branch, Phoenix, AZ.
William C
WC
Knowler
Department of Pediatrics, University of Southern California Keck School of Medicine, Children's Hospital Los Angeles, Los Angeles, CA.
Kevin V
KV
Lemley
Department of Pediatrics and Medicine, University of Minnesota, Minneapolis, MN.
Michael
M
Mauer
Southwest Kidney Institute, Phoenix, AZ.
Berne
B
Yee
Phoenix Epidemiology and Clinical Research Branch, Phoenix, AZ rnelson@nih.gov.
Robert G
RG
Nelson
PreventAGE Health Care, Lebanon, NH.
Paul J
PJ
Beisswenger
D000328:Adult; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D005919:Glomerular Filtration Rate / Q000502:physiology; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000378:metabolism; D007198:Indians, North American; D007668:Kidney / Q000378:metabolism* / Q000503:physiopathology; D007678:Kidney Glomerulus / Q000378:metabolism / Q000503:physiopathology; D019808:Losartan / Q000627:therapeutic use; D008239:Lysine / Q000031:analogs & derivatives / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016016:Proportional Hazards Models; D011765:Pyruvaldehyde / Q000378:metabolism
D017127:Glycation End Products, Advanced; D007093:Imidazoles; C117197:imidazolone; C048496:N(6)-carboxymethyllysine; D011765:Pyruvaldehyde; D019808:Losartan; D008239:Lysine