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Objective: The ACE insertion/deletion (I/D) polymorphism has been widely studied in people with diabetes, albeit not with regard to lower-limb amputation (LLA). We examined associations among this polymorphism, plasma ACE concentration, and LLA in people with type 1 diabetes.Research Design and Methods: ACE I/D genotype and plasma ACE were assessed in three prospective cohorts of participants with type 1 diabetes. LLA was defined as minor (below-the-ankle amputation consisting of at least one ray metatarsal resection) or major (transtibial or transfemoral) amputation. Linear, logistic, and Cox regression models were computed to evaluate the likelihood of prevalent and incident LLA by ACE genotype (XD [ID or ID] vs. II) and plasma ACE, after adjusting for confounders.Results: Among 1,301 participants (male 54%, age 41 ± 13 years), 90 (6.9%) had a baseline history of LLA. Baseline LLA was more prevalent in XD (7.4%) than in II genotype (4.5%, odds ratio [OR] 2.17 [95 %CI 1.03-4.60]). Incident LLA occurred in 53 individuals during the 14-year follow-up and was higher in XD versus II carriers (hazard ratio 3.26 [95% CI 1.16-13.67]). This association was driven by excess risk of minor, but not major, LLA. The D allele was associated with increased prevalent LLA at the end of follow-up (OR 2.48 [1.33-4.65]). LLA was associated with higher mean (95% CI) ACE levels in II (449 [360, 539] vs. 354 [286, 423] ng/mL), but not XD (512 [454, 570] vs. 537 [488, 586]), carriers.Conclusions: This report is the first of an independent association between ACE D allele and excess LLA risk, mainly minor amputations, in patients with type 1 diabetes. [ABSTRACT FROM AUTHOR]

Objective: The deletion (D) allele of the ACE insertion/deletion (I/D) polymorphism is a risk factor for diabetic kidney disease. We assessed its contribution to long-term kidney outcomes and all-cause death in patients with long-standing type 1 diabetes.Research Design and Methods: A total of 1,155 participants from three French and Belgian cohorts were monitored for a median duration of 14 (interquartile range 13) years. The primary outcome was the occurrence of end-stage kidney disease (ESKD) or a 40% drop in the estimated glomerular filtration rate (eGFR). Secondary outcomes were the individual components of the primary outcome, rapid decline in eGFR (steeper than -3 mL/min/1.73 m2 per year), incident albuminuria, all-cause death, and a composite ESKD or all-cause death. Hazard ratios (HRs) for XD versus II genotype and for baseline plasma ACE levels were computed by Cox analysis. Genotype performance in stratifying the primary outcome was tested.Results: Genotype distribution was 954 XD and 201 II. The primary outcome occurred in 20% of XD and 13% of II carriers: adjusted HR 2.07 (95% CI 1.32-3.40; P= 0.001). Significant associations were also observed for rapid decline in eGFR, incident albuminuria, ESKD, all-cause death, and ESKD or all-cause death. Baseline plasma ACE levels were higher in XD carriers and significantly associated with an increased risk of the primary outcome. The ACE genotype enhanced net reclassification improvement (0.154, 95% CI 0.007-0.279; P= 0.04) and integrated discrimination improvement (0.012, 95%CI 0.001-0.021; P= 0.02) for primary outcome stratification.Conclusions: The D-allele of the ACE I/D polymorphism was associated with an increased risk of major kidney events and all-cause death in patients with long-standing type 1 diabetes. [ABSTRACT FROM AUTHOR]

Background Hyperglycaemia impairs tubulo-glomerular feedback. We tested whether variable tubulo-glomerular feedback during hyperglycaemia contributes to renal risk heterogeneity seen in Type 1 diabetes. Methods During the period 1990–92, we studied the tubulo-glomerular feedback in Type 1 diabetic patients at high or low renal risk [21 of 54 with glomerular hyperfiltration and/or microalbuminuria against 11 of 55 with normal glomerular filtration rate (GFR) and urinary albumin despite uncontrolled diabetes]. The GFR, effective renal plasma flow, mean arterial pressure and fractional reabsorptions of glucose, osmols, sodium and lithium were measured sequentially during normo- and hyperglycaemia. All patients were followed up until 2016 for incident proteinuria, estimated GFR <60 mL/min/1.73 m2, doubling of serum creatinine, end-stage renal disease or all-cause death. Results Glycaemia increased from 6.1 ± 1.3 to 15.1 ± 1.9 mmol/L in both high-risk and low-risk patients. Glycosuria was lower in the high- versus low-risk patients: 0.34 ± 0.25 versus 0.64 ± 0.44 mmol/min (P = 0.03). Both groups displayed similar kidney function during normoglycaemia. Hyperglycaemia increased more importantly GFR and fractional reabsorptions, and pre-glomerular vasodilatation in the high- than in the low-risk patients (all P < 0.05). Over 21 years, 31.5% high- versus 12.7% low-risk patients developed endpoints (adjusted P = 0.006). In a multi-adjusted survival analysis of patients having undergone renal tests, each 0.10 mmol/min glycosuria during hyperglycaemia reduced the outcome risk by 0.72 (95% confidence interval 0.49–0.97, P = 0.03). Conclusions Reduced tubulo-glomerular feedback and glycosuria during hyperglycaemia indicate high renal risk for Type 1 diabetic patients. Inter-individual variability in tubulo-glomerular feedback activity determines renal risk in Type 1 diabetes. [ABSTRACT FROM AUTHOR]

Diabetic kidney disease drives premature mortality among patients with type 1 diabetes. The role of age at diabetes onset is controversial. We analyzed risk for diabetic kidney disease according to age at onset of type 1 diabetes using follow-up of type 1 diabetic patients attending our tertiary referral center. 340 type 1 diabetic patients attending the Angers University Hospital in France between 1989 and 2000, were followed-up to 2018 or death. They were divided in tertiles of ages at type 1 diabetes onset: T1:1-13, T2:14-23, and T3: 24-40 years. The primary endpoint was first occurrence of macroalbuminuria (>300mg albumin/g creatinine), doubling of serum creatinine, estimated glomerular filtration rate (eGFR, CK-EPI formula) <60ml/min/1.73m2, end stage renal disease (ESRD), or all-cause death. Multivariate analyses were done. Of 114 T1 participants, 11 (9.6%) developed macroalbuminuria, 5 (4.4%) doubling of serum creatinine, 14 (12.3%) eGFR<60ml/min/1.73m2, 8 (7%) ESRD, and 14(12.3%) died. Of 119 T2 participants, 8 (.6.7%) developed macroalbuminuria, 1 (0.8%) doubling of serum creatinine, 7 (5.9%) eGFR<60ml/min/1.73m2, 4(3.3%) ESRD, and 15(12.6%) died. Of 114 T3 participants, 3 (2.8%) developed macroalbuminuria, 1 (0.93%) doubling of serum creatinine, 4 (3.7%) eGFR<60ml/min/1.73m2, none ESRD, and 31(29%) died. Using multivariate analysis, age<14years at type 1 diabetes onset increased risk for kidney disease: T1 vs. T2 HR=2.35(95% CI1.20-4.58), T1 vs. T3 HR=3.61(1.30-9.27), p<0.01. Conclusions: Age <14 at type 1 diabetes onset was an independent risk factor for kidney disease in this >20-year monocentric follow-up study. Disclosure: C. Carpentier: None. S. Dubois: None. Y. Abouleka: None. B. Duly-Bouhanick: Research Support; Self; Novo Nordisk A/S, Sanofi, Servier. S. Hadjadj: Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk A/S, Sanofi, Servier. Research Support; Self; Bayer AG, Janssen Research & Development. Speaker's Bureau; Self; Abbott, Valbiotis. R. Coutant: None. R. Roussel: Advisory Panel; Self; Merck Sharp & Dohme Corp., Sanofi. Consultant; Self; Abbott, AstraZeneca, Eli Lilly and Company, Medtronic, Novo Nordisk A/S, Physiogenex. Research Support; Self; Janssen Pharmaceuticals, Inc. G. Velho: None. M. Marre: Advisory Panel; Self; Servier. Board Member; Self; Merck Sharp & Dohme Corp., Novo Nordisk A/S. [ABSTRACT FROM AUTHOR]

Objective: The deletion (D) allele of the ACE insertion/deletion (I/D) polymorphism is a risk factor for diabetic kidney disease. We assessed its contribution to long-term kidney outcomes and all-cause death in patients with long-standing type 1 diabetes., Research Design and Methods: A total of 1,155 participants from three French and Belgian cohorts were monitored for a median duration of 14 (interquartile range 13) years. The primary outcome was the occurrence of end-stage kidney disease (ESKD) or a 40% drop in the estimated glomerular filtration rate (eGFR). Secondary outcomes were the individual components of the primary outcome, rapid decline in eGFR (steeper than -3 mL/min/1.73 m 2 per year), incident albuminuria, all-cause death, and a composite ESKD or all-cause death. Hazard ratios (HRs) for XD versus II genotype and for baseline plasma ACE levels were computed by Cox analysis. Genotype performance in stratifying the primary outcome was tested., Results: Genotype distribution was 954 XD and 201 II. The primary outcome occurred in 20% of XD and 13% of II carriers: adjusted HR 2.07 (95% CI 1.32-3.40; P = 0.001). Significant associations were also observed for rapid decline in eGFR, incident albuminuria, ESKD, all-cause death, and ESKD or all-cause death. Baseline plasma ACE levels were higher in XD carriers and significantly associated with an increased risk of the primary outcome. The ACE genotype enhanced net reclassification improvement (0.154, 95% CI 0.007-0.279; P = 0.04) and integrated discrimination improvement (0.012, 95%CI 0.001-0.021; P = 0.02) for primary outcome stratification., Conclusions: The D-allele of the ACE I/D polymorphism was associated with an increased risk of major kidney events and all-cause death in patients with long-standing type 1 diabetes., (© 2021 by the American Diabetes Association.)