Daniel Gordin

The Association Between Dietary Sodium Intake, ESRD, and All-Cause Mortality in Patients With Type 1 Diabetes

OBJECTIVE Many guidelines recommend reduced consumption of salt in patients with type 1 diabetes, but it is unclear whether dietary sodium intake is associated with mortality and end-stage renal disease (ESRD). RESEARCH DESIGN AND METHODS In a nationwide multicenter study (the FinnDiane Study) between 1998 and 2002, 2,807 enrolled adults with type 1 diabetes without ESRD were prospectively followed. Baseline urinary sodium excretion was estimated on a 24-h urine collection. The predictors of all-cause mortality and ESRD were determined by Cox regression and competing risk modeling, respectively. RESULTS The median follow-up for survival analyses was 10 years, during which 217 deaths were recorded (7.7%). Urinary sodium excretion was nonlinearly associated with all-cause mortality, such that individuals with the highest daily urinary sodium excretion, as well as the lowest excretion, had reduced survival. This association was independent age, sex, duration of diabetes, the presence and severity of chronic kidney disease (CKD) (estimated glomerular filtration rate [eGFR] and log albumin excretion rate), the presence of established cardiovascular disease, and systolic blood pressure. During follow-up, 126 patients developed ESRD (4.5%). Urinary sodium excretion was inversely associated with the cumulative incidence of ESRD, such that individuals with the lowest sodium excretion had the highest cumulative incidence of ESRD. CONCLUSIONS In patients with type 1 diabetes, sodium was independently associated with all-cause mortality and ESRD. Although we have not demonstrated causality, these findings support the calls for caution before applying salt restriction universally. Clinical trials must be performed in diabetic patients to formally test the utility/risk of sodium restriction in this setting.

New susceptibility loci associated with kidney disease in Type 1 diabetes

Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genome-wide association studies (GWAS) of T1D DN comprising ∼2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2×10−8) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0×10−9). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-β1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1×10−7), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN.

A1C variability predicts incident cardiovascular events, microalbuminuria, and overt diabetic nephropathy in patients with type 1 diabetes.

OBJECTIVE Recent data from the Diabetes Control and Complications Trial (DCCT) indicated that A1C variability is associated with the risk of diabetes microvascular complications. However, these results might have been influenced by the interventional study design. Therefore, we investigated the longitudinal associations between A1C variability and diabetes complications in patients with type 1 diabetes in the observational Finnish Diabetic Nephropathy (FinnDiane) Study. RESEARCH DESIGN AND METHODS A total of 2,107 patients in the FinnDiane Study had complete data on renal status and serial measurements of A1C from baseline to follow-up (median 5.7 years), and 1,845 patients had similar data on cardiovascular disease (CVD) events. Intrapersonal SD of serially measured A1C was considered a measure of variability. RESULTS During follow-up, 10.2% progressed to a higher albuminuria level or to end-stage renal disease, whereas 8.6% had a CVD event. The SD of serial A1C was 1.01 versus 0.75 (P < 0.001) for renal status and 0.87 versus 0.79 (P = 0.023) for CVD in progressors versus nonprogressors, respectively. In a Cox regression model, SD of serial A1C was independently associated with progression of renal disease (hazard ratio 1.92 [95% CI 1.49–2.47]) and of a CVD event (1.98 [1.39–2.82]) even when adjusting for mean A1C and traditional risk factors. Interestingly for CVD, mean serial A1C itself was not predictive even though SD of A1C was. CONCLUSIONS In patients with type 1 diabetes, A1C variability was not only predictive of incident microalbuminuria and progression of renal disease but also of incident CVD events.

Competing-Risk Analysis of ESRD and Death among Patients with Type 1 Diabetes and Macroalbuminuria

Patients with both type 1 diabetes and CKD have an increased risk of adverse outcomes. The competing risks of death and ESRD may confound the estimates of risk for each outcome. Here, we sought to determine the major predictors of the cumulative incidence of ESRD and pre-ESRD mortality in patients with type 1 diabetes and macroalbuminuria while incorporating the competing risk for the alternate outcome into a Fine-Gray competing-risks analysis. We followed 592 patients with macroalbuminuria for a median of 9.9 years. During this time, 56 (9.5%) patients died and 210 (35.5%) patients developed ESRD. Predictors of incident ESRD, taking baseline renal function and the competing risk for death into account, included an elevated HbA(1c), elevated LDL cholesterol, male sex, weight-adjusted insulin dose, and a shorter duration of diabetes. By contrast, predictors of pre-ESRD death, taking baseline renal function and the competing risk for ESRD into account, included only age, the presence of established macrovascular disease, and elevated cholesterol levels. This competing-risks approach has potential to highlight the appropriate targets and strategies for preventing premature mortality in patients with type 1 diabetes.

Metabolic Phenotypes, Vascular Complications and Premature Deaths in a Population of 4,197 Patients with Type 1 Diabetes

OBJECTIVE—Poor glycemic control, elevated triglycerides, and albuminuria are associated with vascular complications in diabetes. However, few studies have investigated combined associations between metabolic markers, diabetic kidney disease, retinopathy, hypertension, obesity, and mortality. Here, the goal was to reveal previously undetected association patterns between clinical diagnoses and biochemistry in the FinnDiane dataset. RESEARCH DESIGN AND METHODS—At baseline, clinical records, serum, and 24-h urine samples of 2,173 men and 2,024 women with type 1 diabetes were collected. The data were analyzed by the self-organizing map, which is an unsupervised pattern recognition algorithm that produces a two-dimensional layout of the patients based on their multivariate biochemical profiles. At follow-up, the results were compared against all-cause mortality during 6.5 years (295 deaths). RESULTS—The highest mortality was associated with advanced kidney disease. Other risk factors included 1) a profile of insulin resistance, abdominal obesity, high cholesterol, triglycerides, and low HDL2 cholesterol, and 2) high adiponectin and high LDL cholesterol for older patients. The highest population-adjusted risk of death was 10.1-fold (95% CI 7.3–13.1) for men and 10.7-fold (7.9–13.7) for women. Nonsignificant risk was observed for a profile with good glycemic control and high HDL2 cholesterol and for a low cholesterol profile with a short diabetes duration. CONCLUSIONS—The self-organizing map analysis enabled detailed risk estimates, described the associations between known risk factors and complications, and uncovered statistical patterns difficult to detect by classical methods. The results also suggest that diabetes per se, without an adverse metabolic phenotype, does not contribute to increased mortality.

Lipid abnormalities predict progression of renal disease in patients with type 1 diabetes

Aims/hypothesisWe studied the impact of baseline lipid variables on the progression of renal disease in a large nationwide prospective cohort of patients with type 1 diabetes.MethodsA total of 2,304 adult patients with type 1 diabetes and available lipid profiles participating in the Finnish Diabetic Nephropathy Study (FinnDiane) were evaluated. Data on progression of renal disease were verified from medical files and patients were followed for 5.4 ± 2.0 (mean ± SD) years.ResultsHigh triacylglycerol, apolipoprotein (Apo) B, ApoA-II and HDL3-cholesterol concentrations predicted incident microalbuminuria. Progression to macroalbuminuria was predicted by high triacylglycerol and ApoB. When AER was entered into the model, triacylglycerol was no longer an independent predictor, but when patients with normal AER and microalbuminuria at baseline were pooled, triacylglycerol, HbA1c, male sex and AER were all independent predictors of renal disease. High total cholesterol, LDL-cholesterol, non-HDL-cholesterol and triacylglycerol as well as low HDL-cholesterol, HDL2-cholesterol, ApoA-I and ApoA-II concentrations were predictive of progression to end-stage renal disease. However, when estimated GFR was entered into the model, only total cholesterol remained an independent predictor of progression.Conclusions/interpretationLipid abnormalities, particularly high triacylglycerol concentrations, increase the risk of progression of renal disease.

Association Testing of Previously Reported Variants in a Large Case–Control Meta-Analysis of Diabetic Nephropathy

We formed the GEnetics of Nephropathy–an International Effort (GENIE) consortium to examine previously reported genetic associations with diabetic nephropathy (DN) in type 1 diabetes. GENIE consists of 6,366 similarly ascertained participants of European ancestry with type 1 diabetes, with and without DN, from the All Ireland-Warren 3-Genetics of Kidneys in Diabetes U.K. and Republic of Ireland (U.K.-R.O.I.) collection and the Finnish Diabetic Nephropathy Study (FinnDiane), combined with reanalyzed data from the Genetics of Kidneys in Diabetes U.S. Study (U.S. GoKinD). We found little evidence for the association of the EPO promoter polymorphism, rs161740, with the combined phenotype of proliferative retinopathy and end-stage renal disease in U.K.-R.O.I. (odds ratio [OR] 1.14, P = 0.19) or FinnDiane (OR 1.06, P = 0.60). However, a fixed-effects meta-analysis that included the previously reported cohorts retained a genome-wide significant association with that phenotype (OR 1.31, P = 2 × 10−9). An expanded investigation of the ELMO1 locus and genetic regions reported to be associated with DN in the U.S. GoKinD yielded only nominal statistical significance for these loci. Finally, top candidates identified in a recent meta-analysis failed to reach genome-wide significance. In conclusion, we were unable to replicate most of the previously reported genetic associations for DN, and significance for the EPO promoter association was attenuated.

Serum adiponectin concentration is a positive predictor of all‐cause and cardiovascular mortality in type 1 diabetes

Abstract.  Forsblom C, Thomas MC, Moran J, Saraheimo M, Thorn L, Wadén J, Gordin D, Frystyk J, Flyvbjerg A, Groop P‐H, on behalf of the FinnDiane Study Group (Folkhälsan Institute of Genetics, Helsinki; Department of Medicine Helsinki University Central Hospital, Helsinki, Finland; The Baker IDI Heart and Diabetes Institute, Melbourne, Vic.; The Queen Elizabeth Hospital, Woodville, SA, Australia; and Aarhus University Hospital, Aarhus C., Denmark). Serum adiponectin concentration is a positive predictor of all‐cause and cardiovascular mortality in type 1 diabetes. J Intern Med 2011; 270: 346–355.

Circulating ACE2 activity is increased in patients with type 1 diabetes and vascular complications.

Objective: Angiotensin-converting enzyme 2 (ACE2) is a homolog of ACE that counterbalances the actions of angiotensin (AT)II and promotes vasodilatation. Circulating ACE2 activity is increased in diabetes in experimental models. The role of ACE2 in human pathophysiology is unknown. We examined whether ACE2 activity is altered in patients with type 1 diabetes (T1D), with and without diabetic nephropathy. Methods: Quantitative ACE2 activity in serum was measured by a fluorometric assay in 859 patients with T1D in the Finnish Diabetic Nephropathy (FinnDiane) study and in 204 healthy controls. Pulse-wave analysis with augmentation index (AIx) measurement was performed in 319 patients with T1D and 114 controls. Results: ACE2 activity was increased in men with T1D and microalbuminuria (30.2 ± 1.5 ngE/ml) when compared to patients without albuminuria (27.0 ± 0.5 ngE/ml, P < 0.05) or controls (25.6 ± 0.8 ngE/ml, P < 0.05). ACE2 activity was increased in male and female patients who were on ACE inhibitor (ACEi) treatment, also independently of albuminuria. Male and female patients with coronary heart disease (CHD) had significantly increased ACE2 activity (35.5 ± 2.5 vs. 27.0 ± 0.5 ngE/ml, P < 0.001 among male T1D patients vs. male controls). ACE2 activity correlated positively with systolic blood pressure (rs = 0.175, P < 0.001), AIx (rs = 0.191, P = 0.010) and diabetes duration (rs = 0.198, P < 0.001), and negatively with estimated glomerular filtration rate (rs = −0.109, P = 0.016) among male T1D patients. Conclusions: ACE2 activity increases with increasing vascular tone and when the patient with T1D has microvascular or macrovascular disease, indicating that ACE2 may participate as a compensatory mechanism in the regulation of vascular and renal function in patients with T1D.

Diabetes mellitus and ischemic stroke in the young Clinical features and long-term prognosis

Objective: To compare risk factors, stroke characteristics, and long-term prognosis between nondiabetic young ischemic stroke patients and similar patients having either type 1 diabetes mellitus (T1D) or type 2 diabetes mellitus (T2D) to provide information for patient management, counseling, and future research in these patient groups. Methods: Our database comprised 1,008 consecutive patients aged 15 to 49 with first-ever ischemic stroke from 1994 to 2007. Primary outcome measures were 1) nonfatal or fatal recurrent ischemic stroke and 2) composite vascular endpoint (myocardial infarction, any stroke, revascularization, or vascular death). Results: Compared with nondiabetic stroke patients (n = 904), patients with T1D (44) or T2D (60) were more likely to have hypertension and stroke attributable to small-vessel disease (SVD). In addition, when compared with nondiabetic patients, those with T1D more frequently had coronary heart disease and peripheral arterial disease (PAD) and those with T2D more often had obesity, PAD, history of TIA, and stroke attributable to large-artery atherosclerosis, and T2D patients were also more likely to be older and male than were the nondiabetic patients. Mean follow-up in survivors was 9.0 (±3.8) years. Cumulative recurrent ischemic stroke rate at 10 years was 40.9% for T1D (14 events), 29.7% for T2D (15), and 12.0% for nondiabetic patients (94). Corresponding rates for the composite vascular endpoint were 65.1% for T1D (25), 46.9% for T2D (28), and 19.3% for nondiabetic patients (153). Conclusions: Our findings suggest that ischemic stroke patients with T1D or T2D exhibit a distinct risk-factor and etiologic profile and a worse vascular prognosis than do nondiabetic patients.