Valma Harjutsalo

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.

Time trends in mortality in patients with type 1 diabetes: nationwide population based cohort study

Objective To examine short and long term time trends in mortality among patients with early onset (age 0-14 years) and late onset (15-29 years) type 1 diabetes and causes of deaths over time. Design Population based nationwide cohort study. Setting Finland. Participants All Finnish patients diagnosed as having type 1 diabetes below age 30 years between 1970 and 1999 (n=17 306). Main outcome measures Crude mortality, standardised mortality ratios, time trends, and cumulative mortality. Results A total of 1338 deaths occurred during 370 733 person years of follow-up, giving an all cause mortality rate of 361/100 000 person years. The standardised mortality ratio was 3.6 in the early onset cohort and 2.8 in the late onset cohort. Women had higher standardised mortality ratios than did men in both cohorts (5.5 v 3.0 in the early onset cohort; 3.6 v 2.6 in the late onset cohort). The standardised mortality ratio at 20 years’ duration of diabetes in the early onset cohort decreased from 3.5 in the patients diagnosed in 1970-4 to 1.9 in those diagnosed in 1985-9. In contrast, the standardised mortality ratio in the late onset cohort increased from 1.4 in those diagnosed in 1970-4 to 2.9 in those diagnosed in 1985-9. Mortality due to chronic complications of diabetes decreased with time in the early onset cohort but not in the late onset cohort. Mortality due to alcohol related and drug related causes increased in the late onset cohort and accounted for 39% of the deaths during the first 20 years of diabetes. Accordingly, mortality due to acute diabetic complications increased significantly in the late onset cohort. Conclusion Survival of people with early onset type 1 diabetes has improved over time, whereas survival of people with late onset type 1 diabetes has deteriorated since the 1980s. Alcohol has become an important cause of death in patients with type 1 diabetes, and the proportion of deaths caused by acute complications of diabetes has increased in patients with late onset type 1 diabetes.

Incidence of type 1 diabetes in Finland.

Incidence of Type 1 Diabetes in Finland The incidence of type 1 diabetes (T1D), one of the most prevalent chronic disease in children, has increased worldwide.1 The highest recorded incidence in children younger than 15 years was 64.2 per 100 000 person-years in Finland in 2005.2 We examined the incidence rates between 2006 and 2011 in Finnish children younger than 15 years as well as the 32-year trend (1980-2011).

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.

Differential Transmission of Type 1 Diabetes from Diabetic Fathers and Mothers to Their Offspring

We studied the incidence of type 1 diabetes in the offspring of patients with childhood- and adolescent-onset type 1 diabetes and several risk factors predicting the risk. We defined the diabetes status in the offspring of all probands who were included in the nationwide register of Finnish type 1 diabetic patients diagnosed at the age of ≤17 years from 1965 to 1979. A total of 5,291 offspring at risk contributed 72,220 person-years of follow-up between 1970 and 2003. Of them, 259 offspring developed type 1 diabetes by the end of 2003, giving a cumulative incidence of 6.7% (95% CI 5.9–7.5) by the age of 20 years. The incidence of type 1 diabetes in the offspring between the years 1980 and 2003 was 35.3, 44.6, and 44.6 per 10,000 person-years for the age-groups 0–4, 5–9, and 10–14 years, respectively. Poisson regression analyses showed a marked increase in incidence of 5.3% per year from 1983 to 2003. The greatest increase occurred in the youngest offspring, aged 0–4 years. Of the offspring of male probands, 7.8% were affected by the age of 20 years compared with 5.3% of the offspring of female probands (relative risk 1.7 [95% CI 1.3–2.2]). The young age at onset of diabetes increased the risk of type 1 diabetes in the offspring of diabetic fathers but not in the offspring of diabetic mothers. In conclusion, our findings revealed that in the offspring of type 1 diabetic patients, the increase in the recurrence risk of type 1 diabetes was not more rapid compared with that in the background population. In the multivariate analyses, statistically significant predictors of type 1 diabetes in the offspring were male sex of the diabetic parent, young age at diagnosis in the male parent, and the more recent year of birth of the offspring.

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.

Epidemiology and Risk Factors for Diabetic Kidney Disease

Prevalence rates of diabetic kidney disease (DKD) are increasing in parallel with the incidence rates of diabetes mellitus. DKD has already become a significant health problem worldwide. Without radical improvements in prevention and treatment, DKD prevalence will continue to climb. The pathogenesis of DKD is complex and multifactorial, with genetic and environmental factors involved. Several nonmodifiable risk factors contribute to DKD, including genetics, sex, age, age at onset, and duration of diabetes. However, there are also several modifiable risk factors that have a strong effect on the risk of DKD. Traditional modifiable factors include glycemic control, blood pressure, lipids, and smoking. Other recently discovered modifiable risk factors include chronic low-grade inflammation, advanced glycation end products, and lack of physical activity. Efficient management of these modifiable risk factors may improve the prognosis of diabetic patients at risk of DKD.

Age at onset and the risk of proliferative retinopathy in type 1 diabetes

OBJECTIVE Age at onset of type 1 diabetes influences the risk of microvascular complications. However, the long-term risk of proliferative retinopathy within the wide spectrum of age at onset of type 1 diabetes is less well known. RESEARCH DESIGN AND METHODS A sample of 1,117 consecutively recruited patients was drawn from the FinnDiane Study population (4,800 patients). Type 1 diabetes was defi ned as age at onset ≤40 years, insulin treatment initiated within 1 year, and C-peptide ≤0.3 nmol/1. Retinopathy status was graded based on ophthalmic records and/or fundus photographs. The risk of proliferative retinopathy was studied in age-at-onset groups 0–4, 5–14, and 15–40 years. RESULTS The mean durations to proliferative retinopathy were 24.3 (22.7–25.9) years in the 0–4 years group, 20.1 (19.2–21.1) years in the 5–14 years group, and 21.6 (19.8–23.3) years in the 15–40 years group (P < 0.001). In a Cox regression model, with A1C, blood pressure, sex, and BMI as covariates, the highest risk of proliferative retinopathy was observed in the 5–14 years group (hazard ratio 1.90 [95% CI 1.45–2.48], P < 0.001). Diabetes onset 0–4 vs. 5–14 years made no difference in the long-term risk of proliferative retinopathy (P = 0.2). When split into two groups, age at onset < 15 years was associated with a higher long-term risk than age at onset >15 years (1.82 [1.40–2.36], P < 0.001). CONCLUSIONS Age at onset significantly modifies the long-term risk of proliferative retinopathy. The highest risk is in age-at-onset group 5–14 years, whereas the lowest risk is in age-at-onset group 15–40 years.

Serum Concentration of Cystatin C and Risk of End-Stage Renal Disease in Diabetes

OBJECTIVE Patients with diabetes have a high risk of end-stage renal disease (ESRD). We examined whether prediction of this outcome, according to chronic kidney disease (CKD) staging by creatinine-based estimates of the glomerular filtration rate (eGFRcreat), is improved by further staging with serum cystatin C–based estimates (eGFRcyst). RESEARCH DESIGN AND METHODS Patients with diabetes in CKD stages 1–3 were selected from three cohorts: two from Joslin Diabetes Center, one with type 1 diabetes (N = 364) and one with type 2 diabetes (N = 402), and the third from the Finnish Diabetic Nephropathy (FinnDiane) Study of type 1 (N = 399). Baseline serum concentrations of creatinine and cystatin C were measured in all patients. Follow-up averaged 8–10 years and onsets of ESRD (n = 246) and death unrelated to ESRD (n = 159) were ascertained. RESULTS Although CKD staging by eGFRcyst was concordant with that by eGFRcreat for 62% of Joslin patients and 73% of FinnDiane patients, those given a higher stage by eGFRcyst than eGFRcreat had a significantly higher risk of ESRD than those with concordant staging in all three cohorts (hazard ratio 2.3 [95% CI 1.8–3.1]). Similarly, patients at a lower stage by eGFRcyst than by eGFRcreat had a lower risk than those with concordant staging (0.30 [0.13–0.68]). Deaths unrelated to ESRD followed the same pattern, but differences were not as large. CONCLUSIONS In patients with diabetes, CKD staging based on eGFRcyst significantly improves ESRD risk stratification based on eGFRcreat. This conclusion can be generalized to patients with type 1 and type 2 diabetes and to diabetic patients in the U.S. and Finland.