Decreased plasma kallikrein activity is associated with reduced kidney function in individuals with type 1 diabetes

Objective: The bone-related peptide osteoprotegerin (OPG) has recently been found in increased amounts in the vasculature in diabetes. It is produced by vascular smooth muscle and endothelial cells, and may be implicated in the development of vascular calcifications. OPG is present in the circulation, where increased amounts have been observed in patients with diabetes. In this study, we examined whether plasma OPG is associated with the glycaemic and vascular status of patients with type 1 diabetes. Methods: Two gender-, age- and duration-comparable groups of type 1 diabetic patients either with (n = 199) or without (n = 192) signs of diabetic nephropathy were studied. Plasma OPG was determined by an ELISA. Results: The plasma OPG concentration was significantly higher in patients with nephropathy than those without (3.11 (2.49–3.99) vs 2.57 (2.19–3.21) (median (interquartiles), ng/ml), P < 0.001). Plasma OPG correlated with haemoglobin A1c (HbA1c), systolic blood pressure and age in both groups and, in addition, with kidney function in the nephropathic group. These correlations remained significant in multivariate models. In addition, we found that plasma OPG concentrations were increased among patients with cardiovascular diseases (CVD), both in the normoalbuminuric and the nephropathic groups. The differences between nephropathic and normoalbuminuric, as well as subgroups with and without CVD, could largely be ascribed to changes in HbA1c, age, systolic blood pressure and creatinine. Conclusion: OPG is associated with glycaemic control and CVD in patients with type 1 diabetes, compatible with the hypothesis that OPG is associated with the development of diabetic vascular complications.

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Circulating Free Fatty Acid and Phospholipid Signature Predicts Early Rapid Kidney Function Decline in Patients With Type 1 Diabetes

10.2337/figshare.14696676.v1 ◽

2021 ◽

Author(s):

Farsad Afshinnia ◽

Thekkelnaycke M. Rajendiran ◽

Chenchen He ◽

Jaeman Byun ◽

Daniel Montemayor ◽

...

Keyword(s):

Type 1 Diabetes ◽

Fatty Acid ◽

Free Fatty Acid ◽

Kidney Function ◽

Acyl Chain ◽

C Statistic ◽

Unsaturated Acyl ◽

Gfr Decline ◽

Egfr Decline

Objectives: Patients with type 1 diabetes (T1D) exhibit modest lipid abnormalities as measured by traditional metrics. This study aimed to identify lipidomic predictors of rapid decline of kidney function in T1D. Research Design and Methods: In a Case-Control study, 817 T1D patients from 3 large cohorts were randomly split into training and validation subsets. Case was defined as >3 mL/min/1.73 m2/year decline in estimated glomerular filtration rate (eGFR) while Control was defined as <1 mL/min/1.73 m2/year decline over a minimum 4-year follow up. Lipids were quantified in baseline serum samples using a targeted mass spectrometry lipidomic platform. Results: At individual lipids, free fatty-acid (FFA)20:2 was directly, and phosphatidylcholine (PC)16:0/22:6 was inversely and independently associated with rapid eGFR decline. When examined by lipid class, rapid eGFR decline was characterized by higher abundance of unsaturated FFAs, phosphatidylethanolamine (PE)-Ps and PCs with an unsaturated acyl chain at the sn1 carbon, and by lower abundance of saturated FFAs, longer triacylglycerols, and PCs, PEs, PE-Ps, and PE-Os with an unsaturated acyl chain at the sn1 carbon at eGFR ≥90 mL/min. A multi-lipid panel consisting of unsaturated FFAs and saturated PE-Ps predicted rapid eGFR decline better than individual lipids (C-statistic, 0.71) and improved C-statistic of clinical model from 0.816 to 0.841 (p=0.039). Observations were confirmed in the validation subset. Conclusion: Distinct from previously reported predictors of GFR decline in type 2 diabetes, these findings suggest differential incorporation of FFAs at sn1 carbon of the phospholipids’ glycerol backbone as independent predictor of rapid GFR decline in T1D.

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Resistant hypertension and risk of adverse events in individuals with type 1 diabetes: A nationwide prospective study

10.2337/figshare.12137604.v1 ◽

2020 ◽

Author(s):

Raija Lithovius ◽

Valma Harjutsalo ◽

Stefan Mutter ◽

Daniel Gordin ◽

Carol Forsblom ◽

...

Keyword(s):

Type 1 Diabetes ◽

Diabetic Nephropathy ◽

Prospective Study ◽

Resistant Hypertension ◽

Antihypertensive Drugs ◽

Increased Risk ◽

All Cause Mortality ◽

Nationally Representative ◽

Reduced Kidney Function

Objectives. To estimate the risk of diabetic nephropathy (DN) progression, incident coronary heart disease (CHD) and stroke, and all-cause mortality associated with resistant hypertension (RH) in individuals with type 1 diabetes stratified by stages of DN, renal function and sex. Research Design and Methods This prospective study included a nationally representative cohort of individuals with type 1 diabetes from the Finnish Diabetic Nephropathy Study who had purchases of antihypertensive drugs at (±6 months) baseline visit (1995–2008). Individuals (N=1,103) were divided into three groups: (a) RH, (b) uncontrolled BP, but no RH and (c) controlled BP. DN progression, cardiovascular events and deaths were identified from the individuals’ healthcare records and national registries, until 31 December 2015. Results At baseline 18.7% of the participants had RH, while 23.4% had controlled BP. After full adjustments for clinical confounders, RH was associated with increased risk of DN progression (HR 1.95 [95% CI 1.37, 2.79], p=0.0002), while no differences were observed in those with no RH (1.05 [0.76, 1.44], p=0.8), compared with those who had controlled BP. The risk of incident CHD, incident stroke and all-cause mortality was higher in individuals with RH compared with those who had controlled BP, but not beyond albuminuria and reduced kidney function. Notably, in those with normo- and microalbuminuria the risk of stroke remained higher in the RH compared to controlled BP group (3.49 [81.20, 10.15], p=0.02). Conclusion Our findings highlight importance to identify and provide diagnostic and therapeutic counseling to these very high risk individuals with RH.

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Serum Cystatin C as a Biomarker for Early Diabetic Nephropathy and Dyslipidemia in Young Type 1 Diabetes Patients

10.21203/rs.3.rs-91508/v1 ◽

2020 ◽

Author(s):

Lina Radzeviciene ◽

Ingrida Stankute ◽

Ausra Monstaviciene ◽

Rimantė Dobrovolskiene ◽

Evalda Danyte ◽

...

Keyword(s):

Type 1 Diabetes ◽

Kidney Function ◽

Cystatin C ◽

Young Patients ◽

Kidney Injury ◽

Albumin Excretion Rate ◽

Serum Cystatin C ◽

Serum Cystatin ◽

Long Term Follow Up

Abstract Background. Early capture of initial stages of complications is the destination of long term follow up of type 1 diabetes (T1D) patients. The aim of this study was to assess the clinical significance of serum cystatin C in the early diagnosis of renal injury and its association with dyslipidemia in young T1D patients.Methods. 779 subjects were evaluated for kidney function by estimating glomerular filtration rate (eGFR) based on serum creatinine (eGFRcreat) and cystatin C (eGFRcys). Results. Median age of study subjects was 16.2 years (2.1;26.4), diabetes duration – 5.3 years (0.51;24.0). The median of HbA1c was 8% (5.2;19.9) (64 mmol/mol (33.3;194)); 24.2% of participants had HbA1c <7% (53 mmol/mol). Elevated albumin excretion rate was found in 13.5% of subjects. The median of cystatin C was 0.8 mg/L (0.33;1.71), the median of creatinine – 63 µmol/L (6;126). Median of eGFRcys was lower than eGFRcreat (92 ml/min/1.73m2 vs. 101 ml/min/1.73m2, p<0.001). 30.2% of all patients were classified as having worse kidney function when using cystatin C vs. creatinine for eGFR calculation. Linear correlations were found between cystatin C and HbA1c, r=-0.088, p<0.05, as well as cystatin C and HDL, r=-0.097, p<0.01.Conclusion. This study showed that cystatin C might be used as an additional biomarker of early kidney injury for young patients with T1D.

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Resistant hypertension and risk of adverse events in individuals with type 1 diabetes: A nationwide prospective study

10.2337/figshare.12137604.v2 ◽

2020 ◽

Author(s):

Raija Lithovius ◽

Valma Harjutsalo ◽

Stefan Mutter ◽

Daniel Gordin ◽

Carol Forsblom ◽

...

Keyword(s):

Type 1 Diabetes ◽

Diabetic Nephropathy ◽

Prospective Study ◽

Resistant Hypertension ◽

Antihypertensive Drugs ◽

Increased Risk ◽

All Cause Mortality ◽

Nationally Representative ◽

Reduced Kidney Function

Objectives. To estimate the risk of diabetic nephropathy (DN) progression, incident coronary heart disease (CHD) and stroke, and all-cause mortality associated with resistant hypertension (RH) in individuals with type 1 diabetes stratified by stages of DN, renal function and sex. Research Design and Methods This prospective study included a nationally representative cohort of individuals with type 1 diabetes from the Finnish Diabetic Nephropathy Study who had purchases of antihypertensive drugs at (±6 months) baseline visit (1995–2008). Individuals (N=1,103) were divided into three groups: (a) RH, (b) uncontrolled BP, but no RH and (c) controlled BP. DN progression, cardiovascular events and deaths were identified from the individuals’ healthcare records and national registries, until 31 December 2015. Results At baseline 18.7% of the participants had RH, while 23.4% had controlled BP. After full adjustments for clinical confounders, RH was associated with increased risk of DN progression (HR 1.95 [95% CI 1.37, 2.79], p=0.0002), while no differences were observed in those with no RH (1.05 [0.76, 1.44], p=0.8), compared with those who had controlled BP. The risk of incident CHD, incident stroke and all-cause mortality was higher in individuals with RH compared with those who had controlled BP, but not beyond albuminuria and reduced kidney function. Notably, in those with normo- and microalbuminuria the risk of stroke remained higher in the RH compared to controlled BP group (3.49 [81.20, 10.15], p=0.02). Conclusion Our findings highlight importance to identify and provide diagnostic and therapeutic counseling to these very high risk individuals with RH.

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