Elevated Albumin Excretion Research Articles

Prevalence of LDL-hypercholesterolemia and other cardiovascular risk factors in young people with type 1 diabetes

BackgroundMortality and morbidity in people with Type 1 diabetes (T1D) is mainly caused by cardiovascular disease (CVD). Early treatment of cardiovascular risk factors (CVRFs) is of great importance. ObjectiveTo analyze the prevalence of LDL-hypercholesterolemia and other CVRFs in youth with T1D. MethodsClinical and laboratory parameters, and vascular thickness measurement were obtained in youth with T1D (age 6-18 years, T1D duration >1 year) attending a diabetes clinic. LDL-hypercholesterolemia, microalbuminuria and arterial hypertension were defined as CVRFs. ResultsA total of 333 youth (48% girls; age: 13.3 years [10.3-15.5], median [interquartile range]) participated in the study. The T1D duration was 5.9 years [3.5-9.4] with HbA1c of 7.4% [6.8-8.0]. Intima media thickness (N=223) was 538.0 µm [470.0-618.0]). LDL-hypercholesterolemia was present in 30 participants (9%; 18 girls; age: 14.3 years [11.2-15.7]). None of the participants had persistent microalbuminuria, although 59 (18.3%) had elevated albumin excretion in a random urine specimen. LDL-hypercholesterolemia was associated with increased blood pressure (p<0.05), insulin requirement (p<0.05), HbA1c (p<0.05), triglyceride (p<0.001) and total cholesterol (p<0.001), and a family history of premature CVD (p<0.001), but negatively correlated with HDL cholesterol levels (p<0.05). Sex, pubertal status, duration of diabetes, type of therapy, and physical activity did not differ between participants with and without LDL- hypercholesterolemia. Arterial hypertension was present in 11 participants (3.3%; 4 girls; age: 14.1 years [11.1-16.1]). ConclusionLDL-hypercholesterolemia affected 9% of youth with T1D in this cohort and was associated with other CVRFs. A holistic therapeutic concept for these young people is essential.

The Genetics of Type 2 Diabetes in Youth: Where We Are and the Road Ahead

The Genetics of Type 2 Diabetes in Youth: Where We Are and the Road Ahead

The Effect of SGLT2 Inhibition on Diabetic Kidney Disease in a Model of Diabetic Retinopathy.

Diabetic kidney disease (DKD) is a chronic disorder characterized by elevated urine albumin excretion, reduced glomerular filtration rate, or both. At present, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are the standard care for the treatment of DKD, resulting in improved outcomes. However, alternative treatments may be required because although the standard treatments have been found to slow the progression of DKD, they have not been found to halt the disease. In the past decade, sodium glucose co-transporter 2 (SGLT2) inhibitors have been widely researched in the area of cardiovascular disease and diabetes and have been shown to improve cardiovascular outcomes. SGLT2 inhibitors including canagliflozin and dapagliflozin have been shown to slow the progression of kidney disease. There is currently an omission of literature where three SGLT2 inhibitors have been simultaneously compared in a rodent diabetic model. After diabetic Akimba mice were treated with SGLT2 inhibitors for 8 weeks, there was not only a beneficial impact on the pancreas, signified by an increase in the islet mass and increased plasma insulin levels, but also on the kidneys, signified by a reduction in average kidney to body weight ratio and improvement in renal histology. These findings suggest that SGLT2 inhibition promotes improvement in both pancreatic and kidney health.

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

Background and objectives: This study aimed 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. Materials and Methods: A total of 779 subjects were evaluated for kidney function by estimating glomerular filtration rate (eGFR) based on serum creatinine (eGFRcreat) and cystatin C (eGFRcys). Results: The 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). The median of eGFRcys was lower than eGFRcreat (92 mL/min/1.73 m2 vs. 101 mL/min/1.73 m2, p < 0.001). A total of 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. Conclusions: This study showed that cystatin C might be used as an additional biomarker of early kidney injury in young patients with T1D.

Endothelial mineralocorticoid receptor ablation confers protection towards endothelial dysfunction in experimental diabetes in mice.

With diabetes comes a significant risk of macrovascular and microvascular complications. Circulating aldosterone levels increase in patients with diabetes. Aldosterone can directly affect vascular function via activation of the mineralocorticoid receptor (MR). We hypothesized that aldosterone via endothelial MR impairs endothelial function in a murine model of experimental diabetes. Endothelial cell-specific mineralocorticoid receptor knockout MRflox/flox ; Tie2-Cre mice (ECMR-KO) and wild-type FVB littermates were subjected to an experimental type-1 diabetic model by low dose streptozotocin injections (55mg/kg/day) for five consecutive days. After 10weeks of diabetes, second-order mesenteric resistance arteries were perfused ex vivo to evaluate vessel contractility and endothelial function. The effect of ex vivo incubation with aldosterone with and without the antagonist, spironolactone was determined. Diabetic ECMR-KO and wild-type mice had similar, elevated, plasma aldosterone concentration while only diabetic wild-type mice displayed elevated urine albumin excretion and cardiac and kidney hypertrophy at 10weeks. There were no differences in contraction (Emax and EC50 ) to thromboxane receptor agonist (U46619) and elevated K+ between groups. Wild-type diabetic mice showed impaired acetylcholine (ACh)-dependent relaxation, while diabetic ECMR-KO mice had intact ACh-mediated relaxation. Aldosterone incubation ex vivo impaired ACh mediated relaxation and rendered responses similar to diabetic WT arteries. Direct, ex vivo aldosterone effects were absent in ECMR-KO animals. Ex vivo inhibitory effects of aldosterone on endothelial relaxation in arteries from WT were abolished by spironolactone. These findings show that endothelial cell mineralocorticoid receptor activation accounts for diabetes-induced systemic endothelial dysfunction in experimental diabetes and may explain the cardiovascular protection by MR antagonists in diabetes.

1046-P: Automated Early Flagging of Undiagnosed CKD Using Real-World Data

Aims: Early diagnosis and treatment of chronic kidney disease (CKD) may delay disease progression since 45% of patients are not diagnosed until stage 3. We examine the Kidney Disease Improving Global Outcomes (KDIGO) clinical guidelines that define rules based on the longitudinal progression of urine albumin creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) for flagging CKD in people with type 2 diabetes (T2-PwD). Methods: EHR data from over 400,000 T2-PwDs in the Indiana Network for Patient Care (INPC) database were used for this analysis. The KDIGO clinical practice guidelines defines CKD as persistently elevated urine albumin excretion (&amp;gt;=30 mg/g), or persistently reduced eGFR (&amp;lt; 60 ml/min per 1.73m2), or both, for more than 3 months. Our automated system scanned each patient’s longitudinal record and identified those patients with abnormal UACR and eGFR values in the cases where sufficient values were available. A flag associated with either UACR or eGFR or both and the date of flagging is indicated by the system if abnormal marker values persist for more than 3 months. CKD is indicated if one or both flags are triggered. Results: Out of 422,089 patients 35,573 (8%) were identified as diagnosed with CKD. Only 3% of these patients had at least 2 UACR readings and, therefore, the automated system considered primarily eGFR as the marker for flagging CKD. Out of 35,573 patients with CKD diagnosis, 16,342 (46%) had an eGFR warning flag that predated the CKD diagnosis date. The system flagged a potential identification as much as 599 days (median value) in advance of the diagnosis of CKD in the dataset. Conclusion: Our results show that earlier identification of CKD onset can be automated to flag patients wherein a positive diagnosis of CKD is likely. This flag can then prompt a confirmatory diagnosis of CKD, allowing better treatment interventions and management of CKD, reducing the burden of disease, and potentially decreasing costs associated with treatments in later CKD stages. Disclosure D. Malagarriga: None. S. Chittajallu: Employee; Self; Roche Diabetes Care. P. J. Galley: Employee; Self; Roche Diabetes Care. I. Singh: Employee; Self; Roche Diabetes Care. J. T. Odegard: Employee; Self; Roche Diabetes Care.

Interference with TGFβ1-Mediated Inflammation and Fibrosis Underlies Reno-Protective Effects of the CB1 Receptor Neutral Antagonists AM6545 and AM4113 in a Rat Model of Metabolic Syndrome.

The role of cannabinoid receptors in nephropathy is gaining much attention. This study investigated the effects of two neutral CB1 receptor antagonists, AM6545 and AM4113, on nephropathy associated with metabolic syndrome (MetS). MetS was induced in rats by high-fructose high-salt feeding for 12 weeks. AM6545, the peripheral silent antagonist and AM4113, the central neutral antagonist were administered in the last 4 weeks. At the end of study, blood and urine samples were collected for biochemical analyses while the kidneys were excised for histopathological investigation and transforming growth factor beta 1 (TGFβ1) measurement. MetS was associated with deteriorated kidney function as indicated by the elevated proteinuria and albumin excretion rate. Both compounds equally inhibited the elevated proteinuria and albumin excretion rate while having no effect on creatinine clearance and blood pressure. In addition, AM6545 and AM4113 alleviated the observed swelling and inflammatory cells infiltration in different kidney structures. Moreover, AM6545 and AM4113 alleviated the observed histopathological alterations in kidney structure of MetS rats. MetS was associated with a ten-fold increase in urine uric acid while both compounds blocked this increase. Furthermore, AM6545 and AM4113 completely prevented the collagen deposition and the elevated expression of the TGFβ1 seen in MetS animals. In conclusion, AM6545 and AM4113, possess reno-protective effects by interfering with TGFβ1-mediated renal inflammation and fibrosis, via peripheral action.

A higher level of serum furin indicates a higher risk of microalbuminuria: results from a longitudinal study in Chinese adults.

Furin, a key enzyme of natriuretic peptide system, has been suggested to play a role in microalbuminuria, but the association between furin and microalbuminuria has been scarcely studied. Leveraging a longitudinal cohort of Chinese adults who had urinary albumin measured twice 4years apart, we examined the cross-sectional and prospective associations of baseline serum furin with microalbuminuria, adjusting for age, sex, education level, smoking, drinking, obesity, blood pressure, glucose, lipids, and antihypertensive medications. The cross-sectional analysis in 2175 participants (53 ± 10years, 38% men) found that a 10-time higher level of serum furin was significantly associated with a 64% higher risk of having microalbuminuria (OR = 1.64, P = 0.005). The longitudinal analysis found a positive association between baseline serum furin and dynamic elevation of albumin excretion during follow-up. The prospective analysis in 1357 participants free of microalbuminuria at baseline found that a 10-time higher level of serum furin at baseline was significantly associated with a 1.28-time higher risk of developing microalbuminuria 4years later (OR = 2.28, P < 0.001). A higher level of serum furin at baseline predicted an increased risk of developing microalbuminuria in Chinese adults. These findings indicate that furin might be a predictor or a risk factor for microalbuminuria but the causality still needs more investigations.

Elevated copeptin, arterial stiffness, and elevated albumin excretion in adolescents with type 1 diabetes

We sought to evaluate copeptin concentrations in adolescents with and without type 1 diabetes (T1D) and examine the associations between copeptin and measures of arterial stiffness and kidney dysfunction. This analysis included 169 adolescents with T1D (12-19 years of age, 59% girls, mean HbA1c 9.0 ± 1.5% and diabetes duration of 8.6 ± 2.9 years), in addition to 61 controls without T1D. Arterial stiffness including carotid-femoral pulse wave velocity (CF-PWV), carotid-radial PWV (CR-PWV), augmentation index normalized to heart rate of 75 bpm (AIx@HR75), and brachial artery distensibility (BAD). Serum copeptin, urinary albumin-to-creatinine ratio (UACR), and estimated glomerular filtration rate (eGFR) by serum creatinine and cystatin C were also assessed. Compared to controls, adolescents with T1D had higher median (Q1-Q3) copeptin (7.5 [5.2-11.3] vs 6.4 [4.8-8.3] pmol/L, P = .01), mean ± SD eGFR (121 ± 23 vs 112 ± 16 mL/min/1.73m2 , P = .002) and lower BAD (7.1 ± 1.3 vs 7.2 ± 1.2%, P = .02). Adolescents with T1D in the in high tertile copeptin group (>9.1 pmol/L) had higher AIx@HR75 (10.7 ± 1.2 vs 5 ± 1.2, P = .001), CR-PWV (5.30 ± 1.0 vs 5.18 ± 1.0 m/s, P = .04), and UACR (12 ± 1 vs 8 ± 1 mg/g, P = .025) compared to those in low tertile (<5.8 pmol/L) after adjusting for age, sex, and eGFR. Copeptin inversely associated with CF-PWV independent of age, sex, eGFR, SBP, and HbA1c in T1D adolescents. Our data demonstrate that elevated copeptin was associated with worse arterial stiffness in adolescents with T1D. These findings suggest that copeptin could improve CVD risk stratification in adolescents with T1D.

Risk Factors for Retinopathy in Type 1 Diabetes: The DCCT/EDIC Study.

The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive therapy reduced the development and progression of retinopathy in type 1 diabetes (T1D) compared with conventional therapy. The Epidemiology of Diabetes Interventions and Complications (EDIC) study observational follow-up showed persistent benefits. In addition to glycemia, we now examine other potential retinopathy risk factors (modifiable and nonmodifiable) over more than 30 years of follow-up in DCCT/EDIC. The retinopathy outcomes were proliferative diabetic retinopathy (PDR), clinically significant macular edema (CSME), and ocular surgery. The survival (event-free) probability was estimated using the Kaplan-Meier method. Cox proportional hazards models assessed the association between risk factors and subsequent risk of retinopathy. Both forward- and backward-selection approaches determined the multivariable models. Rate of ocular events per 1,000 person-years was 12 for PDR, 14.5 for CSME, and 7.6 for ocular surgeries. Approximately 65%, 60%, and 70% of participants remained free of PDR, CSME, and ocular surgery, respectively. The greatest risk factors for PDR in descending order were higher mean HbA1c, longer duration of T1D, elevated albumin excretion rate (AER), and higher mean diastolic blood pressure (DBP). For CSME, risk factors, in descending order, were higher mean HbA1c, longer duration of T1D, and greater age and DBP and, for ocular surgeries, were higher mean HbA1c, older age, and longer duration of T1D. Mean HbA1c was the strongest risk factor for the progression of retinopathy. Although glycemic control is important, elevated AER and DBP were other modifiable risk factors associated with the progression of retinopathy.

Serum Uromodulin Predicts Less Coronary Artery Calcification and Diabetic Kidney Disease Over 12 Years in Adults With Type 1 Diabetes: The CACTI Study.

Novel biomarkers are needed to better predict coronary artery calcification (CAC), a marker of subclinical atherosclerosis, and diabetic kidney disease (DKD) in type 1 diabetes. We evaluated the associations between serum uromodulin (SUMOD [a biomarker associated with anti-inflammatory and renal protective properties]), CAC progression, and DKD development over 12 years. Participants (n = 527, 53% females) in the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study were examined during 2002-2004, at a mean age of 39.6 ± 9.0 years and a median duration of diabetes of 24.8 years. Urine albumin-to-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR) determined by the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) creatinine equation were measured at baseline and after a mean follow-up period of 12.1 ± 1.5 years. Elevated albumin excretion was defined as ACR ≥30 mg/g, rapid GFR decline (>3 mL/min/1.73 m2/year), and impaired GFR as eGFR <60 mL/min/1.73 m2. SUMOD was measured on stored baseline plasma samples (Meso Scale Discovery). CAC was measured using electron beam computed tomography. CAC progression was defined as a change in the square root-transformed CAC volume of ≥2.5. Higher baseline SUMOD level conferred lower odds of CAC progression (odds ratio 0.68; 95% CI 0.48-0.97), incident elevated albumin excretion (0.37; 0.16-0.86), rapid GFR decline (0.56; 0.35-0.91), and impaired GFR (0.44; 0.24-0.83) per 1 SD increase in SUMOD (68.44 ng/mL) after adjustment for baseline age, sex, systolic blood pressure, LDL cholesterol, and albuminuria/GFR. The addition of SUMOD to models with traditional risk factors also significantly improved the prediction performance for CAC progression and incident DKD. Higher baseline SUMOD level predicted lower odds of both CAC progression and incident DKD over 12 years in adults with type 1 diabetes.

Vitamin D and omega-3 trial to prevent and treat diabetic kidney disease: Rationale, design, and baseline characteristics

Diabetic kidney disease (DKD), defined as reduced glomerular filtration rate (GFR), elevated urine albumin excretion, or both that is clinically attributable to diabetes, is a common and morbid diabetes complication. Animal-experimental data, observational human studies, and short-term clinical trials suggest that vitamin D and omega-3 fatty acid supplements may be safe and inexpensive interventions to reduce the incidence and progression of DKD. The Vitamin D and Omega-3 Trial to Prevent and Treat DKD (VITAL-DKD) was designed as an ancillary study to the VITAL trial of 25,871 US adults. In a 2 × 2 factorial design, VITAL participants were randomly assigned to vitamin D3 (cholecalciferol, 2000 IU daily) or placebo and to marine omega-3 fatty acids (eicospentaenoic acid and docosahexaenoic acid, 1 g/d) or placebo. VITAL-DKD enrolled a subset of 1326 VITAL participants with type 2 diabetes at baseline to test the effects of vitamin D and omega-3 fatty acids on changes in estimated GFR and urine albumin excretion. Over five years of follow-up, VITAL-DKD collected blood and urine samples to quantify changes in estimated GFR (the primary study outcome) and urine albumin excretion. At baseline, mean age of VITAL-DKD participants was 67.6 years, 46% were women, 30% were of racial or ethnic minority, and the prevalence of DKD (estimated GFR <60 mL/min/1.73m2 or urine albumin-creatinine ratio ≥ 30 mg/g) was 17%. In this type 2 diabetes population, VITAL-DKD will test the hypotheses that vitamin D and omega-3 fatty acids help prevent the development and progression of DKD.

Febrile Proteinuria in Hospitalized Children: Characterization of Urinary Proteins.

Background: Transient proteinuria during febrile illness is a common phenomenon. Recent studies have re-examined the pathophysiology of proteinuria and new urinary markers to characterize it, including B7-1 (CD80), which is expressed also in glomerular podocytes and influences the glomerular barrier.Aim: To investigate the pattern of proteinuria in febrile non-renal diseases, including B7-1.Methods: We prospectively analyzed urine samples of 44 febrile children and 28 afebrile controls for different protein components: albumin (glomerular marker), β2-microglobulin (tubular marker), uromodulin (Tamm Horsfall protein-THP, a renal endogenous protein) and B7-1. Febrile illness was characterized as focal bacterial vs. viral. Exclusion criteria were underlying renal disease, steroid treatment or urinary tract infection.Results: Elevated urine albumin (64.5 ± 10.3 vs. 17.8 ± 4 mg/g, mean ± S.E.M., p = 0.0009) and β2-microglobulin (1.44 ± 0.34 vs. 0.182 ± 0.03 mg/g, mean ± S.E.M., p = 0.005] and decreased uromodulin (10.5 ± 1 vs. 26.7 ± 2.2 Arbitrary units, mean ± S.E.M., p = 0.0001) excretion were found during febrile illness vs. controls. Urine B7-1 was also increased in the febrile group (0.27 ± 0.05 vs. 0.07 ± 0.01 ng/ml, mean ± S.E.M., p = 0.001), and was the only marker which was significantly higher in bacterial vs. viral disease.Conclusions: Febrile proteinuria is not generalized: while proteins of both glomerular and tubular origin increase, uromodulin decreases. Urine B7-1 is increased during fever, more significantly in bacterial infections. Thus, urinary B7-1 may be used as an additional marker to differentiate between febrile states of bacterial vs. viral origin.

Serum Uric Acid (SUA), Urinary Albumin Excretion (UAE), and Hypertension (HTN) in Adolescents with Type 2 Diabetes (T2D) in the TODAY Study

Elevated SUA is increasingly recognized as a risk factor for kidney disease in adults with diabetes, yet there are limited data in youth. We hypothesized that elevated SUA would predict development of elevated UAE and HTN over time in teens with T2D. Serum creatinine, cystatin C, SUA, and urine albumin to creatinine ratio (ACR) were assessed in 539 youth, ages 12-17 with T2D duration &amp;lt;2 years at baseline in the TODAY study. Estimated GFR (eGFR) was calculated using creatinine and cystatin C. HTN was defined as systolic (SBP) or diastolic blood pressure (DBP) ≥130/80 mm Hg and elevated albumin excretion (UAE) as ACR ≥30mg/g. Mean arterial pressure (MAP) was calculated ([SBP + 2 (DBP)]/3). Generalized estimating equations and Cox proportional hazard models evaluated the relationship between SUA and outcome variables longitudinally over 7 years, adjusting for age, sex, race/ethnicity, BMI, A1c, eGFR, ACEi/ARB use, and TODAY treatment group assignment. Hyperuricemia (≥6.8 mg/dL) was present in 25.6%, HTN in 18.7%, and elevated UAE in 6.1% at baseline, and boys had higher baseline SUA than girls (6.7±1.4 vs. 5.4±1.2 mg/dl, p&amp;lt;0.0001). Over 7 years, 37.4% developed HTN and 18.0% elevated UAE. Baseline SUA correlated with increase in SBP (β±SE: 0.66±0.16, p&amp;lt;.0001), DBP (0.37±0.15, p=0.01), MAP (0.47±0.14, p=0.001), and log UAE (0.05±0.02, p=0.01) over time in multivariable models. Higher baseline SUA increased risk of incident HTN (HR: 1.20, 95% CI 1.05-1.36, p=0.007, per 1 mg/dL increase in SUA) and incident elevated UAE (HR: 1.23, 95% CI 1.03-1.47, p=0.02, per 1 mg/dL increase in SUA) in fully adjusted models. Hyperuricemia was common in youth with T2D; higher baseline SUA independently increased risk for onset of HTN and elevated UAE over 7 years. Therapies lowering SUA may hold promise to impede development of diabetic kidney disease and HTN in T2D youth. Disclosure P. Bjornstad: Consultant; Self; Boehringer Ingelheim GmbH. L.M. Laffel: Consultant; Self; Eli Lilly and Company, Novo Nordisk Inc., Sanofi US, MannKind Corporation, Roche Diagnostics Corporation, Dexcom, Inc., Insulet Corporation, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Johnson &amp; Johnson Diabetes Institute, LLC. J.L. Lynch: Other Relationship; Self; Novo Nordisk Inc.. Research Support; Self; Daiichi Sankyo Company, Limited. L. El Ghormli: None. R.S. Weinstock: Research Support; Self; Medtronic MiniMed, Inc., Mylan, Kowa Pharmaceuticals America, Inc., Diasome Pharmaceuticals, Inc., Calibra Medical, Dexcom, Inc., Ultradian Diagnostics LLC., JAEB Center For Health Research, JDRF, National Institute of Diabetes and Digestive and Kidney Diseases. S.E. Tollefsen: None. K.J. Nadeau: None.

Role of Kidney Biopsies for Biomarker Discovery in Diabetic Kidney Disease.

Although estimated glomerular filtration rate and albuminuria are well-established biomarkers of diabetic kidney disease (DKD), additional biomarkers are needed, especially for the early stages of the disease when both albuminuria and estimated glomerular filtration rate may still be in the normal range and are less helpful for identifying those at risk of progression. Traditional biomarker studies for early DKD are challenging because of a lack of good early clinical end points, and most rely on changes in existing imprecise biomarkers to assess the value of new biomarkers. There are well-characterized changes in kidney structure, however, that are highly correlated with kidney function, always precede the clinical findings of DKD and, at preclinical stages, predict DKD progression. These structural parameters may thus serve as clinically useful end points for identifying new biomarkers of early DKD. In addition, investigators are analyzing tissue transcriptomic data to identify pathways involved in early DKD which may have associated candidate biomarkers measurable in blood or urine, and differentially expressed microRNAs and epigenetic modifications in kidney tissue are beginning to yield important observations which may be useful in identifying new clinically useful biomarkers. This review examines the emerging literature on the use of kidney tissue in biomarker discovery in DKD.

Tight metabolic control plus ACE inhibitor therapy improves GSD I nephropathy.

The onset of microalbuminuria (MA) heralds the onset of glomerulopathy in patients with glycogen storage disease (GSD) type I. Unlike tubulopathy, which responds to improved metabolic control, glomerulopathy in GSD I is considered refractory to medical intervention, and it is thought to inexorably progress to overt proteinuria and renal failure. Recent reports of reduced microalbuminuria following strict adherence to therapy counter this view. In contrast to type Ia, little is known regarding the prevalence of kidney disease in GSD Ib, 0, III, VI, and IX. Subjects were evaluated with 24-h urine collections between 2005 and 2014 as part of a longitudinal study of the natural history of GSD. ACE inhibitor therapy (AIT) was commenced after documentation of microalbuminuria. Elevated urine albumin excretion was detected in 23 of 195 GSD Ia patients (11.7%) and six of 45 GSD Ib (13.3%). The median age of onset of microalbuminuria in GSD Ia was 24years (range 9-56); in GSD Ib it was 25years (range 20-38). Of 14 with GSD Ia who complied with dietary and AIT during the study period, microalbuminuria decreased in 11, in whom metabolic control improved. All 135 patients with the ketotic forms of GSD (0, III, VI and IX) consistently had normal microalbumin excretion. Strict adherence to dietary therapy and maintenance of optimal metabolic control is necessary to halt the progression of GSD Ia glomerulopathy in patients treated with AIT. With optimal care, protein excretion can be reduced and even normalize.

ABCC8-Related Maturity-Onset Diabetes of the Young (MODY12): Clinical Features and Treatment Perspective.

Maturity-onset diabetes of the young (MODY) is a heterogeneous group of diseases associated with gene mutations leading to dysfunction of pancreatic β-cells. Thirteen identified MODY variants differ from each other by the clinical course and treatment requirement. Currently, MODY subtypes 1–5 are best-studied, descriptions of the other forms are sporadic. This article reports a MODY12 clinical case, caused by a mutation in the gene of the ATP-binding cassette transporter sub-family C member 8 (ABCC8), encoding sulfonylurea receptor 1. Diabetes manifested in a 27-year-old non-obese man with epilepsy in anamnesis. No evidence of ketosis was present, pancreatic antibodies were undetectable, and C-peptide remained within the reference range. During the initial investigation, non-proliferative diabetic retinopathy and elevated albumin excretion rate was revealed. After 4 months, diabetes was complicated by pre-proliferative retinopathy and diabetic macular edema. Recurrent hypoglycemia and an increase in body weight was observed on moderate and even small insulin doses. Taking into account the clinical features and the presence of diabetes in four generations on the maternal side, screening for all MODY subtypes was performed. A mutation in the ABCC8 gene was found in proband and in his mother. After the insulin discontinuation, gliclazide modified release combined with sodium/glucose cotransporter 2 (SGLT2) inhibitors was started. This treatment eliminated hypoglycemia and improved glycemic variability parameters. A decrease in the amplitude of glucose excursions was documented by continuous glucose monitoring. After 3 months of treatment, glycemic control was still optimal, and no hypoglycemic episodes were observed. The case report demonstrates the clinical features of ABCC8-associated MODY and the therapeutic potential of a combination of sulfonylurea with SGLT2 inhibitor in this disease.Electronic supplementary materialThe online version of this article (doi:10.1007/s13300-016-0192-9) contains supplementary material, which is available to authorized users.

Quantification of albumin in urine using preconcentration and near-infrared diffuse reflectance spectroscopy

Urinary albumin is an important diagnostic and prognostic marker for cardiorenal disease. Recent studies have shown that elevation of albumin excretion even in normal concentration range is associated with increased cardiorenal risk. Therefore, accurate measurement of urinary albumin in normal concentration range is necessary for clinical diagnosis. In this work, thiourea-functionalized silica nanoparticles are prepared and used for preconcentration of albumin in urine. The adsorbent with the analyte was then used for near-infrared diffuse reflectance spectroscopy measurement directly and partial least squares model was established for quantitative prediction. Forty samples were taken as calibration set for establishing PLS model and 17 samples were used for validation of the method. The correlation coefficient and the root mean squared error of cross validation is 0.9986 and 0.43, respectively. Residual predictive deviation value of the model is as high as 18.8. The recoveries of the 17 validation samples in the concentration range of 3.39–24.39mg/L are between 95.9%–113.1%. Therefore, the method may provide a candidate method to quantify albumin excretion in urine.

Diabetic peripheral neuropathy may not be as its name suggests: evidence from magnetic resonance imaging.

Diabetic peripheral neuropathy (DPN) affects up to 50% of patients with diabetes and is a major cause of morbidity and increased mortality. Its clinical manifestations include distressing painful neuropathic symptoms and insensitivity to trauma that result in foot ulcerations and amputations. Several recent studies have implicated poor glycemic control, duration of diabetes, hyperlipidemia (particularly hypertryglyceridaemia), elevated albumin excretion rates, and obesity as risk factors for the development of DPN. However, similar data are not available for painful DPN. Moreover, although there is now strong evidence for the importance of peripheral nerve microvascular disease in the pathogenesis of DPN, peripheral structural biomarkers of painful DPN are lacking. However, there is now emerging evidence for the involvement of the central nervous system in both painful and painless DPN afforded by magnetic resonance imaging. This review will focus on this emerging evidence for central changes in DPN, hitherto considered a peripheral nerve disease only.

Diabetic kidney disease: difference in the prevalence and risk factors worldwide

Diabetic nephropathy, which is defined as elevated urine albumin excretion or reduced glomerular filtration rate or both, is a serious complication that occurs in 20–40% of all diabetic patients. In this review, we try to highlight the prevalence of diabetic nephropathy, which is not an uncommon complication of diabetes all over the world. The prevalence of diabetes worldwide has extended epidemic magnitudes and is expected to affect more than 350 million people by the year 2035. There is marked racial/ethnic difference besides international difference in the epidemiology of diabetic nephropathy, which could be attributed to the differences in economic viability and governmental infrastructures. Approximately one-third of diabetic patients showed microalbuminuria after 15 years of disease duration and less than half develop real nephropathy. Diabetic nephropathy is more frequent in African-Americans, Asian-Americans, and Native Americans. Progressive kidney disease is more frequent in Caucasian patients with type 1 than in those with type 2 diabetes mellitus (DM), although its overall prevalence in the diabetic population is higher in patients with type 2 DM because this type of DM is more prevalent. Hyperglycemia is a well-known risk factor for diabetic kidney disease, in addition to other risk factors such as male sex, obesity, hypertension, chronic inflammation, resistance to insulin, hypovitaminosis D, dyslipidemia, and some genetic loci and polymorphisms in specific genes. Diabetic nephropathy is not an uncommon complication of diabetes (type 1 and 2) all over the world and in geriatric population. Management of its modifiable risk factors might help in reducing its incidence in the nearby future.