Early Stages Of Diabetic Kidney Disease Research Articles

#781 Cerebral vessels and early diabetic kidney disease in type 2 diabetes mellitus patients share a common mitochondrial DNA and inflammatory profile

Abstract Background and Aims Cerebrovascular disease accounts for major motor and cognitive disabilities in patients with type 2 diabetes mellitus (DM). Among the multiple pathogenic pathways which involve both the kidney and the brain vasculature, inflammation and mitochondrial dysfunction are of major importance. The aim of the study was to evaluate the association of mitochondrial DNA (mtDNA) modifications in blood and urine and of inflammatory markers with cerebral vessels structural and functional modifications in patients with type 2 DM and early diabetic kidney disease (DKD). Method A cohort of 150 patients (52 patients with normoalbuminuria, 48 patients with microalbuminuria, and 50 patients with macroalbuminuria) and 30 age- and gender-matched healthy controls were enrolled in this case series study. All patients were assessed concerning urinary albumin/creatinine ratio (UACR), biomarkers of podocyte damage (synaptopodin, podocalyxin) and of proximal tubule dysfunction (kidney injury molecule-1-KIM-1, N-acetyl-β-(D)-glucosaminidase-NAG), serum and urinary pro-inflammatory interleukins IL-17A, IL-18, tumor necrosis factor alpha (TNFα), intercellular adhesion molecule-1 (ICAM-1), anti-inflammatory IL-10, and eGFR (creatinine-cystatin C). MtDNA-CN and nuclear DNA (nDNA) were quantified in peripheral blood and urine by qRT-PCR (ABI 7900-HT–Applied BioSystem). TaqMan assays were utilized for the assessment of cytochrome b (CYTB) gene, subunit 2 of NADH dehydrogenase (ND2), and of beta 2 microglobulin nuclear gene (B2M). mtDNA-CN was defined as the ratio of the number of mtDNA/nDNA copies, through analysis of the CYTB/B2M and ND2/B2M ratio. The cerebrovascular hemodynamic indices were evaluated by an ultrasound equipment with high resolution (MYLAB 8-ESAOTE Italy) equipped with a Colour Ultrasound System. Subclinical atherosclerosis and arteriosclerosis were assessed by intima-media thickness (IMT) in the common carotid arteries (CCAs), Gosling's pulsatility index (PI) and Pourcellot's resistivity index (RI) in the internal carotid arteries (ICAs) and middle cerebral arteries (MCAs), bilaterally. Cerebrovascular reactivity (CVR), which represents the vasodilatory reactivity of cerebral vessels in response to a vasodilatory stimulus, was assessed by the breath-holding test where hypercapnia was the vasodilatory stimulus and the breath-holding index (BHI) was calculated. Results Multivariable linear analysis revealed direct correlations of serum TNFα with UACR, KIM-1, NAG, and urinary mtDNA, and a negative correlation with serum mtDNA (R2 = 0.893; p < 0.0001); urinary TNFα correlated directly with UACR, KIM-1, NAG, and urinary mtDNA (R2 = 0.693; p < 0.0001). Serum ICAM-1 had a direct correlation with UACR, KIM-1, NAG, synaptopodin, and podocalyxin, and a negative one with serum mtDNA (R2 = 0.855; p < 0.0001). Urinary ICAM-1 correlated directly with UACR, KIM-1, NAG, and urinary mtDNA, and indirectly with eGFR (R2 = 0.783; p < 0.0001). CCA-IMT had a direct correlation with serum IL-17A and indirect correlations with serum mtDNA and serum IL-10 (R2 = 0.706; p < 0.0001); ICA-PIs and MCA-PIs correlated directly with serum IL-17A and negatively with serum IL-10, respectively (R2 = 0.567; R2 = 0.642; p < 0.0001). ICA-RIs showed a direct correlation with UACR, serum and urinary IL-17A, serum and urinary IL-18, NAG, and urinary TNFα, and a negative correlation with serum mtDNA and with serum and urinary IL-10 (R2 = 0.930; p < 0.0001). MCA-RIs correlated directly with UACR, serum IL-17A, serum IL-18, NAG, urinary mtDNA, and urinary TNFα, and negatively with serum mtDNA and serum IL-10 (R2 = 0.875; p < 0.0001). BHI correlated directly with serum IL-10 and serum mtDNA, and negatively with serum IL-17A, serum ICAM-1, and NAG (R2 = 0.823; p < 0.0001). Conclusion In neurologically asymptomatic type 2 DM patients there is an association of mtDNA changes in blood and urine with cerebral vessels atherosclerotic and arteriosclerotic remodeling, as well as with decreased CVR. MtDNA modifications may exert their effect in parallel with markers of inflammation at both kidney and cerebrovascular level from the early stages of DKD.

Complement Cascade Proteins Correlate with Fibrosis and Inflammation in Early-Stage Type 1 Diabetic Kidney Disease in the Ins2Akita Mouse Model.

Diabetic kidney disease (DKD) is characterized by histological changes including fibrosis and inflammation. Evidence supports that DKD is mediated by the innate immune system and more specifically by the complement system. Using Ins2Akita T1D diabetic mice, we studied the connection between the complement cascade, inflammation, and fibrosis in early DKD. Data were extracted from a previously published quantitative-mass-spectrometry-based proteomics analysis of kidney glomeruli of 2 (early DKD) and 4 months (moderately advanced DKD)-old Ins2Akita mice and their controls A Spearman rho correlation analysis of complement- versus inflammation- and fibrosis-related protein expression was performed. A cross-omics validation of the correlation analyses' results was performed using public-domain transcriptomics datasets (Nephroseq). Tissue sections from 43 patients with DKD were analyzed using immunofluorescence. Among the differentially expressed proteins, the complement cascade proteins C3, C4B, and IGHM were significantly increased in both early and later stages of DKD. Inflammation-related proteins were mainly upregulated in early DKD, and fibrotic proteins were induced in moderately advanced stages of DKD. The abundance of complement proteins with fibrosis- and inflammation-related proteins was mostly positively correlated in early stages of DKD. This was confirmed in seven additional human and mouse transcriptomics DKD datasets. Moreover, C3 and IGHM mRNA levels were found to be negatively correlated with the estimated glomerular filtration rate (range for C3 rs = -0.58 to -0.842 and range for IGHM rs = -0.6 to -0.74) in these datasets. Immunohistology of human kidney biopsies revealed that C3, C1q, and IGM proteins were induced in patients with DKD and were correlated with fibrosis and inflammation. Our study shows for the first time the potential activation of the complement cascade associated with inflammation-mediated kidney fibrosis in the Ins2Akita T1D mouse model. Our findings could provide new perspectives for the treatment of early DKD as well as support the use of Ins2Akita T1D in pre-clinical studies.

Discovery of PRDM16-Mediated TRPA1 Induction as the Mechanism for Low Tubulo-Interstitial Fibrosis in Diabetic Kidney Disease.

The pathogenesis of Diabetic kidney disease(DKD) involves pathological changes in both tubulo-interstitium and the glomerulus. Surprisingly, tubulo-interstitial fibrosis (TIF), does not develop significantly until the late stage of DKD. Here, it is demonstrated that PR domain-containing 16 (PRDM16) is a key to the low level of TIF in DKD. In the experiments, PRDM16 is upregulated in high glucose-treated renal tubular cells, DKD mouse kidneys, and renal biopsy of human DKD patients via activation of NF-κB signal pathway. High glucose-induced expression of fibrotic proteins in renal tubular cells is suppressed by PRDM16. Mechanistically, PRDM16 bound to the promotor region of Transient receptor potential ankyrin 1 (TRPA1) to transactivate its expression and then suppressed MAPK (P38, ERK1/2) activation and downstream expression of TGF-β1. Knockout of PRDM16 from kidney proximal tubules in mice blocked TRPA1 expression and enhanced MAPK activation, TGF-β1 production, TIF development, and DKD progression, whereas knock-in of PRDM16 has opposite effects. In addition, overexpression of PRDM16 or its induction by formononetin ameliorated renal dysfunction and fibrosis in db/db diabetic mice. Finally, the above finding are detected in renal biopsies of DKD patients. Together, these results unveil PRDM16/TRPA1 as the mechanism responsible for the low level of TIF in the early stage of DKD by suppressing and TGF-β1 expression.

Elevated plasma myoglobin level is closely associated with type 2 diabetic kidney disease.

Diabetic kidney disease (DKD) is the most frequent complication in patients with type 2 diabetes mellitus (T2DM). It causes a chronic and progressive decline in kidney function, and ultimately patients require renal replacement therapy. To date, an increasing number of clinical studies have been conducted to explore the potential and novel biomarkers, which can advance the diagnosis, estimate the prognosis, and optimize the therapeutic strategies at the early stage of DKD. In the current study, we sought to investigate the association of plasma myoglobin with DKD. A total of 355 T2DM patients with DKD and 710 T2DM patients without DKD were enrolled in this study. Laboratory parameters including blood cell count, hemoglobin A1c, biochemical parameters, and plasma myoglobin were recorded. Patients were classified on admission according to the tertile of myoglobin and clinical parameters were compared between the groups. Pearson correlation analysis, linear regression, logistic regression, receiver operating characteristics (ROC) analysis, and spline regression were performed. Plasma myoglobin significantly increased in patients with DKD and was associated with renal function and inflammatory parameters. Plasma myoglobin was an independent risk factor for the development of DKD. The area under ROC curve of myoglobin was 0.831. Spline regression showed that there was a significant linear association between DKD incidence and a high level of plasma myoglobin when it exceeded 36.4 mg/mL. This study shows that elevated plasma myoglobin level is closely associated with the development of kidney injury in patients with T2DM.

Better Detection of Peripheral Arterial Disease with Toe-Brachial Index Compared to Ankle-Brachial Index among Taiwanese Patients with Diabetic Kidney Disease

Background: Ankle-brachial index (ABI) is a simple method for diagnosing peripheral artery disease (PAD) but has limited reliability in patients with diabetes mellitus (DM) because of medial artery calcification. Our study aims to investigate whether the toe brachial index (TBI) or the cardio-ankle vascular index (CAVI) has a better detection over the ABI for diagnosing PAD in diabetic kidney disease (DKD). Materials and Methods: A cohort of 368 patients (mean age 68.59 ± 13.14 years, 190 males and 178 females) with type 2 DM underwent ABI, TBI, and CAVI measurements at our outpatient clinic. Results: Of all enrolled patients, the TBI is significant in evaluating PAD, especially in patients whose chronic kidney disease (CKD) stage 3a with adjusted odds ratio (AOR) = 6.50, 95% confidence interval (CI) 1.63–25.97, p = 0.0080, stage 3b AOR = 7.47, 95% CI 1.52–36.81, p = 0.0135, and stage 4–5 AOR = 20.13, 95% CI 1.34–94.24, p = 0.0116. CAVI is also significant in CKD stage 1 with AOR = 0.16, 95% CI 0.03–0.77, p = 0.0223, stage 2 with AOR = 0.18, 95% CI 0.04–0.74, p = 0.0180, and stage 3a AOR = 0.31, 95% CI 0.10–0.93, p = 0.0375. Conclusion: TBI has a better yield of detection of PAD compared to ABI among Taiwanese patients with DKD. CAVI may play a role in the early stage of DKD.

Diagnostic challenges of diabetic kidney disease.

Diabetic kidney disease (DKD) is one of the most common microvascular complications of both type 1 and type 2 diabetes and the most common cause of the end-stage renal disease (ESRD). It has been evidenced that targeted interventions at an early stage of DKD can efficiently prevent or delay the progression of kidney failure and improve patient outcomes. Therefore, regular screening for DKD has become one of the fundamental principles of diabetes care. Long-established biomarkers such as serum-creatinine-based estimates of glomerular filtration rate and albuminuria are currently the cornerstone of diagnosis and risk stratification in routine clinical practice. However, their immanent biological limitations and analytical variations may influence the clinical interpretation of the results. Recently proposed new predictive equations without the variable of race, together with the evidence on better accuracy of combined serum creatinine and cystatin C equations, and both race- and sex-free cystatin C-based equation, have enabled an improvement in the detection of DKD, but also require the harmonization of the recommended laboratory tests, wider availability of cystatin C testing and specific approach in various populations. Considering the complex pathophysiology of DKD, particularly in type 2 diabetes, a panel of biomarkers is needed to classify patients in terms of the rate of disease progression and/or response to specific interventions. With a personalized approach to diagnosis and treatment, in the future, it will be possible to respond to DKD better and enable improved outcomes for numerous patients worldwide.

Active role of amino acid metabolism in early diagnosis and treatment of diabetic kidney disease.

Diabetic Kidney Disease (DKD) is one of the significant microvascular consequences of type 2 diabetes mellitus with a complex etiology and protracted course. In the early stages of DKD, the majority of patients experience an insidious onset and few overt clinical symptoms and indicators, but they are prone to develop end-stage renal disease in the later stage, which is life-threatening. The abnormal amino acid metabolism is tightly associated with the development of DKD, which involves several pathological processes such as oxidative stress, inflammatory response, and immune response and is also closely related to autophagy, mitochondrial dysfunction, and iron death. With a focus on taurine, branched-chain amino acids (BCAAs) and glutamine, we explored the biological effects of various amino acid mechanisms linked to DKD, the impact of amino acid metabolism in the early diagnosis of DKD, and the role of amino acid metabolism in treating DKD, to offer fresh objectives and guidelines for later early detection and DKD therapy.

The UDPase ENTPD5 regulates ER stress-associated renal injury by mediating protein N-glycosylation

Impaired protein N-glycosylation leads to the endoplasmic reticulum (ER) stress, which triggers adaptive survival or maladaptive apoptosis in renal tubules in diabetic kidney disease (DKD). Therapeutic strategies targeting ER stress are promising for the treatment of DKD. Here, we report a previously unappreciated role played by ENTPD5 in alleviating renal injury by mediating ER stress. We found that ENTPD5 was highly expressed in normal renal tubules; however, ENTPD5 was dynamically expressed in the kidney and closely related to pathological DKD progression in both human patients and mouse models. Overexpression of ENTPD5 relieved ER stress in renal tubular cells, leading to compensatory cell proliferation that resulted in hypertrophy, while ENTPD5 knockdown aggravated ER stress to induce cell apoptosis, leading to renal tubular atrophy and interstitial fibrosis. Mechanistically, ENTPD5-regulated N-glycosylation of proteins in the ER to promote cell proliferation in the early stage of DKD, and continuous hyperglycemia activated the hexosamine biosynthesis pathway (HBP) to increase the level of UDP-GlcNAc, which driving a feedback mechanism that inhibited transcription factor SP1 activity to downregulate ENTPD5 expression in the late stage of DKD. This study was the first to demonstrate that ENTPD5 regulated renal tubule cell numbers through adaptive proliferation or apoptosis in the kidney by modulating the protein N-glycosylation rate in the ER, suggesting that ENTPD5 drives cell fate in response to metabolic stress and is a potential therapeutic target for renal diseases.

Pharmacological Targeting of Mitochondria in Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD) in the United States and many other countries. DKD occurs through a variety of pathogenic processes that are in part driven by hyperglycemia and glomerular hypertension, leading to gradual loss of kidney function and eventually progressing to ESRD. In type 2 diabetes, chronic hyperglycemia and glomerular hyperfiltration leads to glomerular and proximal tubular dysfunction. Simultaneously, mitochondrial dysfunction occurs in the early stages of hyperglycemia and has been identified as a key event in the development of DKD. Clinical management for DKD relies primarily on blood pressure and glycemic control through the use of numerous therapeutics that slow disease progression. Because mitochondrial function is key for renal health over time, therapeutics that improve mitochondrial function could be of value in different renal diseases. Increasing evidence supports the idea that targeting aspects of mitochondrial dysfunction, such as mitochondrial biogenesis and dynamics, restores mitochondrial function and improves renal function in DKD. We will review mitochondrial function in DKD and the effects of current and experimental therapeutics on mitochondrial biogenesis and homeostasis in DKD over time. SIGNIFICANCE STATEMENT: Diabetic kidney disease (DKD) affects 20% to 40% of patients with diabetes and has limited treatment options. Mitochondrial dysfunction has been identified as a key event in the progression of DKD, and pharmacologically restoring mitochondrial function in the early stages of DKD may be a potential therapeutic strategy in preventing disease progression.

Calcium dobesilate efficiency in the treatment of diabetic kidney disease through suppressing MAPK and chemokine signaling pathways based on clinical evaluation and network pharmacology.

Aims: To evaluate the effectiveness and potential mechanism of calcium dobesilate (CaD) in diabetic kidney disease (DKD) patients. Methods: We searched for available randomized controlled studies on DKD patients’ treatment with CaD through open databases. Continuous variables were expressed as standardized mean difference (SMD) with a 95% confidence interval (CI). The putative targets and possible pathways of CaD on DKD were analyzed by network pharmacology. Molecular docking was employed to verify the match between CaD and the target genes. Results: In the meta-analysis, 42 trials were included, involving 3,671 DKD patients, of which 1,839 received CaD treatment in addition to conventional treatment, while 1,832 received conventional treatment. Compared with routine therapy, the levels of serum creatinine (Scr) and blood urea nitrogen (BUN) significantly decreased in the CaD treatment (early stage of DKD, Scr: p < 0.00001; BUN: p < 0.0001; clinical stage of DKD, Scr: p < 0.00001; BUN: p < 0.00001; kidney failure stage, Scr: p = 0.001; BUN: p = 0.004). The levels of serum cystatin C (Cys-C), urine levels of molecules reflecting kidney function (urinary albumin excretion rate (UAER) and micro glycoprotein), and inflammatory factors [hypersensitive c-reactive protein (hs-CRP)] were reduced compared with control groups, while glomerular filtration rate (GFR) was increased in patients treated with CaD for 12 weeks. CaD also showed a better effect on improving endothelial function. Network pharmacology results showed that the interaction pathway between CaD and DKD was mainly enriched in MAPK and chemokine signaling pathways. AKT1, CASP3, IGF1, MAPK8, and CCL5 might be the key targets for CaD in treating DKD. Conclusion: Combination with CaD is effective and safe in patients with DKD. Inhibition of MAPK and chemokine signaling pathways might be vital in treating CaD in DKD patients.

FC 126: Association Between Circulating Levels of 25-Hydroxyvitamin D and Metalloproteinase-10 (MMP 10) in Patients With Type 2 Diabetes Mellitus. Cross-Sectional Study

Abstract BACKGROUND AND AIMS Matrix metalloproteinases (MMP) play an important role in diabetic kidney disease (DKD) (1). MMP-10 levels have been shown to increase progressively starting from the early stages of DKD (2). Vitamin D (vitD) deficit is associated with a higher risk of microangiopathy in diabetes. In humans, vitD status correlates inversely with MMP-9 circulating levels and VitD supplementation is associated with a decrease in these levels (3). In vitro, studies demonstrated reduced expression of MMP-10 after an exposure to vitD (4). However, no studies have yet assessed how vitD status is related to MMP-10 circulating levels. We aimed (1) to evaluate the association between the serum levels of 25-hydroxyvitamin D [25(OH)D3] and MMP-10 in a cohort of type 2 diabetes (T2D) patients and (2) to study a potential effect of chronic kidney disease (CKD) stage or estimated glomerular filtration rate (eGFRcr) on this association. METHOD The cross-sectional association between MMP-10 and 25(OH)D3 levels (&amp;gt;30 ng/mL, normal; 20–30 ng/mL, insufficiency; &amp;lt;20 ng/mL, deficiency; and relevant cut-offs 45 and 15 ng/mL) was investigated, by multivariate linear regression analysis after MMP-10 logarithm transformation, in 256 T2D patients recruited (2009–2016) in the Clinica Universidad de Navarra (Spain). Study protocol was approved by the Ethical Committee (2021.183TFG). Covariates were smoking habit, body adiposity percentage estimated by CUN-BAE formula, CKD stage and vitD3 supplement use. Age and sex were already included in the CKD-EPI formula. Interactions and collinearities were also analysed. Statistical analysis was performed using STATA software and two-tailed P-values &amp;lt;0.05 were considered statistically significant. RESULTS Characteristics of patients are given in Table 1. VitD deficit was significantly (P &amp;lt;0.001) more prevalent in patients with CKD (61%) compared with those without CKD (40%). MMP-10 showed a significant negative correlation with 25(OH)D3 (rho = –0.246; P &amp;lt;0.001), which remained significant including only CKD patients (rho = –0.283; P &amp;lt;0.001) and stronger above 45 ng/mL (rho = –0.7308, P &amp;lt;0.001) or moderate between 30 and 45 ng/mL (rho = –0.3290, P = 0.0045) (Fig. 1). In the fully adjusted model, MMP-10 was negatively associated (P = 0.019) with severe vitD deficiency [estimated coefficient –0.86 (–0.76 to –0.97)]. There was no interaction between covariates and 25(OH)D levels and collinearities were also discarded. CONCLUSION In T2D patients, circulating MMP-10 was inversely associated with serum 25(OH)D3 levels, especially in those patients with CKD and at the extremes of vitD level range. These results suggest that higher values of 25(OH)D3 should be targeted in these patients. The efficacy of vitD supplementation in reducing circulating MMP-10 levels should be further examined.

SS31 Ameliorates Podocyte Injury via Inhibiting OMA1-Mediated Hydrolysis of OPA1 in Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is currently one of the leading causes of end-stage renal disease (ESRD). Mitochondrial dysfunction in podocyte is involve in DKD development. However, whether early mitochondrial stabilization delays or reverses DKD progression has not been elucidated. SS31 is a novel tetrapeptide compound that targets the inner mitochondrial membrane and protects mitochondria by reducing ROS and inhibiting cardiolipin oxidation. Our study discovered that SS31 might have a long-term podocyte protection in DKD. In this study, we examined the glomerular pathological damage and proteinuria at different stages of diabetes. Results revealed that podocyte mitochondrial injury appeared at the early stage of DKD. Early treatment with SS31 could protect podocyte and alleviate the development of DKD via inhibiting OMA1-mediated hydrolysis of OPA1. Those data indicate that SS31 might be a promising agent in delaying the development of DKD and OMA1-mediated hydrolysis of OPA1 in mitochondria, and SS31 is a novel therapeutic target for the treatment of DKD.

Proteomic Analysis of Mouse Kidney Tissue Associates Peroxisomal Dysfunction with Early Diabetic Kidney Disease.

Background: The absence of efficient inhibitors for diabetic kidney disease (DKD) progression reflects the gaps in our understanding of DKD molecular pathogenesis. Methods: A comprehensive proteomic analysis was performed on the glomeruli and kidney cortex of diabetic mice with the subsequent validation of findings in human biopsies and omics datasets, aiming to better understand the underlying molecular biology of early DKD development and progression. Results: LC–MS/MS was employed to analyze the kidney proteome of 2 DKD models: Ins2Akita (early and late DKD) and db/db mice (late DKD). The abundance of detected proteins was defined. Pathway analysis of differentially expressed proteins in the early and late DKD versus the respective controls predicted dysregulation in DKD hallmarks (peroxisomal lipid metabolism and β-oxidation), supporting the functional relevance of the findings. Comparing the observed protein changes in early and late DKD, the consistent upregulation of 21 and downregulation of 18 proteins was detected. Among these were downregulated peroxisomal and upregulated mitochondrial proteins. Tissue sections from 16 DKD patients were analyzed by IHC confirming our results. Conclusion: Our study shows an extensive differential expression of peroxisomal proteins in the early stages of DKD that persists regardless of the disease severity, providing new perspectives and potential markers of diabetic kidney dysfunction.

Cellular crosstalk of glomerular endothelial cells and podocytes in diabetic kidney disease.

Diabetic kidney disease (DKD) is a serious microvascular complication of diabetes and is the leading cause of end-stage renal disease (ESRD). Persistent proteinuria is an important feature of DKD, which is caused by the destruction of the glomerular filtration barrier (GFB). Glomerular endothelial cells (GECs) and podocytes are important components of the GFB, and their damage can be observed in the early stages of DKD. Recently, studies have found that crosstalk between cells directly affects DKD progression, which has prospective research significance. However, the pathways involved are complex and largely unexplored. Here, we review the literature on cellular crosstalk of GECs and podocytes in the context of DKD, and highlight specific gaps in the field to propose future research directions. Elucidating the intricates of such complex processes will help to further understand the pathogenesis of DKD and develop better prevention and treatment options.

Cardiac Dysfunction in Early Stages of Diabetic Kidney Disease- Fact or Fiction: A Case-control Study

Introduction: The occurrence of kidney dysfunction in diabetics promotes early cardiac dysfunction. The timing of Diabetic Kidney Disease (DKD) and the impact of the stage of DKD on cardiac dysfunction is far from elucidated in current literature. Aim: To evaluate the association between the early stages of DKD and cardiac dysfunction by echocardiography. Materials and Methods: The present descriptive, case-control study was conducted in the Pondicherry Institute of Medical Sciences (PIMS), Kalapet, Puducherry, India, from November 2018 to November 2020. All diabetic patients between 25- 60 years, who attended the medicine Outpatient Department (OPD) or were admitted into the medical wards, were screened, among which 280 subjects were selected for the study. Patients with Estimated Glomerular Filtration Rate (eGFR) of more than 45 mL/min/1.73m2 were characterised as cases and those with eGFR of more than 90 mL/min/1.73m2 were controls. Echocardiographic parameters were recorded. Chi-square test, Mann-Whitney U test, and unpaired t-test were used for statistical analysis. Multivariate logistic regression analysis was done using an odd’s ratio to assess the association between early DKD and cardiac dysfunction. Results: The number of diabetics with early kidney disease (cases) were 139 and without kidney disease (controls) were 141. The mean age of the cases was 54.63±4.84 years and the controls were 52.61±7.916 years. The number of males among the cases and controls were 68 (48.92%) out of 139 and 96 (68.1%) out of 141, respectively. The prevalence of systolic dysfunction among diabetic patients with early kidney disease was 12.23% (17/139) and diastolic dysfunction was prevalent in 99.29% (138/139). Systolic dysfunction was 9.68 times more common in cases (n=139) than in controls (n=141). Women had a 2.6 times higher likelihood, and hypertension had (an independent association which was) a 2.6 times higher likelihood of developing cardiac dysfunction in the early stages of DKD. Conclusion: Systolic cardiac dysfunction is significantly higher (9.68 times more common) in those with early DKD when compared to those without kidney disease; with female gender and systemic hypertension as independent and significant risk factors.

A qualitative study documenting unmet needs in the management of diabetic kidney disease (DKD) in the primary care setting

BackgroundA majority of diabetic kidney disease (DKD) patients receive medical care in the primary care setting, making it an important opportunity to improve patient management. There is limited evidence evaluating whether primary care physicians (PCPs) are equipped to effectively manage these patients in routine clinical practice. The present study was undertaken to identify gaps in primary care and unmet needs in the diagnosis and monitoring of DKD in type 2 diabetes (T2D) patients among PCPs.MethodsThis was a qualitative analysis based on 30–45-min interviews with PCPs treating T2D patients. PCPs were recruited via email and were board-certified, in practice for more than 3 years, spent most of their time in direct clinical care, and provided care for more than three T2D patients in a week. Descriptive data analysis was conducted to identify and examine themes that were generated by interviews. Two reviewers evaluated interview data to identify themes and developed consensus on the priority themes identified.ResultsA total of 16 PCPs satisfying the inclusion criteria were recruited for qualitative interviews. Although the PCPs recognized kidney disease as an important comorbidity in T2D patients, testing for kidney disease was not consistently top of mind, with 56% reportedly performing kidney function testing in their T2D patients. PCPs most frequently reported using estimated glomerular filtration rate (eGFR) alone to monitor and stage DKD; only 25% PCPs reported testing for albuminuria. Most PCPs incorrectly believed that a majority of DKD patients are diagnosed in early stages. Also, early stages of DKD emerged as ambiguous areas of decision-making, wherein treatments prescribed greatly varied among PCPs. Lastly, early and accurate risk stratification of DKD patients emerged as the most important unmet need; which, if it could be overcome, was consistently identified by PCPs as a key to monitoring, appropriate nephrologist referrals, and intervening to improve outcomes in patients with DKD.ConclusionsOur study highlights important unmet needs in T2D DKD testing, staging, and stratification in the PCP setting that limit effective patient care. Health systems and insurers in the U.S. should prioritize the review and approval of new strategies that can improve DKD staging and risk stratification.

Targeted metabolomics as a tool for the diagnosis of kidney disease in Type II diabetes mellitus

ABSTRACT Background: Diabetic kidney disease (DKD) is an increasing health problem and an extra burden to health services. The study of characteristic metabolic alterations of DKD is crucial for a better understanding of pathogenesis to identify new potential biomarkers and drug targets. We hypothesized that metabolic profiling of amino acids, acylcarnitines, and organic acids are useful new biomarkers for the diagnosis of the early stages of DKD Methods: The hypothesis was testing in a case-control study of 232 patients with type 2 diabetes mellitus and 150 healthy controls. Patients were classified according to urinary albumin and estimated glomerular filtration rate (eGFR) into 100 with normoalbuminuria and 132 with microalbuminuria group. Eighteen AcylCNs and 17 amino acids were measured in the blood by tandem mass spectrometry while 17 urinary organic acids were quantitatively measured by gas chromatography – mass spectrometry. Results: Regression analysis found that dodecanoylcarnitines C12 (effect size 2.03 [95%CI 1.73–2.32]), triglylcarnitine C5:1 (2.01 [1.70–2.30]), and isovalerylcarnitine C5 (1.78 [1.48–2.07]) were stronger predictors of albumin/creatinine ratio than HbA1c (1.50 [1.20–1.78]) and hence they could serve as potential biomarkers for the diagnosis of the early stages of DKD. Conclusions: Targeted metabolic profiling offers a new, non-invasive approach for detecting biomarkers for the early diagnosis of DKD suggesting new pathogenetic phases that might be new targets for treatment.

Molecular Mechanisms in Early Diabetic Kidney Disease: Glomerular Endothelial Cell Dysfunction.

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD), with prevalence increasing at an alarming rate worldwide and today, there are no known cures. The pathogenesis of DKD is complex, influenced by genetics and the environment. However, the underlying molecular mechanisms that contribute to DKD risk in about one-third of diabetics are still poorly understood. The early stage of DKD is characterized by glomerular hyperfiltration, hypertrophy, podocyte injury and depletion. Recent evidence of glomerular endothelial cell injury at the early stage of DKD has been suggested to be critical in the pathological process and has highlighted the importance of glomerular intercellular crosstalk. A potential mechanism may include reactive oxygen species (ROS), which play a direct role in diabetes and its complications. In this review, we discuss different cellular sources of ROS in diabetes and a new emerging paradigm of endothelial cell dysfunction as a key event in the pathogenesis of DKD.

Poor Control of Plasma Triglycerides Is Associated with Early Decline of Estimated Glomerular Filtration Rates in New-Onset Type 2 Diabetes in China: Results from a 3-Year Follow-Up Study.

Objective Diabetic kidney disease (DKD) is the most common cause of end-stage renal disease (ESRD). Even after strict control of obesity, hyperglycemia, and hypertension, some patients still progress rapidly. Previous studies suggested diabetic dyslipidemia might be one of the factors responsible for this high residual risk. This study aims to explore the impact of long-term lipid control on renal outcome in new-onset type 2 diabetes mellitus (T2DM). Methods We conducted a 3-year follow-up study, involving 283 subjects with new-onset T2DM, and observed the effect of baseline and follow-up metabolic abnormalities, especially dyslipidemia, on the early damage of kidney function using multiple logistic regression analysis. Results After 3 years follow-up, patients achieved a better control of body weight, hypertension, and blood glucose. The most reduced eGFR group shared the least reduced BMI and LDL-C, as well as the greatest increase in TG levels. Only TG in the follow-up, not any of the baseline data, nor obesity, blood glucose, BP, or LDL-C in the follow-up, was found to be significantly correlated with the most reduced eGFR. Compared with patients with constantly abnormal TG levels, the risks were even higher in the subjects who experienced a transition from normal TG to hypertriglyceridemia (OR = 2.576 versus OR = 2.184, after multiple adjustment), and by tight controlling of TG, patients started with abnormal baseline TG levels could reduce the risk of DKD progression to the same low levels as the TG-constantly-normal group. Conclusion This study emphasized the importance of long-term TG control in East Asian patients with new-onset T2DM: TG control can delay the decline of kidney function in the early stage of DKD, and reversal of hypertriglyceridemia may undo the risks of the past. It is time to pay more attention to the control of TG in new-onset T2DM.

Feature Set for a Prediction Model of Diabetic Kidney Disease Progression.

In this paper, we propose feature extraction method for prediction model for at the early stage of diabetic kidney disease (DKD) progression. DKD needs continuous treatment; however, a hospital visit interval of a patient at the early stage of DKD is normally from one month to three months, and this is not a short time period. Therefore it makes difficult to apply sophisticated approaches such as using convolutional neural networks because of the data limitation. The propose method uses with hierarchical clustering that can estimate a suitable interval for grouping inputted sequences. We evaluate the proposed method with a real-EMR dataset that consists of 30,810 patient records and conclude that the proposed method outperforms the baseline methods derived from related work.