Stages Of Diabetic Kidney Disease Research Articles

#1669 Gangliosides as biomarkers for early diagnosis of diabetic kidney disease: detection and characterization by high-performance mass spectrometry

Abstract Background and Aims The early identification of diabetic kidney disease (DKD) is crucial as it may facilitate immediate intervention, thus impeding the progression of the condition and the risk of developing end-stage renal disease (ESRD). Enhancing our understanding of the pathophysiology of this microvascular complication as well as developing therapeutic strategies are imperative. Hence, the aim of the current study was to address the problematics of detection and characterization of gangliosides in the urine of type 2 diabetes mellitus (DM) patients with DKD. Method In this cross-sectional study, the urine ganglioside content from 24 h collected urine samples of 60 type 2 DM patients (20 with normal to mildly increased albuminuria—A1 group, 20 with moderately increased albuminuria—A2 group, 20 with severe increased albuminuria—A3 group) was compared to that of 20 healthy controls using a promising technique based on high-resolution (HR) mass spectrometry (MS). Furthermore, for structural elucidation of individual compounds, we isolated the ions GT1 (d18:1/18:0), identified at m/z 708.3379 and, GQ1 (d18:1/18:0) at m/z 812.7068, observed only in the screening analysis of A3 patients, and exposed them to Higher-energy collisional dissociation (HCD MS/MS) in the negative ion mode. Results Patients with type 2 diabetes mellitus display a considerably greater abundance of different species in their urinary gangliosidome, which varies in either glycan or ceramide structure, in comparison to the control group. Even within the A1 group, a greater variety of structures exhibiting varying degrees of sialylation were observed. A wide range of carbohydrate chains were discovered, ranging from short, monosialylated chains (GM) to complex, pentasialylated chains (GP). Additionally, some ganglioside chains were modified with and O-acetyl (O-Ac) attachments. The gangliosidome of the A3 group comprises a higher variety of structures, compared to A1 and A2, differing in their overall sialic acid content, and more complex structures, including various biologically significant modifications, such as O-fucosylation, O-GalNAc and CH3COO− attachments. Both albuminuria and glomerular filtration rate proved to be correlated with the degree of sialylation of species. Furthermore, significant alterations occur also in the ceramide part, with the most noteworthy being the presence of sphingoid base trihydroxylation, which is shown in both A1 and A3 samples. Additionally, A3 exhibits unusual length of the fatty acid chains. GQ1d(d18:1/18:0), GT1α(d18:1/18:0), and GT1b(d18:1/18:0) were identified as predictive for specific isomers linked to the location of Neu5Ac along the oligosaccharide structure using HCD-based MS/MS. Conclusion We concluded that gangliosides may be involved in the development and progression of DKD through the use of mass spectrometry techniques, which provides considerable precision and ultrahigh reproducibility, sensitivity and processing power, and the capability to identify minor elements in complex biological matrices. Thus, a set of promising bioindicators for early detection and progression of DKD was established. Even in the normoalbuminuric stage, the sialylation level of the expressed species appears to be an extremely important biochemical marker of DKD. Moreover, the modifications detected in the composition of ceramide indicate that, alongside the oligosaccharide structure, the lipid component might function as a specific molecular indicator for different stages of DKD. The presence of a few isomers in the A3 group has been discovered to be associated with DKD progression, based on the informative sequence ions obtained from the structural analysis. Moreover, gangliosides might be used as target molecules for the implementation of therapeutic schemes in type 2 DM patients.

#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.

Mitochondrial DNA and Inflammation Are Associated with Cerebral Vessel Remodeling and Early Diabetic Kidney Disease in Patients with Type 2 Diabetes Mellitus.

Cerebrovascular disease accounts for major neurologic disabilities in patients with type 2 diabetes mellitus (DM). A potential association of mitochondrial DNA (mtDNA) and inflammation with cerebral vessel remodeling in patients with type 2 DM was evaluated. A cohort of 150 patients and 30 healthy controls were assessed concerning urinary albumin/creatinine ratio (UACR), synaptopodin, podocalyxin, kidney injury molecule-1 (KIM-1), N-acetyl-β-(D)-glucosaminidase (NAG), interleukins IL-17A, IL-18, IL-10, tumor necrosis factor-alpha (TNFα), intercellular adhesion molecule-1 (ICAM-1). MtDNA-CN and nuclear DNA (nDNA) were quantified in peripheral blood and urine by qRT-PCR. Cytochrome b (CYTB) gene, subunit 2 of NADH dehydrogenase (ND2), and beta 2 microglobulin nuclear gene (B2M) were assessed by TaqMan assays. mtDNA-CN was defined as the ratio of the number of mtDNA/nDNA copies, through analysis of the CYTB/B2M and ND2/B2M ratio; cerebral Doppler ultrasound: intima-media thickness (IMT)-the common carotid arteries (CCAs), the pulsatility index (PI) and resistivity index (RI)- the internal carotid arteries (ICAs) and middle cerebral arteries (MCAs), the breath-holding index (BHI). The results showed direct correlations of CCAs-IMT, PI-ICAs, PI-MCAs, RI-ICAs, RI-MCAs with urinary mtDNA, IL-17A, IL-18, TNFα, ICAM-1, UACR, synaptopodin, podocalyxin, KIM-1, NAG, and indirect correlations with serum mtDNA, IL-10. BHI correlated directly with serum IL-10, and serum mtDNA, and negatively with serum IL-17A, serum ICAM-1, and NAG. In neurologically asymptomatic patients with type 2 DM cerebrovascular remodeling and impaired cerebrovascular reactivity may be associated with mtDNA variations and inflammation from the early stages of diabetic kidney disease.

Epidemiology of Diabetic Kidney Disease among US Veterans.

With a large number of patients and high mortality, diabetic kidney disease (DKD) imposes a significant burden on US health care. Although diabetes is the leading cause of chronic kidney disease and complications, the epidemiology of DKD in the contemporary US veteran population is generally unknown. We aimed to estimate the rate of DKD progression and to measure the general epidemiology of DKD in the United States veteran population. We performed a retrospective observational research using electronic health-care records and administrative databases. The DKD patient cohort was abstracted from the Veterans Health Administration health-record data from January 2016 to March 2022. We defined DKD patients using the laboratory test data based on Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines. Summary statistics include the five-year cumulative incidence of progression to an advanced stage from the DKD stage at the cohort entry date and prevalence at a series of single time points. A total of 685,288 patients (male [96%], mean age 62 years, Caucasian [64%], non-Hispanic [87%]) met our eligibility criteria. The 5-year cumulative incidence of progression to an advanced DKD stage or all-cause death from DKD stages G1 A2/A3, G2 A2/A3, G3a, and G3b were 52.0%, 47.4%, 50.5%, and 60.9%, respectively. In sum, 594,082 patients were classified as moderate or high risk as per KDIGO guidelines in 2021, and stages G3a and G3b accounted for 51.2% and 25.3%, respectively, of cases. More than half of DKD patients underwent a stage progression or death within 5 years. A substantial number of DKD patients at an earlier stage might be left undetermined. The study findings warrant a revision of DKD patient identification and management in US veterans.

The potential for improved outcomes in the prevention and therapy of diabetic kidney disease through 'stacking' of drugs from different classes.

Aggressive therapy of diabetic kidney disease (DKD) can not only slow the progression of DKD to renal failure but, if utilized at an early enough stage of DKD, can also stabilize and/or reverse the decline in renal function. The currently recognized standard of therapy for DKD is blockade of the renin-angiotensin system with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs). However, unless utilized at a very early stage, monotherapy with these drugs in DKD will only prevent or slow the progression of DKD and will neither stabilize nor reverse the progression of DKD to renal decompensation. Recently, the addition of a sodium-glucose cotransporter-2 inhibitor and/or a mineralocorticoid receptor blocker to ACE inhibitors or ARBs has been clearly shown to further decelerate the decline in renal function. The use of glucagon-like peptide-1 (GLP-1) agonists shown promise in decelerating the progression of DKD. Other drugs that may aid in the deceleration the progression of DKD are dipeptidyl peptidase-4 inhibitors, pentoxifylline, statins, and vasodilating beta blockers. Therefore, aggressive therapy with combinations of these drugs (stacking) should improve the preservation of renal function in DKD.

2023 Diabetic Kidney Disease Fact Sheet in Korea.

To investigate the prevalence, incidence, comorbidities, and management status of diabetic kidney disease (DKD) and diabetes-related end-stage kidney disease (ESKD) in South Korea. We used the Korea National Health and Nutrition Examination Survey data (2019 to 2021, n=2,665) for the evaluation of prevalence, comorbidities, control rate of glycemia and comorbidities in DKD, and the Korean Health Insurance Service-customized database (2008 to 2019, n=3,950,857) for the evaluation of trends in the incidence and prevalence rate of diabetes-related ESKD, renin-angiotensin system (RAS) blockers and sodium glucose cotransporter 2 (SGLT2) inhibitors use for DKD, and the risk of atherosclerotic cardiovascular disease (ASCVD) and mortality according to DKD stages. DKD was defined as albuminuria or low estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 in patients with diabetes mellitus. The prevalence of DKD was 25.4% (albuminuria, 22.0%; low eGFR, 6.73%) in patients with diabetes mellitus aged ≥30 years. Patients with DKD had a higher rate of comorbidities, including hypertension, dyslipidemia, and central obesity; however, their control rates were lower than those without DKD. Prescription rate of SGLT2 inhibitors with reduced eGFR increased steadily, reaching 5.94% in 2019. Approximately 70% of DKD patients were treated with RAS blockers. The prevalence rate of diabetesrelated ESKD has been steadily increasing, with a higher rate in older adults. ASCVD and mortality were significantly associated with an in increase in DKD stage. DKD is prevalent among Korean patients with diabetes and is an independent risk factor for cardiovascular morbidity and mortality, which requiring intensive management of diabetes and comorbidities. The prevalence of diabetes-related ESKD has been increasing, especially in the older adults, during past decade.

Insights into serum metabolic biomarkers for early detection of incident diabetic kidney disease in Chinese patients with type 2 diabetes by random forest.

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease (ESRD) worldwide. Early detection is critical for the risk stratification and early intervention of progressive DKD. Serum creatinine (sCr) and urine output are used to assess kidney function, but these markers are limited by their delayed changes following kidney pathology, and lacking of both sensitivity and accuracy. Hence, it is essential to illustrate potential diagnostic indicators to enhance the precise prediction of early DKD. A total of 194 Chinese individuals include 30 healthy participants (Stage 0) and 164 incidents with type 2 diabetes (T2D) spanning from DKD's Stage 1a to 4 were recruited and their serums were subjected for untargeted metabolomic analysis. Random forest (RF), a machine learning approach, together with univariate linear regression (ULR) and multivariate linear regression (MvLR) analysis were applied to characterize the features of untargeted metabolites of DKD patients and to identify candidate DKD biomarkers. Our results indicate that 2-(α-D-mannopyranosyl)-L-tryptophan (ADT), succinyladenosine (SAdo), pseudouridine and N,N,N-trimethyl-L-alanyl-L-proline betaine (L-L-TMAP) were associated with the development of DKD, in particular, the latter three that were significantly elevated in Stage 2-4 T2D incidents. Each of the four metabolites in combination with sCr achieves better performance than sCr alone with area under the receiver operating characteristic curve (AUC) of 0.81-0.91 in predicting DKD stages. An average of 3.9 years follow-up study of another cohort including 106 Stage 2-3 patients suggested that "urinary albumin-to-creatinine ratio (UACR) + ADT + SAdo" can be utilized for better prognosis evaluation of early DKD (average AUC = 0.9502) than UACR without sexual difference.

Glomerular hyperfiltration as a therapeutic target for CKD.

The global burden of chronic kidney disease (CKD) is high and increasing. Early diagnosis and intervention are key to improve outcomes. Single nephron glomerular hyperfiltration is an early pathophysiologic manifestation of CKD that may result in absolute glomerular hyperfiltration, i.e. a high glomerular filtration rate (GFR) or be associated with normal or low GFR because of nephron loss (relative glomerular hyperfiltration). Even though compensatory glomerular hyperfiltration may contribute to maintain kidney function after loss of kidney mass, the associated increased glomerular capillary pressure and glomerular and podocyte size drive podocyte loss, albuminuria and proximal tubular overload, contributing to CKD progression. In this regard, all kidney protective drugs in clinical use so far, from renin-angiotensin system blockers to mineralocorticoid receptor blockers to sodium-glucose cotransporter-2 inhibitors to tolvaptan, induced an early dip in glomerular filtration that is thought to represent reversal of hyperfiltration. As glomerular hyperfiltration may be present early in the course of kidney disease, its recognition may provide an effective intervention window that may predates current criteria based on high albuminuria or loss of GFR. Nevertheless, there is no diagnostic method with high sensitivity and specificity to identify single nephron glomerular hyperfiltration, except when it leads to obvious absolute glomerular hyperfiltration, as observed in the early stages of diabetic kidney disease when nephron mass is still preserved. We now review the concept of glomerular hyperfiltration as an indicator of CKD risk, including definitions, challenges in diagnosis and evaluation, underlying pathophysiological mechanisms, potential therapeutic approaches and unanswered questions.

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.

Serum Aldosterone Level in Different Stages of Diabetic Kidney Disease in Type 2 Diabetes Mellitus

Serum Aldosterone Level in Different Stages of Diabetic Kidney Disease in Type 2 Diabetes Mellitus

Predicting Osteoporotic Fracture in Patients With Early-Stage Diabetic Kidney Disease Using a Radiomic Model: A Longitudinal Cohort Study

ObjectiveThere is an urgent need for effective predictive strategies to accurately evaluate the risk of fragility fractures in elderly patients in the early stages of diabetic kidney disease (DKD). MethodsThis longitudinal cohort study included 715 older patients in the early stages of DKD diagnosed between January 2015 and August 2019. Patients were randomly allocated to a training cohort (n = 499) and a validation cohort (n = 216). The least absolute shrinkage and selection operator method was used to select key features for dual-energy x-ray absorptiometry-based radiomic analysis. A radiomic model was constructed using Cox proportional hazards regression. The performance of the radiomic model was compared with that of traditional fracture assessment tools through a receiver operating characteristic curve, calibration curve, and decision curve analysis. ResultsOver a mean follow-up period of 4.72 ± 1.60 years, 65 participants (9.09%) experienced incident fragility fractures. Seventeen features were ultimately selected to create the radiomic model. The calibration plots of this model demonstrated satisfactory agreement between the observed and predicted outcomes. Moreover, the radiomic model outperformed traditional fracture assessment tools in both the training and validation cohorts according to the area under the receiver operating characteristic curve and decision curve analysis. ConclusionsThe novel radiomic model has demonstrated a more effective prediction of fragility fracture in elderly patients in the early stages of DKDcompared to traditional fracture assessment tools.

Association of systemic immune-inflammation index with diabetic kidney disease in patients with type 2 diabetes: a cross-sectional study in Chinese population.

Systemic immune-inflammation index (SII), a novel inflammatory marker, has been reported to be associated with diabetic kidney disease (DKD) in the U.S., however, such a close relationship with DKD in other countries, including China, has not been never determined. We aimed to explore the association between SII and DKD in Chinese population. A total of 1922 hospitalized patients with type 2 diabetes mellitus (T2DM) included in this cross-sectional study were divided into three groups based on estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (ACR): non-DKD group, DKD stages 1-2 Alb group, and DKD-non-Alb+DKD stage 3 Alb group. The possible association of SII with DKD was investigated by correlation and multivariate logistic regression analysis, and receiver-operating characteristic (ROC) curves analysis. Moving from the non-DKD group to the DKD-non-Alb+DKD stage 3 Alb group, SII level was gradually increased (P for trend <0.01). Partial correlation analysis revealed that SII was positively associated with urinary ACR and prevalence of DKD, and negatively with eGFR (all P<0.01). Multivariate logistic regression analysis showed that SII remained independently significantly associated with the presence of DKD after adjustment for all confounding factors [(odds ratio (OR), 2.735; 95% confidence interval (CI), 1.840-4.063; P < 0.01)]. Moreover, compared with subjects in the lowest quartile of SII (Q1), the fully adjusted OR for presence of DKD was 1.060 (95% CI 0.773-1.455) in Q2, 1.167 (95% CI 0.995-1.368) in Q3, 1.266 (95% CI 1.129-1.420) in the highest quartile (Q4) (P for trend <0.01). Similar results were observed in presence of DKD stages 1-2 Alb or presence of DKD-non- Alb+DKD stage 3 Alb among SII quartiles. Last, the analysis of ROC curves revealed that the best cutoff values for SII to predict DKD, Alb DKD stages 1- 2, and DKD-non-Alb+ DKD stage 3 Alb were 609.85 (sensitivity: 48.3%; specificity: 72.8%), 601.71 (sensitivity: 43.9%; specificity: 72.3%), and 589.27 (sensitivity: 61.1%; specificity: 71.1%), respectively. Higher SII is independently associated with an increased risk of the presence and severity of DKD, and SII might be a promising biomarker for DKD and its distinct phenotypes in Chinese population.

Relation between neutrophil to lymphocyte ratio, platelets to lymphocyte ratio, and early stages of diabetic kidney disease in patients with type 2 diabetes

Relation between neutrophil to lymphocyte ratio, platelets to lymphocyte ratio, and early stages of diabetic kidney disease in patients with type 2 diabetes

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.

Serum branched chain amino acids: an effective indicator of diabetic kidney disease.

In recent years, there has been a growing association between elevated circulating levels of branched-chain amino acids (BCAA) and diabetes mellitus. However, the relationship between serum BCAA levels and diabetic kidney disease (DKD) remains ambiguous. This study aims to investigate serum BCAA levels in DKD patients at various stages and assess the correlation between BCAA and clinical characteristics. We enrolled patients with type 2 diabetes mellitus (T2DM) who were admitted to our hospital and categorized them into three groups based on different DKD stages: normal proteinuria, microproteinuria, and macroalbuminuria groups. Forty healthy volunteers were included as the control group, and we measured serum BCAA concentrations using liquid chromatography-mass spectrometry (LC-MS). Subsequently, we conducted correlation and regression analyses to assess the associations between BCAA and clinical indicators. Serum BCAA levels were significantly elevated in T2DM patients compared to healthy controls. However, these levels exhibited a gradual decline with the progression of DKD. Furthermore, after adjusting for age, gender, and disease duration, we observed an independent association between serum albumin, urinary transferrin, and urinary microalbumin with BCAA. Our findings suggest a noteworthy decline in serum BCAA levels alongside the advancement of DKD. Additionally, serum BCAA exhibits an independent correlation with renal function indicators. These observations point to the possibility that serum BCAA concentrations in individuals with T2DM hold promise as a crucial predictor for both the initiation and progression of DKD.

Association between serum complements and kidney function in patients with diabetic kidney disease.

We aimed to explore the association between serum complements and kidney function of diabetic kidney disease (DKD) in Chinese patients. This is a retrospective study involving 2,441 participants. DKD was diagnosed according to the Kidney Disease: Improving Global Outcomes (KDIGO) categories. Participants were classified as stages G1-G5 by KDIGO glomerular filtration rate (GFR) categories. Effect sizes are expressed as odds ratio (OR) with 95% confidence interval (CI). After balancing age, gender, systolic blood pressure (SBP), hemoglobin A1c (HbA1C), serum triglyceride (TG), and urinary albumin-to-creatinine ratio (UACR) between the G2-G5 and control groups, per 0.1 g/L increment in serum complement C3 was significantly associated with a 27.8% reduced risk of DKD at G5 stage (OR, 95% CI, P: 0.722, 0.616-0.847, <0.001) relative to the G1 stage. Conversely, per 0.1 g/L increment in serum complement C4 was associated with an 83.0-177.6% increased risk of G2-G5 stage (P<0.001). Serum complement C1q was not statistically significant compared to controls at all stages prior to or after propensity score matching. Our results indicate that high concentrations of serum C4 were associated with the significantly elevated risk of kidney function deterioration across all stages, and reduced serum C3 levels with an increased risk of DKD stage G5.

Adaptation to Telehealth of Personalized Group Visits for Late Stage Diabetic Kidney Disease.

The COVID-19 pandemic resulted in an unprecedented shift in the delivery of outpatient medical care, including the rapid transition of services from in-person to telehealth. We adapted an evidence-based personalized health planning group visit care model traditionally offered in-person to telehealth to support the care of patients with type 2 diabetes mellitus (T2D) and chronic kidney disease (CKD). Despite the need to leverage telehealth technologies to better support self-management for patients with CKD, scant evidence exists on how to do so. We conducted prospective adaptations of in-person evidence-based group visit model for telehealth delivery for patients with CKD and T2D. Intervention adaptations are reported using the Framework for Reporting Adaptations and Modifications (FRAME) taxonomy. The adapted virtual group visit care model was pilot tested among adults with T2D and stage 3b or 4 CKD. Feasibility outcomes included recruitment, attendance, satisfaction, and self-reported goal progress. Clinical outcomes were evaluated using Wilcoxon signed rank tests and included hemoglobin A1C (HbA1c), diastolic and systolic blood pressure, body mass index, and estimated glomerular filtration rate. Adaptation areas included outreach, visit format, educational materials design and access, staffing, and patient engagement strategies. 39% (43) of patients (110) contacted verbalized interest, and 58% (25) of those participated. 72% completed >6 group sessions. 68% of patients reported completing one or more health goals, with nutrition and physical activity being the most common. We observed a statistically significant improvement in HbA1c (p = 0.0176) six months post-program participation. Adapting evidence-based interventions for telehealth delivery is challenging due to the risk of altering an intervention's core components responsible for observed benefits. We adapted an in-person group visit model for the care of T2D and CKD for telehealth delivery. The telehealth approach was feasible and preliminary data suggested it improved relevant health and patient-recorded outcomes up to six months post-program completion. The approaches used here may be applicable to the adaptation of other clinical programs for telehealth delivery.

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.