Changes In Diabetic Kidney Disease Research Articles

The retinal blood flow density is related to the pathological severity of diabetic kidney disease.

This study aimed to investigate the correlation between fundus blood flow parameters and the severity of pathological biopsy in patients with diabetic kidney disease (DKD). Data of patients with type 2 diabetes mellitus who completed renal pathology biopsies and optical coherence tomography angiography (OCTA) examinations, including renal function, 24-h urine protein quantification, and macular flow imaging, were collected. DKD pathology biopsies were graded as stages 1-4, and differences and correlations of the parameters were compared between groups. The grading was transformed into early (stage 1) and late (stages 2-4), and regression analyses were conducted to develop a model, draw a nomogram, and test efficacy. This study included 157 eyes from 157 individuals in total. Urinary microalbumin and to urinary creatinine ratio (mALB/NCR) increased with pathological grading, whereas while glomerular filtration rate was decreased (p < 0.01). Corresponding retinal blood flow in superficial, deep, and full paracentral rings was decreased, which correlated with pathological grading (p < 0.01), with the highest blood flow density in the whole layer (r2 = -0.707). Meaningfully, in the early DKD model (area under the curve =0.929 (0.889-0.970), p < 0.01), whole-layer blood flow density, mALB/NCR, and diabetes duration were statistically significant. The decrease in macular retinal blood flow density detected by OCTA is closely associated with the increase in pathological grading of DKD and can be used as a noninvasive parameter for monitoring early changes in DKD.

Chromatin accessibility analysis and architectural profiling of human kidneys reveal key cell types and a regulator of diabetic kidney disease

Diabetes is the leading cause of kidney disease that progresses to kidney failure. However, the key molecular and cellular pathways involved in diabetic kidney disease (DKD) pathogenesis are largely unknown. Here, we performed a comparative analysis of adult human kidneys by examining cell type-specific chromatin accessibility by single-nucleus ATAC-seq (snATAC-seq) and analyzing three-dimensional chromatin architecture via high-throughput chromosome conformation capture (Hi-C method) of paired samples. We mapped the cell type-specific and DKD-specific open chromatin landscape and found that genetic variants associated with kidney diseases were significantly enriched in the proximal tubule- (PT) and injured PT-specific open chromatin regions in samples from patients with DKD. BACH1 was identified as a core transcription factor of injured PT cells; its binding target genes were highly associated with fibrosis and inflammation, which were also key features of injured PT cells. Additionally, Hi-C analysis revealed global chromatin architectural changes in DKD, accompanied by changes in local open chromatin patterns. Combining the snATAC-seq and Hi-C data identified direct target genes of BACH1, and indicated that BACH1 binding regions showed increased chromatin contact frequency with promoters of their target genes in DKD. Thus, our multi-omics analysis revealed BACH1 target genes in injured PTs and highlighted the role of BACH1 as a novel regulator of tubular inflammation and fibrosis.

Metabolite Profiling of the Gut–Renal–Cerebral Axis Reveals a Particular Pattern in Early Diabetic Kidney Disease in T2DM Patients

Type 2 diabetes mellitus (T2DM) represents an important microvascular disease concerning the kidney and the brain. Gut dysbiosis and microbiota-derived metabolites may be in relation with early pathophysiological changes in diabetic kidney disease (DKD). The aim of the study was to find new potential gut-derived biomarkers involved in the pathogenesis of early DKD, with a focus on the complex interconnection of these biomarkers with podocyte injury, proximal tubule dysfunction, renal and cerebrovascular endothelial dysfunction. The study design consisted of metabolite profiling of serum and urine of 90 T2DM patients (subgroups P1-normoalbuminuria, P2-microalbuminuria, P3-macroalbuminuria) and 20 healthy controls (group C), based on ultra-high-performance liquid chromatography coupled with electrospray ionization-quadrupole-time of flight-mass spectrometry analysis (UHPLC-QTOF-ESI+-MS). By multivariate and univariate analyses of serum and urine, which included Partial Least Squares Discriminant Analysis (PLSDA), Variable Importance Plots (VIP), Random Forest scores, One Way ANOVA and Biomarker analysis, there were discovered metabolites belonging to nitrogen metabolic pathway and retinoic acid signaling pathway which differentiate P1 group from P2, P3, C groups. Tyrosine, phenylalanine, indoxyl sulfate, serotonin sulfate, and all-trans retinoic acid express the metabolic fingerprint of P1 group vs. P2, P3, C groups, revealing a particular pattern in early DKD in T2DM patients.

Sodium Magnetic Resonance Imaging Shows Impairment of the Counter-current Multiplication System in Diabetic Mice Kidney.

Sodium magnetic resonance imaging can non-invasively assess sodium distribution, specifically sodium concentration in the countercurrent multiplication system in the kidney, which forms a sodium concentration gradient from the cortex to the medulla, enabling efficient water reabsorption. This study aimed to investigate whether sodium magnetic resonance imaging can detect changes in sodium concentrations under normal conditions in mice and in disease models such as a mouse model with diabetes mellitus. Methods: We performed sodium and proton nuclear magnetic resonance imaging using a 9.4-T vertical standard-bore super-conducting magnet. Results: A condition of deep anesthesia, with widened breath intervals, or furosemide administration in 6-week-old C57BL/6JJcl mice showed a decrease in both tissue sodium concentrations in the medulla and sodium concentration gradients from the cortex to the medulla. Further, sodium magnetic resonance imaging revealed reductions in the sodium concentration of the medulla and in the gradient from the cortex to the medulla in BKS.Cg-Leprdb+/+ Leprdb/Jcl mice at very early type-2 diabetes mellitus stages compared to corresponding control BKS.Cg-m+/m+/Jcl mice. Conclusions: The kidneys of BKS.Cg-Leprdb+/+ Leprdb/Jcl mice aged 6 weeks showed impairments in the countercurrent multiplication system. We propose the utility of 23Na MRI for evaluating functional changes in diabetic kidney disease, not as markers that reflect structural damage. Thus, 23Na MRI may be a potential very early marker for structures beyond the glomerulus; this may prompt intervention with novel efficacious tubule-targeting therapies.

Intercellular mitochondrial transfer as a means of revitalizing injured glomerular endothelial cells.

BACKGROUNDRecent studies have demonstrated that mesenchymal stem cells (MSCs) can rescue injured target cells via mitochondrial transfer. However, it has not been fully understood how bone marrow-derived MSCs repair glomeruli in diabetic kidney disease (DKD).AIMTo explore the mitochondrial transfer involved in the rescue of injured glomerular endothelial cells (GECs) by MSCs, both in vitro and in vivo.METHODS In vitro experiments were performed to investigate the effect of co-culture with MSCs on high glucose-induced GECs. The transfer of mitochondria was visua lized using fluorescent microscopy. GECs were freshly sorted and ultimately tested for apoptosis, viability, mRNA expression by real-time reverse transcri ptase-polymerase chain reaction, protein expression by western blot, and mitochondrial function. Moreover, streptozotocin-induced DKD rats were infused with MSCs, and renal function and oxidative stress were detected with an automatic biochemical analyzer and related-detection kits after 2 wk. Kidney histology was analyzed by hematoxylin and eosin, periodic acid-Schiff, and immunohistochemical staining.RESULTSFluorescence imaging confirmed that MSCs transferred mitochondria to injured GECs when co-cultured in vitro. We found that the apoptosis, proliferation, and mitochondrial function of injured GECs were improved following co-culture. Additionally, MSCs decreased pro-inflammatory cytokines [interleukin (IL)-6, IL-1β, and tumor necrosis factor-α] and pro-apoptotic factors (caspase 3 and Bax). Mitochondrial transfer also enhanced the expression of superoxide dismutase 2, B cell lymphoma-2, glutathione peroxidase (GPx) 3, and mitofusin 2 and inhibited reactive oxygen species (ROS) and dynamin-related protein 1 expression. Furthermore, MSCs significantly ameliorated functional parameters (blood urea nitrogen and serum creatinine) and decreased the production of malondialdehyde, advanced glycation end products, and ROS, whereas they increased the levels of GPx and superoxide dismutase in vivo. In addition, significant reductions in the glomerular basement membrane and renal interstitial fibrosis were observed following MSC treatment.CONCLUSIONMSCs can rejuvenate damaged GECs via mitochondrial transfer. Additionally, the improvement of renal function and pathological changes in DKD by MSCs may be related to the mechanism of mitochondrial transfer.

Integrating image analysis with single cell RNA-seq data to study podocyte-specific changes in diabetic kidney disease.

Podocyte injury plays a crucial role in the progression of diabetic kidney disease (DKD). Injured podocytes demonstrate variations in nuclear shape and chromatin distribution. These morphometric changes have not yet been quantified in podocytes. Furthermore, the molecular mechanisms underlying these variations are poorly understood. Recent advances in omics have shed new lights into the biological mechanisms behind podocyte injury. However, there currently exists no study analyzing the biological mechanisms underlying podocyte morphometric variations during DKD. First, to study the importance of nuclear morphometrics, we performed morphometric quantification of podocyte nuclei from whole slide images of renal tissue sections obtained from murine models of DKD. Our results indicated that podocyte nuclear textural features demonstrate statistically significant difference in diabetic podocytes when compared to control. Additionally, the morphometric features demonstrated the existence of multiple subpopulations of podocytes suggesting a potential cause for their varying response to injury. Second, to study the underlying pathophysiology, we employed single cell RNA sequencing data from the murine models. Our results again indicated five subpopulations of podocytes in control and diabetic mouse models, validating the morphometrics-based results. Additionally, gene set enrichment analysis revealed epithelial to mesenchymal transition and apoptotic pathways in a subgroup of podocytes exclusive to diabetic mice, suggesting the molecular mechanism behind injury. Lastly, our results highlighted two distinct lineages of podocytes in control and diabetic cases suggesting a phenotypical change in podocytes during DKD. These results suggest that textural variations in podocyte nuclei may be key to understanding the pathophysiology behind podocyte injury.

Association of urinary C-megalin with albuminuria and renal function in diabetes: a cross-sectional study (Diabetes Distress and Care Registry at Tenri [DDCRT 21]).

A urinary biomarker sensitive to glomerular functional or structural changes in diabetic kidney disease is required. This study examined whether urinary C-megalin reflects renal function or albuminuria in diabetes. This was a cross-sectional study involving 1576 patients with type 1 or 2 diabetes. The exposure variables were estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR), and the outcomes were urinary C-megalin excretion and concentration. Two-part models were used to examine the associations between eGFR and UACR with urinary C-megalin excretion or concentration. The UACR was linearly associated with urinary C-megalin excretion (per 100mg/gCr of UACR; 11.8 fM/gCr [95% CI 8.9-14.7]). There was no association between decreasing eGFR and increasing urinary C-megalin excretion. The UACR was also linearly associated with the urinary C-megalin concentration (per 100mg/gCr of UACR, 7.7 fM/L [95% CI 5.8-9.6]). At eGFR values > 60mL/min/1.73 m2, the eGFR and urinary C-megalin concentration were inversely linearly related (per 10mL/min/1.73 m2 decline, 7.7 fM/L [95% CI 0.2-15.1]). Urinary C-megalin excretion as well as concentration levels are potentially useful biomarkers to detect early changes in diabetic kidney disease.

Urinary miR-3137 and miR-4270 as potential biomarkers for diabetic kidney disease.

BackgroundAs one of the most prevalent diagnostic indicators of diabetic kidney disease (DKD), albumin‐to‐creatinine ratio (ACR) shows considerably limited predictive power in clinical application. We analyzed microarray expression profiling of urine to seek for differentially expressed miRNAs for potential biomarkers of DKD.MethodsUrine samples from type 2 diabetes mellitus (T2DM) patients with (30 mg/g < ACR < 300 mg/g, DKD group) or without DKD (ACR < 30 mg/g, DM group) were collected for miRNA microarray analysis. The differentially expressed miRNAs were screened by bioinformatics analysis and validated by quantitative real‐time PCR. Target genes of differentially expressed miRNAs were predicted in miRDB, Targetscan, and microRNA.org databases. We also conducted the Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathways analysis to explore for potential mechanisms in DKD.ResultsNine miRNAs were down‐regulated and seventeen miRNAs were up‐regulated in DKD group, compared to DM group. The levels of miR‐3137 and miR‐4270 in DKD group were 0.670 ± 0.505 and 2.116 ± 1.762 times than those in DM group, respectively, showing great significance. A total of 1076 target genes were simultaneously predicted by miRDB, Targetscan, and microRNA.org databases. According to the GO analysis results, disorders of endomembrane system may be one of the major pathological changes in DKD. In addition, Rap 1 signaling pathway is also altered obviously in DKD, discovered by the KEGG analysis.ConclusionMiR‐3137 and miR‐4270 show the potential for urinary biomarkers of DKD. The pathological changes of DKD may be related to disorders of endomembrane system and alternation of Rap1 signaling pathway.

Genetic and Biological Effects of ICAM-1 E469K Polymorphism in Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is a complex disease, in which local inflammatory stress results from both metabolic and hemodynamic derangements. Intercellular adhesion molecule 1 (ICAM-1) is an acute-phase protein marker of inflammation. In the recent years, clinical observations have reported that increased serum/plasma ICAM-1 levels are positively correlated with albuminuria in the patients with type 1 (T1D) and type 2 diabetes (T2D). Genetic association studies have demonstrated that genetic polymorphisms, including SNP rs5498 (E469K, G/A), in the ICAM1 gene is associated with DKD. rs5498 is a nonsynonymous SNP and caused by substitution between E (Glu) and K (Lys) for ICAM-1 protein. In this review, we first summarized the genetic effects of ICAM1 E469K polymorphism in DKD and then demonstrated the possible changes of ICAM-1 protein crystal structures according to the genotypes of this polymorphism. Finally, we discussed the genetic effects of the ICAM1 E469K polymorphism and the biological role of increased circulating ICAM-1 protein and its formation changes in DKD.

Progression of diabetic kidney disease in T2DN rats.

Diabetic kidney disease (DKD) is one of the leading pathological causes of decreased renal function and progression to end-stage kidney failure. To explore and characterize age-related changes in DKD and associated glomerular damage, we used a rat model of type 2 diabetic nephropathy (T2DN) at 12 wk and older than 48 wk. We compared their disease progression with control nondiabetic Wistar and diabetic Goto-Kakizaki (GK) rats. During the early stages of DKD, T2DN and GK animals revealed significant increases in blood glucose and kidney-to-body weight ratio. Both diabetic groups had significantly altered renin-angiotensin-aldosterone system function. Thereafter, during the later stages of disease progression, T2DN rats demonstrated a remarkable increase in renal damage compared with GK and Wistar rats, as indicated by renal hypertrophy, polyuria accompanied by a decrease in urine osmolarity, high cholesterol, a significant prevalence of medullary protein casts, and severe forms of glomerular injury. Urinary nephrin shedding indicated loss of the glomerular slit diaphragm, which also correlates with the dramatic elevation in albuminuria and loss of podocin staining in aged T2DN rats. Furthermore, we used scanning ion microscopy topographical analyses to detect and quantify the pathological remodeling in podocyte foot projections of isolated glomeruli from T2DN animals. In summary, T2DN rats developed renal and physiological abnormalities similar to clinical observations in human patients with DKD, including progressive glomerular damage and a significant decrease in renin-angiotensin-aldosterone system plasma levels, indicating these rats are an excellent model for studying the progression of renal damage in type 2 DKD.

SUN-294 FUNCTIONAL MRI IN PREDICTING DIABETIC KIDNEY DISEASE

There are no known studies evaluating functional renal Magnetic Resonance Imaging (MRI) changes in Type 1 Diabetes (T1DM) compared to healthy controls. This is a prospective pilot study with a primary aim to evaluate if multi-parametric MRI can detect renal hypoxia (utilizing BOLD, Blood Oxygen Level Dependent) and structural changes (utilizing diffusion tensor imaging, DTI) in patients with T1DM, comparing patients with different stages of diabetic kidney disease (DKD) to healthy matched controls. 34 T1DM patients with variable degrees of renal impairment and 10 controls with intact renal function were recruited. Following an overnight fast, participants underwent physical examination, blood tests, 24-hour urine collection and functional MRI with controlled water intake. MRI parameters from two independent readers were obtained and analyzed. A value of T2*, from which resonance transverse relaxation rate (R2*) is calculated (1/T2*) is obtained from BOLD images. Functional anisotropy (FA) and apparent diffusion coefficient (ADC) values were obtained from DTI images. To determine measured Glomerular Filtration Rate (mGFR), each patient with T1DM underwent 99m-technetium- diethylene-triamine-penta-acetic acid (99mTc-DTPA) plasma clearance with Brochner-Mortensen correction. Univariate analysis was conducted with Mann-Whitney tests. The median mGFR for participants with T1DM was 105 (77,120) ml/min/1.73m2. 31% had hyperfiltration arbitrarily defined as an mGFR³120ml/ min/1.73m2. Participants with hyperfiltration were younger than the normofiltering group (31.5 years vs. 49.5 years, p=0.006). There were no other significant baseline characteristic differences between the two groups. There were also no significant baseline differences between participants with T1DM and healthy controlsR2* was significantly lower both in the cortex (14.7 [13.7-15.8] vs 15.7 [15.1-16.6], p<0.001) and medulla (24.8 [21.8,28.2] vs 29.3 [24.3,32.4], p<0.001) in participants with diabetes compared to healthy controls, respectively. Medullary FA was higher; while cortical FA was lower in diabetes compared to controls. On the other hand, there were no significant differences in both cortical and medullary ADC in participants with and without diabetes. Univariate comparison of MRI parameters between normofiltration and hyperfiltration showed no significant difference for cortical R2*, cortical FA and medullary FA. There was a marginally higher medullary R2* in the hyperfiltration 25.8(23.3,28.7)(1/s) compared to normofiltration 24.4(21.4,27.9)(1/s) (p=0.01) group. ADC in the cortex 2.61(2.53,2.74) (103mm2/s) vs. 2.40(2.29,2.53) (103mm2/s) (p<0.001) and medulla 2.46(2.34,2.58) vs. 2.27(2.08,2.48) (p=0.02) were also observed to be higher in the hyperfiltration group. A lower R2* in our diabetes cohort reflect higher intra-renal oxygen content in diabetes. Higher medullary R2* suggest that hypoxic changes in hyperfiltration to those without hyperfiltration. FA changes in T1DM compared to controls; as well as ADC changes in hyperfiltration also suggests that renal structural changes in DKD may be detected with functional MRI. Further larger studies are required to evaluate the utility of functional MRI in T1DM and hyperfiltration.

Functional methylome analysis of human diabetic kidney disease.

In patients with diabetes mellitus, poor metabolic control has a long-lasting impact on kidney disease development. Epigenetic changes, including cytosine methylation, have been proposed as potential mediators of the long-lasting effect of adverse metabolic events. Our understanding of the presence and contribution of methylation changes to disease development is limited because of the lack of comprehensive base-resolution methylome information of human kidney tissue samples and site-specific methylation editing. Base resolution, whole-genome bisulfite sequencing methylome maps of human diabetic kidney disease (DKD) tubule samples, and associated gene expression measured by RNA sequencing highlighted widespread methylation changes in DKD. Pathway analysis highlighted coordinated (methylation and gene expression) changes in immune signaling, including tumor necrosis factor alpha (TNF). Changes in TNF methylation correlated with kidney function decline. dCas9-Tet1-based lowering of the cytosine methylation level of the TNF differentially methylated region resulted in an increase in the TNF transcript level, indicating that methylation of this locus plays an important role in controlling TNF expression. Increasing the TNF level in diabetic mice increased disease severity, such as albuminuria. In summary, our results indicate widespread methylation differences in DKD kidneys and highlights epigenetic changes in the TNF locus and its contribution to the development of nephropathy in patients with diabetes mellitus.

Single-Cell RNA Profiling of Glomerular Cells Shows Dynamic Changes in Experimental Diabetic Kidney Disease.

Recent single-cell RNA sequencing (scRNA-seq) analyses have offered much insight into cell-specific gene expression profiles in normal kidneys. However, in diseased kidneys, understanding of changes in specific cells, particularly glomerular cells, remains limited. To elucidate the glomerular cell-specific gene expression changes in diabetic kidney disease, we performed scRNA-seq analysis of isolated glomerular cells from streptozotocin-induced diabetic endothelial nitric oxide synthase (eNOS)-deficient (eNOS-/-) mice and control eNOS-/- mice. We identified five distinct cell populations, including glomerular endothelial cells, mesangial cells, podocytes, immune cells, and tubular cells. Using scRNA-seq analysis, we confirmed the expression of glomerular cell-specific markers and also identified several new potential markers of glomerular cells. The number of immune cells was significantly higher in diabetic glomeruli compared with control glomeruli, and further cluster analysis showed that these immune cells were predominantly macrophages. Analysis of differential gene expression in endothelial and mesangial cells of diabetic and control mice showed dynamic changes in the pattern of expressed genes, many of which are known to be involved in diabetic kidney disease. Moreover, gene expression analysis showed variable responses of individual cells to diabetic injury. Our findings demonstrate the ability of scRNA-seq analysis in isolated glomerular cells from diabetic and control mice to reveal dynamic changes in gene expression in diabetic kidneys, with variable responses of individual cells. Such changes, which might not be apparent in bulk transcriptomic analysis of glomerular cells, may help identify important pathophysiologic factors contributing to the progression of diabetic kidney disease.

Cobalt treatment does not prevent glomerular morphological alterations in type 1 diabetic rats.

Early renal morphological alterations including glomerular hypertrophy and mesangial expansion occur in diabetic kidney disease and correlate with various clinical manifestations of diabetes. The present study was designed to investigate the influence of pharmacological modulation of HIF-1α (hypoxia inducible factor-1 alpha) protein levels, on these glomerular changes in rodent model of type 1 diabetes. Male wistar rats were made diabetic (Streptozotocin 45mg/kg; i.p.) and afterwards treated with HIF activator cobalt chloride for 4weeks. Renal function was assessed by serum creatinine, albumin, proteinuria levels, oxidative stress: reduced glutathione levels and catalase activity, and renal tissue HIF-1α protein levels were determined by ELISA assay. Histological analysis of kidney sections was done by haematoxylin and eosin (glomeruli diameter), periodic acid Schiff (mesangial expansion and glomerulosclerosis) and sirius red (fibrosis, tubular dilation) staining. Diabetes rats displayed reduced serum albumin levels, marked proteinuria, lower kidney reduced glutathione content, glomerular hypertrophy, glomerulosclerosis, mesangial expansion, tubular dilation and renal fibrosis. Cobalt chloride treatment normalised renal HIF-1α protein levels, reduced development of proteinuria and tubulo-interstitial fibrosis, but the glomerular morphological alterations such as glomerulosclerosis, mesangial expansion, increased glomerular diameter and tubular vacoulations were not abrogated in diabetic kidneys. Glomerular morphological abnormalities might precede the development of proteinuria and renal fibrosis in experimental model of type 1 diabetes. Pharmacological modulation of renal HIF-1α protein levels does not influence glomerular and tubular dilatory changes in diabetic kidney disease.

Shear wave elastography imaging for assessing the chronic pathologic changes in advanced diabetic kidney disease.

ObjectiveThe assessment of the grade of renal fibrosis in diabetic kidney disease (DKD) requires renal biopsy, which may be associated with certain risks. To assess the severity of chronic pathologic changes in DKD, we performed a quantitative analysis of renal parenchymal stiffness in advanced DKD, using shear wave elastography (SWE) imaging.Patients and methodsTwenty-nine diabetic patients with chronic kidney disease (CKD) grades 3–4 due to DKD, and 23 healthy subjects were enrolled. Combined conventional ultrasound and SWE imaging were performed on all participants. The length, width, and cortical thickness and stiffness were recorded for each kidney.ResultsCortical thickness was lower in patients with DKD than in healthy subjects (13.8±2.2 vs 14.8±1.6 mm; P=0.002) and in DKD patients with CKD grade 4 than in those with grade 3 (13.0±3.5 vs 14.7±2.1 mm; P<0.001). Cortical stiffness was greater in patients with DKD than in healthy subjects (23.72±14.33 vs 9.02±2.42 kPa; P<0.001), in DKD patients with CKD grade 4 than in those with grade 3 (30.4±16.2 vs 14.6±8.1 kPa; P<0.001), and in DKD patients with CKD grade 3b, than in those with CKD grade 3a (15.7±6.7 vs 11.0±4.2 kPa; P=0.03). Daily proteinuria was higher in DKD patients with CKD grade 4 than in those with grade 3 (5.52±0.96 vs 1.13±0.72; P=0.001), and in DKD patients with CKD grade 3b, than in those with CKD grade 3a (1.59±0.59 vs 0.77±0.48; P<0.001). Cortical stiffness was inversely correlated with the estimated glomerular filtration rate (r=−0.65, P<0.001) and with cortical thickness (r=−0.43, P<0.001) in patients with DKD.ConclusionsIn patients with advanced DKD, SWE imaging may be utilized as a simple and practical method for quantitative evaluation of the chronic morphological changes and for the differentiation between CKD grades.

Innovative approaches to understanding and addressing health disparities in diabetes care and research.

With the recent published update on the management of hyperglycemia in patients with type 2 diabetes (T2D) as outlined from the American Diabetes Association and the European Association for the Study of Diabetes 2012 position statement, treatment strategies continue to evolve (1). The update is very timely when one considers the growing number of new agents and, as stated by the authors, the “growing uncertainty regarding their proper selection and sequence” (1). The approach to the patient from the position statement clarified the separation of those factors felt to be “modifiable” (i.e., patient attitude, resources, support system, etc.) as opposed to those that usually are not (i.e., disease duration, life expectancy, comorbidities, etc.). However, as timely and up-to-date as the recommendations seem to be, and that the focus continues to be on personalizing treatment strategies, there are other important factors not considered or addressed by the update that greatly affect our treatment decisions. Specifically, we recognize that among the world’s population there are observable differences in diabetes prevalence, incidence, mortality, and disease burden that clearly impact our approach to treatment (2). While these factors contribute to disparities in diabetes presentation, diagnosis, and treatment, they are not easily measured, adequately studied, or routinely considered in daily management. Given the importance of the topic of health disparities in diabetes, our editorial team has featured six articles in this issue of Diabetes Care that report on research related to understanding health disparities. The topics range from discussing the impact of interventions led by community health workers (CHWs) to understanding the role of language barriers on diabetes complications, evaluating cerebral structural changes in diabetic kidney disease in African Americans (AAs), and understanding racial differences in underlying biological factors (3–8). It is reported that minority groups in the U.S. may have less …

Cerebral Structural Changes in Diabetic Kidney Disease: African American–Diabetes Heart Study MIND

OBJECTIVEAlbuminuria and reduced kidney function are associated with cognitive impairment. Relationships between nephropathy and cerebral structural changes remain poorly defined, particularly in African Americans (AAs), a population at higher risk for both cognitive impairment and diabetes than European Americans. We examined the relationship between urine albumin:creatinine ratio (UACR), estimated glomerular filtration rate (eGFR), and cerebral MRI volumes in 263 AAs with type 2 diabetes.RESEARCH DESIGN AND METHODSCross-sectional associations between renal parameters and white matter (WM), gray matter (GM), hippocampal, and WM lesion (WML) volumes were assessed using generalized linear models adjusted for age, education, sex, BMI, hemoglobin A1c (HbA1c) level, and hypertension.RESULTSParticipants had a mean (SD) age of 60.2 years (9.7 years), and 62.7% were female. Mean diabetes duration was 14.3 years (8.9 years), HbA1c level was 8.2% (2.2%; 66 mmol/mol), eGFR was 86.0 mL/min/1.73 m2 (23.2 mL/min/1.73 m2), and UACR was 155.8 mg/g (542.1 mg/g; median 8.1 mg/g). Those with chronic kidney disease (CKD) (eGFR <60 mL/min/1.73 m2 or UACR >30 mg/g) had smaller GM and higher WML volumes. Higher UACR was significantly associated with higher WML volume and greater atrophy (larger cerebrospinal fluid volumes), and smaller GM and hippocampal WM volumes. A higher eGFR was associated with larger hippocampal WM volumes. Consistent with higher WML volumes, participants with CKD had significantly poorer processing speed and working memory. These findings were independent of glycemic control.CONCLUSIONSWe found albuminuria to be a better marker of cerebral structural changes than eGFR in AAs with type 2 diabetes. Relationships between albuminuria and brain pathology may contribute to poorer cognitive performance in patients with mild CKD.

Novel urinary biomarkers in early diabetic kidney disease.

In diabetic kidney disease, detection of urinary albumin is recommended to aid in diagnosis, evaluate disease severity, and determine effects of therapy. However, because typical histopathologic changes in diabetic kidney disease or early progressive renal decline may occur in patients with normoalbuminuria, urinary albumin may not be sufficient to identify patients with early-stage diabetic kidney disease or to predict its progression. Therefore, intensive efforts have been made to identify novel noninvasive urinary biomarkers to discriminate patients with a higher risk of end-stage renal failure. Because diabetic kidney disease progression is associated with the extent of histologic changes in the glomeruli and the degree of tubulointerstitial changes, urinary biomarkers that accurately reflect the degree of histopathologic damage may be excellent biomarkers. This review article summarizes the clinical significance of new urinary biomarkers in the early detection of diabetic kidney disease.

Prediction of diabetic nephropathy: The need for a sweet biomarker.

Diabetes is the leading cause of end stage renal disease, adult-onset blindness, and non-traumatic lower limb amputations. However, there is great variability among patients in the location, severity, and timing of the onset of diabetic complications. For example, one individual with uncontrolled diabetes for more than 30 years may have a mild degree of complications, while another individual with a 10 year history of diabetes may be blind and dialysis-dependent. Current guidelines recommend controlling blood glucose, blood pressure, and lipid levels, smoking cessation, and administration of antiplatelet agents in order to delay the progression of diabetes complications. Annual testing of serum creatinine and urine albumin excretion is recommended to screen for nephropathy (3). However, beyond recommendations for screening and treatment, there is no practical method to predict which patients who develop complications will have a progressive course to end points such as end-stage kidney disease. Glomerular mesangial expansion, thickening of the basement membranes as well as glomerular sclerosis are considered the hallmark pathologic changes in diabetic kidney disease (4). Although the structural changes in diabetic nephropathy may be the same but the clinical manifestations of diabetic kidney disease may not be similar for different patients. We currently treat all diabetic patients with the same strategies, although we are aware that their individual response and risk of renal progression may be different. Currently, there are no reliable biomarkers available that can predict a more progressive course in patients with diabetic nephropathy. In theory and in practice, it would be extremely useful to have a biomarker that can predict a more rapid decline in renal function among diabetic patients. Several clinical, genetic, and cellular markers have been proposed and tested for predicting the development of diabetic nephropathy in the past decade (5). The majority of the markers used in clinical practice, such as microalbuminuria, turn out to be markers of diabetic nephropathy rather than being predictors of its progression (6). The ability to identify diabetic patients at high risk for progressive renal decline should be one of the priorities of the nephrology community. Early identification may lead to improved clinical management, quality of life, and a decrease in the already high burden of morbidity. An ideal biomarker should be relatively inexpensive and readily measured either in serum or urine. Our task is far from being completed.

Histopathological changes in diabetic kidney disease

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) worldwide. Initial stages of DN are characterized by normo-albuminuria with normal glomerular filtration rate (GFR) and are associated with glomerular and tubular hypertrophy and enlarged kidneys, followed by this to microalbuminuria or incipient DN stage. Diabetic nephropathy progresses to macroalbuminuria or overt proteinuria stage with decline in GFR and with further decline in GFR it progresses to ESRD with advanced glomerulosclerosis form within 15–25 years. Early and most characteristic changes of DN includes glomerular basement membrane thickening. The characteristic histologic changes of DN includes thickening of glomerular and tubular basement membrane, increase in mesangial matrix, Kimmelstiel-Wilson nodules sometimes combined with microaneurysms, exudative or hyalinosis lesions, capsular drop and afferent and efferent arteriolar hyalinosis. A careful clinical details and laboratory findings are important in the interpretation of histology of DN. The recent classification system introduced by Renal Pathology Society (RPS) is likely to help discover more about the pathways of DN progression and also in predicting clinical outcome.