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SGLT2 inhibitors (SGLT2i) will change the clinical practice of nephrology with their therapeutic cardiorenal and antidiabetic properties. By inhibiting proximal tubular sodium and glucose reabsorption, these new drugs decrease intraglomerular pressures. Over the last 5 years several breakthrough studies have demonstrated the SGLT2i protective effects on outcomes such as cardiovascular mortality, hospital admission for heart failure, sustained decreases in eGFR in patients with diabetic nephropathy and the development of ESKD. With the new DAPA-CKD study revealing protective effects of SGLT2i in CKD patients without diabetes, therapeutic recommendations will now have to evolve towards including these drugs in the chronic management of all most proteinuric CKD patients.Les inhibiteurs du cotransporteur du sodium-glucose de type 2 (iSGLT2) révolutionnent la pratique clinique en néphrologie par le biais de leurs effets antidiabétique, cardio et néphroprotecteur. Ces molécules inhibent la réabsorption du glucose et du sodium au niveau du tubule proximal, ce qui résulte en une baisse de la pression intraglomérulaire. Plusieurs grandes études ont démontré l’effet protecteur des iSGLT2 sur la mortalité cardiovasculaire, le taux d’hospitalisation pour une insuffisance cardiaque et le ralentissement de la progression de la néphropathie diabétique. La sortie de DAPA-CKD va certainement modifier les recommandations thérapeutiques pour la prise en charge de l’insuffisance rénale chronique (IRC) non diabétique, en démontrant un effet néphroprotecteur majeur chez les IRC protéinuriques d’origine non diabétique également.

Background and Aims. Sulodexide has been reported to have antiproteinuric and nephroprotective properties. We investigated the effects of long-term low-dose Sulodexide on proteinuria and renal function in patients with chronic kidney disease (CKD) caused by diabetic nephropathy (DN), hypertensive nephropathy (HN) and primary glomerulonephritis (GN). Material and Methods. 100 patients with CKD received low-dose Sulodexide 50 mg/day for 12 months. Treatment efficacy was evaluated as proteinuria reduction compared to baseline; response was defined as a decline in proteinuria below 0.3 g/d. Renal function evolution was assessed by eGFR variation from baseline. Results. All patients presented reduction of proteinuria, with global mean value of proteinuria decrease of 0.85 ± 1.34 g/d (p2, p=0.043). Multivariate regression analysis identified that responder status was significantly associated with gender, baseline eGFR, baseline proteinuria and etiology of CKD. Concomitant administration of ACEIs or/and ARBs did not influence the response to Sulodexide therapy. Conclusions. Independently of ACEIs or/and ARBs therapy, long-term low-dose Sulodexide is efficient as antiproteinuric and renoprotective therapy in patients with CKD caused by DN, GN and HN. Better response is achieved in patients with lower degree of renal dysfunction.

We performed a prospective study to evaluate the value of contrast-enhanced ultrasound (CEUS) in quantitative evaluation of renal cortex perfusion in patients suspected of early diabetic nephropathies (DN), with the estimated GFR (MDRD equation) as the gold standard.The study protocol was approved by the hospital review board; each patient gave written informed consent. Our study included 46 cases (21 males and 25 females, mean age 55.6 ± 4.14 years) of clinical confirmed early DN patients. After intravenous bolus injection of 1 ml sulfur hexafluoride microbubbles of ultrasound contrast agent, real time CEUS of renal cortex was performed successively using a 2-5 MHz convex probe. Time-intensity curves (TICs) and quantitative indexes were created with Qlab software. Receiver operating characteristic (ROC) curves were used to predict the diagnostic criteria of CEUS quantitative indexes, and their diagnostic efficiencies were compared with resistance index (RI) and peak systolic velocity (PSV) of renal segmental arteries by chi square test. Our control group included forty-five healthy volunteers. Difference was considered statistically significant with P 0.05.Changes of area under curve (AUC), derived peak intensity (DPI) were statistically significant (P 0.05). DPI less than 12 and AUC greater than 1400 had high utility in DN, with 71.7% and 67.3% sensitivity, 77.8% and 80.0% specificity. These results were significantly better than those obtained with RI and PSV which had no significant difference in early stage of DN (P 0.05).CEUS might be helpful to improve early diagnosis of DN by quantitative analyses. AUC and DPI might be valuable quantitative indexes.

6. Mallek R, Mostbeck GH, Kain R, Sunder-Plassmann G,Helbich T, Tscholakoff D. Polyetiology of renal allograftdysfunction. Does calculation of the resistive index still makesense? Acta Radiol 1992; 33: 434–4397. Scholbach T, Girelli E, Scholbach J. Dynamic tissue perfusionmeasurement: a novel tool in follow-up of renal transplants.Transplantation 2005; 79: 1711–17168. Nankivell BJ, Chapman JR, Gruenewald SM. Detection ofchronic allograft nephropathy by quantitative doppler imaging.Transplantation 2002; 74: 90–969. Jakobsen JA, Oyen R, Thomsen HS, Morcos SK. Safety ofultrasound contrast agents. Eur Radiol 2005; 15: 941–94510. Albrecht T, Blomley M, Bolondi L et al. Guidelines for the useof contrast agents in ultrasound. Ultraschall Med 2004; 25:249–25611. Korosoglou G, Hansen A, Hoffend J et al. Comparison of real-time myocardial contrast echocardiography for the assessmentof myocardial viability with fluorodeoxyglucose-18 positronemission tomography and dobutamine stress echocardiography.Am J Cardiol 2004; 94: 570–57612. Lindner JR, Villanueva FS, Dent JM, Wei K, Sklenar J, Kaul S.Assessment of resting perfusion with myocardial contrastechocardiography: theoretical and practical considerations.Am Heart J 2000; 139(2 Pt 1): 231–240Received for publication: 9.5.06Accepted in revised form: 28.6.06Nephrol Dial Transplant (2006) 21: 2696–2702doi:10.1093/ndt/gfl448Advance Access publication 5 August 2006

To observe the therapeutic effect of type II early diabetic nephropathies intervened by acupoint thread embedding for strengthening spleen and benefiting kidney.Sixty cases of type II early diabetic nephropathies were randomly divided into an acupoint thread embedding group and a routine therapy group, 30 cases in each group. In routine therapy group, western medicine routine therapy was applied to control blood sugar, blood pressure and blood lipid. In acupoint thread embedding group, besides the western medicine routine therapy, thread embedding intervention was given at Pishu (BL 20), Zusanli (ST 36), Shenshu (BL 23) and Yishu (Extra) on both sides as main acupints, and the treatment course was 3 months. Urinary micro-albumin excretion (UAER), total score of TCM syndrome and monitor control indices (blood sugar, blood pressure, blood lipid, urea nitrogen and serum creatinine) in both groups were observed before and after treatment, and the therapeutic effects in both groups were compared.After treatment, the indices of UAER and total score of TCM syndrome were all reduced (P0.001, P0.01); the reduction in acupoint thread embedding group was more obvious (P0.01, P0.05); the total effective rate in acupoint thread embedding group was 76.7% (23/30), superior to that of 63.3% (19/30) in routine therapy group (P0.05). The blood sugar, blood pressure and blood lipid in both groups were remarkably improved (all P0.001) after treatment; the urea nitrogen and creatinine had no notable variation.Acupoint thread embedding combined with western medicine routine therapy can not only reduce the urinary micro-albumin excretion of type II early diabetic nephropathies, but also improve the Chinese medicine symptoms and the therapeutic effect is superior to that of simple western medicine routine therapy.

To probe into clinical therapeutic effect of acupuncture on diabetic nephropathies and the mechanism.Using multi-central, randomized and blind methods, 130 cases of diabetic nephropathy were divided into an observation group and a control group, 65 cases in each group. They were treated by routine diabetic therapy, and in the observation group, acupuncture at Quchi (LI 11), Zhigou (TE 6), Hegu (LI 4), Xuehai (SP 10), Zusanli (ST 36), Yinlingquan (SP 9), Fenglong (ST 40), Diji (SP 8), Sanyinjiao (SP 6), Taichong (LR 3), Tianshu (ST 25), Gaohuang (BL 43), Shenshu (BL 23), Zhongwan (CV 12), Zhongji (CV 3) were added with needling method of harmonizing spleen-stomach. While in the control group, acupuncture at Shenshu (BL 23), Taixi (KI 3), Sanyingjiao (SP 6), Yanglingquan (GB 34), Xuanzhong (GB 39), Guanyuan (CV 4), Shousanli (LI 10), Waiguan (TE 5), Yangxi (LI 5), Liangqiu (ST 34), Shangjuxu (ST 37), Neiting (ST 44), Huaroumen (ST 24), Dachangshu (BL 25). The treatment was given twice a day in the two groups. Clinical therapeutic effects were assessed according to clinical symptoms and signs, blood sugar, blood lipids, urinary albumin excretion rate, urinary monocyte chemotactic protein-1 (MCP-1), glomerular filtration rate (GFR), renal blood flow, etc..The needling method of harmonizing spleen-stomach not only could improve symptoms and signs of the patients, and also had benign regulative action on metabolism of blood sugar and lipids, and GFR, renal blood flow and urinary albumin level, with significant or very significant differences as compared with the control group ( P0.05 or P0.01).The needling method of harmonizing spleen-stomach is an effective method for diabetic nephropathies, which can improve progressive renal lesion induced by abnormal metabolism of blood sugar and lipids, improve renal blood flow and GFR, decrease urinary albumin secretion, inhibit over expression of MCP-1, protect glomerulus and renal tubules, so as to improve renal function and delay renal lesion.

Chronic kidney disease represents a major health problem worldwide. Although the kidney has the ability to repopulate structures that have sustained some degree of injury, the mechanisms underlying its regenerative capacity have been unclear. Recent evidence now supports the existence of a renal progenitor system able to replace podocytes and tubular cells, localized within the urinary pole of Bowman's capsule and along the tubule. Altered growth or differentiation of renal progenitors has been reported in several renal disorders including diabetic nephropathy. Pharmacological modulation of renal progenitor growth or differentiation can enhance kidney regeneration, suggesting that treatments aimed at reversing kidney injury are possible. Renal progenitors may represent a novel target in diabetic nephropathy and other kidney disorders.

Background Rapid and accurate estimation of the glomerular filtation rate (GFR) is required for many major clinical decisions in patients with chronic nephropathies [1]. Direct GFR measurement is time-consuming and expensive, frequently requires urine collection and isotope use, and is routinely available in only a few medical centers [1]. In clinical practice, GFR is usually estimated from the serum creatinine concentration. However, this last is affected by factors other than creatinine glomerular filtration, such as diet, muscle mass, tubular secretion, unstable renal function, colorimetric interference, and day-to-day assay variability [1]. To circumvent these limitations, several equations have been developed to estimate GFR from the serum creatinine concentration adjusted for age, sex, body weight and demographic factors [1]. The equation proposed by Cockcroft and Gault in 1976 is widely used throughout the world [2,3]. Adjustment for body surface area has been shown to improve the accuracy of the original Cockcroft-Gault equation [4]. In recent years, the Modification of Diet in Renal Disease (MDRD) group developed three multiple regression models that improved the prediction of GFR from the plasma creatinine concentration [5]. The first includes urinary urea excretion and the second is derived from demographic factors combined with serum creatinine, urea and albumin; the third, which is slightly less accurate, uses demographic factors and serum creatinine (MDRD abbreviated equation) [5]. Finally, the Mayo Clinic team have developed a quadratic equation (MCQ) based on results of both healthy subjects and patients with chronic renal diseases [6]. The validity of these creatinine-based equations for the follow-up of renal function in patients with known renal disease is uncertain, notably during therapeutic interventions and data on this topic are scarce [7]. Indeed, five studies, all restricted to patients with diabetic nephropathy suggested that, in patients with normal renal function or hyperfiltration (microalbuminuric), prediction equations are not accurate enough to monitor kidney function, whereas in chronic kidney disease (CKD) stages 2 and 3 these equations may be valid [8-12]. The aim of this study was therefore to compare the accuracy of prediction equations (original Cockcroft and Gault equation, Cockcroft and Gault equation adjusted for body surface area, Abbreviated MDRD and Mayo Clinic Quadratic Equation) for the follow-up of non-diabetic nephropathies, by comparison with inulin clearance, the gold standard for GFR estimation. We analyzed data from a prospective cohort of 260 European patients with non-diabetic chronic kidney disease [4], 126 of whom had repeated measures of their GFR based on inulin clearance during their long-term follow-up.

Glycation is the process whereby sugars bind to the free amine residues of proteins. These newly formed modified molecular species are known as 'advanced glycation end-products', or AGEs. AGE toxicity may occur through at least three mechanisms: interaction with the receptor for AGEs (RAGE); tissue deposition; and in situ glycation. AGEs trigger proinflammatory, profibrotic and procoagulant cellular responses that are capable of damaging tissues, often targeting particular organs. In diabetic patients, the conditions needed to promote AGE formation are all present, and are further accentuated by accompanying renal failure. The aim of this review is to outline the involvement of AGEs in the various forms of renal pathology associated with diabetic and non-diabetic nephropathies. AGEs are present in all renal compartments in diabetic patients, including the vessels, glomeruli, tubules and interstitium. Many cell types may be activated-specifically, endothelial, tubular and mesangial cells, and podocytes. AGEs play a major role in the accumulation of extracellular matrix, as occurs in diabetic glomerulosclerosis, and are also involved in most diabetic (renovascular, microangiopathic and glomerular) and non-diabetic renal injury associated with progressive glomerulosclerosis and ageing.

Inflammation is implicated in cardiovascular disease (CVD) and mortality in end-stage renal failure (ESRF). Its importance in early renal disease is yet to be defined.Serum levels of systemic and vascular inflammatory markers in early IgA nephropathy (IgAN) and control subjects were measured and related to renal function and vascular risk factors. A parallel study in type 1 diabetes mellitus subjects with (T1DM Nx) and without nephropathy (T1DM No Nx) was performed.Fifty-one IgAN patients aged 46+/-2 years (mean+/-SEM), calculated creatinine clearance (CrCl) 88+/-5 ml/min, were compared with 51 matched control subjects. Forty-six T1DM Nx patients aged 40+/-2 years, CrCl 84+/-5 ml/min, and 73 T1DM No Nx patients aged 38+/-2 years were also compared. High sensitivity C-reactive protein (hsCRP) was elevated in IgAN, T1DM Nx and T1DM No Nx patients compared with controls [4.2+/-0.6 (P0.001), 4.1+/-0.6 (P0.001), 2.6+/-0.4 (P0.05) vs 1.6+/-0.3 mg/l]. Levels in T1DM Nx patients were higher than in T1DM No Nx patients (P0.05). Inflammation and vascular dysfunction as measured by pulse pressure (PP) were related. HsCRP correlated with PP in IgAN and T1DM Nx (r = 0.47, P = 0.001; r = 0.40, P0.05). PP was the strongest independent predictor of hsCRP in IgAN (T = 2.45, P0.001), while body mass index (T = 7.83, P0.001) was the strongest predictor in T1DM Nx. Endothelial cell adhesion molecules were increased in T1DM NxIgANT1DM No Nx vs controls: soluble vascular adhesion molecule-1 (sVCAM-1) 760+/-30 (P0.001)663+/-34 (P = 0.001)601+/-21 (P0.05) vs 536+/-15 ng/ml; soluble intracellular adhesion molecule-1 (sICAM-1) 320+/-8 (P0.001)313+/-13 (P0.001)307+/-8 (P0.001) vs 244+/-6 ng/ml. sVCAM-1 levels were higher in T1DM Nx than in T1DM No Nx, P0.001. In IgAN and T1DM Nx, hsCRP correlated with sICAM-1 (r = 0.33, P = 0.017; r = 0.37; P = 0.017). sVCAM-1 was related to renal function in IgAN and T1DM Nx: serum cystatin C (r = 0.63, P0.001: r = 0.425, P = 0.002), and urine protein:creatinine ratio in IgAN (r = 0.48; P = 0.001).Systemic and vascular markers of inflammation are increased in early renal disease and relate to renal dysfunction and cardiovascular risk factors. Inflammation may be a common process in various renal diseases and may link and accelerate renal dysfunction and CVD.

The incidence of diabetic nephropathy has declined these last decades, but diabetes mellitus still remains the commonest cause of end-stage renal failure, due to an increased prevalence of diabetes mellitus and a longer life expectancy for diabetic patients. The aim of this review is to describe the natural history of diabetic nephropathy and discuss the influence of many factors such as genetic and non-genetic progression promoters, hypertension, hyperglycemia, dyslipidemia, proteinuria and tobacco. Because only a comprehensive treatment strategy of these promoters will reduce the risk of end-stage renal failure, the inclusion of cardiovascular risk factors management and the screening of cardiovascular disease will further contribute to reduce the very high mortality of diabetic patients suffering of diabetic nephropathy.

Diabetic nephropathy is a serious long-term complication of diabetes characterized by persistent albuminuria (300 mg/24 h or 200 micrograms/min) associated with a decline in GFR, increasing arterial blood pressure, and high risk of cardiovascular morbidity and mortality. Diabetic nephropathy has become the leading cause of end stage renal disease in Europe, USA and Japan. There is a great inter-individual variation in the deterioration in GFR explained by genetic and non-genetic progression promoters (risk factors for losing GFR). In particular arterial blood pressure, glycaemic control, and albuminuria act as non-genetic promoters of progression. These factors are potentially modifiable. Genetic promoters of progression have also been identified, mainly the angiotensin converting enzyme insertion/deletion polymorphism. Knowledge of progression promoters can identify patients with a poor prognosis and direct therapy against modifiable risk factors, in particular hypertension and hyperglycaemia.

The value of polypeptide analyses in the diagnoses of diabetic nephropathy. Early diagnostic signs are rapidly gaining importance in the prevention and care of diabetic complications. The aim of this paper was to review the clinical significance of measurements of the serum and urine levels of beta-2-microglobulin, microalbuminuria and the plasma and urine levels of beta-thromboglobulin. We would like to emphasize their possible role in monitoring and prediction of the chronic sequelae of diabetes mellitus.

Serum creatinine, immunoreactive serum and urine beta-2-microglobulin, plasma and urine thromboglobulin, plasma thromboxane-B2 levels and daily protein excretion were determinated in 61 insulin treated diabetic patients, comparing the different patient groups (complication free, nephropathy without azotaemia and nephropathy with azotaemia) with the control subjects. In the groups of all diabetic patients plasma and urine beta-thromboglobulin and plasma thromboxane-B2 levels were higher that in the controls. There was a positive significant correlation between urine beta-thromboglobulin and beta-2-microglobulin in the group without complication, and between the plasma beta thromboglobulin and beta-2-microglobulin, and plasma beta thromboglobulin and thromboxane levels in the diabetic group with azotaemia. In contradiction to some previous assumptions, the increased level of plasma beta-thromboglobulin reflects a real platelet hyperactivation also in patients with diabetic nephropathy. At the same time urine beta-thromboglobulin also increases. Determination of urine beta-thromboglobulin is more simple with less possibility of methodological error.

Diabetic kidney disease is the most common cause of chronic kidney disease (CKD) and end-stage kidney disease in the world. Risk factor modification, glucose control, and renin-angiotensin-aldosterone system blockade have remained the standard of care for 2 decades. New therapeutic agents have emerged in recent years, demonstrating kidney and cardiovascular benefits, and herein we review recent clinical trials on this topic.After the publication of several cardiovascular outcome trials for sodium-glucose cotransporter 2 inhibitors (SGLT-2i), new trials have focused ON primary kidney-specific outcomes demonstrating safety and benefits among patients with proteinuric CKD; patients with or without diabetes, and heart failure with preserved ejection fraction (HFpEF) respectively. Similarly, nonsteroidal mineralocorticoid receptor antagonists (ns-MRAs) and glucagon-like-peptide 1 receptor agonists (GLP-1 RAs) have improved cardiovascular and kidney outcomes. Recently, clinical practice guidelines have also been updated to reflect this new evidence.In summary, SGLT-2i, GLP-1 RAs, and ns-MRAs have demonstrated cardiovascular and kidney benefits, including all-cause and cardiovascular mortality, progression to end-stage kidney disease, and hospitalizations for heart failure exacerbation among diverse patient population.

BACKGROUND: The endothelin receptor antagonist atrasentan reduced the risk of kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease (CKD) in the SONAR (Study of Diabetic Nephropathy with Atrasentan) trial, although with a numerically higher incidence of heart failure (HF) hospitalization.OBJECTIVES: The purpose of this study was to assess if early changes in B-type natriuretic peptide (BNP) and body weight during atrasentan treatment predict HF risk.METHODS: Participants with type 2 diabetes and CKD entered an open-label enrichment phase to assess response to atrasentan 0.75 mg/day. Participants without substantial fluid retention (>3 kg body weight increase or BNP increase to >300 pg/mL), were randomized to atrasentan 0.75 mg/day or placebo. Cox proportional hazards regression was used to assess the effects of atrasentan vs placebo on the prespecified safety outcome of HF hospitalizations.RESULTS: Among 3,668 patients, 73 (4.0%) participants in the atrasentan and 51 (2.8%) in the placebo group developed HF (HR: 1.39; 95% CI: 0.97-1.99; P = 0.072). In a multivariable analysis, HF risk was associated with higher baseline BNP (HR: 2.32; 95% CI: 1.81-2.97) and percent increase in BNP during response enrichment (HR: 1.46; 95% CI: 1.08-1.98). Body weight change was not associated with HF. Exclusion of patients with at least 25% BNP increase during enrichment attenuated the risk of HF with atrasentan (HR: 1.02; 95% CI: 0.66-1.56) while retaining nephroprotective effects (HR: 0.58; 95% CI: 0.44-0.78).CONCLUSIONS: In patients with type 2 diabetes and CKD, baseline BNP and early changes in BNP in response to atrasentan were associated with HF hospitalization, highlighting the importance of natriuretic peptide monitoring upon initiation of atrasentan treatment. (Study Of Diabetic Nephropathy With Atrasentan [SONAR]; NCT01858532).

The novel nonsteroidal mineralocorticoid receptor antagonist finerenone has been shown to reduce the risk of kidney and cardiovascular outcomes in patients with type 2 diabetes and chronic kidney disease. In this issue of Kidney International, Bakris et al. present new data on the kidney efficacy of finerenone across subgroups of estimated glomerular filtration rate and urinary albumin-to-creatinine ratio, as well as safety data. We attempt to place these results in context by discussing the benefits and risks of finerenone, as well as the generalizability of the study findings to routine care settings.

The signaling molecule stimulator of IFN genes (STING) was identified as a crucial regulator of the DNA-sensing cyclic GMP-AMP synthase (cGAS)-STING pathway, and this signaling pathway regulates inflammation and energy homeostasis under conditions of obesity, kidney fibrosis, and AKI. However, the role of STING in causing CKD, including diabetic kidney disease (DKD) and Alport syndrome, is unknown.To investigate whether STING activation contributes to the development and progression of glomerular diseases such as DKD and Alport syndrome, immortalized human and murine podocytes were differentiated for 14 days and treated with a STING-specific agonist. We used diabeticThe activation of the STING pathway acts as a mediator of disease progression in DKD and Alport syndrome. Targeting STING may offer a therapeutic option to treat glomerular diseases of metabolic and nonmetabolic origin or prevent their development, progression, or both.

San-Huang-Yi-Shen capsule (SHYS) has been used in the treatment of diabetic kidney disease (DKD) in clinics. However, the mechanism of SHYS on DKD remains unclear. In this study, we used a high-fat diet combined with streptozocin (STZ) injection to establish a rat model of DKD, and different doses of SHYS were given by oral gavage to determine the therapeutic effects of SHYS on DKD. Then, we studied the effects of SHYS on PINK1/Parkin-mediated mitophagy and the activation of NLRP3 inflammasome to study the possible mechanisms of SHYS on DKD. Our result showed that SHYS could alleviate DKD through reducing the body weight loss, decreasing the levels of fasting blood glucose (FBG), and improving the renal function, insulin resistance (IR), and inhibiting inflammatory response and oxidative stress in the kidney. Moreover, transmission electron microscopy showed SHYS treatment improved the morphology of mitochondria in the kidney. In addition, western blot and immunoflourescence staining showed that SHYS treatment induced the PINK1/Parkin-mediated mitophagy and inhibited the activation of NLRP3 signaling pathway. In conclusion, our study demonstrated the therapeutic effects of SHYS on DKD. Additionally, our results indicated that SHYS promoted PINK1/Parkin-mediated mitophagy and inhibited NLRP3 inflammasome activation to improve mitochondrial injury and inflammatory responses.

Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease (ESKD). Prognostic biomarkers reflective of underlying molecular mechanisms are critically needed for effective management of DKD. A three-marker panel was derived from a proteomics analysis of plasma samples by an unbiased machine learning approach from participants (N = 58) in the Clinical Phenotyping and Resource Biobank study. In combination with standard clinical parameters, this panel improved prediction of the composite outcome of ESKD or a 40% decline in glomerular filtration rate. The panel was validated in an independent group (N = 68), who also had kidney transcriptomic profiles. One marker, plasma angiopoietin 2 (ANGPT2), was significantly associated with outcomes in cohorts from the Cardiovascular Health Study (N = 3,183) and the Chinese Cohort Study of Chronic Kidney Disease (N = 210). Glomerular transcriptional angiopoietin/Tie (ANG-TIE) pathway scores, derived from the expression of 154 ANG-TIE signaling mediators, correlated positively with plasma ANGPT2 levels and kidney outcomes. Higher receptor expression in glomeruli and higher ANG-TIE pathway scores in endothelial cells corroborated potential functional effects in the kidney from elevated plasma ANGPT2 levels. Our work suggests that ANGPT2 is a promising prognostic endothelial biomarker with likely functional impact on glomerular pathogenesis in DKD.

In diabetic nephropathy, hyperglycemia elevates albumin glycation and also results in increased plasma aldosterone. Both glycation and aldosterone are reported to cause oxidative stress by downregulating the NRF-2 pathway and thereby resulting in reduced levels of antioxidants and glycation detoxifying enzymes. We hypothesize that an interaction between aldosterone and glycated albumin may be responsible for amplified oxidative stress and concomitant renal cell damage. Hence, human serum albumin was glycated by methylglyoxal (MGO) in presence of aldosterone. Different structural modifications of albumin, functional modifications and aldosterone binding were analyzed. HEK-293 T cells were treated with aldosterone+glycated albumin along with inhibitors of receptors for mineralocorticoid (MR) and advanced glycation endproducts (RAGE). Cellular MGO content, antioxidant markers (nitric oxide, glutathione, catalase, superoxide dismutase, glutathione peroxidase), detoxification enzymes (aldose reductase, Glyoxalase I, II), their expression along with NRF-2 and Keap-1 were measured. Aldosterone binds to albumin with high affinity which is static and spontaneous. Cell treatment by aldosterone+glycated albumin increased intracellular MGO, MR and RAGE expression; hampered antioxidant, detoxification enzyme activities and reduced NRF-2, Keap-1 expression. Thus, the glycated albumin-aldosterone interaction and its adverse effect on renal cells were confirmed. The results will help in developing better pharmacotherapeutic strategies for diabetic nephropathy.

Abstract: Diabetic nephropathy (DN) is a leading cause of end-stage renal disorder (ESRD). It is defined as the increase in urinary albumin excretion (UAE) when no other renal disease is present. DN is categorized into microalbuminuria and macroalbuminuria. Factors like high blood pressure, high blood sugar levels, genetics, oxidative stress, hemodynamic and metabolic changes affect DN. Hyperglycemia causes renal damage through activating protein kinase C (PKC), producing advanced end glycation products (AGEs) and reactive oxygen species (ROS). Growth factors, chemokines, cell adhesion molecules, inflammatory cytokines are found to be elevated in the renal tissues of the diabetic patient. Many different and new diagnostic methods and treatment options are available due to the increase in research efforts and progression in medical science. However, until now no permanent cure is available. This article aims to explore the mechanism, diagnosis, and therapeutic strategies in current use for increasing the understanding of DN

Diabetes is accompanied by the worsening of kidney functions. The reasons for kidney dysfunction mainly include high blood pressure (BP), high blood sugar levels, and genetic makeup. Vascular complications are the leading cause of the end-stage renal disorder (ESRD) and death of diabetic patients. Epigenetics has emerged as a new area to explain the inheritance of non-mendelian conditions like diabetic kidney diseases. Aberrant post-translational histone modifications (PTHMs), DNA methylation (DNAme), and miRNA constitute major epigenetic mechanisms that progress diabetic nephropathy (DN). Increased blood sugar levels alter PTHMs, DNAme, and miRNA in kidney cells results in aberrant gene expression that causes fibrosis, accumulation of extracellular matrix (ECM), increase in reactive oxygen species (ROS), and renal injuries. Histone acetylation (HAc) and histone deacetylation (HDAC) are the most studied epigenetic modifications with implications in the occurrence of kidney disorders. miRNAs induced by hyperglycemia in renal cells are also responsible for ECM accumulation and dysfunction of the glomerulus. In this review, we highlight the role of epigenetic modifications in DN progression and current strategies employed to ameliorate DN.

Type 2 diabetes (T2D) is a global health pandemic with significant humanitarian, economic, and societal implications, particularly for youth and young adults who are experiencing an exponential rise in incident disease. Youth-onset T2D has a more aggressive phenotype than adult-onset T2D, and this translates to important differences in rates of progression of diabetic kidney disease (DKD). We hypothesize that youth-onset DKD due to T2D may exhibit morphometric, metabolic, and molecular characteristics that are distinct from adult-onset T2D and develop secondary to inherent differences in renal energy expenditure and substrate metabolism, resulting in a central metabolic imbalance. Kidney structural changes that are evident at the onset of puberty also serve to exacerbate the organ’s baseline high rates of energy expenditure. Additionally, the physiologic state of insulin resistance seen during puberty increases the risk for kidney disease and is exacerbated by both concurrent diabetes and obesity. A metabolic mismatch in renal energetics may represent a novel target for pharmacologic intervention, both for prevention and treatment of DKD. Further investigation into the underlying molecular mechanisms resulting in DKD in youth-onset T2D using metabolomics and RNA sequencing of kidney tissue obtained at biopsy is necessary to expand our understanding of early DKD and potential targets for therapeutic intervention. Furthermore, large-scale clinical trials evaluating the duration of kidney protective effects of pharmacologic interventions that target a metabolic mismatch in kidney energy expenditure are needed to help mitigate the risk of DKD in youth-onset T2D.

Diabetic nephropathy (DN) has become the major cause of end-stage kidney disease and is associated to an extremely high cardiovascular (CV) risk.We screened 318 DN patients for 23 SNPs in four glucose transporters (In the patient's cohort, common carotid intima media thickness values were higher in carriers ofPolymorphisms in genes determining glucose homeostasis may play a relevant role in renal parameters and CV-related outcomes of DN patients.

BACKGROUND: Diabetic kidney disease (DKD) remains the leading cause of end stage kidney disease worldwide. Despite significant advances in kidney care, there is a need to improve noninvasive techniques to predict the progression of kidney disease better for patients with diabetes. After injury, podocytes are shed in urine and may be used as a biologic tool. We previously reported that SHP-1 is upregulated in the kidney of diabetic mice, leading to podocyte dysfunction and loss. Our objective was to evaluate the expression levels of SHP-1 in urinary podocytes and kidney tissues of patients with diabetes. METHODS: In this prospective study, patients with and without diabetes were recruited for the quantification of SHP-1 in kidney tissues, urinary podocytes, and peripheral blood monocytes. Immunochemistry and mass spectrometry techniques were applied for kidney tissues. Urinary podocytes were counted, and expression of SHP-1 and podocyte markers were measured by quantitative PCR. RESULTS: A total of 66 participants (diabetic n=48, nondiabetic n=18) were included in the analyses. Diabetes was associated with increased SHP-1 expression in kidney tissues (P=0.03). Nephrin and podocin mRNA was not significantly increased in urinary podocytes from patients with diabetes compared with those without diabetes, whereas levels of SHP-1 mRNA expression significantly correlated with HbA1c and estimated glomerular filtration rate (eGFR). Additionally, follow-up (up to 2 years post recruitment) evaluation indicated that SHP-1 mRNA expression continued to increase with eGFR decline. CONCLUSIONS: Levels of SHP-1 in urinary podocytes may serve as an additional marker of glomerular disease progression in this population.