Novel therapies are urgently needed to address the rising incidence and prevalence of acute kidney injury (AKI) and chronic kidney disease (CKD). Mesenchymal stem/stromal cells (MSCs) have shown promising results in experimental AKI and CKD, and have been used in the clinic for more than a decade with an excellent safety profile. The regenerative effects of MSCs do not rely on their differentiation and ability to replace damaged tissues, but are primarily mediated by the paracrine release of factors, including extracellular vesicles (EVs), composed of microvesicles and exosomes. MSC-derived EVs contain genetic and protein material that upon transferring to recipient cells can activate several repair mechanisms to ameliorate renal injury. Recent studies have shown that MSC-derived EV therapy improved renal outcomes in several animal models of AKI and CKD, including ischemia-reperfusion injury, drug/toxin-induced nephropathy, renovascular disease, ureteral obstruction, and subtotal nephrectomy. However, data about the renoprotective effects of EV therapy in patients with renal failure are scarce. This review summarizes current knowledge of MSC-derived EV therapy in experimental AKI and CKD, and discusses the challenges that need to be addressed in order to consider MSC-derived EVs as a realistic clinical tool to treat patients with these conditions.

Transplantation of autologous mesenchymal stem cells (MSCs) has been shown to attenuate renal injury and dysfunction in several animal models, and its efficacy is currently being tested in clinical trials for patients with renal disease. Accumulating evidence indicates that MSCs release extracellular vesicles (EVs) that deliver genes, microRNAs and proteins to recipient cells, acting as mediators of MSC paracrine actions. In this context, it is critical to characterize the MSC-derived EV cargo to elucidate their potential contribution to renal repair. In recent years, researchers have performed high-throughput sequencing and proteomic analysis to detect and identify genes, microRNAs, and proteins enriched in MSC-derived EVs. The present review summarizes the current knowledge of the MSC-derived EV secretome to shed light into the mechanisms mediating MSC renal repair, and discusses preclinical and clinical studies testing the efficacy of MSC-derived EVs for treating renal disease.

Background Sodium glucose transporter‐2 (SGLT‐2) inhibitors and glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) effectively lowered cardiovascular risk in large clinical trials for patients with type 2 diabetes at high risk for these complications, and have recommended by guidelines. To evaluate the contemporary landscape in which these recommendations would be implemented, we examined the use of these medications according to clinical guideline practice. Methods and Results In the National Health and Nutrition Examination Survey for 2017‐2018, we defined compelling indications for SGLT‐2 inhibitors by the presence of atherosclerotic cardiovascular disease (ASCVD), heart failure, or chronic kidney disease (CKD), and for GLP‐1RAs by the presence of established or high risk ASCVD, based on large clinical trials that have been incorporated in guideline recommendations of the American College of Cardiology (ACC) and American Diabetes Association (ADA). We then evaluated utilization of these medications among patients with physician‐diagnosed type 2 diabetes. All analyses incorporated complex survey design to produce nationally representative estimates. A total 1104 of 9254 sampled individuals had type 2 diabetes, representing 10.6% (95% CI 9.7‐11.6) of the US population or 33.2 million adults nationally. Of these, 52.6% (47.7‐57.5) had an indication for SGLT‐2 inhibitors, 32.8% (28.8‐37.2) for GLP‐1RAs, and 26.6% (22.2‐31.7) for both medications. During 2017‐2018, 4.5% (2.4‐8.2) were treated with SGLT‐2 inhibitors and 1.5% (0.7‐3.2) with GLP‐1RAs. ASCVD, heart failure, or CKD were not independently associated with SGLT‐2 inhibitor or GLP‐1RA use in patients with diabetes. Conclusions Despite a large number of patients being eligible for guideline recommended cardiorenal protective therapies, there are substantial gaps in the use of SGLT‐2 inhibitors and GLP‐1RAs, limiting their public health benefits.

Heat shock proteins (HSPs) have been repeatedly implicated in the pathogenesis of rheumatoid arthritis (RA). The authors aimed to study applicability of heat shock protein 70 (HSPA1A) serum levels as a diagnostic factor and a severity indicator in patients with RA and to quantify cut-off point that predicts status of RA with highest specificity. A total of 76 patients with RA and 36 healthy adults were studied in this case-control analysis. Patients had a higher HSPA1A level than the control group (0.78 ± 0.13 vs. 0.12 ± 0.02 ng/mL, p = 0.006), irrespective of presence of absence of rheumatoid factor or anti-citrullinated cyclic peptide. Next, diagnostic accuracy of the HSPA1A in diagnosis of RA was evaluated (area under curve 0.71; p < 0.05). HSPA1A predicted status of having RA in levels above 0.42 ng/mL with more than 90 % specificity. In addition to diagnostic value, HSPA1A can distinguish between high disease activity (1.66 ± 0.75 ng/mL) and low (0.49 ± 0.1 ng/mL), moderate (0.52 ± 0.12 ng/mL), or remission phase (0.48 ± 0.11 ng/mL). Moreover, patients in remission still had a higher HSPA1A level compared to normal subject (0.48 ± 0.11 vs. 0.12 ± 0.02 ng/mL, p < 0.05). Our results showed that serum HSPA1A could be implemented as a specific tool to facilitate diagnosis and monitoring disease activity in patients with rheumatoid arthritis.

Metabolic syndrome (MetS) is associated with nutrient surplus and kidney hyperfiltration, accelerating chronic renal failure. The potential involvement of podocyte damage in early MetS remains unclear. Mitochondrial dysfunction is an important determinant of renal damage, but whether it contributes to MetS-related podocyte injury remains unknown. Domestic pigs were studied after 16 wk of diet-induced MetS, MetS treated with the mitochondria-targeted peptide elamipretide (ELAM; 0.1 mg·kg−1·day−1 sc) for the last month of diet, and lean controls ( n = 6 pigs/group). Glomerular filtration rate (GFR) and renal blood flow (RBF) were measured using multidetector computed tomography, and podocyte and mitochondrial injury were measured by light and electron microscopy. Urinary levels of podocyte-derived extracellular vesicles (pEVs; nephrin positive/podocalyxin positive) were characterized by flow cytometry. Body weight, blood pressure, RBF, and GFR were elevated in MetS. Glomerular size and glomerular injury score were also elevated in MetS and decreased after ELAM treatment. Evidence of podocyte injury, impaired podocyte mitochondria, and foot process width were all increased in MetS but restored with ELAM. The urinary concentration of pEVs was elevated in MetS pigs and directly correlated with renal dysfunction, glomerular injury, and fibrosis and inversely correlated with glomerular nephrin expression. Additionally, pEV numbers were elevated in the urine of obese compared with lean human patients. Early MetS induces podocyte injury and mitochondrial damage, which can be blunted by mitoprotection. Urinary pEVs reflecting podocyte injury might represent early markers of MetS-related kidney disease and a novel therapeutic target.

No abstract

No abstract

Here, we aimed to study serum heat shock protein (HSP) 70 levels in diabetic patients with and without albuminuria. We performed a 1:1 matched case control study on 40 diabetic patients with albuminuria as cases and 40 age, sex, body mass index matched diabetic patients without albuminuria (normoalbuminuria) as controls. Normoalbuminuria was defined as urinary albumin excretion rate <15 mg/12 h, and albuminuria was defined as urinary albumin excretion rate between 100-400 mg/12 h. Patients with albuminuria had a higher HSP70 than controls (0.83±0.50 vs. 0.63±0.06; p= 0.02), while they did not differ in any other studied variables. In ten of the studied pairs, the controls had higher HSP70 levels than cases (reverse relationship). Patients in the "direct relationship group" had higher HbA1c values than the patients in the "reverse relationship group" (8.9±0.3 vs. 7.3±0.6, p=0.04). Cases in the reverse pairs had a lower low density lipoprotein cholesterol levels than their controls. The odds ratio of HSP70 in the prediction of albuminuria was (28.69 (3.2-250.1), p=0.002). In conclusion, we have shown an increased HSP70 levels in diabetic patients with albuminuria.