Therapeutic Exercise on Metabolic and Renal Outcomes in Patients with Chronic Kidney Disease: A Narrative Review.

BACKGROUND: Chronic kidney disease (CKD) affects 11-13% of the world population. The main risk factors for CKD include diabetes, hypertension, and obesity. Metabolic syndrome (MS) is associated with the onset of CKD in the nondiabetic population. Obesity and MS are also risk factors for a worse progression of established CKD. Therapeutic exercise is an effective option to treat and manage obesity, MS, and diabetes in the general population. However, the evidence on the effect of exercise on patients with CKD, obesity, and MS is scarce. SUMMARY: We evaluated available evidence on the effect of therapeutic exercise in patients with CKD, excluding dialysis, particularly in improving the metabolic risk factors and main renal outcomes: renal function loss and albuminuria/proteinuria. This review includes prospective studies and clinical trials. A total of 44 studies were analysed in 1,700 subjects with renal disease (2-5), including patients with renal transplantation. Most studies did not prove a major effect of exercise on albuminuria/proteinuria, glomerular filtration rate (GFR), obesity, or MS. These results are intriguing and deserve attention. The exploratory nature of most studies, including a low number of cases and short follow-up, might explain the lack of efficacy of exercise in our analysis. Specific aspects like the type of exercise, frequency, intensity, duration, accommodation during follow-up, individualization, safety, and adherence are crucial to the success of therapeutic exercise. The beneficial role of exercise in patients with CKD remains to be determined. KEY MESSAGES: Key messages of this review are as follows. (1) The effect of therapeutic exercise on renal and metabolic outcomes in patients with CKD remains to be determined. (2) According to the evidence selected, therapeutic exercise seems to be safe to treat patients with CKD. (3) Most studies are exploratory by nature, with results that need further investigation. (4) Therapeutic exercise is a complex procedure that must be specifically designed to treat patients with CKD.

The effect of monomeric and oligomeric FLAVAnols in patients with type 2 diabetes and microalbuminuria (FLAVA-trial): A double-blind randomized controlled trial.

BACKGROUND & AIMS: Microalbuminuria is an early sign of vascular complications of type 2 diabetes and predicts cardiovascular disease and mortality. Monomeric and oligomeric flavanols (MOFs) are linked to improved vascular health. The aim of this study was to assess the effect of 3 months MOFs on albuminuria and endothelial function markers in patients with type 2 diabetes and microalbuminuria. METHODS: We conducted a double-blind, placebo-controlled trial among patients with type 2 diabetes and microalbuminuria. Patients with type 2 diabetes received either 200 mg MOFs or placebo daily on top of their habitual diet and medication. The primary endpoint was the between-group difference of the change in 24-h Albumin Excretion Rate (AER) over three months. Secondary endpoints were the between-group differences of the change in plasma levels of different markers of endothelial dysfunction. Mixed-modelling was applied for the longitudinal analyses. RESULTS: Participants (n = 97) were 63.0 ± 9.5 years old; diabetes-duration was 15.7 ± 8.5 years. Median baseline AER was 60 (IQR 20-120) mg/24 h. There was no within-group difference in median change of AER from baseline to 3 months in the intervention (0 (-35-21) mg/24 h, p = 0.41) or the control group (0 (-20-10) mg/24 h, p = 0.91). There was no between-group difference in the course of AER over three months (log-transformed data: ß = -0.02 (95%CI -0.23-0.20), p = 0.88), nor in the plasma levels of the endothelial dysfunction markers. CONCLUSION: Daily 200 mg MOFs for three months on top of habitual diet and usual care did not reduce AER and plasma markers of endothelial dysfunction compared to placebo, in patients with long-term type 2 diabetes and microalbuminuria. CLINICAL TRIALS REGISTRATION: NTR4669, www.trialregister.nl.

Efficacy and durability of multifactorial intervention on mortality and MACEs: a randomized clinical trial in type-2 diabetic kidney disease.

BACKGROUND: Multiple modifiable risk factors for late complications in patients with diabetic kidney disease (DKD), including hyperglycemia, hypertension and dyslipidemia, increase the risk of a poor outcome. DKD is associated with a very high cardiovascular risk, which requires simultaneous treatment of these risk factors by implementing an intensified multifactorial treatment approach. However, the efficacy of a multifactorial intervention on major fatal/non-fatal cardiovascular events (MACEs) in DKD patients has been poorly investigated. METHODS: Nephropathy in Diabetes type 2 (NID-2) study is a multicentre, cluster-randomized, open-label clinical trial enrolling 395 DKD patients with albuminuria, diabetic retinopathy (DR) and negative history of CV events in 14 Italian diabetology clinics. Centres were randomly assigned to either Standard-of-Care (SoC) (n = 188) or multifactorial intensive therapy (MT, n = 207) of main cardiovascular risk factors (blood pressure < 130/80 mmHg, glycated haemoglobin < 7%, LDL, HDL and total cholesterol < 100 mg/dL, > 40/50 mg/dL for men/women and < 175 mg/dL, respectively). Primary endpoint was MACEs occurrence by end of follow-up phase. Secondary endpoints included single components of primary endpoint and all-cause death. RESULTS: At the end of intervention period (median 3.84 and 3.40 years in MT and SoC group, respectively), targets achievement was significantly higher in MT. During 13.0 years (IQR 12.4-13.3) of follow-up, 262 MACEs were recorded (116 in MT vs. 146 in SoC). The adjusted Cox shared-frailty model demonstrated 53% lower risk of MACEs in MT arm (adjusted HR 0.47, 95%CI 0.30-0.74, P = 0.001). Similarly, all-cause death risk was 47% lower (adjusted HR 0.53, 95%CI 0.29-0.93, P = 0.027). CONCLUSION: MT induces a remarkable benefit on the risk of MACEs and mortality in high-risk DKD patients. Clinical Trial Registration ClinicalTrials.gov number, NCT00535925. https://clinicaltrials.gov/ct2/show/NCT00535925.

Effect of Oral carnosine supplementation on urinary TGF-ß in diabetic nephropathy: a randomized controlled trial.

BACKGROUND: Activation of the transforming growth factor beta (TGF-ß) pathway is a significant contributor to the pathogenesis of diabetic nephropathy. Carnosine is a dipeptide that can inhibit TGF-ß synthesis. We tested the hypothesis that carnosine supplement added to standard therapy will result in reduced urinary TGF-ß levels among patients with diabetic nephropathy. METHODS: We randomly assigned 40 patients with diabetic nephropathy and albuminuria 30-299 mg/day to treatment with carnosine (2 g/day) or placebo for 12 weeks. Urinary TGF-ß level was determined using ELISA, urine albumin was ascertained by immunonephelometric assay, and renal function and metabolic profiles were determined at baseline and during 12 weeks of active treatment. Primary outcome was decrease in urinary levels of TGF-ß. RESULTS: The 2 groups were comparable for baseline characteristics, blood pressure, urine albumin, urine TGF-ß and renal function measurements. Urinary TGF-ß significantly decreased with carnosine supplement (- 17.8% of the baseline values), whereas it tended to increase with placebo (+ 16.9% of the baseline values) (between-group difference P < 0.05). However, blood urea nitrogen, serum creatinine, glomerular filtration rate and other biochemical parameters remained unchanged during the study period including urinary albuminuria. Both groups were well tolerated with no serious side-effects. CONCLUSIONS: These data indicated an additional renoprotective effect of oral supplementation with carnosine to decrease urinary TGF-ß level that serves as a marker of renal injury in diabetic nephropathy. TRIAL REGISTRATION: Thai Clinical Trials, TCTR20200724002 . Retrospectively Registered 24 July 2020.

Correlation between urine ACR and 24-h proteinuria in a real-world cohort of systemic AL amyloidosis patients.

A 24-h urine protein collection (24hUP), the gold standard for measuring albuminuria in systemic AL amyloidosis, is cumbersome and inaccurate. We retrospectively reviewed 575 patients with systemic AL amyloidosis to assess the correlation between a urine albumin to creatinine ratio (uACR) and the 24hUP. The uACR correlated strongly with 24hUP at diagnosis (Pearson's r = 0.87, 95% CI 0.83-0.90) and during the disease course (Pearson's r = 0.88, 95% CI 0.86-0.90). A uACR ≥300 mg/g estimated a 24hUP ≥ 500 mg with a sensitivity of 92% and specificity of 97% (area under the receiver operating curve = 0.938, 95% CI 0.919-0.957). A uACR cutoff of 3600 mg/g best predicted a 24hUP > 5000 g (sensitivity 93%, specificity 94%), and renal stage at diagnosis was strongly concordant using either 24hUP or uACR as the proteinuria measure (k = 0.823, 95% CI 0.728-0.919). In patients with serial urine collections, a > 30% decrease in uACR predicted a > 30% decrease in 24hUP with a sensitivity of 94%. In conclusion, the uACR is a reliable and convenient method for ruling out proteinuria >500 mg per day, prognosticating renal outcomes, and assessing renal response to therapy. Further studies are needed to validate the uACR cutoffs proposed in this study.

[Managing diabetic kidney disease]. / Diabetische Nephropathie.

Managing diabetic kidney disease Abstract. Diabetic kidney disease is a common complication of diabetes associated with an increased cardiovascular mortality and is the leading cause of end-stage renal disease. A heterogeneous set of pathological mechanisms drives the development and progression of diabetic kidney disease. A comprehensive diagnostic work-up and repeated reevaluation are needed since diabetic patients can suffer from other nephropathies with a clinical presentation similar to diabetic kidney disease. Screening, treatment of cardiovascular risk factors and the reduction of albuminuria, using renin-angiotensin-aldosterone system and sodium-dependent glucose transporter 2 inhibitors are crucial in the management of diabetic kidney disease.

Impact of interval walking training managed through smart mobile devices on albuminuria and leptin/adiponectin ratio in patients with type 2 diabetes.

BACKGROUND: Interval walking training has demonstrated more pronounced positive effects on physical fitness and metabolism in type 2 diabetes (T2D), compared to continuous walking. One of the pathogenic mechanisms of T2D is associated with derangements in leptin/adiponectin axis, which might predispose affected individuals to vascular inflammation and albuminuria. The aim of this study was to investigate the effects of interval walking training delivered through smart mobile devices upon albuminuria and leptin/adiponectin ratio in patients with T2D. METHODS: Patients with T2D aged 35-75 were randomized into control (n = 26) and interval training (IT, n = 14) groups. Patients in IT group had to perform three 60-min interval walking sessions (3 min intervals of slow and fast walking with the intensity of 40% and 70% of the peak energy expenditure) per week delivered by smartphone application for four months. The adherence to training was monitored remotely. Outcome measures were albuminuria, leptin/adiponectin ratio, obesity indicators, and glycaemic control. Leptin and adiponectin concentration was measured in serum samples by Luminex technology. RESULTS: In the IT group compared to control group, we observed a statistically significant decrease in albuminuria (p = .002) and leptin/adiponectin ratio (p = .01), as well as a decrease in HbA1c close to statistical significance (p = .09). In IT group, changes in leptin/adiponectin ratio correlated significantly with changes in hip circumference (p = .024). CONCLUSION: Interval walking training is beneficial for vascular health in T2D via impact on albuminuria and leptin/adiponectin ratio.

Reversibility of microalbuminuria with continuous positive airway pressure treatment in obstructive sleep apnea syndrome.

INTRODUCTION: Microalbuminuria is an early marker of kidney damage and an early predictor and risk factor for cardiovascular diseases. We aimed to evaluate the association between albuminuria levels in different severity obstructive sleep apnea syndrome (OSAS) cases and to find out the efficacy of CPAP treatment on microalbuminuria. MATERIALS AND METHODS: We conducted a prospective study on subjects who underwent polysomnography. The polysomnographic data were recorded to establish the presence and severity of OSAS. The blood and urine samples were taken both at the time of diagnosis and 3 months after CPAP therapy. The relationship between the severity of OSAS and microalbuminuria and the effect of CPAP treatment on microalbuminuria were evaluated. RESULTS: The study population consisted of 449 subjects. Better compliance to CPAP was associated with significantly reduced levels of microlbuminuria. Urinary albumin/creatinine was increased in severe cases, but the difference was not statistically significant. In the non-compliant group, microalbumin/creatinine ratio was 25.24 prior to initiation of CPAP treatment and 28.36 at the third month control visit (p = 0.25). In the compliant group, microalbumin/creatinine ratio was 49.71 prior to initiation of CPAP treatment and 22.30 at the third month control visit (p = 0.04). CONCLUSION: Our study demonstrated that good compliance to CPAP therapy is associated with a decrease in microalbuminuria. Patients who used CPAP regularly had a significant decline in albumin/creatinine ratio after 3 months of CPAP therapy.

Peripheral arterial endothelial dysfunction predicts future cardiovascular events in diabetic patients with albuminuria: a prospective cohort study.

BACKGROUND: Reactive hyperemia-peripheral arterial tonometry (RH-PAT) is a noninvasive and simple test for evaluating the endothelial function. There has been sparse evidence on the usefulness of the RH-PAT index (RHI) in predicting future cardiovascular diseases among diabetic patients. METHODS: Asymptomatic diabetic patients with albuminuria were selected; their medical history and laboratory findings were evaluated every 3 to 4 months, respectively. The primary outcome was a composite of three-point major adverse cardiovascular events (3-point MACE): death from cardiovascular causes, acute coronary events, or nonfatal stroke. On the contrary, secondary outcomes included a composite of 3-point MACE, hospitalization for heart failure, or chronic kidney disease (CKD) progression. RHI was measured using the Endo-PAT2000 at the baseline. RHI < 1.67 was considered to indicate peripheral endothelial dysfunction (PED). RESULTS: In total, 149 subjects were included (mean age, 61.8 ± 9.2 years; duration of diabetes was 12 years). During the follow-up period (median, 49.7 months), of the 149 subjects, primary outcomes were detected in 12 (1 [2.3%] and 11 [10.5%] of those without and with PED, respectively). The presence of PED in baseline measurements significantly increased both primary and secondary outcomes, following adjustment for age, sex, hypertension, glycated hemoglobin, low-density lipoprotein cholesterol, triglyceride, systolic blood pressure, baseline estimated glomerular filtration rate, overt proteinuria, duration of diabetes, premedical history of ischemic events, anti-platelet agents, and smoking history (hazard ratio [HR]: 10.95; 95% confidence interval CI 1.00-119.91 for the primary outcome; HR, 4.12; 95% CI 1.37-12.41 for secondary outcome). In addition, PED could predict secondary outcomes independent of the risk score according to the American College of Cardiology/American Heart Association (HR: 3.24; 95% CI 1.14-9.17). CONCLUSIONS: PED can independently predict future cardiovascular events among diabetic patients with albuminuria.

Effects of an Electronic Software "Prompt" With Health Care Professional Training on Cardiovascular and Renal Complications in a Multiethnic Population With Type 2 Diabetes and Microalbuminuria (the GP-Prompt Study): Results of a Pragmatic Cluster-Randomized Trial.

OBJECTIVE: Tight, targeted control of modifiable cardiovascular risk factors can reduce cardiovascular complications and mortality in individuals with type 2 diabetes mellitus (T2DM) and microalbuminuria. The effects of using an electronic "prompt" with a treatment algorithm to support a treat-to-target approach has not been tested in primary care. RESEARCH DESIGN AND METHODS: A multicenter, cluster-randomized trial was conducted among primary care practices across Leicestershire, U.K. The primary outcome was the proportion of individuals achieving systolic and diastolic blood pressure (<130 and <80 mmHg, respectively) and total cholesterol (<3.5 mmol/L) targets at 24 months. Secondary outcomes included proportion of individuals with HbA1c <58 mmol/mol (<7.5%), changes in prescribing, change in the albumin-to-creatinine ratio, major adverse cardiovascular events, cardiovascular mortality, and coding accuracy. RESULTS: A total of 2,721 individuals from 22 practices, mean age 63 years, 41% female, and 62% from black and minority ethnic groups completed 2 years of follow-up. There were no significant differences in the proportion of individuals achieving the composite primary outcome, although the proportion of individuals achieving the prespecified outcome of total cholesterol <4.0 mmol/L (odds ratio 1.24; 95% CI 1.05-1.47; P = 0.01) increased with intensive intervention compared with control. Coding for microalbuminuria increased relative to control (odds ratio 2.05; 95% CI 1.29-3.25; P < 0.01). CONCLUSIONS: Greater improvements in composite cardiovascular risk factor control with this intervention compared with standard care were not achieved in this cohort of high-risk individuals with T2DM. However, improvements in lipid profile and coding can benefit patients with diabetes to alter the high risk of atherosclerotic cardiovascular events. Future studies should consider comprehensive strategies, including patient education and health care professional engagement, in the management of T2DM.

Mouse Umbilical Cord Mesenchymal Stem Cell Paracrine Alleviates Renal Fibrosis in Diabetic Nephropathy by Reducing Myofibroblast Transdifferentiation and Cell Proliferation and Upregulating MMPs in Mesangial Cells.

Transplantation of umbilical cord mesenchymal stem cells (UC-MSCs) is currently considered a novel therapeutic strategy for diabetic nephropathy (DN). However, the mechanisms by which UC-MSCs ameliorate renal fibrosis in DN are not well understood. Herein, we firstly investigated the therapeutic effects of mouse UC-MSC infusion on kidney structural and functional impairment in streptozotocin- (STZ-) induced diabetic mice. We found that the repeated injection with mUC-MSCs alleviates albuminuria, glomerulus injury, and fibrosis in DN mouse models. Next, mesangial cells were exposed to 5.6 mM glucose, 30 mM glucose, or mUC-MSC-conditioned medium, and then we performed western blotting, immunofluorescence, wound healing assay, and cell proliferation assay to measure extracellular matrix (ECM) proteins and matrix metalloproteinases (MMPs), myofibroblast transdifferentiation (MFT), and cell proliferation. We demonstrated that mUC-MSC paracrine decreased the deposition of fibronectin and collagen I by inhibiting TGF-ß1-triggered MFT and cell proliferation mediated by PI3K/Akt and MAPK signaling pathways, and elevating the levels of MMP2 and MMP9. Importantly, we provided evidence that the antifibrosis role of mUC-MSC paracrine in DN might be determined by exosomes shed by MSCs. Together, these findings reveal the mechanisms underlying the therapeutic effects of UC-MSCs on renal fibrosis in DN and provide the evidence for DN cell-free therapy based on UC-MSCs in the future.

An updated overview of diabetic nephropathy: Diagnosis, prognosis, treatment goals and latest guidelines.

Diabetic nephropathy (DN) is a major healthcare challenge. It occurs in up to 50% of those living with diabetes, is a major cause of end-stage kidney disease (ESKD) that requires treatment with dialysis or renal transplantation, and is associated with significantly increased cardiovascular morbidity and mortality. DN is a clinical syndrome characterized by persistent albuminuria and a progressive decline in renal function, but it is increasingly recognized that the presentation and clinical course of kidney disease in diabetes is heterogeneous. The term diabetic kidney disease (DKD) is now commonly used to encompass the spectrum of people with diabetes who have either albuminuria or reductions in renal function. In this article, the clinical presentation and approach to diagnosis of DKD will be discussed, as will its prognosis. The general principles of management of DKD will also be reviewed with reference to current international guidelines.

Clinical update: The important role of dual kidney function testing (ACR and eGFR) in primary care: Identification of risk and management in type 2 diabetes.

Diabetic kidney disease (DKD) is common complication of type 1 and type 2 diabetes and may lead to progressive kidney dysfunction culminating in end-stage kidney disease. Kidney function is evaluated less frequently than other care procedures in patients with diabetes, even though the opportunity to identify DKD early and slow or even halt renal damage early in the disease progression represents a potentially important clinical opportunity for early intervention. The following review provides an overview of the under-recognised importance of kidney function in T2D and current best-practice to support the identification of DKD as part of primary care T2D management.

Intensive multifactorial intervention improved renal impairment in short-duration type 2 diabetes: A randomized, controlled, 7-year follow-up trial.

AIMS: To investigate the effect of multifactorial intervention on the urinary albumin to creatinine ratio (UACR) and the estimated glomerular filtration rate (eGFR) in short-duration type 2 diabetes. METHODS: A total of 150 type 2 diabetes patients, with disease duration <1 year and with no evidence of atherosclerosis were randomized to either the intensive intervention group (IG, n = 75), or the conventional group (CG, n = 75) for 7 years. The predefined endpoint of microvascular complications was the progression of renal impairments (the development of albuminuria and the change of eGFR). RESULTS: The incidence of progression to albuminuria (UACR ≥30 mg/g) was 12% in IG and 28% in CG (HR 0.37, 95% CI: 0.19-0.70, P = .0025). eGFR was significantly lower in IG than that in CG in the year 2 (P = .043) and 3 (P = .032) follow-up. Sex, fasting plasma glucose (FPG), HbA1c, and systolic blood pressure (SBP) were independently associated with the UACR (ß = -5.112, P = .015; ß = 0.908, P = .045; ß = 2.087, P = .038; and ß = 2.787, P = .002, respectively); aging was independently associated with eGFR (ß = -0.447, P = .000). CONCLUSIONS: Intensive multifactorial intervention delayed the progression to albuminuria, and reduced eGFR rapidly in early stage of intervention in short-duration type 2 diabetes. FPG, HbA1c, and SBP were risk factors for UACR increase; aging was a risk factor for eGFR decline.

The association between haemorrhage and markers of endothelial insufficiency and inflammation in patients with hypoproliferative thrombocytopenia: a cohort study.

In daily haematological practice, predicting bleeding in thrombocytopenic patients is difficult, and clinicians adhere to transfusion triggers to guide patients through the aplastic phase of chemotherapy. Platelet count is not the only determinant of bleeding and additional mechanisms for impending haemostasis are likely. Beside clot formation, platelets are essential for the maintenance of integrity of vascular beds. We therefore prospectively investigated associations between biomarkers for endothelial damage (urine albumin excretion) and inflammation (C-reactive protein) and bleeding (WHO grading) in 88 patients with 116 on-protocol episodes. We found an increase in grade 2 bleeding with a higher urine albumin/creatinine ratio one day after the measurement [odds ratio (OR) 1·24 for every doubling of the ratio, 95% CI 1·05-1·46, P-value 0·01] and a 29% increase in the odds of grade 2 bleeding for every doubling of serum C-reactive protein (CRP) (95% CI 1·04-1·60, P-value 0·02) after correction for morning platelet count. The 24 h post-transfusion corrected count increment (CCI24 ) showed a significant association with these biomarkers: increasing urine albumin/creatinine ratio and CRP were associated with lower CCI24. We report two inexpensive and easy-to-apply biomarkers that could be useful in designing a prediction model for bleeding risk in thrombocytopenic patients.

Beneficial impact of intensified multifactorial intervention on risk of stroke: outcome of 21 years of follow-up in the randomised Steno-2 Study.

AIMS/HYPOTHESIS: Epidemiological studies have shown that diabetes is a well-established independent but modifiable risk factor for stroke. The aim of this post hoc analysis of data from the Steno-2 Study was to examine whether multiple risk factor intervention reduced the risk for stroke in individuals with type 2 diabetes and microalbuminuria. METHODS: In the Steno-2 Study, 160 individuals with type 2 diabetes and microalbuminuria were randomised to intensified or conventional multiple risk factor intervention, targeting classical cardiovascular disease risk factors for a mean of 7.8 years, and then followed for a total mean of 21.2 years. The primary endpoint in this post hoc analysis was time to first stroke event. RESULTS: During follow-up, 30 participants experienced a total of 39 strokes. Individuals randomised to conventional therapy were more likely to experience a stroke than those in the intensive-therapy group, with 29 total strokes occurring in 21 participants (26%) in the conventional-therapy group vs a total of ten strokes in nine participants (11%) in the intensive-therapy group (HR 0.31 [95% CI 0.14, 0.69]; p = 0.004). Also, the number of recurrent strokes was significantly reduced with intensive therapy. CONCLUSIONS/INTERPRETATION: Intensified multiple risk factor intervention in patients with type 2 diabetes and microalbuminuria reduces the risk for strokes as well as the number of recurrent cerebrovascular events. TRIAL REGISTRATION: ClinicalTrials.gov NCT00320008.

Elevated levels of circulating microvesicles in coronary artery disease patients with type 2 diabetes and albuminuria: Effects of exercise training.

OBJECTIVE: Circulating microvesicles, released from activated/apoptotic cells, are involved in vascular complications and may be looked upon as biomarkers. Albuminuria is characteristic of disease progression in type 2 diabetes mellitus. We aimed to investigate quantitative and qualitative differences of circulating microvesicles in type 2 diabetes mellitus with and without albuminuria and whether 12-month exercise training influenced expression of circulating microvesicles. METHODS: Coronary artery disease patients with type 2 diabetes mellitus (n = 75), of which 25 had albuminuria, were included. Annexin V+ (AV+) circulating microvesicles were analysed by flow cytometry in citrated plasma. The exercise volume was 150 min per week. RESULTS: In albuminuria patients, circulating microvesicles from endothelial-(CD146+/CD62E+/AV+) and endothelial-progenitor-(CD309+/CD34+/AV+) cells were significantly higher compared to those without (p ⩽ 0.01, both). Receiver operating characteristic curve analysis of the endothelial circulating microvesicles shows an area under the curve of 0.704 (95% confidence interval: 0.57-0.84; p = 0.004). Albuminuria patients had more circulating microvesicles derived from activated leukocytes and monocytes and monocytes carrying tissue factor (CD11b+/AV+, CD11b+/CD14+/AV+, CD142+/CD14+/AV+, respectively, p ⩽ 0.05, all) and higher number of circulating microvesicles from activated platelets (CD62P+/AV+). Within exercising patients, circulating microvesicles from progenitor cells increased (p = 0.023), however, not significantly different from controls. CONCLUSION: Coronary artery disease patients with type 2 diabetes mellitus and albuminuria had elevated number of circulating microvesicles from activated blood and vascular cells, rendering them as potential predictors of disease severity. The circulating microvesicles were limitedly affected by long-term exercise training in our population.

Olmesartan combined with renal denervation reduces blood pressure in association with sympatho-inhibitory and aldosterone-reducing effects in hypertensive mice with chronic kidney disease.

BACKGROUND: Augmented sympathetic nerve activity (SNA) and renin-angiotensin-aldosterone system (RAAS) activity are involved in the pathogenesis of hypertension (HT) accompanied by chronic kidney disease (CKD). Oxidative stress in the hypothalamus increases SNA in HT. Administration of an angiotensin ΙΙ receptor blocker (olmesartan; OLM) or renal denervation (RDN) exerts an antihypertensive effect in HT with CKD; however, the precise mechanisms of the combination therapy are not fully elucidated. In the present study, we examined whether combination therapy with OLM and RDN reduces both SNA by decreasing oxidative stress in the hypothalamus and RAAS activity in hypertensive mice with CKD. METHODS AND RESULTS: In 5/6-nephrectomized ICR-mice (Nx-mice) at 4-weeks after nephrectomy, systolic blood pressure (SBP) was significantly increased, accompanied by increased SNA and albuminuria compared with control-mice. Nx-mice were orally administered OLM, vehicle, or underwent RDN during OLM administration, and divided into Nx-OLM, Nx-VEH, and Nx-OLM/RDN groups, respectively. In Nx-OLM and Nx-OLM/RDN compared with Nx-VEH at 8-weeks after treatment, SBP was significantly decreased and both SNA and oxidative stress levels in the hypothalamus were significantly suppressed, without worsened creatinine clearance. In Nx-OLM and Nx-OLM/RDN compared with Nx-VEH, albuminuria was also suppressed, and the heart per body weight was decreased. In Nx-OLM/RDN, but not in Nx-OLM, the plasma aldosterone concentration was significantly decreased compared with Nx-VEH. CONCLUSION: These findings suggest that combination therapy with OLM/RDN has antihypertensive effects in association with suppressing SNA by reducing oxidative stress in the hypothalamus and the plasma aldosterone concentration in hypertensive mice with CKD.