Identification and characterization of adenosine A1 receptor-cAMP system in human glomeruli

Identification and characterization of adenosine A1 receptor-cAMP system in human glomeruli. Although adenosine is known to affect renal function through stimulating adenosine receptors, little is known about A1 receptors in human glomeruli. Thus, we attempted to identify the adenosine A1 receptor-cyclic AMP (cAMP) system in human glomeruli. Normal renal cortical tissues were obtained at nephrectomy of patients with renal cell carcinoma. Glomeruli were isolated using a graded sieving method or dissected manually under a stereomicroscope. Radioligand binding assay using 2-chloro-N-[3H] cyclopentyl adenosine ([3H]CCPA, an A1 agonist ligand) was performed at 30°C for 90 minutes. Cyclic AMP (cAMP) produced in glomeruli was measured after incubation with different concentrations of N6-cyclohexyladenosine (CHA; A1 agonist) and a phosphodiesterase inhibitor. The specific binding was saturated within 60 minutes and reversible by adding 1 mM of theophylline. Scatchard plot analysis revealed a single class of binding site (Kd = 1.78 ± 0.21 nM, Bmax = 271.7 ± 35.8 fmol/mg protein). The specific binding was inhibited dose-dependently by various agents in an order suggesting A1 receptor specificity. CHA inhibited the production of cAMP in microdissected human glomeruli. This inhibitory effect was antagonized by 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; A1 antagonist). This is the first study revealing the presence of the A1 receptor-cAMP system in human glomeruli using a radioligand binding assay method and by measuring the cAMP production

SAFETY AND EFFICACY OF ROSUVASTATIN FOR HYPERLIPIDEMIA IN PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD) STAGE 3 AND ABOVE

The frequency of hypertriglyceridemia is high in CKD patients, but few medications are available for controlling this lipid parameter when renal insufficiency advances. We evaluated the safety and efficacy of long-term treatment with rosuvastatin, one of the strong statins for hypercholesterolemic control, on lipid abnormalities in patients with CKD stage 3 and above. The protocol consisted of a 4-week run-in period and a 48-week treatment phase with rosuvastatin. Inclusion criteria were CKD stage 3 and above with serum low-density lipoprotein (LDL) cholesterol levels above 100mg/dL and triglyceride levels above 150mg/dL. Patients received 2.5 to 5.0mg rosuvastatin daily. Lipid parameters and myolysis-related indicators were measured. Forty-nine patients (29 men and 20 women aged 61 ± 9 years, serum creatinine levels above 1.5mg/dL) were enrolled in the study. Rosuvastatin significantly decreased (P〈0.05) serum LDL cholesterol from 163 ± 39 to 126 ± 31 mg/dL and apolipoprotein B from 151 ± 36 to 108 ± 24mg/dL at 4 weeks and maintained these parameters at low levels. Rosuvastatin also significantly decreased (P = 0.001) serum triglyceride levels from 194 ± 43mg/dL at baseline to 160 ± 51mg/dL at 48 weeks. High-density lipoprotein (HDL) cholesterol concentrations did not change from baseline (56 ± 16mg/dL) to 48 weeks of treatment (57 ± 17mg/dL). However, LDL/HDL ratio decreased significantly (P = 0.036) from 3.4 ± 0.7 to 2.2 ± 0.9, which approached the target level (2.0). During the rosuvastatin treatment period, serum creatine kinase, aldolase, and myoglobin concentrations did not change. In conclusion, rosuvastatin treatment improved serum triglyceride level as well as the LDL/HDL ratio in hyperlipidemic patients with CKD stage 3 and above, without serious adverse effects, suggesting that rosuvastatin is useful to control not only hypercholesterolemia but also hypertriglyceridemia in CKD patients

EFFECT OF SARPOGRELATE ON FISTULA PATENCY OF FOREARM ARTERIOVENOUS ANASTOMISIS IN UREMIC PATIENTS

Subcutaneous arteriovenous fistula in the forearm is a common vascular access for hemodialysis. However, primary failure of native fistula occurs because of either thrombosis formation within the first several weeks after surgery or immature vein dilatation. To evaluate the effect of platelet inhibition on fistula thrombosis and maturation failure, we used an antiplatelet agent, sarpogrelate hydrochloride, in our study. The study was designed as an open-label, parallel, prospective, randomized study for 8 weeks, comparing patients receiving sarpogrelate 300 mg/day (sarpogrelate group, n=33) with controls receiving no medication (n=46). The primary outcome was fistula patency failure determined by pulse Doppler ultrasound examination of the arteriovenous fistula performed 8 weeks after surgery. Pulse wave velocity was also measured to determine the ankle brachial pressure index (ABI). The drug was well-tolerated and did not increase bleeding events during the 8-week study period. In the sarpogrelate group, patency failure occurred in 1 of 33 patients (3.0%), and the occlusion rate was significantly lower (P=0.001) than that in the control group (3 of 46 patients; 6.5%). Average blood flow rate in the sarpogrelate group was 546±174 mL/min, and was significantly higher (P=0.036) than 448±183 mL/min in the control group. However, the diameter of the shunt vessel in the sarpogrelate group was 5.2±1.3 mm, which was not different from 5.1±0.6 mm in the control group. The Vmax was not significantly different between two groups (1.01±0.56 m/sec in the sarpogrelate group and 0.89±0.66 m/sec in the control group). In all patients (n=79), blood flow correlated with ABI (r=0.34, P=0.045). Our results suggest that sarpogrelate reduces the frequency of fistula patency failure. Sarpogrelate may maintain fistula patency, which is necessary for hemodialysis, by increasing ABI

Timing-adjusted iron dosing enhances erythropoiesis-stimulating agent-induced erythropoiesis response and iron utilization

Abstract Background We recently demonstrated, using an index of recently synthesized hemoglobin, reticulocyte hemoglobin (Ret-Hb), that iron administration remarkably improves hemoglobin (Hb) synthesis during the period of high activation of erythropoiesis induced by the administration of a continuous erythropoietin receptor activator (CERA). We aimed to investigate whether repetition of iron dosing sustains effective erythropoiesis and suppresses iron storage. Methods In a 3-month comparison of monthly CERA administration, 104 hemodialysis patients were randomized into two groups that received 40 mg iron intravenously 3 times; the first-week iron group [n = 51], given iron in the first week after CERA administration, during the period of high activation of erythropoiesis, and the third-week iron group [n = 53], given iron in the third week at the time of mild erythropoiesis activation. Results Initial mean CERA dosages were 123.5 ± 67.5 μg/month and did not differ between the groups. Hb levels were not different between the groups throughout the study. One-week increases in Ret-Hb levels after CERA administration were higher, during the first and the third month, in the group given iron in the first week compared with the third-week iron group (241.9 ± 63.3 vs. 196.2 ± 82.8 mg/dL, P = 0.004; 227.2 ± 83.5 vs. 187.9 ± 88.7 mg/dL, P = 0.037, respectively). The increase in ferritin levels was suppressed 3 months later in the first-week iron group compared with that of the third-week iron group (22.3 ± 64.0 vs. 69.0 ± 76.6 ng/mL, P = 0.002). Hepcidin levels decreased 1 week after CERA administration in both groups and were not different between the groups. Conclusions Timing-adjusted iron administration increased the levels of recently produced Hb and iron utilization and suppressed the ferritin levels. The iron administration timing deserves consideration when optimizing the efficiency of erythropoiesis-stimulating agents in patients undergoing hemodialysis. Trial registration UMIN000016375 . Registered 29 January 2015

Kidney Diseases Enhance Expression of Tetraspanin-8: A Possible Protective Effect against Tubular Injury

Background/Aims:TSPAN8 encoding tetraspanin-8 was identified as a candidate gene for immunoglobulin A nephropathy (IgAN) by a genome-wide association study using microsatellites in the Japanese population. Tetraspanin-8 is a cell surface protein that contributes to the migration and invasion of epithelial cells. Methods: We performed immunohistochemistry for tetraspanin-8 on human renal biopsy specimens associated with IgAN, antineutrophil cytoplasmic antibody-associated nephropathy and interstitial nephritis, as well as normal renal tissue. Furthermore, to study the potential function of tetraspanin-8, we performed cell migration and invasion assays using human renal tubule cells transfected with tetraspanin-8. Results: Tetraspanin-8 was often expressed in vascular smooth muscle cells and occasionally in tubule cells in normal kidney. In the kidneys of all types of nephropathy, tetraspanin-8 staining in the arteries was unaffected, but that in the tubules was enhanced. The degree of tubular staining negatively correlated with the estimated glomerular filtration rate, independently of the type of nephropathy. Tetraspanin-8-expressing tubule cells were found predominantly in distal and collecting tubules, identified by cytokeratin 7 or aquaporin 2 staining. In vitro studies using cultured tubule cells revealed that tetraspanin-8 promoted migration by 2.7-fold without laminin, by 2.8-fold with laminin and invasion into Matrigel by 3.5-fold, suggesting that enhanced tetraspanin-8 may be involved in the repair of tubules. Conclusion: The obtained findings indicate that tetraspanin-8 expression is enhanced in injured distal tubules, which may be involved in the repair of tubules by facilitating migration and invasion

Efficacy of StepAdd, a Personalized mHealth Intervention Based on Social Cognitive Theory to Increase Physical Activity Among Patients With Type 2 Diabetes Mellitus: Protocol for a Randomized Controlled Trial

BackgroundIncreasing physical activity improves glycemic control in patients with type 2 diabetes (T2D). Mobile health (mHealth) interventions have been proven to increase exercise, but engagement often fades with time. As the use of health behavior theory in mHealth design can increase effectiveness, we developed StepAdd, an mHealth intervention based on the constructs of social cognitive theory (SCT). StepAdd improves exercise behavior self-efficacy and self-regulation through the use of goal-setting, barrier-identifying, and barrier-coping strategies, as well as automatic feedback functions. A single-arm pilot study of StepAdd among 33 patients with T2D showed a large increase in step count (mean change of 4714, SD 3638 daily steps or +86.7%), along with strong improvements in BMI (mean change of −0.3 kg/m2) and hemoglobin A1c level (mean change of −0.79 percentage points). ObjectiveIn this study, we aim to investigate the efficacy and safety of StepAdd, an mHealth exercise support system for patients with T2D, via a large, long, and controlled follow-up to the pilot study. MethodsThis is a randomized, open-label, multicenter study targeting 160 patients with T2D from 5 institutions in Japan with a 24-week intervention. The intervention group will record daily step counts, body weight, and blood pressure using the SCT-based mobile app, StepAdd, and receive feedback about these measurements. In addition, they will set weekly step count goals, identify personal barriers to walking, and define strategies to overcome these barriers. The control group will record daily step counts, body weight, and blood pressure using a non–SCT-based placebo app. Both groups will receive monthly consultations with a physician who will advise patients regarding lifestyle modifications and use of the app. The 24-week intervention period will be followed by a 12-week observational period to investigate the sustainability of the intervention’s effects. The primary outcome is between-group difference in the change in hemoglobin A1c values at 24 weeks. The secondary outcomes include other health measures, measurements of steps, measurements of other behavior changes, and assessments of app use. The trial began in January 2023 and is intended to be completed in December 2025. ResultsAs of September 5, 2023, we had recruited 44 patients. We expect the trial to be completed by October 8, 2025, with the follow-up observation period being completed by December 31, 2025. ConclusionsThis trial will provide important evidence about the efficacy of an SCT-based mHealth intervention in improving physical activities and glycemic control in patients with T2D. If this study proves the intervention to be effective and safe, it could be a key step toward the integration of mHealth as part of the standard treatment received by patients with T2D in Japan. Trial RegistrationJapan Registry of Clinical Trials (JRCT) jRCT2032220603; https://rctportal.niph.go.jp/en/detail?trial_id=jRCT2032220603 International Registered Report Identifier (IRRID)DERR1-10.2196/5351