Preventive and therapeutic effects of imatinib in Wistar-Kyoto rats with anti-glomerular basement membrane glomerulonephritis

Imatinib is a selective tyrosine kinase inhibitor that can block activity of the platelet-derived growth factor receptor (PDGFR) and that has immunomodulatory effects on various cell types. Here we measured the protective effects of imatinib in Wistar-Kyoto rats with nephrotoxic serum nephritis, a kidney disease model where CD8+ T cells and macrophages play pathogenetic roles. Groups of animals were given imatinib from one day before up to 13 days following induction of nephritis and from day 7 to 20 following disease induction. Compared to control rats, at each time point imatinib treatment caused significantly less proteinuria, lowered serum blood urea nitrogen and creatinine, and decreased the number of glomeruli with necrosis, crescents, and fibrin deposits. Imatinib-treated rats had a significant reduction in glomerular macrophage accumulation and reduced renal cortical PDGFR-β and M-CSF receptor mRNA expression. Using colocalization we found that glomerular macrophages had reduced IL-1β and MCP-1 protein expression. Late imatinib treatment significantly reduced proteinuria, serum blood urea nitrogen, and creatinine, and reversed renal histopathological changes. We show that imatinib has renoprotective and therapeutic properties and provide pre-clinical work that will need to be confirmed in patients with crescentic glomerulonephritis

Interactive Effectiveness of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers or Their Combination on Survival of Hemodialysis Patients

Bachground: Does the use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers individually or as a combination confer a survival benefit in hemodialysis patients? The answer to this question is yet unclear. Methods: We performed a case-cohort study using data from the Mineral and Bone Disorder Outcomes Study for Japanese CKD stage 5D patients (MBD-5D), a 3-year multicenter prospective case-cohort study, including 8, 229 hemodialysis patients registered from 86 facilities in Japan. All patients had secondary hyperparathyroidism, a condition defined as a parathyroid hormone level ≥180 pg/mL and/or receiving vitamin D receptor activators. We compared all-cause mortality rates between those receiving ACEI, ARB, and their combination and non-users with interaction testing. We used marginal structural Poisson regression (causal model) to estimate the causal effect and interaction adjusted for possible time-dependent confounding. Cardiovascular mortality was also evaluated. Results: Among 3, 762 randomly sampled subcohort patients, those taking ACEI, ARB, and their combination at baseline accounted for 4.0, 31.6, and 3.8%, respectively. Over 3 years, 1, 226 all-cause and 462 cardiovascular deaths occurred. Compared to non-users, ARB-alone users had a lower all-cause mortality rate (adjusted incident rate ratio [aIRR] 0.62, 95% CI 0.50–0.76), whereas ACEI-alone users showed a statistically similar rate (aIRR 1.01, 95% CI 0.57–1.77). On the contrary, combination users had a greater mortality rate (aIRR 2.56, 95% CI 1.22–5.37), showing significant interaction (p = 0.03). Analysis for cardiovascular mortality showed similar results. Conclusion: Among hemodialysis patients with secondary hyperparathyroidism, unlike ACEI use, ARB use was associated with greater survival than non-use. Conversely, combination use was associated with greater mortality. Controlled trials are warranted to verify the causality factors of these associations

Serum Paraoxonase 1 (PON1) Concentration as a Marker of Left Ventricular Mass Index (LVMI) and Atherosclerosis in Hemodialysis Patients

Cardiovascular disease (CVD) is the most common cause of morbidity and mortality among patients on hemodialysis (HD). Increasing evidence suggests that paraoxonase (PON) 1 is an important risk factor for CVD. In this study, we evaluated the correlations between PON1 protein concentration and cardiac function and atherosclerosis in patients on HD. A cohort of 119 patients (59 males) on maintenance HD participated in the study in which we measured common clinical parameters and serum PON1 concentrations. We also evaluated cardiac function by echocardiography after maintenance dialysis sessions. The median serum PON1 concentration was 40.8μg/mL (range, 11.8-81.1μg/mL) in patients on HD and is significantly associated with a history of CVD and peripheral artery disease. The serum PON1 level is positively correlated with the concentration of albumin (r = 0.26, P < 0.01), high-density lipoprotein cholesterol (HDL, r = 0.19, P < 0.05), calcium (r = 0.23, P < 0.05), urea nitrogen (r = 0.20, P < 0.05) and creatinine (r = 0.22, P < 0.05), and negatively correlated with pulse pressure (r = -0.20, P < 0.05). Among the echocardiographic parameters, the PON1 concentration is significantly and negatively correlated with left atrial dimension (LAD, r = -0.31, P < 0.05) and left ventricular mass index (LVMI, r = -0.35, P < 0.005). Stepwise multivariate regression analysis showed that PON1 is an independent predictor of LVMI (adjusted r2 = 0.34). Therefore the serum PON1 concentration could contribute to the development of LVH and it could be an independent predictor of CVD in patients on maintenance HD

Relationship between serum calcium or phosphate levels and mortality stratified by parathyroid hormone level: an analysis from the MBD-5D study

Introduction: There is limited evidence about the association between calcium and phosphate levels and mortality stratified by intact parathyroid hormone (iPTH) level. Methods: We investigated whether differences in iPTH level affect the relationship between calcium and phosphate levels and all-cause mortality in hemodialysis patients with secondary hyperparathyroidism (SHPT). Calcium and phosphate levels were categorized as low (< 8.5 mg/dL,  < 4.0 mg/dL), medium (≥ 8.5–< 9.5 mg/dL,  ≥ 4.0–< 7.0 mg/dL), and high (≥ 9.5 mg/dL,  ≥ 7.0 mg/dL), respectively. iPTH levels were grouped into < 300 or ≥ 300 pg/mL. Adjusted incidence rate ratios (aIRRs) were analyzed by weighted Poisson regression. Results: For calcium, patients with higher iPTH (≥ 300 pg/mL) had significantly higher all-cause mortality rates in the high than in the medium category (aIRR 1.99, 95% confidence interval [CI] 1.16–3.42), and tended to have a higher mortality rate in the low category (aIRR 2.04, 95% CI 0.94–4.42). Patients with lower iPTH (< 300 pg/mL) had higher mortality rates in the high than in the medium category (aIRR 1.65, 95% CI 1.39–1.96). For phosphate, the mortality rate was significantly higher in the high than in the medium category in patients with higher and lower iPTH (aIRR 3.23, 95% CI 1.63–6.39 for iPTH ≥ 300 pg/mL; aIRR 1.58, 95% CI 1.06–2.36 for iPTH < 300 pg/mL). Conclusion: High calcium and phosphate levels were associated with increased risk of mortality irrespective of iPTH level

Changes in anemia management and hemoglobin levels following revision of a bundling policy to incorporate recombinant human erythropoietin

In April 2006, Japan's health insurance system instituted a bundling policy that included recombinant human erythropoietin (rHuEPO) in outpatient hemodialysis therapy. To evaluate outcomes of this, we analyzed a prospective cohort of hemodialysis patients in the Japan Dialysis Outcomes and Practice Patterns Study, in 53 facilities using prevalent cross-sections of 1584 patients before and 1622 patients after the rHuEPO reimbursement change. Patient data included hemoglobin levels, iron management profiles, and anemia treatment with rHuEPO and intravenous iron. No significant differences were found in pre- or post-policy cross-sections for hemoglobin distributions or the percentage of patients prescribed rHuEPO. Among patients receiving rHuEPO, the mean dose significantly decreased by 11.8 percent. The percentage of patients prescribed intravenous iron over 4months significantly increased; however, the mean dose of iron did not significantly change. Thus, this bundling policy was associated with reduced rHuEPO doses, increased intravenous iron use, and stable hemoglobin levels in Japanese patients receiving hemodialysis

Predictors and consequences of altered mineral metabolism: The Dialysis Outcomes and Practice Patterns Study

Predictors and consequences of altered mineral metabolism: The Dialysis Outcomes and Practice Patterns Study.BackgroundAltered mineral metabolism contributes to bone disease, cardiovascular disease, and other clinical problems in patients with end-stage renal disease.MethodsThis study describes the recent status, significant predictors, and potential consequences of abnormal mineral metabolism in representative groups of hemodialysis facilities (N = 307) and patients (N = 17,236) participating in the Dialysis Outcomes and Practice Patterns Study (DOPPS) in the United States, Europe, and Japan from 1996 to 2001.ResultsMany patients fell out of the recommended guideline range for serum concentrations of phosphorus (8% of patients below lower target range, 52% of patients above upper target range), albumin-corrected calcium (9% below, 50% above), calcium-phosphorus product (44% above), and intact PTH (51% below, 27% above). All-cause mortality was significantly and independently associated with serum concentrations of phosphorus (RR 1.04 per 1 mg/dL, P = 0.0003), calcium (RR 1.10 per 1 mg/dL, P < 0.0001), calcium-phosphorus product (RR 1.02 per 5 mg2/dL2, P = 0.0001), PTH (1.01 per 100 pg/dL, P = 0.04), and dialysate calcium (RR 1.13 per 1 mEq/L, P = 0.01). Cardiovascular mortality was significantly associated with the serum concentrations of phosphorus (RR 1.09, P < 0.0001), calcium (RR 1.14, P < 0.0001), calcium-phosphorus product (RR 1.05, P < 0.0001), and PTH (RR 1.02, P = 0.03). The adjusted rate of parathyroidectomy varied 4-fold across the DOPPS countries, and was significantly associated with baseline concentrations of phosphorus (RR 1.17, P < 0.0001), calcium (RR 1.58, P < 0.0001), calcium-phosphorus product (RR 1.11, P < 0.0001), PTH (RR 1.07, P < 0.0001), and dialysate calcium concentration (RR 0.57, P = 0.03). Overall, 52% of patients received some form of vitamin D therapy, with parenteral forms almost exclusively restricted to the United States. Vitamin D was potentially underused in up to 34% of patients with high PTH, and overused in up to 46% of patients with low PTH. Phosphorus binders (mostly calcium salts during the study period) were used by 81% of patients, with potential overuse in up to 77% patients with low serum phosphorus concentration, and potential underuse in up to 18% of patients with a high serum phosphorus concentration.ConclusionThis study expands our understanding of the relationship between altered mineral metabolism and outcomes and identifies several potential opportunities for improved practice in this area

Type I Angiotensin II Receptor Blockade Reduces Uremia-Induced Deterioration of Bone Material Properties

Chronic kidney disease (CKD) is associated with a high incidence of fractures. However, the pathophysiology of this disease is not fully understood, and limited therapeutic interventions are available. This study aimed to determine the impact of type 1 angiotensin II receptor blockade (AT-1RB) on preventing CKD-related fragility fractures and elucidate its pharmacological mechanisms. AT-1RB use was associated with a lower risk of hospitalization due to fractures in 3276 patients undergoing maintenance hemodialysis. In nephrectomized rats, administration of olmesartan suppressed osteocyte apoptosis, skeletal pentosidine accumulation, and apatite disorientation, and partially inhibited the progression of the bone elastic mechanical properties, while the bone mass was unchanged. Olmesartan suppressed angiotensin II-dependent oxidation stress and apoptosis in primary cultured osteocytes in vitro. In conclusion, angiotensin II-dependent intraskeletal oxidation stress deteriorated the bone elastic mechanical properties by promoting osteocyte apoptosis and pentosidine accumulation. Thus, AT-1RB contributes to the underlying pathogenesis of abnormal bone quality in the setting of CKD, possibly by oxidative stress. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).Wakamatsu T., Iwasaki Y., Yamamoto S., et al. Type I Angiotensin II Receptor Blockade Reduces Uremia-Induced Deterioration of Bone Material Properties. Journal of Bone and Mineral Research, 36, 1, 67. https://doi.org/10.1002/jbmr.4159