Relationship between mortality and speed of eGFR decline in the 3 months prior to dialysis initiation.

BACKGROUND: The timing for initiating dialysis in chronic kidney disease is often determined by the clinical symptoms and estimated glomerular filtration rate (eGFR). However, very few studies have examined how the speed of kidney function decline before initiating dialysis relates to mortality after dialysis initiation. Here, we report our examination of the relationship between the speed of eGFR decline in the 3 months prior to dialysis initiation and mortality. METHODS: The study included 1292 new dialysis patients who were registered in the Aichi Cohort Study of Prognosis in Patients Newly Initiated into Dialysis. The subjects were placed in 4 groups based on the speed of eGFR decline in the 3 months before initiating dialysis (eGFR at 3 months before initiation-eGFR at initiation) <2: ≥2, <4: ≥4, <6: ≥6 mL/min/1.73 m2. All-cause, cardiovascular, and infection-related mortality rates were compared using Kaplan-Meier curves. A multivariate analysis using the Cox proportional hazard model was used to extract the factors that contributed to all-cause mortality. RESULTS: The group with faster eGFR decline exhibited significantly more heart failure symptoms when dialysis was initiated. Rapid eGFR decline correlated with prognosis (log-rank test: all-cause mortality p < 0.001, cardiovascular mortality p < 0.001). The speed of eGFR decline was related to elevated all-cause mortality rates [eGFR decline 10 mL/min/1.73 m2, HR (95 % CI) = 1.53 (1.12-2.08)]. CONCLUSIONS: This study showed that patients with rapid eGFR decline in the 3 months before initiating dialysis more often presented with heart failure symptoms when dialysis was initiated and had poorer survival prognoses.

Nutritional status and management of risks due to physical therapy in patients hospitalized for long periods.

[Purpose] This study aimed to understand the nutritional status of patients hospitalized for long periods and the risk of physical therapy (PT) for such patients. [Subjects and Methods] Participants were selected from patients who were hospitalized at a designated medical long-term care sanatorium. The participants were divided into 5 groups (A-E) depending on their mode of energy intake and ambulatory ability during PT. The serum albumin level, energy intake, total daily energy expenditure, and total daily energy expenditure per session of PT (EEPT) were evaluated for each group. [Results] Protein-energy malnutrition was observed in 69.6% of the participants. No significant association was identified between the serum albumin level and body mass index. Energy intake was significantly higher in Groups D and E, whose energy intake was via ingestion, than in Groups A and B, whose intake was via tube feeding. EEPT was highest in patients of Group E who had gait independence different from the ability of those in groups A-D. [Conclusion] The actual energy intake is lower with tube feeding than with ingestion. Risk management and energy intake should be revisited in elderly patients who have been hospitalized for long periods and subsequently obtain gait independence.

Ability of vitamin D receptor activator to prevent pulmonary congestion in advanced chronic kidney disease.

BACKGROUND: Vitamin D deficiency is common among patients with chronic kidney disease (CKD). However, the benefits of vitamin D supplementation versus vitamin D receptor activator (VDRA) administration have yet to be established. Recently, an association between activated vitamin D and cardiovascular factors was reported. To evaluate the benefits of VDRA in advanced CKD, we analyzed the association between VDRA administration and the prevalence of pulmonary congestion. METHODS: This retrospective, cross-sectional analysis included patients initiated on dialysis between October 2011 and September 2013 at 17 Japanese institutions. Data from 952 participants were analyzed using a multivariate logistic regression model and a linear regression model. We also analyzed subgroup data for groups classified by selection of peritoneal dialysis or hemodialysis. RESULTS: Of the 952 participants, 303 patients received VDRA. VDRA administration was associated with a low prevalence of pulmonary congestion in the multivariate logistic regression model (odds ratio [OR], 0.64; 95 % confidence interval [CI], 0.44-0.94; P = 0.02). There was no significant association between VDRA administration and systolic blood pressure, diastolic blood pressure, or pulse pressure. Subgroup analysis revealed a tendency that VDRA administration was associated with low prevalence of pulmonary congestion in both groups. CONCLUSIONS: In this study, VDRA administration was associated with a low prevalence of pulmonary congestion in patients initiated on dialysis. Appropriate VDRA administration may prevent pulmonary congestion.

Impact of an angulated aorto-septal relationship on cardio-cerebrovascular outcomes in patients undergoing hemodialysis.

Aortic and valvular calcification are well-known risk factors for cardio-cerebrovascular events in patients undergoing hemodialysis. We investigated the clinical impact of an angulated aorto-septal angle as a result of aortic elongation due to aortic calcification on cardio-cerebrovascular outcomes in patients undergoing hemodialysis. We investigated 306 patients (mean age 65.4 years, 68% male) who underwent pre-scheduled routine echocardiography between April and September 2018. The angle between the anterior wall of the aorta and the ventricular septal surface (ASA) was quantified. We determined aortic and mitral valve calcification scores based on calcified cardiac changes; the aortic and mitral valve scores ranged between 0-9 and 0-6, respectively. The primary endpoint was a composite including cardio-cerebrovascular events and cardio-cerebrovascular death. The mean duration of dialysis among the patients in this analysis was 9.6 years. The primary endpoint was observed in 54 patients during the observational period (median 1095 days). Multivariable Cox proportional hazards analyses identified left ventricular ejection fraction (per 10% increase: hazard ratio [HR] 0.67; 95% confidential interval [CI] 0.53-0.84, P = 0.001), left ventricular mass index (per 10 g/m2 increase: HR 1.14; 95% CI 1.05-1.24, P = 0.001), ASA (per 10 degree increase: HR 0.69; 95% CI 0.54-0.88; P = 0.003), and aortic valve calcification score (HR 1.15; 95% CI 1.04-1.26, P = 0.005) as independent determinants of the primary endpoint. Kaplan-Meier analysis showed a higher incidence of the primary endpoint in patients with ASA <119.4 degrees than those with ASA ≥119.4 degrees (Log-rank P < 0.001). An angulated aorto-septal angle is an independent risk factor for cardio-cerebrovascular events and cardio-cerebrovascular death in patients undergoing hemodialysis.

Layilin, a talin-binding hyaluronan receptor, is expressed in human articular chondrocytes and synoviocytes and is down-regulated by interleukin-1ß.

OBJECTIVE: Layilin (LAYN), a 55-kDa transmembrane protein with homology to C-type lectins, has been identified as a receptor of hyaluronan (HA). Interestingly, LAYN does not share any sequence homology with CD44, a primary HA receptor. The primary aim of our study was to examine the expression and potential function of LAYN in human articular chondrocytes and synoviocytes. METHODS: Samples were obtained from patients undergoing joint arthroplasty. Cells were grown in vitro, then stimulated with interleukin (IL)-1ß or tumor necrosis factor alpha (TNFα) for 24 h and the expression of LAYN was analyzed. To assess the function of LAYN, we transfected chondrocytes with siRNA against LAYN, treated them with HA and IL-1ß, and then analyzed the production of matrix metalloproteinase (MMP)-1 and MMP-13 in the treated chrondrocytes. RESULTS: The results showed that LAYN was constitutively expressed in human articular chondrocytes and synoviocytes and that IL-1ß significantly suppressed the expression of LAYN in these cells. HA repressed IL-1ß-induced MMP-1 and MMP-13 production in chondrocytes, but this was significantly abrogated in chondrocytes transfected with siRNA against LAYN. CONCLUSIONS: Our results show that human chondrocytes express LAYN, a novel HA receptor, and that LAYN may contribute to the regulation of HA functions in the arthritic condition. Further investigation of the HA receptor may lead to the development of novel therapeutics to regulate HA signaling in inflammatory arthritis.

Galactose-deficient IgA1 Is Involved in IgA Deposition in Renal Grafts Biopsied One Hour after Kidney Transplantation.

Objective Asymptomatic renal immunoglobulin A (IgA) deposition occurs in healthy subjects, but its etiologic role in disease is unclear. Galactose-deficient IgA1 (Gd-IgA1) is involved in the pathogenesis of IgA nephropathy. We investigated Gd-IgA1 deposition in transplanted kidneys that were considered healthy showing subclinical latent IgA deposition one hour after transplantation. Methods A total of 723 transplanted kidney specimens biopsied 1 h after kidney transplantation from 2009 to 2016 at Nagoya Red Cross Hospital were examined. A total of 81 cases of IgA deposition were extracted, and 41 were ultimately studied. Double immunofluorescence staining for Gd-IgA1 and IgA was conducted to investigate the role of Gd-IgA1 in subclinical IgA deposition. Results Light microscopy findings for the 41 cases indicated only minor glomerular abnormalities. Immunofluorescence analyses revealed that all cases were positive for IgA. C3, IgG, and IgM positivity rates were 78.0%, 7.3%, and 60.9%, respectively. All 41 cases were positive for Gd-IgA1, which merged with IgA deposition in immunofluorescence double staining. IgA disappeared in 26 of 40 cases (65.0%) 1 year after kidney transplantation. In contrast, IgA redeposition was observed in three cases. Conclusion Gd-IgA1 was demonstrated in all transplanted kidneys, with latent IgA deposition noted in otherwise healthy kidneys. Deposition of Gd-IgA1 might indicate the initial stage of IgA nephropathy; however, additional factors, such as IgG deposition, are required for the ultimate development of IgA nephropathy.

Non-A Blood Type Is a Risk Factor for Poor Cardio-Cerebrovascular Outcomes in Patients Undergoing Dialysis.

The clinical impact of ABO blood type on cardio-cerebrovascular outcomes in patients undergoing dialysis has not been clarified. A total of 365 hemodialysis patients participated in the current study. The primary endpoint was defined as a composite including cardio-cerebrovascular events and cardio-cerebrovascular death. The primary endpoint was observed in 73 patients during a median follow-up period of 1182 days, including 16/149 (11%) with blood type A, 22/81 (27%) with blood type B, 26/99 (26%) with blood type O, and 9/36 (25%) with blood type AB. At baseline, no difference was found in the echocardiographic parameters. Multivariable Cox regression analyses revealed that blood type (type A vs. non-A type; hazard ratio (HR): 0.46, 95% confidence interval (95% CI): 0.26-0.81, p = 0.007), age (per 10-year increase; HR: 1.47, 95% CI: 1.18-1.84), antiplatelet or anticoagulation therapy (HR: 1.91, 95% CI: 1.07-3.41), LVEF (per 10% increase; HR: 0.78, 95% CI: 0.63-0.96), and LV mass index (per 10 g/m2 increase; HR: 1.07, 95% CI: 1.01-1.13) were the independent determinants of the primary endpoint. Kaplan-Meier curves also showed a higher incidence of the primary endpoint in the non-A type than type A (Log-rank p = 0.001). Dialysis patients with blood type A developed cardio-cerebrovascular events more frequently than non-A type patients.

Peculiar renal endarteritis in a patient with acute endocapillary proliferative glomerulonephritis.

Acute glomerulonephritis (AGN) is one of the most common renal diseases. They are often associated with infections and can result in diffuse proliferative glomerulonephritis (GN). This case report reviews an interesting case in which renal endarteritis coexisted in AGN with diffuse endocapillary proliferation. The discussion highlights important pathological findings and clinical aspects in acute endocapillary proliferative GN with renal endarteritis. Coexisting endarteritis should be in the differential diagnosis of AGN in patients with persistent clinical courses.

Is arteriolar vacuolization a predictor of calcineurin inhibitor nephrotoxicity?

Calcineurin inhibitors (CNI) have been commonly used as pivotal immunosuppressive agents to renal transplant recipients and have contributed significantly to improving short-term allograft survival. However, long-term administration of CNI may cause an adverse effect on kidney function, known as chronic nephrotoxicity. Chronic CNI nephrotoxicity (CNI-NT) shows characteristic histopathological findings that involve arteriolar hyalinosis. Recently, the term alternative arteriolar hyalinosis (aah) is used to discriminate CNI-specific arteriolar hyaline deposition from non-specific arteriolar hyalinosis. We studied whether arteriolar vacuolization represents an early lesion of aah as a predictor of CNI-NT. We retrospectively studied the 79 patients under treatment with a CNI immunosuppressant, who underwent living-related renal transplantation (RTx) from January 2007 to March 2009. We examined serial protocol graft biopsies at one h, one, six, and 12 months after RTx. We classified histological findings into two groups on the basis of aah lesion (with or without aah) in serial biopsies for 12 months. Arteriolar vacuolization was more frequently observed in the aah group than in the non-aah group with a significant difference. Arteriolar vacuolization was found even in the one-h biopsy specimens, indicating a non-specific histopathological finding. But in the aah group, arteriolar vacuolization tended to be more frequently observed later on. Aah can be a predictor of CNI-NT.

Intravenously administered darbepoetin alfa once a week could maintain hemoglobin level more efficiently than once every 2 weeks in patients on hemodialysis.

BACKGROUND: Darbepoetin alfa, which has a much longer half-life than recombinant human erythropoietin, is used to treat renal anemia. However, there are few reports investigating the efficacy of darbepoetin alfa administered every 2 weeks (Q2W). METHODS: We performed the single-center, prospective, and randomized study in chronic hemodialysis patients. Clinically stable patients on hemodialysis were recruited, and darbepoetin alfa 15-40 microg/week was administered intravenously once a week (QW) to achieve a hemoglobin (Hb) level of 10.5-12.0 g/dl for 8 weeks prior to randomization. The patients were randomly assigned to 2 different dosing frequency groups: once a week (QW) or every 2 weeks (Q2W). We switched to a double dose in the Q2W group. We measured Hb level every 2 weeks and administered darbepoetin alfa to achieve an Hb level of 10.5-11.5 g/dl. The primary endpoints were the weekly dose of darbepoetin alfa administered at week 24. RESULTS: We assigned 19 and 20 patients into QW and Q2W, respectively. There were no significant differences between the groups in Hb, transferrin saturation, ferritin, and weekly dose of darbepoetin alfa at end of the baseline period. There was no significant difference in Hb level at week 24, at which time the weekly dose requirement and dose per dry body weight were much higher in the Q2W than in the QW group. CONCLUSION: Administration of darbepoetin alfa Q2W could maintain Hb level similarly to to that obtained QW, but we did not confirm efficiency at a higher dose requirement or blood pressure elevation.

Administration of alfacalcidol for patients with predialysis chronic kidney disease may reduce cardiovascular disease events.

BACKGROUND: Besides its effect on calcium metabolism, vitamin D may play a part in preventing the onset and progression of cardiovascular disease (CVD) events. Only a few reports on the studies relating to whether vitamin D may reduce CVD events in patients with predialysis chronic kidney disease (CKD) are available, and many ambiguities remain. METHODS: We conducted a retrospective cohort study of 665 patients with predialysis CKD. With log-rank test using the Kaplan-Meyer survival curve, comparison of incidences of CVD events, CVD-related mortality, and all-cause mortality were made between patients in the alfacalcidol treatment group (107 patients) in the predialysis stage to whom alfacalcidol 0.25-0.5 microg/day was orally administered for at least 24 weeks, and patients in the nontreatment group (558 patients) who received no administration of alfacalcidol or other type of activated vitamin D and its analogues. Patients to whom alfacalcidol administration was discontinued within 24 weeks as well as initiation of dialysis of <24 weeks were excluded for this study. Factors relating to CVD events were examined using Cox's proportional hazards analysis. RESULTS: The mean follow-up period was 55.1 +/- 38.9 months in the alfacalcidol treatment group and 41.9 +/- 38.4 months in the nontreatment group. CVD events occurred in 172 patients during the follow-up period, and 74 of those occurred during the predialysis period. In the alfacalcidol treatment group, the incidence of cumulative CVD events was significantly lower. In relation to all-cause deaths and CVD-related deaths, the cumulative mortality rate was significantly lower in the alfacalcidol treatment group during the follow-up period. Throughout the follow-up period, the association between CVD events and alfacalcidol use was detected when adjusted for age, sex, diabetes, hypertension, use of renin-angiotensin system inhibitors, estimated glomerular filtration rate, and albumin and parathyroid hormone. CONCLUSION: These data showed that oral administration of alfacalcidol for predialysis CKD patients was associated with reduced risk for CVD.

Study of Glomerulopathy in Donors after Kidney Transplantation.

INTRODUCTION: Living kidney donation improves the lives of individuals with kidney failure; however, recent studies have suggested that living kidney donors may be at a relatively higher risk of reduced renal function than healthy non-donors. We therefore aimed to evaluate the clinical and pathological findings in living kidney donors who developed kidney disease. METHODS: From January 1991 to May 2019, 1,625 live kidney donations were performed at our hospital. Among the donors, 7 developed kidney disease after donation and underwent open renal biopsy. We studied the clinical and pathological findings of these patients from their clinical records. RESULTS: There were 3 patients with immunoglobulin A (IgA) nephropathy, 2 with membranous nephropathy, 1 with anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis, and 1 with secondary focal segmental glomerulosclerosis (FSGS). All patients with IgA nephropathy had latent IgA deposition on their baseline biopsy. One patient with membranous nephropathy demonstrated findings of membranous nephropathy on the baseline biopsy, despite being asymptomatic. All patients, except for those with ANCA-associated nephropathy and secondary FSGS, recovered from the nephritis or maintained an adequate renal function after treatment. DISCUSSION/CONCLUSION: Baseline biopsy is necessary for assessing the renal condition of kidney donors, and these donors require long-term follow-up based on their baseline biopsy findings. If donors develop kidney disease, appropriate diagnosis and treatment are essential.

Successful treatment of peritoneal dialysis-related peritonitis caused by Dermacoccus nishinomiyaensis.

A 53-year-old man receiving peritoneal dialysis (PD) for 4 months presented with PD-related peritonitis (abdominal pain, turbid peritoneal dialysate effluent, white blood cell in peritoneal dialysate effluent 5350/µL, C-reactive protein 25.56 mg/dL) caused by Dermacoccus (D.) nishinomiyaensis. He was first treated empirically with cefazolin and ceftazidime. After detection of D. nishinomiyaensis in the peritoneal effluent culture collected on the first day of hospitalization, the antibiotics were changed to amoxicillin and vancomycin. After confirming negative-conversion of peritoneal effluent culture, treatment was continued for more than 6 weeks. The peritonitis resolved; he continues peritoneal dialysis without withdrawal from PD or catheter removal. D. nishinomiyaensis is part of resident microbiota of the skin, and its pathogenicity is rarely reported. To date, there is no report of PD-related peritonitis caused by D. nishinomiyaensis. Because it is a slow grower, it may be missed and the peritonitis categorized as culture-negative. Long-term culture is important to detect it. It is difficult to determine the antibiotics that can be used because susceptibility to antibiotics is unknown due to the organism's rarity. Furthermore, the appropriate treatment period is also unknown. Long-term treatment may be useful in PD-related peritonitis caused by D. nishinomiyaensis because it is a slow grower.

Relationship Between Mortality and Cancer-Bearing Status in Patients With Chronic Kidney Disease Who Attended an Educational Program.

Patients with malignancy have a poorer prognosis than others do, which must be taken into consideration when treating them for chronic kidney disease (CKD). However, there are few studies investigating their prognosis. This was an observational study of 515 (394 men and 121 women) stable non-dialysis patients with CKD who attended a CKD educational program. Mean age was 68.8 ± 13.0 years. Median follow-up was 968.5 days. Mean creatinine was 3.4 ± 1.6 mg/dL. Of these, 63 had malignancy and 452 did not; 20.6% of the former and 11.9% of the latter group died by the end of the study period (P = 0.0548). Malignancy was not associated with all-cause mortality (HR: 1.3475, 95% CI: 0.7202-2.5214, P = 0.3507) but with malignancy-associated mortality (HR: 3.9477, 95% CI: 1.6348-9.5331, P = 0.0023). Renal replacement therapy was not associated with mortality. Since malignancy greatly affects the prognosis, it must be taken into consideration when treating these patients.

Sphingosine-1-phosphate attenuates proteoglycan aggrecan expression via production of prostaglandin E2 from human articular chondrocytes.

BACKGROUND: Sphingosine-1-phosphate (S1P), a downstream metabolite of ceramide, induces various bioactivities via two distinct pathways: as an intracellular second messenger or through receptor activation. The receptor for S1P (S1PR) is the family of Endothelial differentiation, sphingolipid G-protein-coupled receptor (EDG). We have here attempted to reveal the expression of EDG/S1PR in human articular chondrocytes (HAC), exploring the implications of S1P in cartilage degradation. METHODS: Articular cartilage specimens were obtained from patients with rheumatoid arthritis (RA), osteoarthritis (OA) or traumatic fracture (representing normal chondrocytes) who underwent joint surgery. Isolated HAC were cultured in vitro by monolayer and stimulated with S1P in the presence or absence of inhibitors of signaling molecules. Stimulated cells and culture supernatants were collected and subjected to analyses using reverse transcription-polymerase chain reaction (RT-PCR), Western blotting, and enzyme-linked immunosorbent assay (ELISA). RESULTS: All of the tested HAC samples showed positive results in terms of EDG/S1PR expression in basal condition. When HAC was stimulated with S1P, a significant increase in prostaglandin (PG) E2 production was observed together with enhanced expression of cyclooxygenase (COX)-2. S1P stimulated extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) in HAC, and the PGE2 induction was abrogated by PD98059 and SB203580. Pertussis toxin inhibited the PGE2 induction from HAC by S1P, suggesting an essential role for Gi protein. S1P also attenuated the expression of proteoglycan aggrecan, a component of cartilage matrix, in HAC at transcriptional level. CONCLUSION: It was suggested that the S1P-induced PGE2 was at least in part involved in the aggrecan-suppressing effect of S1P, seeing as COX inhibitors attenuated the effect. Accordingly, S1P might play an important role in cartilage degradation in arthritides.

Relationship Between Mortality and Cancer-Bearing Status at Time of Dialysis Initiation.

Patients with malignancy are reported to have poorer prognosis than those without malignancy. When patients with malignancy develop end-stage kidney disease, clinicians must determine treatment with consideration of prognosis. Furthermore, malignancy is sometimes found at time of dialysis initiation. However, prognosis of patients with malignancy at time of dialysis initiation has not been investigated. A total of 1524 patients with chronic kidney disease who initiated dialysis at 17 centers participating in the Aichi Cohort Study of Prognosis in Patients Newly Initiated into Dialysis were included. Patients initiated dialysis between October 2011 and September 2013. Mortality rates were compared between patients with and without malignancy. Types of malignancy and respective prognoses also were assessed. The study included 1030 men and 492 women with a mean age of 67.5 ± 13.1 years. Of these, 92 had malignancy and 1430 did not; 45.7% of the former group and 16.0% of the latter group died by March 2015 (P < 0.01). Even after adjusting for various factors, presence of malignancy remained an independent risk factor for mortality (P < 0.01). Patients with performance status (PS) of 0 had significantly lower mortality (P < 0.01). Patients with malignancy at time of dialysis initiation had poor prognosis. Therefore, presence of malignancy should be taken into consideration when patients initiate dialysis. In patients with malignancy, better PS was associated with better prognosis.

Distinct signaling pathways are involved in hypoxia- and IL-1-induced VEGF expression in human articular chondrocytes.

Recent data suggest that vascular endothelial growth factor (VEGF) is involved in the pathogenesis of osteoarthritis (OA). Cartilage is an avascular tissue, leading to a low cartilage O2 level. Thus, in a variety of pathologic or physiologic conditions, VEGF is partly regulated by hypoxic stress. The implications of hypoxia for VEGF expression by OA chondrocytes, however, are not known. We investigated the regulatory system of VEGF in OA chondrocytes under hypoxic conditions. Chondrocytes were obtained from articular cartilage of patients with OA. Cells were cultured and then incubated under hypoxic (95% N2, 5% CO2) or normoxic conditions, with or without interleukin (IL)-1 (10 ng/mL) stimulation. The mitogen activated protein kinase (MAPK) inhibitors were also used. VEGF levels in the culture supernatants were measured using an enzyme-linked immunosorbent assay. Western blot analysis was used to examine the expression of hypoxia inducible factor (HIF)-1alpha. Hypoxia significantly increased VEGF levels (p<0.05). Hypoxia-induced VEGF secretion was abolished by p38MAPK inhibitor, but not by JNK inhibitor. In contrast, IL-1-induced VEGF secretion was blocked by JNK inhibitor, and not by p38MAPK inhibitor. Both hypoxia and IL-1-induced HIF-1alpha were attenuated by p38 MAPK and JNK inhibitors. We demonstrate that hypoxia and IL-1 induce VEGF production in chondrocytes through distinct MAPK signaling pathways, indicating that VEGF is induced in a HIF-1-dependent or -independent manner in chondrocytes.

Predialysis Vitamin D Receptor Activator Treatment and Cardiovascular Events after Dialysis Initiation: A Multicenter Observational Study.

BACKGROUND: Vitamin D receptor activator (VDRA) administration has been linked with a reduced incidence of cardiovascular disease (CVD). However, it is unclear whether VDRA administration during the predialysis stage is associated with CVD incidence after dialysis initiation in patients with chronic kidney disease. Therefore, we examined the association between VDRA use and CVD events. METHODS: This multicenter observational study included 1,516 patients; they were divided into 2 groups: those who did and did not receive oral VDRA for at least 3 months before dialysis initiation. The CVD incidence was compared between these groups. Factors that impacted CVD incidence were extracted through a multivariate analysis. Subgroups were created based on prior CVD history and serum CRP levels. RESULTS: The incidence of CVD was significantly lower in the VDRA group (log-rank test, p = 0.014). Stepwise multivariate analyses identified age, gender, diabetes, CVD history, calcium-channel blockers, beta-blockers, loop diuretics, anti-platelet agents, phosphate binders, VDRA, erythropoiesis stimulating agents, and cardiothoracic ratio as factors affecting CVD incidence. In the group with no CVD history, VDRA use was associated with a low incidence of CVD (HR 0.35). In the group with serum CRP levels <1.0 mg/dl, VDRA use was associated with a low incidence of CVD (HR 0.47). CONCLUSION: Administration of VDRA during predialysis was associated with a low incidence of CVD onset after dialysis initiation.

Presence of Atrial Fibrillation at the Time of Dialysis Initiation Is Associated with Mortality and Cardiovascular Events.

BACKGROUND: Death in dialysis patients results mainly from cardiovascular and cerebrovascular diseases. To our knowledge, no prospective study has compared the rates of mortality or cardiovascular events between patients with and without atrial fibrillation (AF) at the time of dialysis initiation. METHODS: This study included 1,516 patients who were initiated into dialysis between October 2011 and August 2013. Rates of mortality and cardiovascular events were compared between patients with and without AF, and between AF patients with and without warfarin (WF) treatment. RESULTS: The study comprised 1,025 men and 491 women with a mean age of 67.5 ± 13.1. Of these patients, 93 had AF, while 1,423 did not; 22.6% of the former group and 9.7% of the latter group died by March 2014 (p < 0.01). Cardiovascular events occurred in 34.4% of patients with AF and 15.1% of patients without (p < 0.01). Even after adjustments for various factors, AF remained an independent risk factor for mortality (hazard ratio (HR) 1.873, 95% CI 1.168-3.002, p < 0.01). It was also an independent risk factor for cardiovascular events (HR 1.872, 95% CI 1.262-2.778, p < 0.01). No difference in any parameter was noted between the groups that did and did not receive WF treatment. CONCLUSION: Patients with AF at the time of dialysis initiation show a poor prognosis and are at high risk of cardiovascular events. Therefore, AF should be taken into consideration in dialysis patients.

Sphingosine-1-phosphate modulates expression of vascular endothelial growth factor in human articular chondrocytes: a possible new role in arthritis.

AIM: Although sphingosine-1-phosphate (S1P) is suggested to have an important role in arthritis, its function in chondrocytes remains unknown. In contrast, vascular endothelial growth factor (VEGF) has been speculated to contribute to the pathogenesis of osteoarthritis (OA), most likely by regulating angiogenesis. We here investigated the in vitro effect of S1P on VEGF expression in human articular chondrocytes from OA patients. METHODS: Human articular cartilage samples were obtained from patients with OA under informed consent. Chondrocytes were isolated by an enzymatic procedure, grown in monolayer culture, and then stimulated with S1P in the presence or absence of mitogen-activated protein kinase (MAPK) inhibitors or the Gi protein inhibitor pertussis toxin (PTX). VEGF expression and secretion in culture supernatants were analyzed using real-time polymerase chain reaction and enzyme-linked immunosorbent assay. RESULTS: Although S1P did not enhance basal secretion of matrix metalloproteinase (MMP)-1 and MMP-13, it stimulated VEGF expression in human articular chondrocytes, both at the messenger RNA and protein levels. MAPK inhibitors SB203580 and PD98059 were not effective at suppressing VEGF induction; rather, blocking extracellular signal-regulated kinase (ERK) MAPK enhanced VEGF expression. The Gi protein inhibitor PTX partially attenuated S1P-induced VEGF secretion. CONCLUSION: Our results suggest that S1P may contribute to the regulation of VEGF expression in human chondrocytes. S1P may therefore play a unique role in the pathophysiology of OA by regulating VEGF expression in chondrocytes.