Prevalence of mild cognitive impairment and its association with handgrip strength in patients on hemodialysis.

Dementia is associated with a high risk of death and hospitalization among patients on hemodialysis (HD). We retrospectively evaluated the prevalence of mild cognitive impairment (MCI) in 421 patients on maintenance HD across nine facilities and investigated whether decreased handgrip strength was associated with decreased cognitive function. The Montreal Cognitive Assessment-Japan (MoCA-J) score and handgrip strength were measured. The mean age was 69.8 ± 11.2 years, and the median dialysis vintage 74.5 (IQR 30-150) months. The median MoCA-J score was 25 (IQR 21-27), and MCI was confirmed in 245 (58.2%) patients. Both the MoCA-J score and MoCA-J executive score were associated with age, history of cerebrovascular disease (CVA), and handgrip strength after adjustments. We found, among patients on HD aged under 70 years with a history of CVA, a handgrip strength < 90% (25.2 kg in males and 16.2 kg in females) correlated with significantly lower MoCA-J scores. A high prevalence of MCI and decreased handgrip strength were observed in patients on HD. Handgrip strength may be useful for the easy detection of MCI. A decrease in handgrip strength would allow for the early detection of MCI, especially among patients on HD aged under 70 years with a history of CVA.

Clinical significance of a novel reticulocyte-based erythropoietin resistance index in HD patients: A retrospective study.

INTRODUCTION: The erythropoietin resistance index (ERI) is an indicator of erythropoiesis-stimulating agent (ESA) responsiveness and is typically calculated using Hb. However, Hb does not directly reflect ESA-induced erythropoiesis because of its long-term nature. We thus designed a novel ERI calculated with reticulocyte Hb (RetHb), a real-time index, and investigated its association with mortality in HD patients. METHODS: We calculated the ERI using the change in RetHb before and after ESA administration (ERIΔRetHb ) and retrospectively analyzed its association with 3-year all-cause mortality using Kaplan-Meier survival curves and Cox regression analyses. RESULTS: A total of 102 patients were included. Patients with the highest ERIΔRetHb had the worst prognosis according to the Kaplan-Meier survival curves (Log-rank p = 0.02). Multivariate Cox regression analysis showed that the ERIΔRetHb was significantly and independently associated with all-cause mortality (hazard ratio: 9.82, 95% CI [1.50, 64.41], p = 0.02). CONCLUSION: The ERIΔRetHb was significantly and independently associated with all-cause mortality in HD patients.

Potential effective treatment of shortening continuous erythropoietin receptor activator treatment interval combined with iron supplementation in hemodialysis patients.

Our previous randomized controlled trial comparing the total dose of weekly versus biweekly continuous erythropoietin receptor activator (CERA) therapy to maintain optimal hemoglobin (Hb) levels showed no significant differences between the two therapies. This post-hoc analysis assessed whether the total dose of weekly versus biweekly CERA therapy to maintain Hb levels among HD patients differed among groups with or without iron supplementation. Of 107 patients, 40 received intravenous iron supplementation due to iron deficiency (iron group) and 67 did not (non-iron group). In the iron group, the weekly therapy tended to require a lower total CERA dose compared with the biweekly therapy (274 ± 274 vs 381 ± 223 µg/12 weeks, P = 0.051). Changes in circulating hepcidin levels, a negative regulator of intestinal iron uptake, after 2 weeks of CERA treatment were significantly lower in the weekly therapy compared with the biweekly therapy (-4.2 ± 6.3 vs 11.1 ± 7.3 ng/mL, P = 0.015). In the non-iron group, there were no significant differences in total CERA dose or changes in hepcidin levels between the two therapies. Shortening the CERA treatment interval combined with iron supplementation may lead to the more efficient treatment of HD patients with iron deficiency.

Comparison of the effects of weekly and biweekly intravenous CERA administration on erythropoiesis: A randomized controlled trial.

Although continuous erythropoietin receptor activators (CERAs) are widely used erythropoiesis-stimulating agents for correcting renal anemia in patients undergoing hemodialysis (HD), few reports have examined weekly CERA administration. In this randomized controlled trial, we compared the efficacy and changes in the parameters of iron metabolism and erythropoiesis between weekly and biweekly CERA administration. In total, 120 patients undergoing maintenance HD were randomized to the weekly or biweekly group. The primary end point was the total CERA dose needed to maintain the target hemoglobin (Hb) levels during a 12-week evaluation period. There was no significant difference in the total dose between the weekly and biweekly groups (median 175.0 [interquartile range (IQR) 93.8-337.5] µg/12 weeks vs. 300.0 [IQR 125.0-375.0] µg/12 weeks, P = .18). The mean Hb levels during the evaluation period were 10.9 ± 0.8 g/dL in the weekly group and 10.7 ± 0.8 g/dL in the biweekly group (P = .25). Weekly CERA administration was well tolerated. Weekly CERA administration similarly managed anemia as biweekly administration in patients undergoing HD.

Plasma Cystine Levels and Cardiovascular and All-Cause Mortality in Hemodialysis Patients.

Oxidative stress accelerates the development of cardiovascular disease. Plasma cystine, a thiol oxidative stress marker, is related to several established factors for cardiovascular disease risk and prognosis. Although a comprehensive oxidative stress index is clinically required for hemodialysis patients with high oxidative stress, there are few reports concerning thiol oxidative stress markers predicting their prognosis. We investigated the relationship between plasma amino acids including cystine levels and cardiovascular disease-related and all-cause mortality in 132 maintenance hemodialysis patients. Higher cystine levels were associated with old age, longer hemodialysis duration, hemodialysis-associated hypotension, higher cardiothoracic ratio, higher blood urea nitrogen, and lower ankle-brachial index. Multivariate Cox regression analysis revealed that high plasma cystine was independently related with both cardiovascular disease mortality and all-cause mortality. Thus, high plasma cystine levels predict the prognosis of hemodialysis patients. High cystine levels necessitate a careful investigation for the cause of oxidative stress and comorbidities like vascular injury.

Relationship between Arterial Stiffness and Blood Pressure Drop During the Sit-to-stand Test in Patients with Diabetes Mellitus.

AIM: Patients with orthostatic hypotension (OH) have high arterial stiffness. Patients with diabetes mellitus (DM) often have cardiac autonomic neuropathy that leads to OH; however, whether OH is an indicator of arterial stiffness progression is unclear. We aimed to investigate whether the cardio-ankle vascular index (CAVI) varies between DM patients with and without OH using the sit-to-stand test (STST). METHODS: One hundred and fifty-nine patients with DM underwent CAVI assessment and blood pressure (BP) and heart rate change evaluation during the STST. OH was defined as a decline in systolic BP (SBP) and/or diastolic BP of at least 20 mmHg or 10 mmHg, respectively, in the initial and late upright positions compared with that in the sitting position. RESULTS: OH was diagnosed in 42 patients (26.4%). DM patients with OH had significantly higher CAVI (9.36±1.15 versus 8.89±1.18, p=0.026) than those without OH. CAVI was significantly inversely correlated with systolic and diastolic BP changes (R=－0.347, p＜0.001 and R=－0.314, p＜0.001, respectively) in the initial upright position. Multivariate regression analysis revealed that age, SBP changes, and low frequency component in the initial upright position were independent determinants of CAVI. CONCLUSION: Patients with DM having large BP drops occurring when moving from sitting to standing have high arterial stiffness. A significant BP drop during the STST necessitates careful evaluation of advanced arterial stiffness in patient with DM.

Acceleration of iron utilization after intravenous iron administration during activated erythropoiesis in hemodialysis patients: a randomized study.

This study aimed to evaluate the effect of different timings of iron administration during erythropoiesis activated by continuous erythropoietin receptor activator (CERA) on reticulocyte iron uptake in hemodialysis patients. In total, 110 patients were randomized to receive 40 mg intravenous elemental iron doses at all three hemodialysis sessions in the first week (IW1 group: n = 57) or in the third week (IW3 group: n = 53) after CERA administration. Following CERA administration at day 0, reticulocyte count increased, peaking at day 7. At days 7 and 14, the observed changes in Ret-He were higher in the IW1 group than in the IW3 group. Increases in total reticulocyte hemoglobin at day 7 were higher in the IW1 group than in the IW3 group. In contrast, there was only tendency toward greater total reticulocyte hemoglobin after iron administration in the third week in the IW3 group. Intravenous iron supplementation in the first week of CERA administration increases reticulocyte iron uptake; however, iron supplementation in the third week does not. The findings indicate that iron should be intravenously administered to increase the efficacy of CERA within 1 week of CERA administration during highly active erythropoiesis.

Changes in hepcidin and reticulocyte hemoglobin equivalent levels in response to continuous erythropoietin receptor activator administration in hemodialysis patients: a randomized study.

Inadequate iron availability limits the response to erythropoiesis-stimulating agents (ESA) and hepcidin is a key regulator of iron metabolism. However, there is little information concerning time-dependent changes in hepcidin in response to the change of accelerated iron demand due to ESA-induced erythropoiesis. In this study, iron-related parameters, including hepcidin levels, were explored in comparison to patients receiving continuous erythropoietin receptor activator (CERA) and epoetin beta (EPO) treatment. Ninety-four patients were randomized to receive monthly CERA (N = 47) or EPO three times/week (N = 47). After the titration period, hemoglobin levels and iron-related parameters were examined. Data for 71 patients were evaluated (CERA, N = 34; EPO, N = 37). Compared with EPO treatment, CERA treatment caused significant decreases within 1 week in hepcidin (-93.5 ± 46.9 vs. -1.3 ± 38.3 ng/mL, P < 0.01), reticulocyte hemoglobin equivalent (Ret-He) (-4.03 ± 2.64 vs. -1.13 ± 1.41 pg, P < 0.01), ferritin (-58.9 ± 30.5 vs. -12.2 ± 23.8 ng/mL, P < 0.01) and transferrin saturation (-13.2 ± 9.1 vs. 1.0 ± 11.9%, P < 0.01) and significant increases within 2 weeks in the levels of hemoglobin (0.42 ± 0.38 vs. -0.02 ± 0.48 g/dL, P < 0.01). In conclusion, hepcidin, Ret-He, ferritin and transferrin saturation levels decreased within 1 week and hemoglobin increased within 2 weeks after CERA administration. Time course of iron-related parameters including hepcidin demonstrated accelerated iron utilization appropriately according to ESA-induced erythropoiesis.

Effects of angiotensin II receptor blockers on relationships between 24-hour blood pressure, autonomic function, and health-related QOL.

We report the relationship between 24-hour (24-h) blood pressure, autonomic function, and health-related quality of life (HRQOL) in normotensives and hypertensives. The aim of this study was to determine whether there is a relationship between 24-h blood pressure, autonomic function, and HRQOL during treatment with an angiotensin receptor blocker (ARB) in patients with hypertension. Thirteen patients with hypertension were randomly treated with losartan (25-50 mg, n = 5), candesartan (4-8 mg, n = 4), valsartan (80 mg, n = 1), telmisartan (40 mg, n = 2), and olmesartan (10 mg, n = 1), daily. 24-h ambulatory blood pressure (BP) was measured before treatment and 3 months after treatment. Sympathetic nervous activity (the ratio of low frequency to high frequency component (LF/HF)) and parasympathetic nervous activity (high frequency component (HF)) were calculated by analyzing heart rate variability. HRQOL was assessed using a medical outcome study short-form 36-item health survey (SF-36) questionnaire. All of the participants completed the study. Angiotensin receptor blocker treatment reduced 24-h mean BP (MBP) from 107 +/- 9 to 100 +/- 9 mmHg. 24-h MBP positively correlated with 24-h LF/HF in all subjects who received ARB (R = 0.568, p < 0.04). There were no differences in heart rate, serum albumin level, BUN level, creatinine level, potassium level, or HRQOL score. These findings indicated that ARB reduced BP; however, treatment with ARB did not affect the scores of HRQOL and the relationship between 24-h blood pressure and autonomic function.

Behçet's disease complicated by IgA nephropathy with nephrotic syndrome.

A 65-year-old woman with a 48-year history of Behçet's disease associated with nephrotic syndrome is described. Immunofluorescence study revealed IgA nephropathy. Following treatment with an angiotensin II type-I receptor-blocker, an anti-platelet drug, and an HMG-CoA reductase inhibitor, accompanied by dietary restrictions of protein and sodium, proteinuria was markedly decreased. This report describes our experience with a rare entity of Behçet's disease complicated by nephrotic syndrome due to IgA nephropathy. Routine urine examination and renal biopsy are needed for the detection and diagnosis of renal problems with Behçet's disease.

Cellular and morphological changes during neointimal hyperplasia development in a porcine arteriovenous graft model.

BACKGROUND: Implantation of a haemodialysis arteriovenous graft is often followed by the development of neointimal hyperplasia (NH) at the venous anastomosis. The nature of the proliferating cells in these lesions is not well understood. A better understanding of the cells contributing to NH is important to the development of preventive strategies. METHODS: Carotid-jugular PTFE grafts were placed in 21 pigs and characterized at various time points following implantation. Venous anastomotic tissues were harvested at 1, 7, 14, 21, 28 or 49 post-operative days for histology and immunohistochemistry. RESULTS: Van Gieson staining of the tissues showed that NH was apparent as early as day 7 and progressed over time. Even by day 1, there were cells expressing the proliferation marker Ki-67 in the venous adventitia, but not the media, at the anastomosis. Double immunohistochemical staining showed that these cells were positive for alpha-smooth muscle actin (alpha-SMA), but negative for smooth muscle myosin heavy chain (SM MHC), suggesting that the proliferating cells were myofibroblasts rather than smooth muscle cells. By day 7, proliferating cells were abundant in the adventitia and began to appear in the media, surrounded by extracellular matrix visualized using Trichrome staining. By day 49, alpha-SMA-positive, SM MHC-negative cells were predominant in the NH, and Ki-67 staining had largely vanished. CONCLUSIONS: These results are consistent with the hypothesis that adventitial fibroblasts are transformed into myofibroblasts and begin to proliferate within hours after graft placement. Migration of these cells towards the vessel lumen with subsequent proliferation appears to be a major contributor to NH formation. The pivotal role of the adventitial fibroblasts in the pathogenesis of NH provides a compelling rationale for therapies that target the transformation, proliferation and migration of these cells to prevent arteriovenous graft stenosis.

Expression of C-reactive protein in myointimal hyperplasia in a porcine arteriovenous graft model.

BACKGROUND: The migration and proliferation of myofibroblasts are prominent features of myointimal hyperplasia associated with haemodialysis polytetrafluoroethylene (PTFE) grafts. Since C-reactive protein (CRP) possesses functional activities on vascular smooth muscle cells (SMCs), we examined the expression of this protein in PTFE grafts early in the course of myointimal hyperplasia development in a porcine model. METHOD: Bilateral carotid-jugular PTFE loop grafts were placed in pigs. After euthanasia at 2-4 weeks, the graft-venous and graft-arterial anastomoses and the adjacent blood vessels were excised en bloc and subjected to immunohistochemical analyses and in situ hybridization for CRP. The ability of CRP to stimulate proliferation was examined in cultured porcine venous SMCs using the bromodeoxyuridine assay after incubation for 48 h. RESULTS: Severe myointimal hyperplasia was found at 3 weeks after graft placement at both graft-venous and graft-arterial anastomoses. Compared to normal tissues, staining for CRP was far more intense in cells in the hyperplastic lesions at both anastomoses, which also stained positive for smooth muscle alpha-actin. In situ hybridization showed that these cells also expressed mRNA for CRP. At 1 microg/ml, CRP increased the proliferation of cultured porcine venous SMCs by 45.9+/-5.8%. CONCLUSION: CRP was produced in venous and arterial SMCs and its expression was enhanced in the hyperplastic lesions associated with arteriovenous PTFE grafts in a porcine model. Together with the ability of CRP to promote SMC proliferation, these data suggest that CRP might play a pathogenic role in the development of myointimal hyperplasia in PTFE grafts.

Evaluation of histological techniques for quantifying haemodialysis arteriovenous (AV) graft hyperplasia.

BACKGROUND: Assessing treatment efficacies for preventing haemodialysis arteriovenous (AV) graft stenosis requires a reproducible method for quantifying intimal hyperplasia. We identified sources of variability in three histological methods for assessing hyperplasia in a porcine AV graft model. METHODS: Carotid-jugular synthetic grafts were placed in pigs. After explantation at 3-6 weeks, the tissue was stained with haematoxylin and eosin (H&E), Masson's trichrome or elastic tissue Van Gieson (EVG) stains and examined histologically. Hyperplasia at the anastomosis of 14 grafts was quantified using three different methods, each by four blinded observers. These methods were visual scoring, ratio of intima-to-media surface area (I/M ratio), and ratio of intra-graft hyperplasia to graft surface area (H/G ratio) at the graft-vessel interface. RESULTS: The EVG stain proved superior in delineation of the elastic lamina yet quantification of the intimal and medial layers was still often difficult. This is illustrated by the greater inter-observer median coefficient of variances (CV) found using the I/M ratio method (intimal area CV=13.7%; medial area CV=32.7%; I/M ratio CV=44.0%) than with the H/G method (intra-graft hyperplasia area CV=7.3%, graft area CV=5.3%; H/G ratio CV=6.9%) or by visual scoring (CV=26.8%). The H/G ratios correlated positively with visual scores (r=0.941; P=0.0007; n=14) and the I/M ratio (r=0.719; P=0.0095; n=14). While hyperplasia was seen in both native vessel and graft lumen, in only one of the 14 anastomoses was the degree of hyperplasia greater in the native vessel than in the graft lumen, suggesting that the degree of hyperplasia occurring within the graft lumen predicted the total hyperplasia around the anastomosis. CONCLUSIONS: The H/G method for assessing hyperplasia is preferred in a porcine model of AV graft because it is quantitative, less variable and does not require the delineation of the elastic lamina, although it infrequently underestimates the total hyperplasia that occurs.

Perivascular tissue pharmacokinetics of dipyridamole.

PURPOSE: The tissue diffusivity (D(g)) and partitioning (K) for dipyridamole were determined and a model was developed to examine the relationship between perivascular dose and local dipyridamole tissue concentrations. METHODS: Experiments were performed using an in vitro perfusion apparatus that recirculated buffer through different graft samples or normal porcine femoral arteries and veins. The grafts or blood vessels were immersed in a compartment containing Krebs-Henseleit (KH) buffer and dipyridamole (30 microg/mL). The recirculating buffer was sampled at multiple time points and dipyridamole was assayed. Estimates of the effective diffusivity (D(g)) and partition coefficient (K) of the drug in the vessel wall were determined and used to simulate dipyridamole tissue concentration after perivascular delivery. RESULTS: Dipyridamole diffusivity within native femoral veins (D(g) = 3.87 +/- 0.93 x 10(-6) cm2/s) was approximately twice that within femoral arteries (D(g) = 2.06 +/- 0.79 x 10(-6) cm2/s, p < 0.01). Explanted grafts showed the lowest diffusivity. Partition coefficients of femoral arteries (K = 4.11 +/- 0.99) were higher than those of femoral veins (K = 2.05 +/- 0.85, p < 0.01) and explanted graft (K = 0.89 +/- 0.56, p < 0.01). DISCUSSION: The results demonstrate that local drug kinetics vary greatly for different types of blood vessels and grafts. The pharmacokinetic parameters and resulting computational simulations are helpful in exploring perivascular drug delivery strategies.

Safety and efficacy of fluvastatin in hyperlipidemic patients with chronic renal disease.

BACKGROUND: There are few reports on the safety and efficacy of long-term treatment with statins in patients with chronic renal disease and hyperlipidemia. We evaluated these subjects treated with fluvastatin. METHODS: After a 4-week run-in period, a total of 80 patients with diabetic nephropathy or chronic glomerulonephritis were randomly allocated to receive dietary therapy and fluvastatin 20 mg/day (n=39), or dietary therapy alone (n=41) for a period of 48 weeks. Lipid parameters, rhabdomyolysis-related indicators, 24-hour urinary albumin excretion and creatinine clearance were measured. The pharmacokinetics of fluvastatin was examined in 8 patients. RESULTS: Creatinine clearance and 24-hour urinary albumin excretion did not differ between the two groups. The peak serum fluvastatin concentration (Cmax) was 141+/-67 microg/L and the mean AUC0-6 h was 341+/-149 microgh/L. Fluvastatin treatment significantly lowered serum total cholesterol, low-density lipoprotein (LDL) cholesterol and apo-lipoprotein B concentrations by 16%, 25%, and 22%, respectively, compared with patients receiving dietary therapy alone. There were no significant differences in serum triglyceride and high-density lipoprotein (HDL) cholesterol concentrations between the two treatment groups. Serum creatine kinase and aldolase concentrations did not change throughout treatment in both groups. CONCLUSIONS: Fluvastatin treatment significantly improved lipid parameters in patients with chronic renal disease. Fluvastatin was well tolerated, with no adverse effects on renal function and no muscular toxicity. However, the drug showed no direct renoprotective effects.

Thyroid storm-induced multiple organ failure relieved quickly by plasma exchange therapy.

We report a 54-year-old female patient in whom thyroid storm was improved dramatically by plasma exchange. The patient presented with tachycardia, high fever and pulmonary congestion, in addition to left hemiparalysis and dysarthria. Serum thyroid hormone concentrations were markedly increased and computed tomography showed a fresh cerebral infarct, suggesting that she had thyroid storm precipitated by cerebral infarction. As there was no remarkable improvement even after 24 h of conventional therapy, plasma exchange was carried out using fresh frozen plasma. Consequently, her critical condition improved quickly. The half-life of thyroid hormones is so long that quick improvement is not always achieved even by sufficient doses of antithyroid drugs. Thus, plasma exchange in combination with conventional therapy appears to be effective in relieving the life-threatening state in our patient with thyroid storm precipitated by acute cerebral infarction.

Perindopril effects on ambulatory blood pressure: relation to sympathetic nervous activity in subjects with diabetic nephropathy.

BACKGROUND: Few studies have reported the effect of angiotensin-converting enzyme inhibitors on 24-h blood pressure (BP) and regulation of sympathetic nervous activity in hypertensive patients with diabetic nephropathy. Using ambulatory BP monitoring (ABPM) devices equipped with spectral analysis of heart rate variability, we assessed the effects of perindopril on 24-h BP and autonomic nervous activity in these patients. METHODS: Thirty-four hypertensive patients with non-insulin-dependent diabetic nephropathy underwent ABPM before and after treatment with perindopril (final dose: 4.9 +/- 1.8 mg/d). Simultaneously, spectral analysis was performed to calculate the high frequency components (HF) as a marker of parasympathetic nervous activity, and the low frequency components (LF)/HF ratios as an index of the sympathovagal balance. RESULTS: Perindopril significantly and equally decreased the waking and sleeping BP in the diabetic patients. During the sleeping period, the magnitude of change of mean BP induced by perindopril correlated inversely with the sleeping/waking ratio of mean BP before treatment. However, there was no correlation between these parameters during the waking period. Perindopril decreased both waking and sleeping LF/HF ratios, although no differences in HF components were observed between before and after treatment. CONCLUSIONS: In patients with diabetic nephropathy, perindopril decreased 24-h BP. Spectral analysis suggested that this finding was partially related to inhibited sympathetic nervous activity. During sleeping periods, the BP-lowering effect of perindopril was more pronounced in patients showing no nocturnal decrease in BP. Perindopril may be a potent antihypertensive agent to reduce increased nocturnal BP, a risk factor of target organ damage in these patients.