Denosumab Improves Glomerular Filtration Rate in Osteoporotic Patients With Normal Kidney Function by Lowering Serum Phosphorus.

Higher serum phosphorus (Pi) increases the risk for chronic kidney disease (CKD). It was reported that a single administration of denosumab or zoledronate significantly suppressed serum Pi levels as well as those of bone resorption markers in serum. Also, previous evidences suggest a link between bone anti-resorptive therapy and vasoprotective/renoprotective effects through mechanisms that remain unexplored. The aim of this study is to assess the renoprotective effect of denosumab and involvement of denosumab-induced reduction in serum Pi in osteoporotic patients. Osteoporotic patients (n = 73) without overt proteinuria in dipstick test results were treated with denosumab (60 mg) every 6 months during the study period (24 months). Estimated glomerular filtration rate based on serum cystatin C (eGFRcys) was used as a filtration marker and tartrate-resistant acid phosphatase-5b (TRACP-5b) as a bone resorption marker. For analysis of non-CKD patients (n = 56), those with eGFRcys <60 mL/min/1.73 m2 were excluded. A single injection of denosumab suppressed serum Pi as well as TRACP-5b during the first 6 months, whereas age-related decline in eGFRcys was significantly reversed, with an increase of 2.75 ± 1.2 mL/min/1.73 m2 after 24 months noted. Multivariate analysis showed that serum Pi reduction following the initial denosumab injection was positively associated with serum TRACP-5b suppression during that same period (ß = 0.241, p = 0.049). In addition, a positive association of serum Pi suppression, but not of corrected calcium or TRACP-5b, with eGFRcys increase after 24 months (ß = 0.321, p = 0.014) was found after adjustments for gender, age, BMI, antihypertensive drug use, albumin, and eGFRcys. The same was observed in osteoporotic cases restricted to non-CKD patients. In conclusion, serum Pi reduction resulting from phosphorus load decrement from bone induced by denosumab is a determinant for eGFRcys increase. Early introduction of bone antiresorptive therapy can retain glomerular filtration in osteoporosis cases, including non-CKD patients. © 2019 American Society for Bone and Mineral Research.

Effects of nutritional supplementation on fatigue, and autonomic and immune dysfunction in patients with end-stage renal disease: a randomized, double-blind, placebo-controlled, multicenter trial.

BACKGROUND: Fatigue is a predictor of cardiovascular events in patients with end-stage renal disease (ESRD) undergoing hemodialysis treatment. We hypothesized that multinutritional support would improve quality of life, fatigue symptoms, and potential quantitative measures including endocrine, immune and autonomic functions in patients with ESRD undergoing hemodialysis. METHODS: Two hundred and two hemodialysis patients were randomly assigned to receive active treatment (containing vitamin B1, vitamin B2, niacin, vitamin B6, vitamin B12, folic acid, vitamin C, carnitine, coenzyme Q10, naïve galacto-oligosaccharide, and zinc) or placebo after each dialysis session for 12 weeks. The patients and attending physicians were blinded to the treatment, and 172 patients (86 in each group) completed the study. Fatigue was evaluated via fatigue questionnaire at 0, 4, and 12 weeks. To assess human herpes virus (HHV) 6 and 7 reactivation, numbers of viral DNA copies were determined in saliva by polymerase chain reaction at weeks 0 and 12. Autonomic function was determined via measurement of beat-to-beat variation by using acceleration plethysmography. RESULTS: Clinical characteristics, changes in fatigue, quality of life score, endocrine functions, and laboratory data did not differ significantly between the two groups. Several parameters of heart rate variability significantly increased after nutritional treatment compared to placebo. Nutritional drink for 12 weeks significantly suppressed HHV7 DNA copy numbers. Similarly, HHV6 DNA copy numbers tended to be decreased by treatment but without reaching statistical significance. CONCLUSIONS: Nutritional supplementation may modulate immune and autonomic dysfunction in ESRD patients undergoing hemodialysis.

Serum n-3 and n-6 polyunsaturated fatty acid profile as an independent predictor of cardiovascular events in hemodialysis patients.

BACKGROUND: Unlike the n-6 polyunsaturated fatty acid (PUFA) arachidonic acid (AA), n-3-PUFAs such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) appear to have beneficial effects on inflammation, thrombosis, and cardiovascular disease (CVD). We examined possible alterations in serum PUFA profiles in patients on maintenance hemodialysis therapy and its association with CVD risk. STUDY DESIGN: An observational study including cross-sectional and longitudinal analyses. SETTING & PARTICIPANTS: Single-center study of 517 maintenance hemodialysis patients in an urban area in Japan. PREDICTORS: Serum EPA, DHA, and AA concentrations and EPA:AA, DHA:AA, and (EPA+DHA):AA ratios. OUTCOMES: CVD events, including ischemic heart disease, stroke, peripheral artery disease, pulmonary edema, and valve disease. RESULTS: Hemodialysis patients showed lower (EPA+DHA):AA, EPA:AA, and DHA:AA ratios than 122 controls similar in age and sex. During follow-up, 190 CVD events were recorded. (EPA+DHA):AA ratio was not associated significantly with CVD in unadjusted analysis, but was associated significantly and inversely with CVD in Cox models adjusted for age and other confounding variables, with HRs in the range of 1.71-1.99 in the lowest versus highest quartile of (EPA+DHA):AA ratios. Similarly, EPA:AA and DHA:AA ratios showed inverse associations with CVD, whereas serum EPA, DHA, and AA concentrations were not predictive of CVD. LIMITATIONS: No information for dietary intake, use of dietary supplements, or cell membrane PUFA content. CONCLUSIONS: In hemodialysis patients, serum PUFA profile is unfavorably altered, and the low n-3-PUFA:AA ratios are independent predictors of CVD.

Impact of lanthanum carbonate on cortical bone in dialysis patients with adynamic bone disease.

Among the most serious problems in patients with chronic kidney disease (CKD) is fragility of cortical bone caused by cortical thinning and increased cortical porosity; the cortical fragility is sometimes irreversible, with fractures generally initiating from cortical bone. Therefore, development of treatments for problems of cortical bone is urgently desired. Cortical bone has the three surfaces, including the periosteal surface, intracortical spaces and endocortical surface. Bone turnover at the endocortical surface and intracortical resorption spaces are increased as compared with that at cancellous surface. Bone growth sometimes depends on apposition at the periosteal surface. We treated hyperphosphatemia in two hemodialysis patients with adynamic bone disease with 750-1500 mg/day of lanthanum carbonate, which is a non-calcium containing phosphate binder; the treatment resulted in a decrease of the serum phosphorus levels (P levels), without significant change of the serum intact parathyroid hormone levels. We now report that treatment of these patients with lanthanum carbonate increased mineralization of the periosteal surface, increased bone mass within the intracortical resorption spaces and increased mineralization of the minimodeling surface at the endocortical surface. In addition, woven bone volume in cortical bone was decreased and mineralization of bone units, namely, osteons, was increased. Although these findings were not observed across all surfaces of the cortical bone in the patients, it is expected that lanthanum carbonate would increase the cortical stability in CKD patients, with consequent reduction in the fracture rate in these patients.

Evaluation of bone markers in hypophosphatemic rickets/osteomalacia.

N-terminal propeptide of type I procollagen (PINP) is a marker of newly formed type I collagen. However, its role in hypophosphatemic rickets/osteomalacia has not yet been established. Metabolic bone markers were examined in patients with oncogenic osteomalacia (OOM) and X-linked hypophosphatemic rickets (XLH), and in healthy controls. OOM and XLH patients were found to have hypophosphatemia secondary to elevated levels of serum fibroblast growth factor 23 (FGF-23). OOM patients had reduced levels of 1,25-dihydroxy vitamin D (1,25D) compared with XLH patients and healthy controls, despite attenuation of the reduction in these levels in the XLH patients secondary to active vitamin D supplementation. In contrast to patients with XLH, OOM patients showed a significant increase in serum PINP, which is suggestive of accelerated bone matrix formation. Bone alkaline phosphatase (BAP) and the BAP/PINP ratio were also increased in OOM but not in XLH patients, suggesting the presence of a disturbance in bone mineralization in OOM. Long-term supplementation of active form vitamin D and inorganic phosphate (IP) may have attenuated the defect in bone mineralization in the XLH patients, resulting in the normalization of PINP, BAP, and the BAP/PINP ratio. The present results suggest that, as with BAP, PINP is an appropriate metabolic bone marker in the assessment of hypophosphatemic rickets/osteomalacia.

Active vitamin D and acute respiratory infections in dialysis patients.

BACKGROUND AND OBJECTIVES: Vitamin D has gained attention for its pleiotropic effects in areas other than bone metabolism, and the effects of vitamin D in preventing respiratory infections have been reported as one of its immunomodulating properties. This study assessed the preventive effect of vitamin D receptor activator (VDRA) on respiratory infections in dialysis patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Maintained Japanese hemodialysis patients (n = 508) were observed for 5 years, and the incidence of hospitalization during this period because of acute respiratory infection (ARI) was recorded. RESULTS: Of the 508 patients, 212 had taken oral VDRA at the start of the study, whereas 296 patients had not received it. During the 5-year follow-up period, 57 patients were hospitalized because of ARIs. Kaplan-Meier analysis revealed that the incidence of hospitalization because of respiratory infection was significantly lower in patients who had been treated with VDRA compared with patients who had not (log rank test; P = 0.02). The multivariate Cox proportional hazards model demonstrated that the patients who had taken oral VDRA were at a significantly lower risk of hospitalization because of respiratory disease (hazard ratio 0.47, 95% confidence interval 0.25 to 0.90). CONCLUSIONS: The findings of this study suggest that the administration of oral VDRA has a preventive effect on the incidence of ARIs in dialysis patients.

Trace elements in the hair of hemodialysis patients.

Trace element disturbance is often observed in hemodialysis patients. While trace element concentrations have been reported in blood samples from hemodialysis patients, they have not been well investigated in scalp hair. In the present study, 22 trace elemental concentrations were measured by inductively coupled plasma-atomic emission spectrometry in the scalp hair of 80 male hemodialysis patients and compared with those of 100 healthy male subjects. In hemodialysis patients, the concentrations of beryllium, arsenic, magnesium, chromium, manganese, iron, selenium, molybdenum, iodine, vanadium, and cobalt were significantly higher than those in healthy subjects, while lead, mercury, copper, germanium, and bromine were significantly lower than those in the former group. No significant differences were observed for lithium, aluminum, cadmium, zinc, boron, or nickel. There were significant positive correlations between the duration of hemodialysis and the magnesium and manganese concentrations. There was a significant negative correlation between cadmium concentration and the duration of hemodialysis. There were significant positive correlations between dialysis efficacy (Kt/V) and magnesium, manganese, zinc, and selenium concentrations. In conclusion, trace element concentrations of the scalp hair are different between hemodialysis patients and healthy subjects. Essential trace elements, such as magnesium, manganese, zinc, and selenium, may be affected by the duration of hemodialysis and Kt/V.

[Chronic kidney disease (CKD) and bone. Impact of diabetes mellitus on the development of CKD-MBD].

Chronic kidney disease-mineral and bone disorder (CKD-MBD) develops as renal function deteriorates. The presence of diabetes mellitus as comorbidity modulates the severity of CKD-MBD. The prevalence of vascular calcification, which becomes higher in diabetic CKD patients than in non-CKD counterparts, increases cardiovascular mortality in diabetic patients. The main factor which causes vascular calcification in diabetic CKD patients is poor glycemic control, in contrast to hyperphosphatemia in non-diabetic CKD patients. Diabetes directly impairs osetoblasts to decrease bone mass, suppresses bone turnover to impair bone quality by impairing secretion of parathyroid hormone and increase AGE-modification of bone collagen. Therefore, therapeutic regimens for CKD-MBD should be considered specifically for diabetic CKD patients since the mode of its development differs between diabetic and non-diabetic CKD patients.

[A case of metastatic breast cancer with liver metastasis effectively treated with capecitabine and vinorelbine].

A 31-year-old woman with cancer of the right breast underwent surgery in 1996. Histological examination demonstrated a solid tubular carcinoma that was positive lymph node metastasis and hormonal receptor, but negative for HER2 expression. The patient underwent adjuvant therapy with CAF and tamoxifen. At the age of 40 years old, Multiple liver metastasis appeared to the patient. We treated her with paclitaxel. But multiple liver metastasis became progressive disease. Next we treated with capecitabine and vinorelbine. The liver metastasis reduced, and, in the eighth month, the liver metastasis disappeared after 9 cycles. We changed treatment to goserelin, and anastrozole. The period of complete response was 1 year 3 months.

Annual change in bone mineral density in predialysis patients with chronic renal failure: significance of a decrease in serum 1,25-dihydroxy-vitamin D.

Bone disease occurs in the predialysis phase of chronic renal failure (CRF). The aim of this study was to examine how a decrease in renal function affects annual bone mineral density (BMD) changes in predialysis CRF patients and to examine the factors that affect BMD. The BMD of the distal radius in 53 predialysis CRF patients (age, 61.3 +/- 10.8 years; serum creatinine 2.7 +/- 1.2 mg/dl) was measured by peripheral quantitative computed tomography (pQCT) twice with a 1-year interval. The total BMD of the radius significantly decreased over a year (P < 0.001), and both trabecular and cortical BMD showed a significant decrease. Significant positive correlations with BMD changes were found for estimated creatinine clearance (r = 0.375, P < 0.01) and baseline serum 1,25(OH)(2)D (r = 0.434, P < 0.005), indicating that BMD decreased to a greater extent with larger reductions in creatinine clearance and serum 1,25(OH)(2)D. Of several bone metabolic markers examined, baseline serum osteocalcin was significantly positively correlated with annual BMD changes (r = -0.276, P < 0.05). Multiple regression analysis showed that baseline serum 1,25(OH)(2)D (beta = 0.434) was a significant predictor of decreases in total and trabecular BMD (R (2) = 0.188, P < 0.01; and R (2) = 0.207, P < 0.01), independent of other confounding factors. These results indicate that BMD decreases as renal function deteriorates in predialysis CRF patients, and that osteocalcin is a clinically useful marker associated with the decrease in BMD. The serum 1,25(OH)(2)D level is the principal factor affecting BMD of the radius, suggesting that supplementation with an active form of vitamin D is of importance for predialysis CRF patients.

[Bone metabolic marker; recent progress].

Measurement of bone markers has been established to supplement measurement of bone mineral density (BMD) in the diagnosis and treatment of osteoporosis. Bone marker provide a clinical useful mean to predict BMD reduction in near future, to assess fracture risk independent of BMD, to select therapeutic regimens for osteoporosis, to assess the effectiveness of drugs much earlier than BMD measurement. On the basis of the findings that a selective estrogen receptor modulator, raloxifene, showed a protective effect of bone fracture far more potent than its BMD-increasing effect, the hypothesis that bone marker indicates fracture risk independent of BMD has been raised and established.

[Acute response of serum PTH and bone markers after injection of 1alpha,25 (OH)2D3 and 22-oxacalcitrol in hemodialysis patient].

Time-course changes of serum PTH and various bone markers were compared after injection of 1alpha,25 (OH)(2)D(3) with that of 22-oxacalcitriol (OCT) in hemodialysis patients. Five patients (M/F; 3/2, mean ages of 61.6 years) were enrolled into the present study. Oral administration of vitamin D(3) derivatives was stopped at least one week before initiation of vitamin injection. After 1 week of single intravenous injection of OCT (5 microg), 1alpha,25 (OH)(2)D(3) (0.5 microg) was followed. Serum levels of intact PTH, intact osteocalcin, bone alkaline phosphatase, cross-linked N-telopeptides of type I collagen, calcium, and phosphate were measured before, 24h, and 48 h after injections of vitamin D(3) derivatives. Significant difference did not exist in time-course changes of serum PTH, any of bone markers, calcium and phosphate between after OCT and 1alpha,25 (OH)(2)D(3) injection. In conclusion, the present study may not support the presence of significant direct effect of vitamin D(3) derivatives on bone metabolism in hemodialysis patients.

Introduction to sevelamer hydrochloride and its clinical effects.

Sevelamer hydrochloride (SH) is widely used for the treatment of hyperphosphatemia in patients with renal failure who are on maintenance hemodialysis. In this study, we investigated the clinical effects of SH, administered as either monotherapy or combined with a calcium carbonate formulation, on the metabolism of calcium (Ca) and phosphorus (P) in patients who had been taking a Ca-based binder. Patients were divided into three groups (i): switched completely from a Ca-based binder to SH (complete switch); (ii) dosage of the Ca-based binder was reduced, and SH introduced (partial switch); and (iii) dosage of the Ca-based binder was not reduced and SH introduced (combination therapy). We also examined the effects of the introduction of SH on the lipid profile and parathyroid hormone (PTH) concentration. Comparison between groups of the numbers of successfully treated cases (reaching target concentrations of serum P=5.5 mg/dL and Ca x P product=55 mg2/dL2 within 6 months of treatment) showed that the likelihood of reaching target levels was higher if Ca-based binder was maintained as much as possible (combination therapy>partial changeover>complete changeover). Furthermore, treatment with SH decreased total cholesterol and non-HDL cholesterol concentrations significantly, and also increased HDL cholesterol and PTH concentrations compared to pre-treatment. These results suggest that when a calcium carbonate formulation is already in use, as far as compliance allows, the dosage should not be reduced when SH is added. Despite its beneficial effects on the lipid and PTH concentrations, preventing an excessive increase in the PTH concentration is essential when using SH.

Lower risk for cardiovascular mortality in oral 1alpha-hydroxy vitamin D3 users in a haemodialysis population.

BACKGROUND: Renal failure results in deficiency of active vitamin D3 that has diverse effects on metabolism and organ functions. Treatment with active forms of vitamin D(3) ameliorates abnormalities in bone and mineral metabolism, cardiac function, immune response and others. We hypothesized that treatment with vitamin D(3) may be beneficial for survival in patients with end-stage renal disease (ESRD). METHODS: We compared the risk of death between regular users (n = 162) and non-users (n = 80) of oral 1alpha-hydroxyvitamin D3 (alfacalcidol) in a cohort of ESRD patients undergoing haemodialysis for a follow-up of 61 +/- 23 months. The daily dose of alfacalcidol ranged from 0.25 to 1.5 microg, with a median of 0.5 microg. RESULTS: The alfacalcidol users showed a lower risk of death from cardiovascular disease than the non-users in a univariate Cox model [hazards ratio (HR) 0.287, 95% confidence interval (CI) 0.127-0.649, P = 0.003], whereas the risk for death from non-cardiovascular disease was not different between the two groups. Stepwise multivariate Cox analysis showed that cardiovascular mortality was significantly associated with age, presence of diabetes mellitus and treatment with alfacalcidol (HR 0.377, 95% CI 0.246-0.578, P = 0.022). CONCLUSIONS: These results indicate that use of oral alfacalcidol was associated with reduced risk for cardiovascular death in this cohort of ESRD patients. The result of this observational study warrants further randomized controlled trials with 1alpha-hydroxy vitamin D3 to confirm the possibility that such medication improves survival of ESRD patients.