The effects of denosumab and alendronate on glucocorticoid-induced osteoporosis in patients with glomerular disease: A randomized, controlled trial.

INTRODUCTION: The clinical utility of denosumab for the treatment of glucocorticoid-induced osteoporosis (GIOP) has yet to be established. This study aimed to compare the effects of denosumab on bone mineral density (BMD) and bone turnover markers to those of alendronate in patients with GIOP. METHODS: A prospective, single-center study of 32 patients (18 men; median age, 66.0 years) with glomerular disease receiving prednisolone (PSL) who were diagnosed as having GIOP and had not received bisphosphonates before was conducted. Participants were randomized to either alendronate (35 mg orally once a week) or denosumab (60 mg subcutaneously once every 6 months), and all subjects received calcitriol. The primary endpoint was the percent change in lumbar spine (LS) BMD at 12 months of treatment. RESULTS: The demographic and clinical characteristics at baseline were not significantly different between the groups. Denosumab treatment markedly decreased serum levels of t-PINP, BAP, and TRACP-5b at 12 months compared to baseline (-57.4%, p<0.001; -30.9%, p<0.01; -57.7%, p<0.001, respectively). After 12 months of alendronate treatment, serum levels of t-PINP, BAP, and TRACP-5b were also significantly decreased compared to pretreatment (-38.9%, p<0.01; -16.3%, p<0.05; -43.5%, p<0.01, respectively). However, no significant differences in the changes of bone turnover markers were found between the two groups. As for the effects on BMD, denosumab treatment markedly increased LS BMD from 6 months compared to baseline, whereas no significant difference compared to pretreatment was found in the alendronate group during the study period. In the comparison of the two groups, a large increase of LS BMD was found in the denosumab treatment group compared to the alendronate treatment group at 12 months (p<0.05). CONCLUSIONS: In patients with GIOP, denosumab treatment markedly suppressed bone turnover, which led to a significantly greater increase in LS BMD than with alendronate treatment. These results suggest that denosumab is a therapeutic option for the treatment of GIOP.

High fibroblast growth factor 23 levels are associated with decreased ferritin levels and increased intravenous iron doses in hemodialysis patients.

A recent study demonstrated the association between inflammation, iron metabolism and fibroblast growth factor (FGF) 23. The present clinical study aimed to assess associations between anemia, iron metabolism and FGF23 in hemodialysis (HD) patients. This prospective observational study examined a cohort of prevalent HD patients (n = 282). Blood samples were obtained before dialysis sessions to measure baseline levels of hemoglobin (Hb), transferrin saturation (TSAT), ferritin, albumin-adjusted calcium (Ca), phosphate (P), intact (i)-PTH, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, intact (i)-FGF23, high sensitive (hs)-CRP, and interleukin-6. After the baseline measurement, study patients were followed-up for 6 months. Biochemical measurements were subsequently performed at 1 (Hb), 2 (TSAT and ferritin) or 3 (Ca, P and hs-CRP) month intervals. Doses of ESAs and intravenous iron supplementation during the study period were recorded. i-FGF23 was positively correlated with Ca, P, i-PTH and inversely correlated with TSAT and ferritin. However, levels of Hb and hs-CRP and doses of ESAs during the study period did not differ among the i-FGF23 tertiles, with levels of ferritin and TSAT in the higher i-FGF23 tertile being consistently lower than in the middle to lower i-FGF23 tertiles. Multivariate repeated measures analysis indicated that the higher i-FGF23 tertile was independently associated with repeated measurements of ferritin, but not of TSAT. Doses of intravenous iron supplementation were significantly increased in the higher i-FGF23 tertile in multivariate models. In conclusion, high i-FGF23 levels may be associated with prolongation of low levels of ferritin, resulting in increased usages of iron supplementation in HD patients.

Associations among apolipoproteins, oxidized high-density lipoprotein and cardiovascular events in patients on hemodialysis.

Apolipoproteins are associated with survival among patients on hemodialysis (HD), but these associations might be influenced by dysfunctional (oxidized) high-density lipoprotein (HDL). We assessed associations among apolipoproteins and oxidized HDL, mortality and cardiovascular disease (CVD) events in patients on HD. This prospective observational study examined 412 patients on prevalent HD. Blood samples were obtained before dialysis at baseline to measure lipids, apolipoproteins, oxidized LDL, oxidized HDL, high-sensitivity C-reactive protein (hs-CRP) and interleukin (IL)-6 at baseline, and HDL-C and hs-CRP were measured 12 months later. Patients were then prospectively followed-up (mean, 40 months) and all-cause mortality and composite CVD events were analyzed. Associations between variables at baseline and clinical outcome were assessed by Cox proportional hazards modeling (n = 412) and Cox hazards modeling with a time-varying covariate with HDL-C and hs-CRP (n = 369). Quartiles of apolipoproteins and oxidized HDL were not associated with all-cause mortality. However, Cox proportional hazards models with quartiles of each variable adjusted for confounders and hs-CRP or IL-6 identified apolipoprotein (apo)B-to-apoA-I ratio (apoB/apoA-I) and oxidized HDL, but not apoA-I or apoA-II, as independent risk factors for composite CVD events. These associations were confirmed by Cox proportional hazards modeling with time-varying covariates for hs-CRP. ApoB/apoA-I was independently associated with composite CVD events in 1-standard deviation (SD) increase-of-variables models adjusted for the confounders, oxidized HDL and hs-CRP. However, these associations disappeared from the model adjusted with IL-6 instead of hs-CRP, and oxidized HDL and IL-6 were independently associated with composite CVD events. Findings resembled those from Cox proportional hazards modeling using time-varying covariates with HDL-C adjusted with IL-6. In conclusion, both oxidized HDL and apoB/apoA-I might be associated with CVD events in patients on prevalent HD, while associations of apoB/apoA-I with CVD events differed between models of apoB/apoA-I quartiles and 1-SD increases, and were influenced by IL-6.

Diffuse Leukoencephalopathy Associated with Dialysis Disequilibrium Syndrome.

A 52-year-old woman, previously treated for gastric cancer, began hemodialysis (HD) to treat the onset of severe acidemia. After her initial HD sessions, she suffered from a prolonged coma for approximately ten days. Magnetic resonance imaging revealed diffuse leukoencephalopathy, with increased apparent diffusion coefficient. Magnetic resonance spectroscopy showed a reduction of the N-acetylaspartate/creatine ratio. Her neuroimaging findings gradually resolved. Her transient cerebral white matter lesions were thought to be interstitial edema derived from dialysis disequilibrium syndrome (DDS), which might have been amplified by subclinical brain injury due to past chemotherapy. Her history of cancer chemotherapy may be a risk factor for an exacerbation of DDS.

Granulomatous interstitial nephritis in a renal allograft.

We describe a middle-aged woman in whom granulomatous interstitial nephritis (GIN) developed in a renal allograft. She had undergone bowel resection due to an uncertain diagnosis of active granulomatous bowel disease 30 years earlier. Thereafter, frequent hyperoxaluria as well as calcium oxalate stone and recurrent urinary tract infections had resulted in a progressive deterioration in kidney function over a period of 20 years. She underwent living donor kidney transplantation; however, her kidney function progressively deteriorated, despite transplantation. A biopsy of the renal allograft revealed GIN with granulomatous vasculitis accompanied by calcium oxalate crystals. These as well as the laboratory findings indicated a diagnosis of sarcoidosis. We considered that the aggravated granulomatous inflammation on the allograft was caused by recurrent sarcoidosis accompanied by hyperoxaluria.

A case of tuberculous peritonitis in a hemodialysis patient with high serum soluble interleukin-2 receptor and CA-125 levels.

A hemodialysis patient with tuberculous peritonitis with hypercalcemia and high serum soluble interleukin-2 receptor (sIL-2R) and CA-125 levels is reported. An 82-year-old woman who had been on hemodialysis therapy for 6 years was admitted to our hospital for evaluation and treatment of hypercalcemia. Laboratory examination and radiologic studies revealed markedly increased serum sIL-2R and CA-125 levels and exudative ascites, with high levels of adenosine deaminase (ADA) and CA-125, which was suggestive of malignancy or tuberculosis. She was finally diagnosed as having tuberculous peritonitis based on positivity for Mycobacterium tuberculosis in ascitic fluid. The ascites subsided with normalization of hypercalcemia and a marked decrease in serum sIL-2R and CA-125 levels in response to anti-tuberculosis treatment. This case indicates that serum sIL-2R and CA-125 levels can rise to levels suggestive of malignancy in tuberculous peritonitis, and that they can be used to monitor the response to anti-tuberculosis treatment.

Impact of fibroblast growth factor 23 on lipids and atherosclerosis in hemodialysis patients.

Levels of fibroblast growth factor (FGF) 23, a phosphatonin, are frequently elevated in patients with end-stage renal disease (ESRD) who are on maintenance hemodialysis (MHD). However, the role of FGF23 remains unclear because renal FGF receptor function might be impaired. The present cross-sectional study examines a cohort of patients (n = 196) on MHD who were not undergoing therapy with lipid-lowering drugs including sevelamer. Non-fasting venous blood samples were withdrawn before the hemodialysis (HD) session on the third day after the previous HD session to measure serum levels of albumin, calcium (Ca), phosphate (P), alkaline phosphatase, intact parathyroid hormone (PTH), total cholesterol (C), high-density lipoprotein (HDL)-C, low-density lipoprotein(LDL)-C, oxidative LDL-C, high-sensitivity C-reactive protein (HsCRP), interleukin-6 (IL-6), and FGF23. Nutritional status was assessed using the geriatric nutritional risk index (GNRI). Carotid intima-medial thickness (CIMT) was assessed using a B-mode ultrasound scanner. FGF23 was positively correlated with P, Ca(alb)xP product, and intact PTH, and inversely correlated with C and non-HDL-C. In the higher FGF23 tertile, levels of both non-HDL-C and C were significantly decreased and CIMT was less elevated compared to the lower FGF23 tertile. Multivariate analysis showed that the higher FGF23 tertile was independently associated with decreases in C (adjusted r(2) = 0.14) and non-HDL-C (adjusted r(2) = 0.20) levels and with a less-pronounced increase in CIMT (adjusted r(2) = 0.14). High FGF23 appears to be an independent biomarker of a decrease in C and non-HDL-C that is negatively associated with atherosclerosis in patients on MHD.

Ultrapure dialysate influences serum myeloperoxidase levels and lipid metabolism.

BACKGROUND: Ultrapure dialysate (UD) might contribute to improvements in the morbidity and mortality of hemodialysis (HD) patients. However, it is unclear whether increasing dialysate purity affects chronic inflammation, oxidative stress, and lipid abnormalities. METHODS: In a prospective cohort study, 126 patients undergoing maintenance HD using conventional dialysate (CD) with one endotoxin cut filter were assigned to either continuation of the same HD or HD using UD (more purified dialysate). At baseline and 6 months we measured lipids, high-sensitive (hs)CRP, oxidative LDL-cholesterol, and myeloperoxidase. RESULTS: Serum myeloperoxidase and hsCRP levels in the UD group were significantly decreased at 6 months compared with the CD group. Multivariate analysis showed that decreases in non-HDL-cholesterol and ApoB at 6 months were independently correlated with changes in myeloperoxidase. CONCLUSION: Endotoxin-free UD can improve the chronic inflammatory status, oxidative stress, and lipid abnormalities, suggesting a possible contribution to reduced cardiovascular disease risk and ultimately to lowered mortality in HD patients.

[Novel phosphate binders under development].

Controlling serum phosphorus levels in patients with chronic kidney disease is crucial. Since hyperphosphatemia is an established risk factor for not only secondary hyperparathyroidism, but also cardiovascular mortality in these patients, the adequate control of serum phosphorus is necessary. The target levels of serum phosphorus, however, are not consistently being met. To achieve better control of serum phosphorus levels, some novel phosphate binders, which do not contain calcium or metal, have been developed. In this manuscript we discuss some novel phosphate binders, which are now in clinical trials.

MPO-ANCA crescentic glomerulonephritis complicated by membranous nephropathy: MPO demonstrated in epimembranous deposits.

An elderly woman presented with haematuria and proteinuria accompanied by elevated serum myeloperoxidase (MPO)-specific anti-neutrophil cytoplasmic antibodies (MPO-ANCA). A renal biopsy revealed mild mesangial proliferation with fibrocellular crescent formation and a membranous glomerular lesion. Immunofluorescence microscopy using FITC-labelled rabbit anti-human MPO antibodies revealed granular MPO deposition along the glomerular capillary walls (GCW) with a staining profile similar to that of glomerular IgG deposition. The one-year follow-up renal biopsy revealed minimal IgG and undetectable MPO deposition. Both MPO and MPO-ANCA might have been responsible for the IgG immune depositions along the GCW in this patient.

[Vitamin D metabolism and chronic kidney disease].

Vitamin D is finally converted into the active form in the kidney, which is regulated and affected by several factors such as calcium . phosphate balance, parathyroid hormone (PTH), calcitonin and fibroblast growth factor 23 (FGF23). Activated vitamin D works as hormone and engages in calcium . bone metabolism. In chronic kidney disease, the active form can be decreased and therefore, renal osteodystrophy can be lead as consequences of mineral metabolism abnormality and unregulated PTH production/secretion as increased activity of the parathyroid glands (2HPT). Moreover, because chronic kidney disease (CKD)-associated abnormal states in above are detrimental to CKD patients not only in terms of renal osteodystrophy, but progress of cardiovascular disease and mortality. Therefore new concept is proposed as chronic kidney disease-mineral bone disorder (CKD-MBD).