Multicentre, open-label, randomised, controlled trial to compare early intervention with calcimimetics and conventional therapy in preventing coronary artery calcification in patients with secondary hyperparathyroidism (UPCOMING): a study protocol.

INTRODUCTION: Coronary artery and heart valve calcification is a risk factor for cardiovascular death in haemodialysis patients, so calcification prevention should be started as early as possible. Treatment with concomitant calcimimetics and low-dose vitamin D receptor activators (VDRAs) is available, but not enough evidence has been obtained on the efficacy of this regimen, particularly in patients with short dialysis duration. Therefore, this study will evaluate the efficacy and safety of early intervention with upacicalcet, a calcimimetic used to prevent coronary artery calcification in this patient population. METHODS AND ANALYSIS: This multicentre, open-label, randomised, parallel-group controlled study will compare an early intervention group, which received upacicalcet and a low-dose VDRA, with a conventional therapy group, which received a VDRA. The primary endpoint is a change in log coronary artery calcium volume score from baseline to 52 weeks. The main inclusion criteria are as follows: (1) age 18 years or older; (2) dialysis is planned or dialysis duration is less than 60 months; (3) intact parathyroid hormone (PTH) >240 pg/mL or whole PTH level>140 pg/mL; (4) serum-corrected calcium≥8.4 mg/dL and (5) Agatston score >30. The main exclusion criteria are as follows: (1) history of parathyroid intervention or fracture in the past 12 weeks; (2) history of myocardial infarction, stroke or leg amputation in the past 12 weeks; (3) history of coronary angioplasty and (4) heart failure of New York Heart Association class III or worse. ETHICS AND DISSEMINATION: The study will comply with the Declaration of Helsinki and the Japanese Clinical Trials Act. The study protocol has been approved by the Fujita Health University Certified Review Board (file no. CR22-052). Written informed consent will be obtained from all participants. Study results will be presented in academic meetings and peer-reviewed academic journals. TRIAL REGISTRATION NUMBER: jRCTs041220126.

Clinical characteristics of anti-GBM disease with thrombotic microangiopathy: a case report and literature review.

The coexistence of anti-glomerular basement membrane (anti-GBM) disease with thrombotic microangiopathy (TMA) is rarely encountered, and the clinical characteristics of this phenomenon are not well known.A 76-year-old Japanese woman with a history of idiopathic pulmonary disease was diagnosed with anti-GBM disease due to rapidly progressive glomerulonephritis and a positive anti-GBM antibody test result. We treated the patient with hemodialysis, glucocorticoids, and plasmapheresis. During treatment, the patient suddenly became comatose. TMA was then diagnosed because of thrombocytopenia and microangiopathic hemolytic anemia. The activity of a disintegrin-like and metalloproteinase with thrombospondin type 1 motif 13 (ADAMTS-13) was retained at 48%. Although we continued the treatment, the patient died of respiratory failure. An autopsy revealed the cause of respiratory failure to be an acute exacerbation of interstitial pneumonia. The clinical findings of the renal specimen indicated anti-GBM disease; however, there were no lesions suggestive of TMA. A genetic test did not reveal an apparent genetic mutation of the atypical hemolytic uremic syndrome.We conducted a literature review of past case reports of anti-GBM disease with TMA. The following clinical characteristics were obtained. First, 75% of the cases were reported in Asia. Second, TMA tended to appear during the treatment course for anti-GBM disease and usually resolved within 12 weeks. Third, ADAMTS-13 activity was retained above 10% in 90% of the cases. Fourth, central nervous system manifestations occurred in more than half of the patients. Fifth, the renal outcome was very poor. Further studies are required to understand the pathophysiology of this phenomenon.

Overlapping Atypical Hemolytic Uremic Syndrome and C3 Glomerulopathy with Mutation in CFI in a Japanese Patient: A Case Report.

A 34-year-old Japanese man presented with blurred vision, headache, nausea, anemia, thrombocytopenia, and severe renal dysfunction. Thrombotic microangiopathy was initially suspected to have been caused by malignant hypertension. Antihypertensive medications did not improve his thrombocytopenia or renal dysfunction, and other diseases causing thrombotic microangiopathy were ruled out. Therefore, the patient was diagnosed with atypical hemolytic uremic syndrome. A renal biopsy revealed an overlap of thrombotic microangiopathy and C3 glomerulopathy. Genetic testing revealed c.848A>G (p.Asp283Gly), a missense heterozygous variant in the gene encoding complement factor I. Overlapping atypical hemolytic uremic syndrome and C3 glomerulopathy with complement factor I mutation is very rare, especially in Japan.

Rationale and study design of a randomized controlled trial to investigate the renoprotective effect of canagliflozin assessed by test of renal hemodynamics in diabetic kidney disease (the FAGOTTO study).

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are considered to have the potential to maintain renal function by correcting glomerular hypertension in patients with diabetic kidney disease (DKD). The aim of this study is to demonstrate the renoprotective effect of SGLT2i by measuring renal hemodynamics, including glomerular filtration fraction (FF), in type 2 diabetic patients with moderate renal dysfunction. METHODS: Renoprotective effect of canagliflozin derived from test of renal hemodynamics in diabetic kidney disease (FAGOTTO) study is a 12-week multicenter, open-label, randomized (1:1), parallel-group trial of type 2 diabetic patients with diabetic kidney disease (30 ≤ estimated glomerular filtration rate [eGFR] ≤ 60 mL/min/1.73 m2). A total of 110 patients are to be randomly allocated to receive once-daily canagliflozin 100 mg or control (standard therapy). FF will be calculated by dividing the measured GFR (mGFR) by the effective renal plasma flow (eRPF). mGFR and eRPF will be measured by the clearance of inulin and para-aminohippuric acid (PAH), respectively. The primary endpoint of this trial is the percentage change in FF after 4 weeks of treatment in the canagliflozin and control groups. DISCUSSION: The FAGOTTO study will elucidate the mechanism of the renoprotective action of SGLT2i. The background, rationale, and study design of this trial are presented. To date, > 80 patients have been enrolled in this trial. The study will end in 2025. TRIAL REGISTRATION: jRCT (Japan Registry Of Clinical Trials) jRCTs041200069. Date of registration: November 27, 2020.

Relationship between serum sodium level at dialysis initiation and all-cause mortality.

BACKGROUND: Hyponatremia is a common electrolyte disorder in patients with chronic kidney disease. In addition, hyponatremia is associated with mortality in patients with chronic kidney disease, including those on dialysis. However, few studies have examined this relationship in patients with incident dialysis. METHODS: We used a database of multicenter prospective cohort studies that included 1520 incident dialysis patients. The baseline was set at the time of dialysis initiation. The enrolled patients were classified into five groups according to their serum sodium levels (< 130 mEq/L, 130-134 mEq/L, 135-139 mEq/L, 140-144 mEq/L, and ≥ 145 mEq/L). Multivariate Cox proportional hazards analysis was conducted to determine factors associated with all-cause mortality. RESULTS: A total of 392 all-cause deaths occurred during the follow-up period. The ultrafiltration volume per body weight during the first dialysis session was more significant in the groups with the lowest and highest sodium levels. The percentage of patients using loop diuretics and thiazide was higher in the group with lower sodium levels (< 130 mEq/L and 130-134 mEq/L). All-cause mortality was significantly different among the five groups (p = 0.025). Multivariate analysis indicated that all-cause mortality was significantly higher in the group with the lowest sodium level compared to the group with a serum sodium level of 135-139 mEq/L (hazard ratio: 1.61, 95% confidence interval: 1.04-2.49). CONCLUSION: Hyponatremia of < 130 mEq/L at dialysis initiation was significantly associated with all-cause mortality. We considered the results relevant to underlying conditions, including cardiovascular disease and medications.