Publications by authors named "Shinichi Nishi"

189 Publications

X-chromosome inactivation patterns in females with Fabry disease examined by both ultra-deep RNA sequencing and methylation-dependent assay.

Clin Exp Nephrol 2021 Jun 14. Epub 2021 Jun 14.

Department of Nephrology, Kobe University Graduate School of Medicine, Kobe, Japan.

Background: Fabry disease is an X-linked inherited lysosomal storage disorder caused by mutations in the gene encoding α-galactosidase A. Males are usually severely affected, while females have a wide range of disease severity. This variability has been assumed to be derived from organ-dependent skewed X-chromosome inactivation (XCI) patterns in each female patient. Previous studies examined this correlation using the classical methylation-dependent method; however, conflicting results were obtained. This study was established to ascertain the existence of skewed XCI in nine females with heterozygous pathogenic variants in the GLA gene and its relationship to the phenotypes.

Methods: We present five female patients from one family and four individual female patients with Fabry disease. In all cases, heterozygous pathogenic variants in the GLA gene were detected. The X-chromosome inactivation patterns in peripheral blood leukocytes and cells of urine sediment were determined by both classical methylation-dependent HUMARA assay and ultra-deep RNA sequencing. Fabry Stabilization Index was used to determine the clinical severity.

Results: Skewed XCI resulting in predominant inactivation of the normal allele was observed only in one individual case with low ⍺-galactosidase A activity. In the remaining cases, no skewing was observed, even in the case with the highest total severity score (99.2%).

Conclusion: We conclude that skewed XCI could not explain the severity of female Fabry disease and is not the main factor in the onset of various clinical symptoms in females with Fabry disease.
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http://dx.doi.org/10.1007/s10157-021-02099-4DOI Listing
June 2021

Serum hemoglobin concentration, as a reflection of renal fibrosis, and risk of renal decline in early-stages of diabetic kidney disease: a nationwide, biopsy-based cohort study.

Nephrol Dial Transplant 2021 May 24. Epub 2021 May 24.

Okayama University, Okayama, Japan.

Background: Prognosticating disease progression in patients with diabetic kidney disease (DKD) is challenging, especially in the early stages of kidney disease. Anemia can occur in the early stages of kidney disease in diabetes. We therefore postulated that serum hemoglobin concentration, as a reflection of incipient renal tubulointerstitial impairment, can be used as a marker to predict DKD progression.

Methods: Drawing on nationally representative data of patients with biopsy-proven DKD, 246 patients who had an estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 at renal biopsy were identified: aged 56 (45, 63); 62.6% men; Hb 13.3 (12.0, 14.5) g/dL; eGFR 76.2 (66.6, 88.6) mL/min/1.73 m2; urine albumin-to-creatinine ratio [UACR] 534 (100, 1480) mg/g Crea. Serum hemoglobin concentration were divided into quartiles: ≤12, 12.1-13.3, 13.4-14.5, and ≥14.6 g/dL. The association between serum hemoglobin concentration and the severity of renal pathological lesions was explored. A multivariable Cox regression model was used to estimate the risk of DKD progression (new onset of end-stage kidney disease, 50% reduction of eGFR, or doubling of serum creatinine). The incremental prognostic value of DKD progression by adding serum hemoglobin concentration to the known risk factors of DKD was assessed.

Results: Serum hemoglobin levels negatively correlated with all renal pathological features, especially with the severity of interstitial fibrosis (ρ =-0.52; P < 0.001). During a median follow-up of 4.1 years, 95 developed DKD progression. Adjusting for known risk factors of DKD progression, the hazard ratio in the first, second, and third quartile (the fourth quartile as a reference) were 2.74 (95% CI 1.26-5.97), 2.33 (95% CI 1.07-5.75), and 1.46 (95% CI 0.71-3.64), respectively. Addition of the serum hemoglobin concentration to the known risk factors of DKD progression improved the prognostic value of DKD progression (the global chi-statistics increased from 55.1 to 60.8; P < 0.001).

Conclusions: Serum hemoglobin concentration, which reflects incipient renal fibrosis, can be useful for predicting DKD progression in the early stages of kidney disease.
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http://dx.doi.org/10.1093/ndt/gfab185DOI Listing
May 2021

Fatal hypoglycemia with ciprofloxacin in a dialysis patient: A case report.

Clin Case Rep 2021 Apr 12;9(4):1902-1904. Epub 2021 Mar 12.

Intensive Care Unit Hyogo College of Medicine Nishinomiya Japan.

In patients with renal dysfunction, it is important to avoid prescribing fluoroquinolones including ciprofloxacin.
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http://dx.doi.org/10.1002/ccr3.3871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077382PMC
April 2021

The Modified Chronic Kidney Disease Epidemiology Collaboration Equation for the Estimated Glomerular Filtration Rate is Better Associated with Comorbidities than Other Equations in Living Kidney Donors in Japan.

Intern Med 2021 Mar 15. Epub 2021 Mar 15.

National Hospital Organization Mito Medical Center, Japan.

Objective We studied three types of estimated glomerular filtration rate (eGFR) equations and evaluated which type was strongly associated with comorbidities in living kidney transplantation (LKT) donors. Methods We compared the Japanese modified estimated glomerular filtration (eGFR), Modification of Diet in Renal Disease, and Chronic Kidney Disease Epidemiology Collaboration equations (Jm-eGFR, Jm-MDRD, and Jm-CKD-EPI, respectively) for Japanese LKT donors with respect to their relationships with obesity, hypertension, diabetes, cardiovascular disease, and stroke. Results Of the 8,176 enrolled Japanese LKT donors, the eGFR calculated using Jm-CKD-EPI (eGFR/Jm-CKD-EPI) detected significant differences in 4 of 5 comorbidities between the comorbidity-positive and comorbidity-negative groups, whereas the eGFR calculated using Jm-MDRD (eGFR/Jm-MDRD) and Jm-eGFR (eGFR/Jm-eGFR) detected only 3 and 1 comorbidities, respectively. The area under the receiver operating characteristic curve of Jm- CKD-EPI was larger than those of Jm-eGFR and Jm-MDRD for all five comorbidities. Conclusion We found that the eGFR/Jm-CKD-EPI correlated better with comorbidities than the eGFR/Jm-eGFR and eGFR/Jm-MDRD in Japanese LKT donors. We recommend using the eGFR/Jm-CKD-EPI for the initial assessment of the renal function in LKT donor candidates when evaluating the presence of associated comorbidities.
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http://dx.doi.org/10.2169/internalmedicine.6934-20DOI Listing
March 2021

Comparative Effects of Etelcalcetide and Maxacalcitol on Serum Calcification Propensity in Secondary Hyperparathyroidism: A Randomized Clinical Trial.

Clin J Am Soc Nephrol 2021 04 8;16(4):599-612. Epub 2021 Mar 8.

Shirasagi Hospital, Osaka, Japan

Background And Objectives: Vitamin D receptor activators and calcimimetics (calcium-sensing receptor agonists) are two major options for medical treatment of secondary hyperparathyroidism. A higher serum calcification propensity (a shorter T value) is a novel surrogate marker of calcification stress and mortality in patients with CKD. We tested a hypothesis that a calcimimetic agent etelcalcetide is more effective in increasing T value than a vitamin D receptor activator maxacalcitol.

Design, Setting, Participants, & Measurements: A randomized, multicenter, open-label, blinded end point trial with active control was conducted in patients with secondary hyperparathyroidism undergoing hemodialysis in Japan. Patients were randomly assigned to receive intravenous etelcalcetide 5 mg thrice weekly (etelcalcetide group) or intravenous maxacalcitol 5 or 10 g thrice weekly (maxacalcitol group). The primary, secondary, and tertiary outcomes were changes in T value, handgrip strength, and score of the Dementia Assessment Sheet for Community-Based Integrated Care System from baseline to 12 months, respectively.

Results: In total, 425 patients from 23 dialysis centers were screened for eligibility, 326 patients were randomized (etelcalcetide, =167; control, =159), and 321 were included in the intention-to-treat analysis (median age, 66 years; 113 women [35%]). The median (interquartile range) of T value was changed from 116 minutes (interquartile range, 90-151) to 131 minutes (interquartile range, 102-176) in the maxacalcitol group, whereas it was changed from 123 minutes (interquartile range, 98-174) to 166 minutes (interquartile range, 127-218) in the etelcalcetide group. The increase in T value was significantly greater in the etelcalcetide group (difference in change, 20 minutes; 95% confidence interval, 7 to 34 minutes; =0.004). No significant between-group difference was found in the change in handgrip strength or in the Dementia Assessment Sheet for Community-Based Integrated Care System score.

Conclusions: Etelcalcetide was more effective in increasing T value than maxacalcitol among patients on hemodialysis with secondary hyperparathyroidism. There was no difference in handgrip strength or cognition between the two drugs.

Clinical Trial Registry Name And Registration Number: VICTORY; UMIN000030636 and jRCTs051180156.
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http://dx.doi.org/10.2215/CJN.16601020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092049PMC
April 2021

Changes in blood pressure during treatment with the tyrosine kinase inhibitor lenvatinib.

Clin Kidney J 2021 Jan 21;14(1):325-331. Epub 2020 Oct 21.

Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, Kobe, Japan.

Background: Within the class of tyrosine kinase inhibitors (TKIs), which are used for the treatment of numerous advanced cancers, lenvatinib is associated with a higher prevalence of hypertension (HT) compared with other TKIs. In this study, we investigated the effect of lenvatinib on blood pressure (BP) and associated factors.

Methods: This single-centre, retrospective observational study included 25 consecutive patients treated with lenvatinib for unresectable hepatocellular carcinoma from April 2018 to December 2018 at the study institution. We assessed changes in BP using ambulatory BP monitoring, urinary sodium excretion, kidney function, use of antihypertensive agents and diuretics, and fluid retention following treatment initiation with lenvatinib.

Results: At 1 week after treatment initiation, the mean BP and the percentage of patients with riser pattern significantly increased compared with those at the baseline. Although there were no significant changes at 1 week, urinary sodium excretion (153.4 ± 51.7 and 112.5 ± 65.0 mEq/day at 1 and 3 weeks, respectively, P < 0.05) and estimated glomerular filtration rate significantly decreased and the number of patients with fluid retention increased at 3 weeks. Furthermore, patients with fluid retention had significantly higher BP or required more intensive BP treatment compared with those without fluid retention.

Conclusions: Lenvatinib might lead to HT without fluid retention soon after the initiation of treatment, subsequently leading to a reduction in urinary sodium excretion, thereby contributing to a rise in BP by fluid retention.
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http://dx.doi.org/10.1093/ckj/sfaa137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857786PMC
January 2021

Renal prognoses by different target hemoglobin levels achieved by epoetin beta pegol dosing to chronic kidney disease patients with hyporesponsive anemia to erythropoiesis-stimulating agent: a multicenter open-label randomized controlled study.

Clin Exp Nephrol 2021 May 7;25(5):456-466. Epub 2021 Jan 7.

Fukuoka Renal Clinic, Fukuoka, Japan.

Background: There is no evidence regarding appropriate target hemoglobin levels in chronic kidney disease (CKD) patients with an erythropoiesis-stimulating agent (ESA)-hyporesponsiveness. Therefore, we conducted a randomized controlled study in non-dialysis dependent CKD (NDD-CKD) patients with ESA-hyporesponsiveness, comparing results of intensive versus conservative treatment to maintain hemoglobin levels.

Methods: This was a multicenter, open-label, randomized, parallel-group study conducted at 89 institutions. Among NDD-CKD patients, those with ESA-hyporesponsive renal anemia were randomly assigned to an intensive treatment group, to which epoetin beta pegol was administered with target hemoglobin level of 11 g/dL or higher, or conservative treatment group, in which the hemoglobin levels at enrollment (within ± 1 g/dL) were maintained. The primary endpoint was the time to the first kidney composite event defined as (1) transition to renal replacement therapy (dialysis or renal transplantation); (2) reduction of estimated glomerular filtration rate (eGFR) to less than 6.0 mL/min/1.73 m; or (3) reduction of eGFR by 30% or more. Secondary endpoints were kidney function (change rate in eGFR), cardiovascular (CV) events, and safety.

Results: Between August 2012 and December 2015, 385 patients were registered, and 362 patients who met the eligibility criteria were enrolled. There was no significant difference in kidney survival or in CV events between the two groups. However, the incidences of the 3 types of kidney composite events tended to differ.

Conclusions: In NDD-CKD patients with ESA-hyporesponsive renal anemia, the aggressive administration of ESA did not clearly extend kidney survival or result in a significant difference in the incidence of CV events.
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http://dx.doi.org/10.1007/s10157-020-02005-4DOI Listing
May 2021

Validation of the diagnostic criteria for IgG4-related kidney disease (IgG4-RKD) 2011, and proposal of a new 2020 version.

Clin Exp Nephrol 2021 Feb 4;25(2):99-109. Epub 2021 Jan 4.

Division of Nephrology and Rheumatology, Department of Internal Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan.

Background: In 2011, the IgG4-related kidney disease (IgG4-RKD) working group of the Japanese Society of Nephrology proposed diagnostic criteria for IgG4-RKD. The aim of the present study was to validate those criteria and develop a revised version.

Methods: Between April 2012 and May 2019, we retrospectively collected Japanese patients with kidney disease, for whom data on serum IgG4 values and/or immunohistological staining for IgG4 in renal biopsy samples were available. These patients were classified as IgG4-RKD or non-IgG4-RKD based on the diagnostic criteria for IgG4-RKD 2011, and the results were evaluated by expert opinion. Accordingly, we developed some revised versions of the criteria, and the version showing the best performance in the present cohort was proposed as the IgG4-RKD criteria for 2020.

Results: Of 105 included patients, the expert panel diagnosed 55 as having true IgG4-RKD and 50 as mimickers. The diagnostic criteria for IgG4-RKD 2011 had a sensitivity of 72.7% and a specificity of 90.0% in this cohort. Of the 15 patients with true IgG4-RKD who were classified as non-IgG4-RKD, all lacked biopsy-proven extra-renal lesions, although many had clinical findings highly suggestive of IgG4-RD. The revised version to which "bilateral lacrimal, submandibular or parotid swelling, imaging findings compatible with type 1 autoimmune pancreatitis or retroperitoneal fibrosis" was added as an item pertaining to extra-renal organ(s) improved the sensitivity to 90.9% while the specificity remained at 90.0%.

Conclusion: The revised version has considerably improved test performance after addition of the new extra-renal organ item (imaging and clinical findings).
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http://dx.doi.org/10.1007/s10157-020-01993-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880946PMC
February 2021

Influence of oxidative stress on vascular calcification in the setting of coexisting chronic kidney disease and diabetes mellitus.

Sci Rep 2020 11 26;10(1):20708. Epub 2020 Nov 26.

Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan.

Vascular calcification (VC) is a common complication in patients with chronic kidney disease (CKD). Particularly, CKD patients with diabetes mellitus (DM) develop severe VC. Specific mechanisms of VC remain unclear; this study aimed to investigate them in the context of coexisting CKD and DM, mainly regarding oxidative stress. Sprague Dawley rats were randomly divided into six groups as follows: control rats (Control), 5/6 nephrectomized rats (CKD), streptozotocin-injected rats (DM), 5/6 nephrectomized and streptozotocin-injected rats (CKD + DM), CKD + DM rats treated with insulin (CKD + DM + INS), and CKD + DM rats treated with antioxidant apocynin (CKD + DM + APO). At 18 weeks old, the rats were sacrificed for analysis. Compared to the control, DM and CKD groups, calcification of aortas significantly increased in the CKD + DM group. Oxidative stress and osteoblast differentiation-related markers considerably increased in the CKD + DM group compared with the other groups. Moreover, apocynin considerably reduced oxidative stress, osteoblast differentiation-related markers, and aortic calcification despite high blood glucose levels. Our data indicate that coexisting CKD and DM hasten VC primarily through an increase in oxidative stress; anti-oxidative therapy may prevent the VC progression.
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http://dx.doi.org/10.1038/s41598-020-76838-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693179PMC
November 2020

Evaluation of aortic calcification using a three-dimensional volume-rendering method in patients with end-stage kidney disease.

J Bone Miner Metab 2021 May 3;39(3):439-445. Epub 2020 Nov 3.

Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan.

Introduction: Very few studies have been performed to evaluate both the severity and site of aortic calcification (AC) in both end-stage kidney disease (ESKD) and diabetes mellitus (DM). The purpose of our study was to examine the utility of a newly developed three-dimensional (3D) visualization and quantification method compared with other methods to evaluate vascular calcification in ESKD patients with and without DM.

Materials And Methods: Fifty patients with ESKD before initiating hemodialysis at our hospital were included in the present study. They were divided into the two groups, depending on the presence or absence of DM: Control group (n = 31) and DM group (n = 19). The volume and site of AC were evaluated via computed tomography (CT) scan using a 3D visualization and quantification method.

Results: Total calcification volume was significantly greater in the DM group than in the Control group. Calcification volume in the descending and abdominal aortas was greater in the DM group compared to the Control group. There were no significant differences in calcification volume in the aortic root, ascending aorta, and aortic arch. Calcification volume of the whole aorta, the descending aorta, and the abdominal aorta were each significantly correlated with age, diastolic blood pressure and pulse pressure.

Conclusion: This study using a 3D visualization and quantification method demonstrated that AC was more severe and occurred more frequently in the abdominal aorta in ESKD patients with DM compared to those without DM. This method would enable us to precisely evaluate the volume and distribution of AC.
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http://dx.doi.org/10.1007/s00774-020-01172-4DOI Listing
May 2021

Relationship between parathyroid hormone and renin-angiotensin-aldosterone system in hemodialysis patients with secondary hyperparathyroidism.

J Bone Miner Metab 2021 Mar 12;39(2):230-236. Epub 2020 Sep 12.

Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan.

Introduction: Hyperparathyroidism (HPT) is associated with mortality and cardiovascular disease (CVD) in dialysis patients. However, its mechanism is still unclear. It is suspected that parathyroid hormone (PTH) is associated with the renin-angiotensin-aldosterone system (RAAS) as a possible mechanism. Thus, we examined their hormonal interaction in hemodialysis patients with secondary HPT.

Materials And Methods: Seventeen hemodialysis patients with HPT were included. All patients underwent total parathyroidectomy (PTx). Serum intact PTH (iPTH), calcium and phosphate levels, plasma renin activity (PRA), and plasma aldosterone levels (ALD) were measured pre- and post-PTx.

Results: Pre-serum iPTH tended to be correlated with pre-PRA and were significantly correlated with pre-ALD (pre-PRA: r = 0.44, p = 0.07, pre-ALD: r = 0.49, p < 0.05). With the reduction in serum iPTH after PTx, PRA and ALD significantly decreased after PTx. Additionally, the change in serum iPTH tended to be correlated with the changes in PRA and ALD (PRA; r = 0.46, p = 0.05, ALD; r = 0.45, p = 0.06).

Conclusion: Our results suggest that PTH could be interrelated with RAAS in hemodialysis patients with secondary HPT.
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http://dx.doi.org/10.1007/s00774-020-01139-5DOI Listing
March 2021

Histological changes of a kidney in a recipient who received an allograft from a patient with Fabry disease.

J Nephrol 2020 08 13;33(4):657-659. Epub 2020 Jun 13.

Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan.

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http://dx.doi.org/10.1007/s40620-020-00782-5DOI Listing
August 2020

Clinicopathological features of fast eGFR decliners among patients with diabetic nephropathy.

BMJ Open Diabetes Res Care 2020 06;8(1)

Department of Nephrology and Laboratory Medicine, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan.

Introduction: The speed of declining kidney function differs among patients with diabetic nephropathy. This study was undertaken to clarify clinical and pathological features that affect the speed of declining kidney function in patients with diabetic nephropathy.

Research Design And Methods: This study was design as multicenter retrospective study. The subjects (377 patients with diabetic nephropathy diagnosed by kidney biopsy at 13 centers in Japan) were classified into three groups based on the estimated glomerular filtration rate (eGFR) declining speed. The eGFR increasing group, the control group, and the eGFR declining group were divided at 0 and 5 mL/min/1.73 m/year, respectively. Characteristics of clinicopathological findings of declining kidney function were evaluated.

Results: The mean observation period of this study was 6.9 years. The control group, the eGFR increasing group, and the eGFR declining group included 81, 66, and 230 patients, respectively. The incidences of composite kidney events represented by 100 persons/year were 25.8 in the eGFR declining group and 2.0 in the eGFR increasing group. After adjustment for age, sex, systolic blood pressure, hemoglobin, and urinary albumin levels, three clinicopathological findings (urinary albumin levels, presence of nodular lesion, and mesangiolysis) were risk factors for inclusion in the eGFR declining group (the ORs were 1.49, 2.18, and 2.08, respectively). In contrast, the presence of subendothelial space widening and polar vasculosis were characteristic findings for inclusion in the eGFR increasing group (the ORs were 0.53 and 0.41, respectively).

Conclusions: As well as urinary albumin elevation, nodular lesion and mesangiolysis were characteristic pathological features of patients with fast declining kidney function.
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http://dx.doi.org/10.1136/bmjdrc-2019-001157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282298PMC
June 2020

Current Situation of Chronic Kidney Disease Management in General Practice in Japan: A Questionnaire Survey for General Physicians.

Kobe J Med Sci 2020 Mar 27;65(5):E164-E173. Epub 2020 Mar 27.

Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, Kobe, Japan.

Total management of chronic kidney disease has been well established, and the screening using dipstick urine test has already been widespread in Japan. Nevertheless, the number of dialysis patients is still rising. While clinical cooperation between general physicians and nephrologists is expected to improve prognoses of chronic kidney disease patients, real situation of the management in general practice has not been obvious. We conducted a questionnaire survey for the doctors of Hyogo Prefecture Medical Association excluding nephrologists to clarify the situation and the issue about chronic kidney disease management in general practice. Total 169 doctors replied to the questionnaire. In 74.0% of medical facilities, estimated glomerular filtration rate was automatically calculated and indicated in the result report with the measurement of serum creatinine. The compliance rates of the chronic kidney disease clinical guideline for Japanese regarding referral to nephrologists were 33.7% in cases of urine abnormality and 57.4% in cases of decreased kidney function. For the patients of diabetes without previous diagnosis of nephropathy, only 30.8% of doctors examined urine albumin at least every 6 months. In general practice, there is still much possibility to improve chronic kidney disease management. We have to continue to advocate the significance of clinical cooperation between general physicians and nephrologists, with high level of evidence.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447093PMC
March 2020

An Incidental Diagnosis of Microscopic Renal Angiomyolipoma Completely Excised on Renal Biopsy: A Case Report.

Am J Case Rep 2020 Mar 15;21:e921353. Epub 2020 Mar 15.

Department of Diagnostic Pathology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.

BACKGROUND Microscopic tumor foci have been detected incidentally on renal biopsy, including renal cell carcinoma and renomedullary interstitial cell tumor (medullary fibroma). A report is presented of a case of an incidental finding of microscopic renal angiomyolipoma that was diagnosed and completely excised on core needle biopsy. CASE REPORT A 44-year-old woman was referred to our hospital for evaluation of persistent mild proteinuria. Three years previously, she was diagnosed with Cushing's syndrome associated with a right adrenal cortical adenoma, which was successfully treated with unilateral adrenalectomy. At the time of surgery, abdominal computed tomography (CT) showed no renal lesions. During the present admission, a renal biopsy was performed that showed minimal changes in the renal glomeruli and interstitium. Immunofluorescence showed weakly positive staining for IgM in the glomeruli and no dense deposits. A microscopic focus of a predominantly spindle-cell tumor was found in the corticomedullary region. Immunohistochemistry showed positive immunostaining for HMB-45, Melan-A, and alpha-smooth muscle actin (ASMA), which supported a diagnosis of angiomyolipoma. Abdominal ultrasound at one-year follow-up showed no evidence of residual renal tumor. CONCLUSIONS To our knowledge, this is the first reported case of a completely excised incidental microscopic renal angiomyolipoma. This case demonstrated that even when imaging findings are normal, renal biopsy may detect microscopic foci of primary renal tumors.
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http://dx.doi.org/10.12659/AJCR.921353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7092777PMC
March 2020

Comparison of the effects of lanthanum carbonate and calcium carbonate on the progression of cardiac valvular calcification after initiation of hemodialysis.

BMC Cardiovasc Disord 2020 01 30;20(1):39. Epub 2020 Jan 30.

Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan.

Background: Although mineral metabolism disorder influences cardiac valvular calcification (CVC), few previous studies have examined the effects of non-calcium-containing and calcium-containing phosphate binders on CVC in maintenance hemodialysis patients. The aim of the present study was to compare the effects of lanthanum carbonate (LC) with calcium carbonate (CC) on the progression of CVC in patients who initiated maintenance hemodialysis and to investigate clinical factors related to CVC.

Methods: The current study included 50 subjects (mean age 65 years, 72% males) from our previous randomized controlled trial (LC group, N = 24; CC group, N = 26). CVC was evaluated as CVC score (CVCS) using echocardiography at baseline and 18 months after initiation of hemodialysis. We compared CVCS and the changes between the two groups. We also analyzed the associations between CVCS and any other clinical factors including arterial plaque score (PS) and serum phosphorus levels.

Results: Baseline characteristics of study participants including CVCS were almost comparable between the two groups. At 18 months, there were no significant differences in mineral metabolic markers or CVCS between the two groups, and CVCS were significantly correlated with PS (r = 0.39, p < 0.01). Furthermore, changes in CVCS were significantly correlated with average phosphorus levels (r = 0.36, p < 0.05), which were significantly higher in high serum phosphorus and high PS group compared to low serum phosphorus and low PS group (p < 0.05).

Conclusions: In the present study, there were no significant differences between LC and CC with regard to progression of CVC. However, serum phosphorus levels and arterial plaque seem to be important for the progression and formation of CVC in hemodialysis patients.
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http://dx.doi.org/10.1186/s12872-020-01343-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993404PMC
January 2020

Changes in the whole/intact parathyroid hormone ratio and their clinical implications in patients with chronic kidney disease.

J Nephrol 2020 Aug 9;33(4):795-802. Epub 2020 Jan 9.

Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan.

Background: Although a previous study has reported the relationship between intact parathyroid hormone (iPTH) and whole parathyroid hormone (wPTH) levels in patients undergoing dialysis, the w/i PTH ratio (whole/intact PTH ratio) among predialysis chronic kidney disease (CKD) patients remains unclear. The present study therefore aimed to examine the relationship between w/i PTH ratio and kidney function and determine other factors affecting the w/i PTH ratio.

Methods: An observational study including 773 predialysis CKD patients was conducted. The correlation between w/i PTH ratio and kidney function, as well as clinical factors at different CKD stages, were assessed using univariate and multivariate analyses. In addition, the relationship between w/i PTH ratio and composite renal outcome [kidney transplantation, dialysis, and 30% decline in estimated glomerular filtration rate (eGFR)] was examined.

Results: The w/i PTH ratio decreased as the CKD stage progressed. Patients in each CKD stage (1/2, 3, 4, and 5) had a w/i PTH ratio of 0.85, 0.81, 0.78, and 0.59, respectively. The inflection point in the correlation lines between eGFR and w/i PTH ratio was 24.1 mL/min/1.73 m. In multivariate analysis, the w/i PTH ratio was significantly correlated with serum calcium levels only in the CKD5 group and with eGFR in the CKD3, CKD4 and CKD5 group. Furthermore, w/i PTH ratio, eGFR, serum phosphate levels, and urinary protein/creatinine ratio were determined to be significant independent predictors for composite renal outcome.

Conclusions: Our study demonstrated that changes in the w/i PTH ratio were associated with kidney function, abnormal mineral metabolism, and renal outcome.
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http://dx.doi.org/10.1007/s40620-019-00690-3DOI Listing
August 2020

Pregnant Patient on Hemodialysis Who Showed Remarkable Improvement of Severe Hyperparathyroidism by Strict Serum Phosphorus Control.

Intern Med 2020 Mar 18;59(5):689-694. Epub 2019 Nov 18.

Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, Japan.

We encountered a pregnant hemodialysis patient with severe hyperparathyroidism (HPT). Although her disease was considered to be refractory to medical treatment, the serum intact parathyroid hormone (PTH) level remarkably improved without manifestation of hypercalcemia through only strict serum phosphorus control, mainly via intensification of dialysis. The very strong correlation between the serum phosphorus level and serum intact PTH level suggested the possibility of secondary HPT. She ultimately gave birth to a healthy baby. The clinical course of the patient's HPT and the growth of the child have been good for more than six years.
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http://dx.doi.org/10.2169/internalmedicine.3774-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7086312PMC
March 2020

JR-131, a Biosimilar of Darbepoetin Alfa, for the Treatment of Hemodialysis Patients With Renal Anemia: A Randomized, Double-Blinded, Parallel-Group Phase 3 Study.

Ther Apher Dial 2020 Apr 21;24(2):126-135. Epub 2019 Aug 21.

Department of General Internal Medicine, Saitama Medical University, Saitama, Japan.

The aim of this study was to compare the efficacy and safety of intravenous JR-131, a darbepoetin alfa biosimilar, to darbepoetin alfa in hemodialysis patients with renal anemia. In this 24-week, multicenter, randomized, double-blinded, parallel-group phase 3 study, 334 hemodialysis patients with renal anemia who had been receiving darbepoetin alfa were randomized to either JR-131 or darbepoetin alfa group. The initial dose was set based on the darbepoetin alfa dose during the observation period. The primary endpoint was change in hemoglobin level from baseline to end of treatment. The 95% confidence interval of the difference in the change in hemoglobin level between the groups was -0.19 to -0.20 g/dL, within the equivalent margin of -0.5 to 0.5 g/dL. No notable treatment-emergent adverse events were observed in either group. JR-131 was therapeutically equivalent to darbepoetin alfa, and the safety profile of JR-131 was similar to that of darbepoetin alfa.
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http://dx.doi.org/10.1111/1744-9987.13422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7079119PMC
April 2020

Long-Term Safety and Efficacy of JR-131, a Biosimilar of Darbepoetin Alfa, in Japanese Patients With Renal Anemia Undergoing Hemodialysis: Phase 3 Prospective Study.

Ther Apher Dial 2020 Apr 19;24(2):136-145. Epub 2019 Aug 19.

Department of General Internal Medicine, Saitama Medical University, Saitama, Japan.

The objective of this study was to evaluate the safety and efficacy of JR-131, a biosimilar of darbepoetin alfa, for long-term treatment of renal anemia patients undergoing hemodialysis. In this multicenter, single-arm, phase 3 study, 159 patients with renal anemia who had been receiving darbepoetin alfa or recombinant human erythropoietins were treated with intravenous JR-131 for 52 weeks. In patients receiving darbepoetin alfa, JR-131 was administered at the same dose, while in patients receiving recombinant human erythropoietin the dose was determined based on the 1:200 conversion ratio following the Japanese darbepoetin alfa package insert. No notable adverse drug reactions were reported, and no anti-JR-131 antibodies were detected. The hemoglobin levels were maintained in the range of 10.0-12.0 g/dL throughout the study. JR-131 proved to be a useful and lower-cost alternative to darbepoetin alfa in the management of renal anemia in patients undergoing hemodialysis.
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http://dx.doi.org/10.1111/1744-9987.13420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078934PMC
April 2020

Effects of lanthanum carbonate on bone markers and bone mineral density in incident hemodialysis patients.

J Bone Miner Metab 2019 Nov 18;37(6):1075-1082. Epub 2019 Jun 18.

Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan.

Introduction: Recent clinical studies demonstrated the favorable effects of calcium-free phosphate binders on mortality and vascular calcification in hemodialysis (HD) patients. The aim of the present study was to investigate the effects of a calcium-free phosphate binder, lanthanum carbonate (LC), on bone metabolic markers and bone mineral density (BMD), compared with those of calcium carbonate (CC), in subjects new to HD.

Materials And Methods: The present study included 65 subjects from our previous randomized controlled trial (LC group, N = 31; CC group, N = 34). We investigated the effects of LC on serum intact parathyroid hormone (iPTH), osteocalcin (OC), bone-specific alkaline phosphatase (BAP), tartrate-resistant acid phosphatase 5b (TRACP-5b), sclerostin levels, and BMD, compared with those of CC in patients new to HD at baseline and at 12 and 18 months.

Results: Serum OC levels at 18 months were significantly higher in the LC group than in the CC group. During the study period, serum BAP and TRACP-5b and iPTH levels tended to be higher in the LC group than in the CC group. At 18 months, the percentage of low bone turnover, based on a serum BAP cutoff value, was significantly lower in the LC group than in the CC group. There were no significant differences in the lumbar and femoral BMD between the two groups.

Conclusions: The results of the present study suggest that LC has potential in preventing low bone turnover, in comparison to CC, in patients new to HD.
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http://dx.doi.org/10.1007/s00774-019-01018-8DOI Listing
November 2019

One-Year Impact of Kidney Transplantation on Cardiac Abnormalities and Blood Pressure in Hemodialysis Patients.

Ther Apher Dial 2019 Dec 20;23(6):529-533. Epub 2019 May 20.

Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, Kobe, Japan.

Cardiac abnormalities, including left ventricular hypertrophy and systolic dysfunction, are frequently observed among patients with CKD, including kidney transplant recipients; they are closely linked to cardiovascular disease and mortality. Although several studies have been performed for elucidating changes and mechanisms of cardiac abnormalities after kidney transplantation, details remain unclear. This study included 43 consecutive patients who underwent HD and received kidney transplantation between 2008 and 2012 at our institution. All subjects underwent echocardiography before and 1 year after kidney transplantation. One year after kidney transplantation, left ventricular mass index, cardiac chamber sizes, BP, and the number of antihypertensive agents were reduced. Although the percentage of patients with concentric hypertrophy did not change, the percentage of those with eccentric hypertrophy significantly decreased after kidney transplantation. Volume reduction due to the recovery of kidney function may be primarily attributed to the improvement of cardiac abnormalities, including left ventricular hypertrophy.
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http://dx.doi.org/10.1111/1744-9987.12808DOI Listing
December 2019

Clinicopathological characteristics of thrombospondin type 1 domain-containing 7A-associated membranous nephropathy.

Virchows Arch 2019 Jun 14;474(6):735-743. Epub 2019 Mar 14.

Department of Diagnostic Pathology, Kobe University Graduate School of Medicine, Kobe, Japan.

Thrombospondin type 1 domain-containing 7A (THSD7A) is a recently identified target antigen of idiopathic membranous nephropathy (iMN). The clinicopathological characteristics of THSD7A-associated MN are poorly characterised due to low prevalence among MN patients. Among 469 consecutive cases of pathologically confirmed MN diagnosed at four centres in Japan, 14 cases were confirmed positive for THSD7A by immunohistochemistry (3.0%). The prevalence of THSD7A-associated MN tended to be higher in northern Japan. Most cases demonstrated nephrotic-range proteinuria (12/14 cases, 86%). In two patients, cancer was detected at the time of renal biopsy (small-cell carcinoma of the lung and prostatic adenocarcinoma with neuroendocrine differentiation). Both tumours were negative for THSD7A. Four patients had concurrent or previous incidence of allergic diseases, including one patient with Kimura's disease. Pathological analysis of kidney biopsy tissue revealed slight mesangial cell proliferation in three cases and spike formation in one case. Immunofluorescence studies demonstrated that IgG subclass was mainly IgG4-dominant/codominant (12/13, 92% cases), while the case with prostatic cancer had an IgG2-dominant distribution. The immunostaining profile for components of the lectin complement pathways was not significant in three cases including two patients with malignancy. One case was dual positive for THSD7A and PLA2R. Of 10 cases with known clinical follow-up data, 6 demonstrated reduced serum creatinine and 8 presented reduced proteinuria. In summary, although the major IgG phenotype was usually IgG4-dominant/codominant, clinical background was otherwise heterogeneous. Further investigation of regional differences in THSD7A-associated MN prevalence may reveal genetic and environmental risk factor and associated pathogenic mechanisms.
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http://dx.doi.org/10.1007/s00428-019-02558-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581930PMC
June 2019

Nonproteinuric Versus Proteinuric Phenotypes in Diabetic Kidney Disease: A Propensity Score-Matched Analysis of a Nationwide, Biopsy-Based Cohort Study.

Diabetes Care 2019 05 4;42(5):891-902. Epub 2019 Mar 4.

Department of Nephrology and Laboratory Medicine, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Graduate School of Medical Sciences, Kanazawa University, Ishikawa, Japan

Objective: Clinicopathological characteristics, renal prognosis, and mortality in patients with type 2 diabetes and reduced renal function without overt proteinuria are scarce.

Research Design And Methods: We retrospectively assessed 526 patients with type 2 diabetes and reduced renal function (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m), who underwent clinical renal biopsy and had follow-up data, from Japan's nationwide multicenter renal biopsy registry. For comparative analyses, we derived one-to-two cohorts of those without proteinuria versus those with proteinuria using propensity score-matching methods addressing the imbalances of age, sex, diabetes duration, and baseline eGFR. The primary end point was progression of chronic kidney disease (CKD) defined as new-onset end-stage renal disease, decrease of eGFR by ≥50%, or doubling of serum creatinine. The secondary end point was all-cause mortality.

Results: Eighty-two patients with nonproteinuria (urine albumin-to-creatinine ratio [UACR] <300 mg/g) had lower systolic blood pressure and less severe pathological lesions compared with 164 propensity score-matched patients with proteinuria (UACR ≥300 mg/g). After a median follow-up of 1.9 years (interquartile range 0.9-5.0 years) from the date of renal biopsy, the 5-year CKD progression-free survival was 86.6% (95% CI 72.5-93.8) for the nonproteinuric group and 30.3% (95% CI 22.4-38.6) for the proteinuric group (log-rank test < 0.001). The lower renal risk was consistent across all subgroup analyses. The all-cause mortality was also lower in the nonproteinuric group (log-rank test = 0.005).

Conclusions: Patients with nonproteinuric diabetic kidney disease had better-controlled blood pressure and fewer typical morphological changes and were at lower risk of CKD progression and all-cause mortality.
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http://dx.doi.org/10.2337/dc18-1320DOI Listing
May 2019

Characteristics of coronary artery disease in chronic kidney disease.

Clin Exp Nephrol 2019 Jun 4;23(6):725-732. Epub 2019 Mar 4.

Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan.

Patients with chronic kidney disease (CKD) commonly experience cardiovascular disease (CVD), and a major cause of death in these patients is CVD. Therefore, the prevention of CVD progression is very crucial in patients with CKD. Recently, this relationship between CKD and CVD has increasingly been examined, and a concept termed "cardiorenal syndrome" has been advocated. Coronary artery disease (CAD) and myocardial injury are crucial factors that contribute to the occurrence of CVD. The initial step CAD is endothelial dysfunction that can be detected as a decrease in the coronary flow reserve (CFR). The previous studies have reported that decreased CFR is significantly correlated to coronary events and mortality. Furthermore, CFR reduces with a decline in the kidney function. Another important presentation of CAD is coronary artery calcification. Vascular calcification is a crucial pathophysiological state, particularly in patients with CKD, and it affects the stability of coronary atherosclerotic plaque. In CKD, not only the traditional risk factors but also CKD-related non-traditional risk factors play key roles in CVD progression. Therefore, the mechanisms responsible for CVD progression are very complex; however, their clarification is crucial to improve the prognosis in patients with CKD.
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http://dx.doi.org/10.1007/s10157-019-01718-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511359PMC
June 2019

Amplified Association Between Blood Pressure and Albuminuria in Overweight Patients With Biopsy-Proven Hypertensive Nephrosclerosis.

Am J Hypertens 2019 04;32(5):486-491

Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan.

Background: An overweight person is at high risk for hypertensive renal damage. The effect of weight on the association between systolic blood pressure (SBP) and albuminuria remains unknown in patients with histologically diagnosed hypertensive nephrosclerosis.

Methods: A total of 97 patients with biopsy-confirmed hypertensive nephrosclerosis were recruited from 13 centers throughout Japan. We examined the relationship between SBP and proteinuria among those who were overweight, which is defined as a body mass index ≥25 kg/m2, and those who were not. We examined the interaction of weight and SBP with albuminuria at baseline and with the changes in estimated glomerular filtration rate (eGFR) during the observational period.

Results: Our results included mean age (54 years old), blood pressure (138/80), eGFR (53 ml/min/1.73 m2), and urine albumin levels (0.2 g/day). SBP was significantly correlated with log-transformed urine albumin levels (r = 0.4, P = 0.01) in patients who were overweight (n = 38) compared with patients who were not overweight (n = 59). Multiple regression analysis revealed that the interaction between being overweight and SBP with respect to albuminuria was significantly correlated with the log-transformed urine albumin level (β = 0.39, P = 0.047) and was independent of age, sex, and potential confounding factors. The interaction between weight and SBP ≥140 mm Hg was significantly associated with a greater decrease in eGFR in the following 3 years.

Conclusions: Being overweight may enhance susceptibility to hypertensive glomerular damage and may eventually lead to renal progression in patients with hypertensive nephrosclerosis.
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http://dx.doi.org/10.1093/ajh/hpz010DOI Listing
April 2019

Changes in serum and intracardiac fibroblast growth factor 23 during the progression of left ventricular hypertrophy in hypertensive model rats.

Clin Exp Nephrol 2019 May 11;23(5):589-596. Epub 2018 Dec 11.

Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan.

Background: Recent clinical studies have demonstrated that serum fibroblast growth factor 23 (FGF23) levels have a significant association with left ventricular hypertrophy (LVH). Although LVH is commonly seen in hypertensive patients, the association between FGF23, hypertension, and LVH remains unclear. We aimed to examine the changes in serum and intracardiac FGF23 during the progression of hypertension using spontaneously hypertensive rats (SHR).

Methods: Male SHR comprised the experimental group (HT group) and Wistar Kyoto rats served as controls. At 10 weeks, urinary and blood biochemical analyses and blood pressure measurements were performed for both the groups. At 18 weeks, the rats were sacrificed: urinary and blood biochemical analyses and real-time PCR were performed.

Results: At 18 weeks, the relative heart weight and serum N-terminal pro-brain natriuretic peptide and aldosterone levels were significantly greater in the HT group. Serum calcium and phosphate levels were significantly lower, while serum FGF23 levels were significantly higher in the HT group compared to the control group. Further analyses showed that the mRNA expression of FGF23 in the heart was significantly increased in the HT group compared to the control group. Both serum FGF23 levels and intracardiac mRNA expression of FGF23 showed significant correlation with the relative heart weight.

Conclusions: During LVH progression, serum and intracardiac FGF23 increased in hypertension. Although it is unclear whether the change in FGF23 is the cause or result of LVH, the interaction between FGF23 and aldosterone may be associated with the development of LVH in hypertension.
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http://dx.doi.org/10.1007/s10157-018-1680-1DOI Listing
May 2019

Effect of Oral Alfacalcidol on Clinical Outcomes in Patients Without Secondary Hyperparathyroidism Receiving Maintenance Hemodialysis: The J-DAVID Randomized Clinical Trial.

JAMA 2018 12;320(22):2325-2334

Department of Kidney Disease, Kawashima Hospital, Tokushima, Japan.

Importance: Patients with chronic kidney disease have impaired vitamin D activation and elevated cardiovascular risk. Observational studies in patients treated with hemodialysis showed that the use of active vitamin D sterols was associated with lower risk of all-cause mortality, regardless of parathyroid hormone levels.

Objective: To determine whether vitamin D receptor activators reduce cardiovascular events and mortality in patients without secondary hyperparathyroidism undergoing hemodialysis.

Design, Setting, And Participants: Randomized, open-label, blinded end point multicenter study of 1289 patients in 207 dialysis centers in Japan. The study included 976 patients receiving maintenance hemodialysis with serum intact parathyroid hormone levels less than or equal to 180 pg/mL. The first and last participants were enrolled on August 18, 2008, and January 26, 2011, respectively. The final date of follow-up was April 4, 2015.

Interventions: Treatment with 0.5 μg of oral alfacalcidol per day (intervention group; n = 495) vs treatment without vitamin D receptor activators (control group; n = 481).

Main Outcomes And Measures: The primary outcome was a composite measure of fatal and nonfatal cardiovascular events, including myocardial infarctions, hospitalizations for congestive heart failure, stroke, aortic dissection/rupture, amputation of lower limb due to ischemia, and cardiac sudden death; coronary revascularization; and leg artery revascularization during 48 months of follow-up. The secondary outcome was all-cause death.

Results: Among 976 patients who were randomized from 108 dialysis centers, 964 patients were included in the intention-to-treat analysis (median age, 65 years; 386 women [40.0%]), and 944 (97.9%) completed the trial. During follow-up (median, 4.0 years), the primary composite outcome of cardiovascular events occurred in 103 of 488 patients (21.1%) in the intervention group and 85 of 476 patients (17.9%) in the control group (absolute difference, 3.25% [95% CI, -1.75% to 8.24%]; hazard ratio, 1.25 [95% CI, 0.94-1.67]; P = .13). There was no significant difference in the secondary outcome of all-cause mortality between the groups (18.2% vs 16.8%, respectively; hazard ratio, 1.12 [95% CI, 0.83-1.52]; P = .46). Of the 488 participants in the intervention group, 199 (40.8%) experienced serious adverse events that were classified as cardiovascular, 64 (13.1%) experienced adverse events classified as infection, and 22 (4.5%) experienced malignancy-related serious adverse events. Of 476 participants in the control group, 191 (40.1%) experienced cardiovascular-related serious adverse events, 63 (13.2%) experienced infection-related serious adverse events, and 21 (4.4%) experienced malignancy-related adverse events.

Conclusions And Relevance: Among patients without secondary hyperparathyroidism undergoing maintenance hemodialysis, oral alfacalcidol compared with usual care did not reduce the risk of a composite measure of select cardiovascular events. These findings do not support the use of vitamin D receptor activators for patients such as these.

Trial Registration: UMIN-CTR Identifier: UMIN000001194.
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http://dx.doi.org/10.1001/jama.2018.17749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583075PMC
December 2018
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