Publications by authors named "Yoshihide Fujigaki"

130 Publications

Characterization of pendrin in urinary extracellular vesicles in a rat model of aldosterone excess and in human primary aldosteronism.

Hypertens Res 2021 Jul 29. Epub 2021 Jul 29.

Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan.

Pendrin is a Cl/HCO exchanger selectively present in the intercalated cells of the kidney. Although experimental studies have demonstrated that pendrin regulates blood pressure downstream of the renin-angiotensin-aldosterone system, its role in human hypertension remains unclear. Here, we analyzed the quantitative changes in pendrin in urinary extracellular vesicles (uEVs) isolated from a total of 30 patients with primary aldosteronism (PA) and from a rat model of aldosterone excess. Western blot analysis revealed that pendrin is present in dimeric and monomeric forms in uEVs in humans and rats. In a rodent model that received continuous infusion of aldosterone with or without concomitant administration of the selective mineralocorticoid receptor (MR) antagonist esaxerenone, pendrin levels in uEVs, as well as those of epithelial Na channel (ENaC) and Na-Cl-cotransporter (NCC), were highly correlated with renal abundance. In patients with PA, pendrin levels in uEVs were reduced by 49% from baseline by adrenalectomy or pharmacological MR blockade. Correlation analysis revealed that the magnitude of pendrin reduction after treatment significantly correlated with the baseline aldosterone-renin ratio (ARR). Finally, a cross-sectional analysis of patients with PA confirmed a significant correlation between the ARR and pendrin levels in uEVs. These data are consistent with experimental studies showing the role of pendrin in aldosterone excess and suggest that pendrin abundance is attenuated by therapeutic interventions in human PA. Our study also indicates that pendrin analysis in uEVs, along with other proteins, can be useful to understand the pathophysiology of hypertensive disorders.
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http://dx.doi.org/10.1038/s41440-021-00710-5DOI Listing
July 2021

Renal Involvement as Rare Acute Tubulointerstitial Nephritis in a Patient with Eosinophilic Disorder Treated with Early Add-on Administration of Mepolizumab.

Intern Med 2021 Jun 5. Epub 2021 Jun 5.

Department of Internal Medicine, Teikyo University School of Medicine, Japan.

A 39-year-old man presented with peripheral eosinophilia, pulmonary eosinophilic infiltrate, and renal failure due to acute tubulointerstitial nephritis (TIN). He had experienced childhood asthma and was negative for anti-neutrophil cytoplasmic antibody (ANCA). He was tentatively diagnosed with ANCA-negative eosinophilic granulomatous polyangiitis (EGPA) or idiopathic hypereosinophilic syndrome (HES). Renal involvement of isolated TIN with eosinophil infiltration is rare in EGPA and HES and does not seem to have a good prognosis in the literature. However, his condition improved well with corticosteroids and mepolizumab. The revised classification of EGPA based on the etiology should dictate the proper treatment in suspected EGPA patients with nonsystemic vasculitis.
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http://dx.doi.org/10.2169/internalmedicine.7490-21DOI Listing
June 2021

A Ruptured Jejunal Arterial Aneurysm in a Young Woman Undergoing Chronic Hemodialysis Due to Myeloperoxidase-antineutrophil Cytoplasmic Antibody-associated Vasculitis.

Intern Med 2021 Sep 29;60(18):2939-2945. Epub 2021 Mar 29.

Department of Internal Medicine, Teikyo University School of Medicine, Japan.

A 21-year-old woman was admitted to our hospital because of massive intestinal bleeding. She started hemodialysis due to myeloperoxidase antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) at 18 years of age. Her ANCA titers remained stable; however, her C-reactive protein increased on 5 mg/day prednisolone before admission. Computed tomography angiography revealed a ruptured jejunal arterial aneurysm. Transcatheter arterial embolization, blood transfusion and the reinforcement of steroid therapy resolved her symptoms of AAV. Our case of a young patient with AAV and medium-sized arterial vasculitis is rare and emphasizes that the ANCA titer does not always rise, especially in patients with nonrenal vasculitis flare-ups.
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http://dx.doi.org/10.2169/internalmedicine.6721-20DOI Listing
September 2021

A case of hypertensive disorders of pregnancy that developed at 9 weeks of gestation.

CEN Case Rep 2021 Mar 15. Epub 2021 Mar 15.

Department of Internal Medicine 1, Hamamatsu University School of Medicine, 1-20-1 Handayama Higashi-ku Hamamatsu, Hamamatsu, 431-3192, Japan.

Preeclampsia and superimposed preeclampsia usually develop after 20 weeks of gestation. We report a case of a 35-year-old Japanese woman who developed hypertensive disorders of pregnancy (HDP) before 20 weeks of gestation. She presented with hypertension and proteinuria at 9 and 11 weeks of gestation, respectively, and developed nephrotic syndrome at 17 weeks of gestation. She did not have definite hypertension or urinary abnormalities before pregnancy. The patient was serologically positive for the antinuclear antibody. However, the complement levels were normal and anti-phospholipid antibody was not detected. A renal biopsy performed at 18 weeks of gestation showed diffuse endotheliosis and tip lesions of secondary focal segmental glomerulosclerosis but no hypertensive changes of the arterioles. Although electron microscopic examination showed electron-dense deposits in the subendothelial lesions, they were considered nonspecific plasma exudation by mass spectrometry. An abortion was performed at 20 weeks gestation because the patient's congestive symptoms due to nephrotic syndrome had worsened and marked fetal growth restriction was observed. After delivery, the patient's symptoms resolved immediately without any additional treatment; however, continuous antihypertensive medication was required. Finally, the patient was diagnosed with HDP based on the renal biopsy findings and her clinical course after delivery. Compared to previous reports, this case describes the earliest onset of HDP. Thus, HDP should be considered as a differential diagnosis in pregnant women with hypertension or proteinuria presenting with symptoms before 20 weeks of gestation.
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http://dx.doi.org/10.1007/s13730-021-00592-zDOI Listing
March 2021

Pyuria without Casts and Bilateral Kidney Enlargement Are Probable Hallmarks of Severe Acute Kidney Injury Induced by Acute Pyelonephritis: A Case Report and Literature Review.

Intern Med 2021 Jan 5;60(2):293-298. Epub 2020 Sep 5.

Department of Internal Medicine, Teikyo University School of Medicine, Japan.

The patient was a 38-year-old man who had experienced nausea and fever for a few days and presented with back pain, oliguria, and pyuria, suggesting acute pyelonephritis (APN). He showed acute kidney injury (AKI) with bilateral kidney enlargement and was using nonsteroidal anti-inflammatory drugs (NSAIDs). AKI-induced by APN was confirmed by kidney biopsy. The AKI was successfully treated with antibiotic therapy. A search of the relevant literature for reports on histopathologically-proven APN-induced severe AKI revealed that the key characteristics were bilateral kidney enlargement with pyuria without casts. Oligoanuria was frequently associated with APN-induced severe AKI, and NSAID use may be a possible risk factor. Prompt antibiotic treatment based on the clinical characteristics of APN-induced AKI can improve the renal outcome.
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http://dx.doi.org/10.2169/internalmedicine.5721-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872795PMC
January 2021

Upregulation of renal Na-K-2Cl cotransporter 2 in obese diabetes mellitus via a vasopressin receptor 2-dependent pathway.

Biochem Biophys Res Commun 2020 04 5;524(3):710-715. Epub 2020 Feb 5.

Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, 173-8605, Japan. Electronic address:

Na-K-2Cl cotransporter 2 (NKCC2) in thick ascending limb (TAL) in the kidney plays a central role in tubuloglomerular feedback (TGF) system by sensing NaCl delivery to the distal tubules. Although accumulating data indicate that dysregulated TGF contributes to the progression of diabetic complications, the regulation of NKCC2 in diabetes mellitus (DM) remains unclear. We here show that NKCC2 is overactivated via a vasopressin receptor 2 (V2R)-dependent mechanism in db/db mice, a mouse model of obese DM. Compared with db/+ mice, we found that both aquaporin 2 and NKCC2 levels were significantly increased in the kidney in db/db mice. Immunohistochemical analysis of V2R and NKCC2 in the kidney demonstrated that V2R is present in the TAL, as well as in the collecting duct. Moreover, the administration of tolvaptan, a selective V2R antagonist, sharply decreased aquaporin 2 and NKCC2 in db/db mice, confirming the causal role of V2R signaling in NKCC2 induction in this model. Although tolvaptan reduced aquaporin 2 abundance also in db/+ mice, its effect on NKCC2 was modest compared with db/db mice. In total kidney lysates, uromodulin expression was not altered between db/+ and db/db mice, suggesting that V2R signaling alters NKCC2 without altering uromodulin levels. These data implicate the dysregulation of NKCC2 in the pathophysiology of type 2 DM, and underscore the complex nature of fluid volume disorders in diabetic kidney disease.
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http://dx.doi.org/10.1016/j.bbrc.2020.01.142DOI Listing
April 2020

Clinicopathological Implications of Proteinuria after Long-Term Isolated Hematuria due to Thin Basement Membrane Nephropathy and Focal Segmental Glomerulosclerosis.

Case Rep Nephrol 2019 17;2019:1627392. Epub 2019 Dec 17.

Department of Internal Medicine, Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan.

A 45-year-old obese man presented with persistent hematuria for 21 years. At the age of 37, he developed hypertension and proteinuria which later increased up to 1.6 g/g creatinine. Kidney biopsy revealed thin basement membrane nephropathy (TBMN) and focal segmental glomerulosclerosis (FSGS), which explained his urinary abnormalities. Although a subgroup of TBMN can be complicated by FSGS, his FSGS was associated with obesity because of its histological features. Reduction of body weight and increasing a dose of angiotensin-receptor blocker could transiently reduce the amount of proteinuria. Clinicopathological implications of proteinuria after long-term hematuria by TBMN and FSGS were further discussed.
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http://dx.doi.org/10.1155/2019/1627392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959157PMC
December 2019

25(OH)D stimulates the expression of vitamin D target genes in renal tubular cells when Cyp27b1 is abrogated.

J Steroid Biochem Mol Biol 2020 05 13;199:105593. Epub 2020 Jan 13.

Department of Biochemistry, Teikyo University School of Medicine, Tokyo, Japan.

Recently, it was reported that 25(OH)D (25D3) has physiological bioactivity in certain tissues derived from Cyp27b1 knockout mice. To investigate the function of 25D3 in the kidney as an informational crossroad of various calciotropic substances, we employed the CRISPR-Cas9 system to knock out Cyp27b1 in the mouse renal distal tubular mDCT cell line. Unlike the previously reported mice in which Cyp27b1 was targeted systemically, Cyp27b1 knockout mDCT cells did not produce any measurable 1α,25(OH)D (1,25D3) after 25D3 administration. As was seen with treatment of Cyp27b1 knockout mDCT cells with ≥10 M of 1,25D3, the administration of 10 M of 25D3 translocated the vitamin D receptor (VDR) into the nucleus and promoted the expression of the representative 1,25D3-responsive gene Cyp24a1. The exhaustive target gene profiles of 25D3 were similar to those of 1,25D3. Subsequently, we confirmed that 25D3 induced the expression of the calcium reabsorption-related gene calbindin-D9K, in a way similar to 1,25D3. We also found that 1,25D3 and 25D3 induced the expression of the megalin gene. A chromatin immunoprecipitation assay identified two vitamin D response elements in the upstream region of the megalin gene that seemed to contribute to its expression. Together, we surmise that the ability of 25D3 to stimulate VDR target genes may provide a novel perspective for its role in certain tissues.
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http://dx.doi.org/10.1016/j.jsbmb.2020.105593DOI Listing
May 2020

Monoclonal immunoglobulin G1 κ-type atypical antiglomerular basement membrane disease accompanied by necrotizing glomerulonephritis
.

Clin Nephrol 2020 Mar;93(3):152-157

Introduction: Patients without detectable serum antiglomerular basement membrane (GBM) antibodies but with GBM staining for immunoglobulins (Ig), absence of a crescentic phenotype, mild renal insufficiency, and absence of pulmonary hemorrhage have atypical anti-GBM diseases. We report the case of a 64-year-old man with slowly progressive glomerulonephritis.

Case History: A 64-year-old Peruvian man presented with persistent microscopic hematuria, proteinuria of 2.1 g/g creatinine (Cr), serum Cr 1.00 mg/dL, and C-reactive protein 0.80 mg/dL. Renal biopsy revealed necrotizing glomerulonephritis with 39% cellular crescent formation and diffuse segmental endocapillary proliferation. He had linear staining of monoclonal IgG1-κ in the capillary walls but no detectable serum anti-GBM antibodies. Because renal dysfunction was slowly progressing, steroid monotherapy was initiated, and serum Cr level decreased from 1.48 to 1.13 mg/dL. However, serum Cr increased again to 1.35 mg/dL owing to active glomerular damage with crescent formation and endocapillary proliferation, confirmed by the second renal biopsy at 9 months after therapy. Renal function improved after cyclophosphamide therapy.

Conclusion: We described an atypical variant of anti-GBM disease due to monoclonal IgG1-κ. Unlike usual atypical anti-GBM disease cases, we observed crescent formation in our patient. Further investigations are needed to identify the cause of nondetectable serum anti-GBM antibodies and to describe the causal relationships between clinicopathological features and the pattern of IgG subclass and light chain in atypical anti-GBM disease.
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http://dx.doi.org/10.5414/CN109889DOI Listing
March 2020

A Case of Rheumatoid Arthritis Presenting with Renal Thrombotic Microangiopathy Probably due to a Combination of Chronic Tacrolimus Arteriolopathy and Severe Hypertension.

Case Rep Nephrol 2019 6;2019:3923190. Epub 2019 Mar 6.

Department of Internal Medicine, Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan.

A 51-year-old woman with rheumatoid arthritis presented with mild hypertension 20 months after tacrolimus treatment and developing proteinuria 24 months after the treatment. Tacrolimus was discontinued 27 months after the treatment, followed by heavy proteinuria, accelerated hypertension, and deteriorating renal function without ocular fundus lesions as a clinical sign of malignant hypertension. Renal biopsy revealed malignant nephrosclerosis characterized by subacute and chronic thrombotic microangiopathy (TMA), involving small arteries, arterioles, and glomeruli. Focal segmental glomerulosclerosis, probably secondary to chronic TMA, was identified as a cause of heavy proteinuria. The zonal tubulointerstitial injury caused by subacute TMA may have mainly contributed to deteriorating renal function. The presence of nodular hyalinosis in arteriolar walls was indicative of tacrolimus-associated nephrotoxicity. Together with other antihypertensive drugs, administration of aliskiren stabilized renal function with reducing proteinuria. Owing to the preexisting proteinuria prior to severe hypertension and the complex renal histopathology, we postulated that chronic TMA, which was initially triggered by tacrolimus, was aggravated by severe hypertension, resulting in overt renal TMA.
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http://dx.doi.org/10.1155/2019/3923190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6431373PMC
March 2019

A Patient with MPO-ANCA-positive IgA Nephropathy Diagnosed with the Clinical Onset of Macrohematuria.

Intern Med 2019 Jul 28;58(14):2051-2056. Epub 2019 Mar 28.

Department of Internal Medicine, Teikyo University School of Medicine, Japan.

A 21-year-old woman presented with renal dysfunction during macrohematuria. A kidney biopsy revealed IgA nephropathy with a small percentage of crescent formation and macrohematuria-associated tubular injury. Macrohematuria-associated acute kidney injury could explain her renal dysfunction. However, she was seropositive for myeloperoxidase (MPO)-anti-neutrophil cytoplasmic antibody (ANCA) and showed fibrin deposition around one arteriole. Corticosteroids and mycophenolate mofetil were administered as for ANCA vasculitis, and the serum creatinine, abnormal urinalysis and MPO-ANCA titer all gradually ameliorated. The presence of extra-glomerular vasculitis, which was probably induced by ANCA, suggested that MPO-ANCA was an exacerbating factor for her prolonged renal dysfunction. This condition has so far only rarely been addressed in ANCA-positive IgA nephropathy.
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http://dx.doi.org/10.2169/internalmedicine.2475-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702016PMC
July 2019

Inhibition of Sodium Glucose Cotransporter 2 Attenuates the Dysregulation of Kelch-Like 3 and NaCl Cotransporter in Obese Diabetic Mice.

J Am Soc Nephrol 2019 05 26;30(5):782-794. Epub 2019 Mar 26.

Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan;

Background: Mechanisms underlying the frequent association between salt-sensitive hypertension and type 2 diabetes remain obscure. We previously found that protein kinase C (PKC) activation phosphorylates Kelch-like 3 (KLHL3), an E3 ubiquitin ligase component, at serine 433. We investigated whether impaired KLHL3 activity results in increased renal salt reabsorption NaCl cotransporter (NCC).

Methods: We used the db/db diabetes mouse model to explore KLHL3's role in renal salt handling in type 2 diabetes and evaluated mechanisms of KLHL3 dysregulation in cultured cells.

Results: We observed PKC activity in the db/db mouse kidney and phosphorylation of serine 433 in KLHL3 (KLHL3). This modification prevents binding of with-no-lysine (WNK) kinases; however, total KLHL3 levels were decreased, indicating severely impaired KLHL3 activity. This resulted in WNK accumulation, activating NCC in distal convoluted tubules. Ipragliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, lowered PKC activity in distal convoluted tubule cells and reduced KLHL3 and NCC levels, whereas the thiazolidinedione pioglitazone did not, although the two agents similarly reduced in blood glucose levels. We found that, in human embryonic kidney cells expressing KLHL3 and distal convoluted tubule cells, cellular glucose accumulation increased KLHL3 levels through PKC. Finally, the effect of PKC inhibition in the kidney of db/db mice confirmed PKC's causal role in KLHL3 and NCC induction.

Conclusions: Dysregulation of KLHL3 is involved in the pathophysiology of type 2 diabetes. These data offer a rationale for use of thiazide in individuals with diabetes and provide insights into the mechanism for cardiorenal protective effects of SGLT2 inhibitors.
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http://dx.doi.org/10.1681/ASN.2018070703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6493993PMC
May 2019

Significance of Earlier Initiation of Chemotherapy for Lung Cancer Complicated with Primary or Secondary Nephrotic Syndrome following Its Appropriate Differential Diagnosis.

Case Rep Oncol 2019 Jan-Apr;12(1):53-58. Epub 2019 Jan 11.

Division of Medical Oncology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan.

We encountered a case of primary lung cancer complicated with membranous nephropathy as primary nephrotic syndrome. Because treatment approaches vary greatly for primary and secondary nephrotic syndrome, a renal biopsy was performed for diagnosis. Much time was required to make a definitive diagnosis of primary nephrotic syndrome, as opposed to paraneoplastic nephrotic syndrome. Consequently, the subsequent chemotherapy was ineffective and caused significant toxicity due to reduced performance status (PS) and progression of hypoalbuminemia. Therefore, it is imperative that a diagnosis be made and treatment be initiated without delay before PS declines and hypoalbuminemia progresses.
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http://dx.doi.org/10.1159/000493851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6381920PMC
January 2019

Phosphate binding by sucroferric oxyhydroxide ameliorates renal injury in the remnant kidney model.

Sci Rep 2019 02 11;9(1):1732. Epub 2019 Feb 11.

Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan.

Recent clinical studies indicate that the disturbed phosphate metabolism in chronic kidney disease (CKD) may facilitate kidney injury; nonetheless, the causal role of phosphate in CKD progression remains to be elucidated. Here, we show that intestinal phosphate binding by sucroferric oxyhydroxide (SF) ameliorates renal injury in the rat remnant kidney model. Sprague-Dawley rats received 5/6 nephrectomy (RK) and had a normal chow or the same diet containing SF (RK + SF). RK rats showed increased plasma FGF23 and phosphate levels, which were suppressed by SF administration. Of note, albuminuria in RK rats was significantly ameliorated by SF at both 4 and 8 weeks. SF also attenuated glomerulosclerosis and tubulointerstitial injury. Moreover, several different approaches confirmed the protective effects on podocytes, explaining the attenuation of glomerulosclerosis and albuminuria observed in this study. As a possible mechanism, we found that SF attenuated renal inflammation and fibrosis in RK rats. Interestingly, von Kossa staining of the kidney revealed calcium phosphate deposition in neither RK nor RK + SF rats; however, plasma levels of calciprotein particles were significantly reduced by SF. These data indicate that latent positive phosphate balance accelerates CKD progression from early stages, even when overt ectopic calcification is absent.
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http://dx.doi.org/10.1038/s41598-018-38389-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6370755PMC
February 2019

Calcineurin dephosphorylates Kelch-like 3, reversing phosphorylation by angiotensin II and regulating renal electrolyte handling.

Proc Natl Acad Sci U S A 2019 02 4;116(8):3155-3160. Epub 2019 Feb 4.

Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, 173-8605 Tokyo, Japan;

Calcineurin is a calcium/calmodulin-regulated phosphatase known for its role in activation of T cells following engagement of the T cell receptor. Calcineurin inhibitors (CNIs) are widely used as immunosuppressive agents; common adverse effects of CNIs are hypertension and hyperkalemia. While previous studies have implicated activation of the Na-Cl cotransporter (NCC) in the renal distal convoluted tubule (DCT) in this toxicity, the molecular mechanism of this effect is unknown. The renal effects of CNIs mimic the hypertension and hyperkalemia that result from germ-line mutations in with-no-lysine (WNK) kinases and the Kelch-like 3 (KLHL3)-CUL3 ubiquitin ligase complex. WNK4 is an activator of NCC and is degraded by binding to KLHL3 followed by WNK4's ubiquitylation and proteasomal degradation. This binding is prevented by phosphorylation of KLHL3 at serine 433 (KLHL3) via protein kinase C, resulting in increased WNK4 levels and increased NCC activity. Mechanisms mediating KLHL3 dephosphorylation have heretofore been unknown. We now demonstrate that calcineurin expressed in DCT is a potent KLHL3 phosphatase. In mammalian cells, the calcium ionophore ionomycin, a calcineurin activator, reduces KLHL3 levels, and this effect is reversed by the calcineurin inhibitor tacrolimus and by siRNA-mediated knockdown of calcineurin. In vivo, tacrolimus increases levels of KLHL3, resulting in increased levels of WNK4, phosphorylated SPAK, and NCC. Moreover, tacrolimus attenuates KLHL3-mediated WNK4 ubiquitylation and degradation, while this effect is absent in KLHL3 with S433A substitution. Additionally, increased extracellular K induced calcineurin-dependent dephosphorylation of KLHL3 These findings demonstrate that KLHL3 is a calcineurin substrate and implicate increased KLHL3 phosphorylation in tacrolimus-induced pathologies.
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http://dx.doi.org/10.1073/pnas.1817281116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6386661PMC
February 2019

Gender Differences in Plasma Ghrelin Levels in Hemodialysis Patients.

Ther Apher Dial 2019 Feb 24;23(1):65-72. Epub 2018 Oct 24.

Internal Medicine I, Hamamatsu University School of Medicine, Shizuoka, Japan.

Ghrelin is an orexigenic hormone mainly secreted by the stomach, and it decreases according to the severity of gastric atrophy. Ghrelin has multiple favorable functions, including protein anabolism enhancement, anti-inflammatory activity, and cardiovascular protection, and is associated with survival in hemodialysis (HD) patients. Although the plasma level and role of ghrelin may be different depending on gender, they have not been completely assessed in HD patients. We enrolled 80 (male/female: 51/29) maintenance HD patients. An upper gastrointestinal endoscopic examination was performed for all patients to determine the severity of gastric mucosal atrophy and Helicobacter pylori infection. We measured plasma acyl and desacyl ghrelin levels and assessed the association between ghrelin levels and relevant clinical parameters, including nutrition, inflammation, atherosclerosis, and bone metabolism, by gender. Both acyl and desacyl ghrelin levels in female HD patients were significantly higher than those in male HD patients. When stratified by gastric mucosal atrophy, these gender differences were observed only in patients without gastric atrophy. In female patients, acyl ghrelin level was negatively correlated with age. In male patients, both acyl and desacyl ghrelin levels were positively correlated with bone mineral density. Multiple regression analysis showed significant positive correlations between both ghrelin levels and female gender after adjusting for confounding factors. Plasma ghrelin levels were higher in female HD patients than in male HD patients. The gender difference was more evident in patients without gastric atrophy.
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http://dx.doi.org/10.1111/1744-9987.12764DOI Listing
February 2019

Case of human immunodeficiency virus infection presenting as a tip variant of focal segmental glomerulosclerosis: A case report and review of the literature.

World J Nephrol 2018 Aug;7(4):90-95

Division of Nephrology, Hamamatsu Medical Center, Hamamatsu 432-8580, Japan.

The incidence of the collapsing variant of focal segmental glomerulosclerosis (FSGS) as a human immunodeficiency virus (HIV)-associated nephropathy has reduced since the introduction of antiretroviral therapy (ART). However, the incidence of other variants of FSGS, except for the collapsing variant, is increasing, and its therapeutic strategies remain uncertain. A 60-year-old HIV infected man in remission with ART was admitted for progressive renal insufficiency and nephrotic-ranged proteinuria. Renal biopsy revealed a tip variant of FSGS and his clinical manifestations resolved with corticosteroid therapy. HIV infected patients might develop non-collapsing FSGS, including tip variant of FSGS and corticosteroid therapy might be effective for them. A renal biopsy might be essential to determine the renal histology and to decide on corticosteroid therapy.
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http://dx.doi.org/10.5527/wjn.v7.i4.90DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6081390PMC
August 2018

The impact of serum uric acid reduction on renal function and blood pressure in chronic kidney disease patients with hyperuricemia.

Clin Exp Nephrol 2018 Dec 26;22(6):1300-1308. Epub 2018 Apr 26.

Internal Medicine 1, Division of Nephrology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka, 431-3192, Japan.

Background: Febuxostat is tolerable in chronic kidney disease (CKD) patients with hyperuricemia. However, the long-term effect of lowering uric acid with febuxostat on renal function and blood pressure has not been elucidated.

Methods: This was a 2 years retrospective observational study. 86 CKD patients with hyperuricemia who continued with allopurinol (allopurinol group, n = 30), switched from allopurinol to febuxostat (switched group, n = 25), or were newly prescribed febuxostat (febuxostat group, n = 31) were included in this study. Serum uric acid, estimated glomerular filtration rate (eGFR), blood pressure, and urinary protein were analyzed. Moreover, the impact of serum uric acid reduction on renal function and blood pressure was assessed.

Results: Serum uric acid in the switched and febuxostat groups was significantly reduced at 6 months (switched group; 8.49 ± 1.32-7.19 ± 1.14 mg/dL, p < 0.0001, febuxostat group; 9.43 ± 1.63-6.31 ± 0.90 mg/dL, p < 0.0001). In the allopurinol group, serum uric acid was increased (6.86 ± 0.87-7.10 ± 0.85 mg/dL, p = 0.0213). eGFR was significantly increased (35.2 ± 12.8-37.3 ± 13.9 mL/min/1.73 m, p = 0.0232), while mean arterial pressure (93.1 ± 10.8-88.2 ± 9.5 mmHg, p = 0.0039) was significantly decreased at 6 months in the febuxostat group, resulting in the retention of eGFR for 2 years.

Conclusions: The impact of serum uric acid reduction might have beneficial effects on CKD progression and blood pressure. However, a large prospective study is needed to determine the long-term efficacy of febuxostat therapy in CKD patients with hyperuricemia.
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http://dx.doi.org/10.1007/s10157-018-1580-4DOI Listing
December 2018

A patient presenting with isolated hematuria and renal dysfunction as rare manifestation of cryoglobulinemic glomerulonephritis in the course of autoimmune diseases including Sjögren's syndrome.

CEN Case Rep 2018 11 18;7(2):211-216. Epub 2018 Apr 18.

Department of Internal Medicine, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, Japan.

Autoimmune diseases are sometimes associated with immune-mediated renal diseases and cryoglobulinemia is one of the causes. Cryoglobulinemia and cryoglobulinemic glomerulonephritis associated with primary Sjögren's syndrome are most frequent condition among non-hepatitis C virus-related condition. Its typical renal manifestation shows high amount of proteinuria with microscopic hematuria and renal insufficiency. We describe a case of 72-year-old woman with Hashimoto disease, autoimmune hepatitis, Sjögren's syndrome, and immune-related pancytopenia complicated by cryoglobulinemic glomerulonephritis. Before kidney biopsy, tubulointerstitial nephritis probably due to Sjögren's syndrome was suspected because of persistent hematuria without significant proteinuria and developing mild renal dysfunction over 6 months. The developing renal dysfunction associated with isolated hematuria is uncommon in glomerular diseases. Kidney biopsy, however, revealed established membranoproliferative glomerulonephritis with subendothelial deposits consisting of tubular structures with IgM, IgG, and C3 staining. Corticosteroids plus mycophenolate mofetil therapy successfully normalized renal function. Physician should not overlook cryoglobulinemic glomerulonephritis, which is potentially poor prognosis, even if urinalysis shows only persistent isolated hematuria in patients with autoimmune diseases.
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http://dx.doi.org/10.1007/s13730-018-0329-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6181880PMC
November 2018

A Rare Case of Lupus Nephritis Presenting as Thrombotic Microangiopathy with Diffuse Pseudotubulization Possibly Caused by Atypical Hemolytic Uremic Syndrome.

Intern Med 2018 Jun 9;57(11):1617-1623. Epub 2018 Feb 9.

Division of Nephrology, First Department of Medicine, Hamamatsu University School of Medicine, Japan.

A 31-year-old woman was admitted to our hospital for thrombotic microangiopathy (TMA). She was diagnosed with systemic lupus erythematosus (SLE) and class V lupus nephritis. She had no aggravated SLE activity, Shiga toxin positivity, ADAMTS13 abnormality, or other causes of secondary TMA. Plasma exchange partially improved TMA, and eculizumab was introduced for suspected atypical hemolytic uremic syndrome (aHUS), as eculizumab was effective in suppressing the TMA activity. A kidney biopsy revealed diffusely organized crescents (pseudotubulization) with glomerular and arteriolar endothelial injury and subepithelial immune deposits. Thus, this was a rare case of lupus nephritis presenting as TMA with pseudotubulization possibly caused by aHUS.
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http://dx.doi.org/10.2169/internalmedicine.0228-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6028688PMC
June 2018

Uric Acid in the Follow-Up Determines 30% Decline in Estimated GFR Over 2 Years: a Propensity Score Analysis.

Kidney Blood Press Res 2017 4;42(6):1053-1067. Epub 2017 Dec 4.

Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan.

Background/aims: Higher level of serum uric acid (SUA) predicts early entry to dialysis in chronic kidney disease (CKD) patients. However, a short-term effect of SUA remains to be elucidated using a novel surrogate endpoint.

Methods: Japanese CKD stage 3 to 4 patients were retrospectively examined (n= 701). The follow-up level of SUA was estimated as time-averaged uric acid (TA-UA). A propensity score for 6.0, 6.5 or 7.0 mg/dL of TA-UA was respectively calculated using baseline 23 covariates. The time-to-event analysis was performed for 30% decline in estimated GFR over 2 years.

Results: Incidence rates over 2 years were 90 of 440 in men and 36 of 261 in women (p = 0.03). Despite the negative result of baseline SUA, stratified Cox regression on the quintiles of the estimated propensity score showed that higher TA-UA of the three thresholds were all significant (crude HR 2.10 to 2.44) even after adjusting for the confounders. Kaplan-Meier analysis after propensity score matching likewise showed worse survival in the patients with the higher TA-UA (HR 3.11 to 4.26).

Conclusion: Higher SUA increases likelihood of reaching a surrogate endpoint over 2 years. Early intervention for SUA less than 6.0 mg/dL is recommended for slowing CKD progression.
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http://dx.doi.org/10.1159/000485593DOI Listing
August 2018

Remission of Refractory Ascites and Discontinuation of Hemodialysis after Additional Rituximab to Long-term Glucocorticoid Therapy in a Patient with TAFRO Syndrome.

Intern Med 2018 May 11;57(10):1433-1438. Epub 2018 Jan 11.

Department of Internal Medicine, Teikyo University School of Medicine, Japan.

Thrombocytopenia, ascites, myelofibrosis, renal dysfunction, and organomegaly (TAFRO) syndrome is a newly recognized but rare disease, and its treatment has not yet been established. We reported a 50-year-old woman with TAFRO syndrome diagnosed 2 years after the initial symptoms of a fever, fatigue, epigastric pain, edema, ascites, lymphadenopathy, thrombocytopenia and renal insufficiency. The patient showed refractory ascites and required hemodialysis under corticosteroid mono-therapy for suspected immune-mediated disease but was successfully treated with additive rituximab, resulting in improvement in her laboratory data, the withdrawal of hemodialysis and the disappearance of ascites. This case underscores the therapeutic utility of rituximab in patients with corticosteroid-resistant TAFRO syndrome, even long after the onset of the disease.
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http://dx.doi.org/10.2169/internalmedicine.0116-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995702PMC
May 2018

Emergence of Smoldering ANCA-associated Glomerulonephritis during the Clinical Course of Mixed Connective Tissue Disease and Sjögren's Syndrome.

Intern Med 2018 Jun 21;57(12):1757-1762. Epub 2017 Dec 21.

Department of Internal Medicine, Teikyo University School of Medicine, Japan.

A 67-year-old woman presented with hematuria and proteinuria 16 and 11 months ago, respectively. She had been followed up as mixed connective tissue disease and Sjögren's syndrome for over 19 years. Blood chemistry showed no elevated serum creatinine or C-reactive protein but did reveal myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) of 300 U/dL. A kidney biopsy showed pauci-immune focal necrotizing glomerulonephritis. She was treated with prednisolone and rituximab, resulting in normal urinalysis and decreased MPO-ANCA. The complication of ANCA-associated glomerulonephritis should not be overlooked when abnormal urinalysis findings appear in the course of connective tissue disease, irrespective of the presence of rapidly progressive glomerulonephritis.
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http://dx.doi.org/10.2169/internalmedicine.9844-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6047994PMC
June 2018

Unique proximal tubular cell injury and the development of acute kidney injury in adult patients with minimal change nephrotic syndrome.

BMC Nephrol 2017 Nov 28;18(1):339. Epub 2017 Nov 28.

Department of Internal Medicine, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, Japan.

Background: Adult patients with minimal change nephrotic syndrome (MCNS) are often associated with acute kidney injury (AKI). To assess the mechanisms of AKI, we examined whether tubular cell injuries unique to MCNS patients exist.

Methods: We performed a retrospective analysis of clinical data and tubular cell changes using the immunohistochemical expression of vimentin as a marker of tubular injury and dedifferentiation at kidney biopsy in 37 adult MCNS patients. AKI was defined by the criteria of the Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guidelines for AKI.

Results: Thirteen patients (35.1%) were designated with AKI at kidney biopsy. No significant differences in age, history of hypertension, chronic kidney disease, diuretics use, proteinuria, and serum albumin were noted between the AKI and non-AKI groups. Urinary N-acetyl-β-D-glucosaminidase (uNAG) and urinary alpha1-microglobulin (uA1MG) as markers of tubular injury were increased in both groups, but the levels were significantly increased in the AKI group compared with the non-AKI group. The incidence of vimentin-positive tubules was comparable between AKI (84.6%) and non-AKI (58.3%) groups, but vimentin-positive tubular area per interstitial area was significantly increased in the AKI group (19.8%) compared with the non-AKI group (6.8%) (p = 0.011). Vimentin-positive injured tubules with tubular simplification (loss of brush-border of the proximal tubule/dilated tubule with flattening of tubular epithelium) were observed in the vicinity of glomeruli in both groups, suggesting that the proximal convoluted tubules were specifically injured. Two patients exhibited relatively severe tubular injuries with vimentin positivity and required dialysis within 2 weeks after kidney biopsy. The percentage of the vimentin-positive tubular area was positively correlated with uNAG but not with uA1MG in the non-AKI group.

Conclusions: Proximal tubular injuries with increased uNAG exist in MCNS patients without renal dysfunction and were more severe in the AKI group than they were in the non-AKI group. The unique tubular injuries probably due to massive proteinuria might be a predisposing factor for the development of severe AKI in adult MCNS patients.
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http://dx.doi.org/10.1186/s12882-017-0756-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5704628PMC
November 2017

Discontinuation of Hemodialysis in a Patient with Anti-GBM Disease by the Treatment with Corticosteroids and Plasmapheresis despite Several Predictors for Dialysis-Dependence.

Case Rep Nephrol 2017 11;2017:7143649. Epub 2017 Oct 11.

Department of Internal Medicine, Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan.

A 26-year-old man highly suspected of having antiglomerular basement membrane (GBM) disease was treated with corticosteroid pulse therapy 9 days after initial infection-like symptoms with high procalcitonin value. The patient required hemodialysis the next day of the treatment due to oliguria. In addition to corticosteroid therapy, plasmapheresis was introduced and the patient could discontinue hemodialysis 43 days after the treatment. Kidney biopsy after initiation of hemodialysis confirmed anti-GBM disease with 86.3% crescent formation. Physician should keep in mind that active anti-GBM disease shows even high procalcitonin value in the absence of infection. To pursue recovery of renal function, the challenge of the immediate and persistent treatment with high-dose corticosteroids plus plasmapheresis for highly suspected anti-GBM disease is vitally important despite the presence of reported predictors for dialysis-dependence including oliguria and requiring hemodialysis at presentation.
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http://dx.doi.org/10.1155/2017/7143649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5660776PMC
October 2017

Focal segmental glomerulosclerosis associated with cutaneous and systemic plasmacytosis.

CEN Case Rep 2017 Nov 22;6(2):206-209. Epub 2017 Sep 22.

Internal Medicine 1, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan.

Cutaneous and systemic plasmacytosis (CSP) is a rare lymphoproliferative disorder that mainly affects middle-aged Asian individuals. Although Castleman disease is often complicated with various renal involvements, glomerulonephritis associated with CSP, which is considered as a variant of Castleman disease, is rare. This report presents the case of a 41-year-old Japanese man with nephrotic syndrome associated with CSP. Renal biopsy findings showed focal segmental glomerulosclerosis (FSGS) and diffusely mild segmental mesangial proliferation. Plasma cell infiltration in the interstitium was not observed. Electron microscopic findings showed diffuse foot process effacement, localized involvement of subendothelial space widening with amorphous materials, and endothelial cell swelling. Lymph node biopsy findings denied Castleman disease. His skin regions and proteinuria were successfully treated with prednisolone and cyclosporine. The causal relationship between CSP and FSGS is unknown. However, increased serum levels of IL-6 and VEGF and decreased VEGF expression in the podocyte may contribute to renal lesions in patients with CSP. To our best knowledge, this is the first case of a patient with FSGS associated with CSP.
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http://dx.doi.org/10.1007/s13730-017-0276-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5694413PMC
November 2017

Renoprotective effect of topiroxostat via antioxidant activity in puromycin aminonucleoside nephrosis rats.

Physiol Rep 2017 Aug;5(15)

Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan

Topiroxostat is a novel inhibitor of xanthine oxidase, and is postulated to exert a renoprotective effect. Puromycin aminonucleoside nephrosis (PAN) is a rat model of minimal change nephrotic syndrome. In this study, we examined whether topiroxostat ameliorates the kidney injury in PAN rats that was induced by a single intraperitoneal injection of PA (100 mg/kg body weight). Rats were divided into four groups: control rats, PAN rats, control rats treated with topiroxostat (1.0 mg/kg/day), and PAN rats treated with topiroxostat. Topiroxostat significantly reduced the amount of uric acid in the kidney cortex, while serum UA concentration remained unaffected by this treatment. Urinary protein excretion decreased significantly on day 10 in PAN rats upon topiroxostat treatment. Podocyte injury in PAN rats, as indicated by the reduction in WT-1-positive cell numbers and podocin immunoreactivity and foot process effacement, was partially yet significantly alleviated with topiroxostat treatment. In the kidney cortex, the increase in oxidative stress markers such as nitrotyrosine and 8-hydroxy-2-deoxyguanosine (8-OHdG) and the enhanced expressions of xanthine oxidase and NADPH oxidase 4 (NOX4) in PAN rats were significantly ameliorated by topiroxostat. Using cultured podocytes NOX4 expression was upregulated by adding 12 mg/dL UA into the culture medium. These results suggest that topiroxostat ameliorates proteinuria and kidney injury in PAN rats by lowering oxidative stress and tissue UA concentration. The renoprotective effects of topiroxostat could be attributed to its potential to inhibit xanthine oxidase and NOX4 in concert with suppression of intracellular UA production.
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http://dx.doi.org/10.14814/phy2.13358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5555887PMC
August 2017
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