Publications by authors named "Yoshifuru Tamura"

50 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

Urinary phosphate-containing nanoparticle contributes to inflammation and kidney injury in a salt-sensitive hypertension rat model.

Commun Biol 2020 10 15;3(1):575. Epub 2020 Oct 15.

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

Although disturbed phosphate metabolism frequently accompanies chronic kidney disease (CKD), its causal role in CKD progression remains unclear. It is also not fully understood how excess salt induces organ damage. We here show that urinary phosphate-containing nanoparticles promote kidney injury in salt-sensitive hypertension. In Dahl salt-sensitive rats, salt loading resulted in a significant increase in urinary phosphate excretion without altering serum phosphate levels. An intestinal phosphate binder sucroferric oxyhydroxide attenuated renal inflammation and proteinuria in this model, along with the suppression of phosphaturia. Using cultured proximal tubule cells, we confirmed direct pathogenic roles of phosphate-containing nanoparticles in renal tubules. Finally, transcriptome analysis revealed a potential role of complement C1q in renal inflammation associated with altered phosphate metabolism. These data demonstrate that increased phosphate excretion promotes renal inflammation in salt-sensitive hypertension and suggest a role of disturbed phosphate metabolism in the pathophysiology of hypertensive kidney disease and high salt-induced kidney injury.
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http://dx.doi.org/10.1038/s42003-020-01298-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7562875PMC
October 2020

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

Cardio-renal protective effect of the xanthine oxidase inhibitor febuxostat in the 5/6 nephrectomy model with hyperuricemia.

Sci Rep 2020 06 9;10(1):9326. Epub 2020 Jun 9.

Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, 173-8605, Japan.

Although hyperuricemia has been shown to be associated with the progression of cardiovascular disorder and chronic kidney disease (CKD), there is conflicting evidence as to whether xanthine oxidase (XO) inhibitors confer organ protection besides lowering serum urate levels. In this study, we addressed the cardio-renal effects of XO inhibition in rodent CKD model with hyperuricemia. Sprague-Dawley rats underwent 5/6 nephrectomy and received a uricase inhibitor oxonic acid for 8 weeks (RK + HUA rats). In some rats, a XO inhibitor febuxostat was administered orally. Compared with control group, RK + HUA group showed a significant increase in albuminuria and renal injury. Febuxostat reduced serum uric acid as well as urinary albumin levels. Histological and immunohistochemical analysis of the kidney revealed that febuxostat alleviated glomerular, tubulointerstitial, and arteriolar injury in RK + HUA rats. Moreover, in the heart, RK + HUA showed individual myofiber hypertrophy and cardiac fibrosis, which was significantly attenuated by febuxostat. We found that renal injury and the indices of cardiac changes were well correlated, confirming the cardio-renal interaction in this model. Finally, NF-E2-related factor 2 (Nrf2) and the downstream target heme oxygenase-1 (HO-1) protein levels were increased both in the heart and in the kidney in RK + HUA rats, and these changes were alleviated by febuxostat, suggesting that tissue oxidative stress burden was attenuated by the treatment. These data demonstrate that febuxostat protects against cardiac and renal injury in RK + HUA rats, and underscore the pathological importance of XO in the cardio-renal interaction.
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http://dx.doi.org/10.1038/s41598-020-65706-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283314PMC
June 2020

Adsorptive Granulocyte and Monocyte Apheresis Is Effective in Ulcerative Colitis Patients Both with and without Concomitant Prednisolone.

Inflamm Intest Dis 2020 Feb 28;5(1):36-41. Epub 2020 Jan 28.

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

Background: The number of ulcerative colitis (UC) patients is increasing in Japan and other countries. Selective depletion of myeloid lineage leucocytes by adsorptive granulocyte and monocyte apheresis (GMA) with an Adacolumn (JIMRO, Takasaki, Japan) was introduced as a nonpharmacologic treatment strategy in UC patients in 2000. GMA has been reported to be effective in clinical trials; however, the effect of concomitant prednisolone (PSL) on GMA needs to be clarified.

Methods: Thirty-nine patients with active UC were treated with GMA at our institute between June 2009 and September 2018. All patients received GMA therapy once or twice a week with the Adacolumn. Conventional medication was to be continued during the whole GMA treatment course. The clinical response was retrospectively evaluated.

Results: According to the partial Mayo score, remission was 33.3%, significant efficacy 25.6%, effective 25.6%, and no response 15.4%. The average partial Mayo score was 6.2 ± 1.4 at entry and significantly declined to 1.8 ± 1.8 after GMA sessions ( < 0.0001). The average number of bowel movements was 9.5 ± 5.6 at entry and significantly declined to 3.0 ± 2.8 after GMA sessions ( < 0.0001). In a comparison between the group treated with concomitant PSL and the group without PSL, the change in partial Mayo score or the number of bowel movements from entry to after GMA sessions was not significantly different. Among 24 patients treated by GMA with concomitant PSL, 75% (18/24) became steroid free.

Conclusions: The effect of GMA with concomitant PSL and that of GMA without PSL were not different, and GMA was effective irrespective of PSL administration. The present study showed that GMA had efficacy and led many UC patients treated by PSL to be steroid free with no safety concern in the real world, although there is the possibility of recruitment bias due to the retrospective nature of the study.
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http://dx.doi.org/10.1159/000505484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098276PMC
February 2020

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

ABCG2 expression and uric acid metabolism of the intestine in hyperuricemia model rat.

Nucleosides Nucleotides Nucleic Acids 2020 25;39(5):744-759. Epub 2020 Jan 25.

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

To elucidate roles of the intestine in uric acid (UA) metabolism, we examined ABCG2 expression, tissue UA content and xanthine oxidoreductase (XOR) activity in different intestinal segments. Male SD rats were assigned to control group or oxonic acid-induced hyperuricemia (HUA) group. In control rats, ABCG2 was present both in villi and crypts in each segment. Tissue UA content and XOR activity were relatively high in duodenum and jejunum. However, in HUA rats, tissue UA content was significantly elevated in the ileum, whereas it remained unaltered in other segments. Moreover, ABCG2 expression in the HUA group was upregulated both in the villi and crypts of the ileum. These data indicate that the ileum may play an important role in the extra-renal UA excretion.
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http://dx.doi.org/10.1080/15257770.2019.1694684DOI Listing
December 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

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

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

Time to Target Uric Acid to Retard Chronic Kidney Disease Progression.

Contrib Nephrol 2018 23;192:56-68. Epub 2018 Jan 23.

Uric acid (UA) remains a risk factor for the progression of chronic kidney disease (CKD). Most observational studies showed a slight elevation in the serum UA level and this independently predicts the incidence and development of CKD. The recent meta-analysis, however, did not reach the conclusion that urate-lowering therapy with allopurinol retards the progression of CKD. The target level of serum UA if treated is another issue of debate. Our recent analysis by propensity score analysis has shown that the serum UA should be targeted below 6.0 mg/dL to inhibit the progression towards end-stage renal disease. Underlying mechanisms whereby an increase in serum UA induces kidney injury have been elucidated in animal models. Hyperuricemic models can lead to systemic hypertension, arteriolosclerosis including afferent arteriolopathy as well as albuminuria probably due to the activation of oxidative stress. Discoveries of urate transporters have elucidated the novel mechanism of UA transport in the kidney and intestine. The intestinal ABCG2 may play a compensatory role in light of decreased renal clearance of UA in CKD model rats, the trigger of which is not a uremic toxin but serum UA itself. Insulin directly upregulates URAT1 and downregulates ABCG2 in the kidney tubules, suggesting a possible link between UA and metabolic syndrome. This review summarizes the recent knowledge on the causal effect of serum UA on the kidney injury.
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http://dx.doi.org/10.1159/000484279DOI Listing
April 2019

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

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

A Rare Adult Case with Diffuse Segmental Membranous Glomerulonephritis.

Intern Med 2017 1;56(13):1691-1695. Epub 2017 Jul 1.

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

A 71-year-old man with hypertension and diabetes mellitus presented with proteinuria. Laboratory data showed proteinuria of 3.1 g/g creatinine, serum albumin of 3.5 g/dL and serum creatinine of 1.03 mg/dL without autoantibodies. A renal biopsy revealed segmental granular IgG depositions on glomerular capillary walls. Electron microscopy showed segmentally subepithelial, intramembranous and mesangial deposits. Diffuse segmental membranous glomerulonephritis (MGN) was diagnosed with only IgG1 deposition and without M-type phospholipase A2 receptor or thrombospondin type-1 domain-containing 7A staining, suggesting secondary MGN with an unknown target antigen in immune deposits. Physicians should keep in mind the existence of segmental MGN to better understand the clinicopathological characteristics.
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http://dx.doi.org/10.2169/internalmedicine.56.8298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519472PMC
January 2018

Podocyte Injury and Albuminuria in Experimental Hyperuricemic Model Rats.

Oxid Med Cell Longev 2017 28;2017:3759153. Epub 2017 Feb 28.

Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan.

Although hyperuricemia is shown to accelerate chronic kidney disease, the mechanisms remain unclear. Accumulating studies also indicate that uric acid has both pro- and antioxidant properties. We postulated that hyperuricemia impairs the function of glomerular podocytes, resulting in albuminuria. Hyperuricemic model was induced by oral administration of 2% oxonic acid, a uricase inhibitor. Oxonic acid caused a twofold increase in serum uric acid levels at 8 weeks when compared to control animals. Hyperuricemia in this model was associated with the increase in blood pressure and the wall-thickening of afferent arterioles as well as arcuate arteries. Notably, hyperuricemic rats showed significant albuminuria, and the podocyte injury marker, desmin, was upregulated in the glomeruli. Conversely, podocin, the key component of podocyte slit diaphragm, was downregulated. Structural analysis using transmission electron microscopy confirmed podocyte injury in this model. We found that urinary 8-hydroxy-2'-deoxyguanosine levels were significantly increased and correlated with albuminuria and podocytopathy. Interestingly, although the superoxide dismutase mimetic, tempol, ameliorated the vascular changes and the hypertension, it failed to reduce albuminuria, suggesting that vascular remodeling and podocyte injury in this model are mediated through different mechanisms. In conclusion, vasculopathy and podocytopathy may distinctly contribute to the kidney injury in a hyperuricemic state.
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http://dx.doi.org/10.1155/2017/3759153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5350416PMC
April 2017

Targeting gene expression to specific cells of kidney tubules in vivo, using adenoviral promoter fragments.

PLoS One 2017 2;12(3):e0168638. Epub 2017 Mar 2.

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

Although techniques for cell-specific gene expression via viral transfer have advanced, many challenges (e.g., viral vector design, transduction of genes into specific target cells) still remain. We investigated a novel, simple methodology for using adenovirus transfer to target specific cells of the kidney tubules for the expression of exogenous proteins. We selected genes encoding sodium-dependent phosphate transporter type 2a (NPT2a) in the proximal tubule, sodium-potassium-2-chloride cotransporter (NKCC2) in the thick ascending limb of Henle (TALH), and aquaporin 2 (AQP2) in the collecting duct. The promoters of the three genes were linked to a GFP-coding fragment, the final constructs were then incorporated into an adenovirus vector, and this was then used to generate gene-manipulated viruses. After flushing circulating blood, viruses were directly injected into the renal arteries of rats and were allowed to site-specifically expression in tubule cells, and rats were then euthanized to obtain kidney tissues for immunohistochemistry. Double staining with adenovirus-derived EGFP and endogenous proteins were examined to verify orthotopic expression, i.e. "adenovirus driven NPT2a-EGFP and endogenous NHE3 protein", "adenovirus driven NKCC2-EGFP and endogenous NKCC2 protein" and "adenovirus driven AQP2-EGFP and endogenous AQP2 protein". Owing to a lack of finding good working anti-NPT2a antibody, an antibody against a different protein (sodium-hydrogen exchanger 3 or NHE3) that is also specifically expressed in the proximal tubule was used. Kidney structures were well-preserved, and other organ tissues did not show EGFP staining. Our gene transfer method is easier than using genetically engineered animals, and it confers the advantage of allowing the manipulation of gene transfer after birth. This is the first method to successfully target gene expression to specific cells in the kidney tubules. This study may serve as the first step for safe and effective gene therapy in the kidney tubule diseases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0168638PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5333796PMC
August 2017

Clinical Presentation of Tubulointerstitial Nephritis Caused by Amyloid Light-chain Amyloidosis in a Patient with Sjögren's Syndrome.

Intern Med 2017 15;56(4):419-423. Epub 2017 Feb 15.

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

We report a 70-year-old woman with Sjögren's syndrome who had severe renal dysfunction with mild proteinuria and elevated urinary low-molecular-weight proteins. Based on these clinical presentations, interstitial nephritis due to Sjögren's syndrome was strongly suspected. Unexpectedly, renal pathology revealed amyloid light-chain (AL) lambda-type depositions predominantly in the vasculatures with severe tubulointerstitial damage. Concentrated urine immunofixation was positive for Bence Jones lambda-type monoclonal proteins. Given the involvement in other organs, systemic AL amyloidosis was diagnosed. The patient underwent chemotherapy, but hemodialysis was ultimately instituted. It should be remembered that renal amyloidosis occurs as a clinical presentation of interstitial nephritis.
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http://dx.doi.org/10.2169/internalmedicine.56.7548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5364195PMC
April 2017

Immunohistochemical and in situ hybridization study of urate transporters GLUT9/URATv1, ABCG2, and URAT1 in the murine brain.

Fluids Barriers CNS 2016 Dec 12;13(1):22. Epub 2016 Dec 12.

Department of Human Physiology and Pathology, Faculty of Pharma-Sciences, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo, 173-8605, Japan.

Background: Uric acid (UA) is known to exert neuroprotective effects in the brain. However, the mechanism of UA regulation in the brain is not well characterized. In our previous study, we described that the mouse urate transporter URAT1 is localized to the cilia and apical surface of ventricular ependymal cells. To further strengthen the hypothesis that UA is transported transcellularly at the ependymal cells, we aimed to assess the distribution of other UA transporters in the murine brain.

Methods: Immunostaining and highly-sensitive in situ hybridization was used to assess the distribution of UA transporters: GLUT9/URATv1, ABCG2, and URAT1.

Results: Immunostaining for GLUT9 was observed in ependymal cells, neurons, and brain capillaries. Immunostaining for ABCG2 was observed in the choroid plexus epithelium and brain capillaries, but not in ependymal cells. These results were validated by in situ hybridization.

Conclusions: We propose that given their specific expression patterns in ependymal, choroid plexus epithelial, and brain capillary endothelial cells in this study, UA may be transported by these UA transporters in the murine brain. This may provide a novel strategy for targeted neuroprotection.
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http://dx.doi.org/10.1186/s12987-016-0046-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5154092PMC
December 2016

Uric acid metabolism of kidney and intestine in a rat model of chronic kidney disease.

Nucleosides Nucleotides Nucleic Acids 2016 Dec;35(10-12):550-558

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

Uric acid (UA) is a potential risk factor of the progression of chronic kidney disease (CKD). Recently, we reported that intestinal UA excretion might be enhanced via upregulation of the ATP-binding cassette transporter G2 (Abcg2) in a 5/6 nephrectomy (Nx) rat model. In the present study, we examined the mRNA and protein expressions of UA transporters, URAT1, GLUT9/URATv1, ABCG2 and NPT4 in the kidney and ileum in the same rat model. Additionally, we investigated the Abcg2 mRNA expression of ileum in hyperuricemic rat model by orally administering oxonic acid. Male Wistar rats were randomly assigned to three groups consisting of Nx group, oxonic acid-treated (Ox) group and sham-operated control group, and sacrificed at 8 weeks. Creatinine and UA were measured and the mRNA expressions of UA transporters in the kidney and intestine were evaluated by a real time PCR. UA transporters in the kidney sections were also examined by immunohistochemistry. Serum creatinine elevated in the Nx group whereas serum UA increased in the Ox group. Both the mRNA expression and the immunohistochemistry of the UA transporters were decreased in the Nx group, suggesting a marginal role in UA elevation in decreased kidney function. In contrast, the mRNA expression of Abcg2 in the ileum significantly increased in the Ox group. These results suggest that the upregulation of Abcg2 mRNA in the ileum triggered by an elevation of serum UA may play a compensatory role in increasing intestinal UA excretion.
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http://dx.doi.org/10.1080/15257770.2016.1163379DOI Listing
December 2016

Pathological implications of linear immunoglobulin G staining on the glomerular capillary walls in a case of infection-related glomerulonephritis.

Pathol Int 2016 Sep 27;66(9):524-8. Epub 2016 Jul 27.

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

We report a 32-year-old man with nephrotic syndrome and preceding symptom of infection. He had renal insufficiency, hypocomplementemia, and elevated titer of anti-streptolysin O. Renal biopsy showed mesangial hypercellularity and focal segmental endocapillary hypercellularity with double contour of the glomerular basement membrane (GBM). Immunofluorescence study showed granular C3 staining on the mesangial areas and glomerular capillary walls (GCWs) and linear immunoglobulin G (IgG) staining on GCWs. Electron microscopy revealed sporadic subepithelial humps, discontinuous small and thin deposits in the endothelial side of the GBM and mesangial deposits. He was diagnosed with infection-related glomerulonephritis (IRGN) with the striking finding of linear IgG staining, which is unusual in IRGN. The patient did not have diabetes mellitus or anti-GBM disease. The patient's serum seemed not to contain IgG, which can bind to GCW. He showed normalization of complement within two months after relief from infection symptoms and a trend toward improvement in proteinuria, hematuria and renal function over 14 months. We discuss the possible mechanisms of linear IgG staining in our case based on clinical and experimental studies on IRGN with cationic bacterial protein as antigen.
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http://dx.doi.org/10.1111/pin.12441DOI Listing
September 2016
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