A case report of minimal change disease associated with Kimura disease complicated by optic neuritis.

Kimura disease (KD) is a rare chronic inflammatory disease that typically presents with soft subcutaneous granulomas in the head and neck regions characterized by elevated blood eosinophils and immunoglobulin E (IgE) level, whose aetiology remains poorly elucidated. Minimal change disease (MCD) has been reported as one of the renal manifestations that KD can present with, indicating that they may share a common pathology. Herein we describe a case of recurrent MCD associated with KD. During a follow-up period of 15 years, MCD recurred three times with increased disease activity of KD as reflected by flares of skin lesions and elevated peripheral eosinophils, and responded well to increased doses of prednisolone and cyclosporin. Notably, visual field defects in his right monocular vision appeared at the time of third recurrence of MCD, leading to the diagnosis of optic neuritis (ON). Optic nerve involvement associated with KD is extremely rare, and this case is noteworthy in that inflammation in the optic nerve was observed at the time of MCD recurrence with increased disease activity of KD, suggesting the existence of a common pathology between KD, MCD, and ON. In patients with KD, an imbalance of T helper (Th) cells with Th2 cells predominating over Th1 cells is observed, which results in hyperIgEemia and eosinophilia. This Th2-predominant immunological status in KD considered to predispose to MCD may also predispose to ON. MCD with a background of Th2-predominant immune state may require attention to the possibility of complication of ON.

Evaluating the safety and efficacy of vadadustat for the treatment of anemia associated with chronic kidney disease.

INTRODUCTION: The breakthrough in erythropoietin-stimulating agents in the 1990s improved the prognosis and treatment of complications in chronic kidney disease patients and renal anemia. Discovery of the novel molecular mechanisms for hypoxia-inducible factor (HIF) transcription factor under hypoxic conditions has led to the development of oral drugs, HIF-Prolyl Hydroxylase inhibitors (HIF-PHIs), that constantly activate erythropoietin by inhibiting prolyl hydroxylase. HIF-PHIs have gained rapid approval in Asian countries, including Japan, with six distinct types entering clinical application. AREAS COVERED: This article provides a comprehensive review of the latest literature, with a particular focus on the effectiveness and safety of vadadustat. EXPERT OPINION: A phase 3, randomized, open-label, clinical trial (PRO2TECT) demonstrated that vadadustat had the prespecified non-inferiority for hematologic efficacy as compared with darbepoetin alfa in non-dialysis-dependent patients not previously treated with ESA. However, vadadustat did not show non-inferiority in major adverse cardiovascular events in the non-US/non-Europe patients. It may partly because of imbalances of the baseline eGFR level in those countries. In dialysis-dependent patients, a phase 3 clinical trial (INNO2VATE) showed vadadustat was non-inferior to darbepoetin alfa in cardiovascular safety and maintenance of hemoglobin levels. Adverse events including cancer, retinopathy, thrombosis, and vascular calcification should be evaluated in future clinical studies.

Epigenetic roles in clonal hematopoiesis and aging kidney-related chronic kidney disease.

Accumulation of somatic hematopoietic stem cell mutations with aging has been revealed by the recent genome-wide analysis. Clonal expansion, known as clonal hematopoiesis of indeterminate potential (CHIP), is a premalignant condition of hematological cancers. It is defined as the absence of definitive morphological evidence of a hematological neoplasm and occurrence of ≥2% of mutant allele fraction in the peripheral blood. In CHIP, the most frequently mutated genes are epigenetic regulators such as DNMT3A, TET2, and ASXL1. CHIP induces inflammation. CHIP is shown to be associated with not only hematological malignancy but also non-malignant disorders such as atherosclerosis, cardiovascular diseases and chronic liver disease. In addition, recent several large clinical trials have shown that CHIP is also the risk factor for developing chronic kidney disease (CKD). In this review article, we proposed novel findings about CHIP and CHIP related kidney disease based on the recent basic and clinical research. The possible mechanism of the kidney injury in CHIP is supposed to be due to the clonal expansion in both myeloid and lymphoid cell lines. In myeloid cell lines, the mutated macrophages increase the inflammatory cytokine level and induce chronic inflammation. It leads to epigenetic downregulation of kidney and macrophage klotho level. In lymphoid cell lines, CHIP might be related to monoclonal gammopathy of renal significance (MGRS). It describes any B cell or plasma cell clonal disorder that does not fulfill the criteria for cancer yet produces a nephrotoxic monoclonal immunoglobulin that leads to kidney injury or disease. MGRS causes M-protein related nephropathy frequently observed among aged CKD patients. It is important to consider the CHIP-related complications such as hematological malignancy, cardiovascular diseases and metabolic disorders in managing the elderly CKD patients. There are no established therapies for CHIP and CHIP-related CKD yet. However, recent studies have supported the development of effective CHIP therapies, such as blocking the expansion of aberrant HSCs and inhibiting chronic inflammation. In addition, drugs targeting the epigenetic regulation of Klotho in the kidney and macrophages might be therapeutic targets of CHIP in the kidney.

Dznep, a histone modification inhibitor, inhibits HIF1α binding to TIMP2 gene and suppresses TIMP2 expression under hypoxia.

Epidemiological studies have shown that patients who recovered from acute kidney injury (AKI) may subsequently develop chronic kidney disease (CKD). AKI is primarily caused by renal hypoxia, and it causes epigenetic alterations, known as hypoxic memory. 3-Deazaneplanocin A (Dznep), an inhibitor of histone modification, suppresses renal fibrosis and the expression of tissue inhibitor of metalloproteinases-2 (TIMP2), a profibrotic factor, in mouse ischemia-reperfusion models. The current study investigated the epigenetic regulation of TIMP2 in human kidney 2 (HK-2) cells. The expression of TIMP2 was upregulated in HK-2 cells under hypoxic conditions and was suppressed by Dznep. ChIP-qPCR showed that Dznep reduced the amount of H3K4me3 at the promoter region of the TIMP2 gene under hypoxic condition. Formaldehyde-assisted isolation of regulatory elements-qPCR of the TIMP2 gene showed that Dznep reduced open chromatin area. In addition, based on ChIP-qPCR of hypoxia-inducible factor 1 alpha (HIF1α), Dznep inhibited the binding of HIF1α to the TIMP2 gene under hypoxic conditions. The reporter assays for the binding region of HIF1α showed enhanced transcriptional activity by hypoxia. Dznep suppresses the expression of TIMP2 under hypoxic conditions by inhibiting the binding of HIF1α to the TIMP2 gene.

Chromatin remodeling factor, INO80, inhibits PMAIP1 in renal tubular cells via exchange of histone variant H2A.Z. for H2A.

Epigenetic modifications such as DNA methylation, histone modifications, and chromatin structures in the kidney contribute towards the progression of chronic kidney disease (CKD). In this study, the role of chromatin remodeling factor inositol requiring 80 (INO80) was investigated. Although INO80 regulates transcription by altering the chromatin structure at the nucleosome level, its role in the kidney remains unknown. We demonstrated that the expression of INO80 in impaired kidneys decreased in rats with unilateral urethral obstruction. We investigated INO80 expression in a proximal tubular cell line and observed that its expression decreased under hypoxic condition. Additionally, INO80 knockdown promoted apoptosis, suggesting that INO80 plays a role in inhibiting tubular cell apoptosis. We identified downstream target genes of INO80 via genome-wide analysis using RNA-sequences and found that the expression of apoptosis-related genes, such as TP53 and E2F1, and pro-apoptotic genes, such as PMAIP1, increased upon INO80 knockdown. ChIP-qPCR of the loci of PMAIP1 showed that the amount of H2A.Z. increased instead of decreasing the amount of H2A when INO80 was knocked down. These results indicated that INO80 plays a role in the exchange of H2A.Z. for H2A in the promoter region of PMAIP1 in tubular cells to inhibit apoptosis during CKD progression.

ABCA1 deficiency contributes to podocyte pyroptosis priming via the APE1/IRF1 axis in diabetic kidney disease.

Decreased ATP Binding Cassette Transporter A1 (ABCA1) expression and caspase-4-mediated noncanonical inflammasome contribution have been described in podocytes in diabetic kidney disease (DKD). To investigate a link between these pathways, we evaluated pyroptosis-related mediators in human podocytes with stable knockdown of ABCA1 (siABCA1) and found that mRNA levels of IRF1, caspase-4, GSDMD, caspase-1 and IL1ß were significantly increased in siABCA1 compared to control podocytes and that protein levels of caspase-4, GSDMD and IL1ß were equally increased. IRF1 knockdown in siABCA1 podocytes prevented increases in caspase-4, GSDMD and IL1ß. Whereas TLR4 inhibition did not decrease mRNA levels of IRF1 and caspase-4, APE1 protein expression increased in siABCA1 podocytes and an APE1 redox inhibitor abrogated siABCA1-induced expression of IRF1 and caspase-4. RELA knockdown also offset the pyroptosis priming, but ChIP did not demonstrate increased binding of NFκB to IRF1 promoter in siABCA1 podocytes. Finally, the APE1/IRF1/Casp1 axis was investigated in vivo. APE1 IF staining and mRNA levels of IRF1 and caspase 11 were increased in glomeruli of BTBR ob/ob compared to wildtype. In conclusion, ABCA1 deficiency in podocytes caused APE1 accumulation, which reduces transcription factors to increase the expression of IRF1 and IRF1 target inflammasome-related genes, leading to pyroptosispriming.

Hypoxia-inducible lncRNA MIR210HG promotes HIF1α expression by inhibiting miR-93-5p in renal tubular cells.

Chronic hypoxia in the renal tubular interstitium has been reported to contribute to the progression of chronic kidney disease. Recently, long-noncoding RNAs have been shown to be involved in various pathological conditions, including hypoxia, one of which is the MIR210 host gene (MIR210HG). To elucidate the function of MIR210HG in renal hypoxia, we exposed primary cultured renal proximal tubular epithelial cells to hypoxia and examined the temporal profile of MIR210HG expression and the role of MIR210HG interaction with hypoxia-inducible factor1α (HIF1α, encoded by HIF1A). MIR210HG expression was induced by hypoxia. HIF1A silencing and cobalt chloride exposure showed that MIR210HG expression in hypoxia is HIF1α-dependent. MIR210HG silencing significantly reduced both the mRNA and protein levels of HIF1α, pointing to positive feedback regulation. To further investigate the details of this regulation, we turned to the in-silico miRNA targets of MIR210HG. We found that miR-93-5p levels increased when MIR210HG was knocked down. We then showed that miR-93-5p reduced the expression of HIF1A mRNA and MIR210HG. Furthermore, a dual luciferase assay confirmed that miR-93-5p binds to MIR210HG and HIF1A 3' UTR, inhibiting their expression. In conclusion, the long-noncoding RNA MIR210HG is induced shortly after hypoxia, and it promotes HIF1α expression by competing for miR-93-5p and inhibiting it. MIR210HG plays a crucial role in the biological response to hypoxia in renal tubular epithelial cells.

Effect of M2-like macrophages of the injured-kidney cortex on kidney cancer progression.

Chronic kidney disease (CKD) affects kidney cancer patients' mortality. However, the underlying mechanism remains unknown. M2-like macrophages have pro-tumor functions, also exist in injured kidney, and promote kidney fibrosis. Thus, it is suspected that M2-like macrophages in injured kidney induce the pro-tumor microenvironment leading to kidney cancer progression. We found that M2-like macrophages present in the injured kidney promoted kidney cancer progression and induced resistance to anti-PD1 antibody through its pro-tumor function and inhibition of CD8+ T cell infiltration. RNA-seq revealed Slc7a11 was upregulated in M2-like macrophages. Inhibition of Slc7a11 with sulfasalazine inhibited the pro-tumor function of M2-like macrophages and synergized with anti-PD1 antibody. Moreover, SLC7A11-positive macrophages were associated with poor prognosis among kidney cancer patients. Collectively, this study dissects the characteristic microenvironment in the injured kidney that contributed to kidney cancer progression and anti-PD1 antibody resistance. This insight offers promising combination therapy with anti-PD1 antibody and macrophage targeted therapy.

Epigenetic memory contributing to the pathogenesis of AKI-to-CKD transition.

Epigenetic memory, which refers to the ability of cells to retain and transmit epigenetic marks to their daughter cells, maintains unique gene expression patterns. Establishing programmed epigenetic memory at each stage of development is required for cell differentiation. Moreover, accumulating evidence shows that epigenetic memory acquired in response to environmental stimuli may be associated with diverse diseases. In the field of kidney diseases, the "memory" of acute kidney injury (AKI) leads to progression to chronic kidney disease (CKD); epidemiological studies show that patients who recover from AKI are at high risk of developing CKD. The underlying pathological processes include nephron loss, maladaptive epithelial repair, inflammation, and endothelial injury with vascular rarefaction. Further, epigenetic alterations may contribute as well to the pathophysiology of this AKI-to-CKD transition. Epigenetic changes induced by AKI, which can be recorded in cells, exert long-term effects as epigenetic memory. Considering the latest findings on the molecular basis of epigenetic memory and the pathophysiology of AKI-to-CKD transition, we propose here that epigenetic memory contributing to AKI-to-CKD transition can be classified according to the presence or absence of persistent changes in the associated regulation of gene expression, which we designate "driving" memory and "priming" memory, respectively. "Driving" memory, which persistently alters the regulation of gene expression, may contribute to disease progression by activating fibrogenic genes or inhibiting renoprotective genes. This process may be involved in generating the proinflammatory and profibrotic phenotypes of maladaptively repaired tubular cells after kidney injury. "Priming" memory is stored in seemingly successfully repaired tubular cells in the absence of detectable persistent phenotypic changes, which may enhance a subsequent transcriptional response to the second stimulus. This type of memory may contribute to AKI-to-CKD transition through the cumulative effects of enhanced expression of profibrotic genes required for wound repair after recurrent AKI. Further understanding of epigenetic memory will identify therapeutic targets of future epigenetic intervention to prevent AKI-to-CKD transition.

Therapies Targeting Epigenetic Alterations in Acute Kidney Injury-to-Chronic Kidney Disease Transition.

Acute kidney injury (AKI) was previously thought to be a merely transient event; however, recent epidemiological evidence supports the existence of a causal relationship between AKI episodes and subsequent progression to chronic kidney disease (CKD). Although the pathophysiology of this AKI-to-CKD transition is not fully understood, it is mediated by the interplay among multiple components of the kidney including tubular epithelial cells, endothelial cells, pericytes, inflammatory cells, and myofibroblasts. Epigenetic alterations including histone modification, DNA methylation, non-coding RNAs, and chromatin conformational changes, are also expected to be largely involved in the pathophysiology as a "memory" of the initial injury that can persist and predispose to chronic progression of fibrosis. Each epigenetic modification has a great potential as a therapeutic target of AKI-to-CKD transition; timely and target-specific epigenetic interventions to the various temporal stages of AKI-to-CKD transition will be the key to future therapeutic applications in clinical practice. This review elaborates on the latest knowledge of each mechanism and the currently available therapeutic agents that target epigenetic modification in the context of AKI-to-CKD transition. Further studies will elucidate more detailed mechanisms and novel therapeutic targets of AKI-to-CKD transition.

Treatment of Diabetic Kidney Disease: Current and Future.

Diabetic kidney disease (DKD) is the major cause of end-stage kidney disease. However, only renin-angiotensin system inhibitor with multidisciplinary treatments is effective for DKD. In 2019, sodium-glucose cotransporter 2 (SGLT2) inhibitor showed efficacy against DKD in Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial, adding a new treatment option. However, the progression of DKD has not been completely controlled. The patients with transient exposure to hyperglycemia develop diabetic complications, including DKD, even after normalization of their blood glucose. Temporary hyperglycemia causes advanced glycation end product (AGE) accumulations and epigenetic changes as metabolic memory. The drugs that improve metabolic memory are awaited, and AGE inhibitors and histone modification inhibitors are the focus of clinical and basic research. In addition, incretin-related drugs showed a renoprotective ability in many clinical trials, and these trials with renal outcome as their primary endpoint are currently ongoing. Hypoxia-inducible factor prolyl hydroxylase inhibitors recently approved for renal anemia may be renoprotective since they improve tubulointerstitial hypoxia. Furthermore, NF-E2-related factor 2 activators improved the glomerular filtration rate of DKD patients in Bardoxolone Methyl Treatment: Renal Function in chronic kidney disease/Type 2 Diabetes (BEAM) trial and Phase II Study of Bardoxolone Methyl in Patients with Chronic Kidney Disease and Type 2 Diabetes (TSUBAKI) trial. Thus, following SGLT2 inhibitor, numerous novel drugs could be utilized in treating DKD. Future studies are expected to provide new insights.

Are women more susceptible to renal dysfunction than men?

Is there any difference in sensitivity to kidney function between men and women? Paterson et al. have focused on sex differences in chronic kidney disease. Surprisingly, their experimental results show that only one microRNA, miR-146b-5p, affected the susceptibility of renocardiac pathology. They generated miR-146b knockout rats and found that miR-146b-/- females developed exacerbated renal hypertrophy and fibrosis and had less cardiac remodeling. Although miR-146b-5p has been reported to be upregulated in various types of cancers, this article reveals the novel role of miR-146b in the kidney.

Kidney aging: an irresistible slope.

Kidney aging is a multifactorial process. Using genome-wide database analysis, Rowland et al. identified testis-specific Y-encoded-like protein 5 as a candidate age-related renal gene, and reported that with aging, testis-specific Y-encoded-like protein 5 expression decreases in response to increased testis-specific Y-encoded-like protein 5 promoter methylation. Genome-wide databases are readily available, and we should carefully analyze them to find a mechanism to fight kidney aging on the experiments using cells and animals, not just in silico calculations.

Nutcracker Syndrome with the Superimposition of Thin Basement Membrane Syndrome.

A 21-year-old woman was referred to our hospital because of proteinuria and hematuria. She had occasional flank pain. A renal biopsy was performed and revealed a thin basement membrane. Therefore, she was diagnosed with thin basement membrane disease. However, the frequency of her flank pain increased. Since her left kidney was slightly larger than the right, nutcracker syndrome (NCS) was suspected. Renal vein ultrasonography and venography were performed, and NCS was confirmed. Her hematuria was multifactorial, and NCS can go unnoticed if there is a comorbidity that also causes hematuria.

Intravital phosphorescence lifetime imaging of the renal cortex accurately measures renal hypoxia.

Renal tubulointerstitial hypoxia is recognized as a final common pathway of chronic kidney disease and is considered a promising drug target. However, hypoxia in the tubules is not well examined because of limited detection methods. Here, we devised a method to visualize renal tubular oxygen tension with spatial resolution at a cellular level using the cell-penetrating phosphorescent probe, BTPDM1 (an iridium-based cationic lipophilic dye), and confocal phosphorescence lifetime imaging microscopy to precisely assess renal hypoxia. Imaging with BTPDM1 revealed an oxygen gradient between S1 and S2 segments in mouse kidney. We also demonstrated that our microscopy system can detect subtle changes of hypoxemia and reoxygenation, and the acquired phosphorescence lifetime can be converted to partial pressure of oxygen. This new method allows, for the first time, visualization of intravital oxygen gradients at the renal surface with high spatial resolution. Thus, the confocal phosphorescence lifetime imaging microscopy platform, combined with BTPDM1, will promote an accurate understanding of tissue hypoxia, including renal hypoxia.

Genome-wide analysis revealed that DZNep reduces tubulointerstitial fibrosis via down-regulation of pro-fibrotic genes.

Tubulointerstitial fibrosis has been recently reported to be caused by the collapse of the epigenetic regulation of kidney diseases. We examined whether pharmacological inhibition of histone modification is effective against renal fibrosis. DZNep (3-deazaneplanocin A) was originally developed as an anti-cancer drug to inhibit the repressive histone mark, H3K27me3. We used a model of chronic tubulointerstitial fibrosis induced by unilateral ischaemia/reperfusion and administered DZNep intravenously to the mice for 8 weeks. We found DZNep contributes to the reduction of tubulointerstitial fibrosis. We selected only tubular cells from in vivo samples using laser-capture microdissection because epigenetic regulation is specific to the cell types, and we focused on the changes in the tubular cells. We performed a genome-wide analysis of tubular cells using high-throughput sequencing (RNA-seq) to identify novel epigenetic factors associated with renal fibrosis. We found that pro-fibrotic genes such as COL3A1 (collagen type 3a1) and TIMP2 (tissue inhibitor of metalloproteinase 2) were suppressed by DZNep in vivo. In addition, pro-fibrotic genes such as COL4A1 (collagen type 4a1), TIMP2 and MMP14 were down-regulated by DZNep in vitro. In conclusion, we found that pharmacological epigenetic modification by DZNep decreased the expression levels of fibrogenic genes in tubular cells and inhibited tubulointerstitial fibrosis.

Epigenetic Changes in the Acute Kidney Injury-to-Chronic Kidney Disease Transition.

Previously acute kidney injury (AKI) had been believed to be a transient event, and recovery from AKI had been thought to lead to no consequences. However, recent epidemiological studies have shown that even if there is complete recovery of the kidney function, AKI can eventually result in chronic kidney disease (CKD) and eventually in end-stage kidney disease in the long term. Transition of AKI to CKD is mediated by multiple mechanisms, including aberrant cell cycle arrest and hypoxia. Hypoxia of the kidney is induced by rarefaction of the peritubular capillaries after AKI episodes, and induces inflammation and fibrosis. It should also be noted that epigenetic changes are closely related to hypoxia, and epigenetic changes induced by hypoxia, called "hypoxic memory" can explain the AKI-to-CKD transition in the long term after complete recovery from the initial AKI episode. Targeting hypoxia and subsequent epigenetic changes are promising strategies to block the transition from AKI to CKD.

Novel lnc RNA regulated by HIF-1 inhibits apoptotic cell death in the renal tubular epithelial cells under hypoxia.

Chronic tubulointerstitial hypoxia plays an important role as the final common pathway to end-stage renal disease. HIF-1 (hypoxia-inducible factor-1) is a master transcriptional factor under hypoxia, regulating downstream target genes. Genome-wide analysis of HIF-1 binding sites using high-throughput sequencers has clarified various kinds of downstream targets and made it possible to demonstrate the novel roles of HIF-1. Our aim of this study is to identify novel HIF-1 downstream epigenetic targets which may play important roles in the kidney. Immortalized tubular cell lines (HK2; human kidney-2) and primary cultured cells (RPTEC; renal proximal tubular cell lines) were exposed to 1% hypoxia for 24-72 h. We performed RNA-seq to clarify the expression of mRNA and long non-coding RNA (lncRNA). We also examined ChIP-seq to identify HIF-1 binding sites under hypoxia. RNA-seq identified 44 lncRNAs which are up-regulated under hypoxic condition in both cells. ChIP-seq analysis demonstrated that HIF-1 also binds to the lncRNAs under hypoxia. The expression of novel lncRNA, DARS-AS1 (aspartyl-tRNA synthetase anti-sense 1), is up-regulated only under hypoxia and HIF-1 binds to its promoter region, which includes two hypoxia-responsive elements. Its expression is also up-regulated with cobalt chloride exposure, while it is not under hypoxia when HIF-1 is knocked down by siRNA To clarify the biological roles of DARS-AS1, we measured the activity of caspase 3/7 using anti-sense oligo of DARS-AS1. Knockdown of DARS-AS1 deteriorated apoptotic cell death. In conclusion, we identified the novel lncRNAs regulated by HIF-1 under hypoxia and clarified that DARS-AS1 plays an important role in inhibiting apoptotic cell death in renal tubular cells.