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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 effica cy 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 glu cose. Temporary hyperglycemia causes advanced glycation end product (AGE) accumulations and epigenetic changes as meta bolic 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 tri als, and these trials with renal outcome as their primary endpoint are currently ongoing. Hypoxia-inducible factor prolyl hydrox ylase inhibitors recently approved for renal anemia may be renoprotective since they improve tubulointerstitial hypoxia. Further more, NF-E2-related factor 2 activators improved the glomerular filtration rate of DKD patients in Bardoxolone Methyl Treat ment: Renal Function in chronic kidney disease/Type 2 Diabetes (BEAM) trial and Phase II Study of Bardoxolone Methyl in Pa tients 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.

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.

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.

Chronic kidney disease presents a complex and distinct pathological landscape in men and women, yet this difference is poorly understood. microRNAs are powerful molecular regulators of pathophysiology in the kidney and other organs. We previously reported a significant upregulation of miR-146b-5p in the 5/6 nephrectomy rat model of chronic kidney disease. Here we investigated the sex-specific contribution of miR-146b-5p to renocardiac pathology by generating a novel miR-146b(−/−) rat and characterized the expression of miR-146b-5p in both wild-type and knockout animals. The 5/6 nephrectomy or sham surgery was performed on rats of each genotype and sex. Renal pathology was examined through gross histology, plasma and urinary analysis of electrolytes and metabolites, and by chronic blood pressure monitoring. Cardiac pathology was monitored via echocardiography and pressure-volume analysis. The miR-146b(−/−) rats show functional knockout of miR-146b-5p in both the kidney and heart. While 5/6 nephrectomy induced tissue hypertrophy, miR-146b(−/−) female rats displayed exacerbated renal hypertrophy. Additionally, miR-146b(−/−) female rats exhibited a marked elevation of renal fibrosis and significant renal dysfunction yet lower blood pressure and less pronounced cardiac remodeling. These phenotypic differences were not exhibited in miR-146b(−/−) male rats. Ovariectomy ameliorated renal pathology and abolished genotypic differences. In vitro examination of transforming growth factor-β signaling in combination with miR-146b-5p manipulation supports a role for miR-146b-5p in mediating the protective benefit of estrogen from renal pathologies. Thus, our data highlight an important role of miR-146b-5p in modulating kidney disease progression and provide new avenues for the study of sex-specific pathology

Background: Kidney injury, including chronic kidney disease and acute kidney injury, is a worldwide health problem. Hypoxia and transforming growth factor-β (TGF-β) are well-known factors that promote kidney injury. Hypoxia-inducible factor (HIF) and SMAD3 are their main downstream transcriptional factors. Hypoxia-HIF pathway and TGF-β/SMAD3 pathway play a crucial role in the progression of kidney injury. However, reports on their interactions are limited, and the global transcriptional regulation under their control is almost unknown. Methods: Kidney tubular epithelial cells were cultured and stimulated by hypoxia and TGF-β. We detected global binding sites of HIF-1α and SMAD3 in cells using chromatin immunoprecipitation-sequencing (ChIP-Seq), and measured the gene expression using RNA-sequencing (RNA-Seq). ChIP-quantitative PCR (qPCR) was used to quantitatively evaluate bindings of SMAD3. Results: ChIP-Seq revealed that 2,065 and 5,003 sites were bound by HIF-1α and SMAD3, respectively, with 614 sites co-occupied by both factors. RNA-Seq showed that hypoxia and TGF-β stimulation causes synergistic upregulation of 249 genes, including collagen type I alpha 1 (COL1A1) and serpin peptidase inhibitor, clade E, member 1, which are well-known to be involved in fibrosis. Ontology of the 249 genes implied that the interaction of HIF-1α and SMAD3 is related to biological processes such as fibrosis. ChIP-qPCR of SMAD3 at HIF-1α binding sites near COL1A1 and SERPINE1 indicated that HIF-1α promotes the bindings of SMAD3, which is induced by TGF-β. Conclusions: These findings suggest that HIF-1α induced by hypoxia activates the TGF-β/SMAD3 pathway. This mechanism may promote kidney injury, especially by upregulating genes related to fibrosis.

Renal anemia is caused by the deficiency of endogenous erythropoietin (Epo) due to renal dysfunction. We think that it is possible to slow the progression of chronic kidney disease (CKD) in case we initiate Epo early in pre-dialysis patients, especially in the non-diabetic population. Erythropoiesis stimulating agent (ESA) treatments targeting mild anemia (10-12 g/dl) can decrease the risk of occurrence of cardiovascular disease (CVD) in patients with hypertension, diabetes mellitus and congestive heart failure. As the large randomized controlled trials such as Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta, Correction of Hemoglobin and Outcomes in Renal Insufficiency and Trial to Reduce Cardiovascular Events with Aranesp Thearpy in the Western countries suggested, we do not recommend high doses of ESA to achieve the target hemoglobin (Hb) level. The target Hb of >13 g/dl might lead to increase in the risk of CVD although maintaining a high Hb of >12 g/dl without ESA is not harmful for CKD patients. It is desirable to determine the target Hb in dialysis patients depending on their ages. Renal anemia should be monitored constantly to start ESA and iron replacement therapy at an appropriate time, while avoiding their excess in order to minimize the occurrence of CVD and other complications. Taken all the international guidelines and our clinical experiences together, we should consider administration of ESA when the Hb level becomes

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.

Chronic kidney disease (CKD) is placing an increasing burden on patients and societies because no decisive therapy has been established. Tubulointerstitial lesions accompanied by fibrosis, inflammatory cells, and capillary rarefaction not only characterize, but also aggravate renal dysfunction in CKD. In this setting, renal cells, particularly tubular cells, suffer from hypoxia caused by the imbalance of blood perfusion and oxygen demand despite their adaptive responses represented by upregulation of hypoxia-inducible factors (HIFs). Fibrosis is a pathological state characterized by excess extracellular matrix (ECM) deposition, which is also a hallmark and causative factor of many chronic diseases including CKD. Recent studies have suggested that the dominant origin of ECM-producing myofibroblasts (MFs) may be pericytes, which are indispensable cells for maintaining proper capillary functions, as they wrap capillaries and stabilize them through a fine-tuned interplay with endothelial cells. During fibrosis, pericytes are activated and detach from capillaries before conversion into MFs, which compromises capillaries and worsens hypoxia. We also discuss how hypoxia and HIFs affect fibrogenesis. Given that hypoxia is caused by insufficient angiogenesis and that fibrosis results from pericyte loss, restoration of pericytes should be an intriguing target for overcoming both hypoxia and fibrosis. We propose the deactivation of MFs to recover lost pericytes as a promising therapy for CKD.

Aim: In end-stage renal disease (ESRD) patients, left ventricular hypertrophy (LVH) is common and a risk for cardiovascular events. LVH is geometrically classified into two major groups, concentric and eccentric, and accumulating evidence suggests eccentric LVH has a more negative effect than concentric LVH on ESRD outcome. However, there have been very few studies on the cardiac findings from ESRD patient autopsy in which the relationship between LVH geometry and mortality was analyzed. Methods: An observational study was performed with the autopsy findings in 30 haemodialysis patient cases between 2001 and 2006 at Mitsui Memorial Hospital, Tokyo. Between those who died of a cardiovascular cause and those who died of non-cardiovascular causes, we compared the heart/bodyweight ratio, left ventricular dilatation, and the extent of fibrosis of the left ventricle. Results: Heart/bodyweight ratio was significantly higher (P

Objective:To clarify whether agraphia or alexia occurs in lesions of the left posterior middle temporal gyrus.Methods:We assessed the reading and writing abilities of two patients with this lesion using kanji (Japanese morphograms) and kana (Japanese syllabograms).Results:Patient 1 first presented with pure alexia more impaired for kana after an infarction in the left middle and inferior occipital gyri and right basal occipital cortex, and after a second infarction in the left posterior middle temporal gyrus adjoining the first lesion he showed alexia with agraphia for kanji and worsened alexia for kana; kanji alexia recovered over the following six to 10 months. Patient 2 presented with alexia with agraphia for kanji following a hemorrhage in the left posterior middle and inferior temporal gyri, which resolved to agraphia for kanji at two months after onset. Kana nonword reading was also slightly impaired, but became normal by six months post-onset. In both patients, kanji agraphia was mostly due to impaired character recall.Conclusion:The present patients demonstrate that damage to the left posterior middle temporal gyrus alone can cause agraphia for kanji. If the adjacent mid fusiform/inferior temporal gyri (Area 37) are spared, the kanji alexia is transient.

70歳，男性．糖尿病性腎症を原疾患とし，15年の透析歴がある．1995年頃から下血を主訴に他院で消化管精査行うも出血源特定できず．AB型Rh(－）と特殊な血液型のため製剤入手に苦慮した．精査加療目的で2006年6月当院初診．小腸内視鏡上，Treitz靭帯を越えて3mの部分の拍動性の出血性病変に対してAPC焼灼とクリップで止血を行った．その後も2006年11月，2007年8月，9月に同様のエピソードがあり，内視鏡上，別部位に出血を認めたが，同様の処置を行い止血が可能であった．本例では，頻回の再発を認め，また入手困難な血液型であったため治療に苦慮したが，小腸内視鏡による止血を得た．ESRD患者は消化管出血の頻度が高く，上部下部内視鏡上，出血源が特定できず診断，治療が困難なことも多い．小腸内視鏡はこうした例でも開腹術を行わずに止血が得られ，有効な手段である．

血液透析に不可欠のバスキュラーアクセスの必要条件は，安定した血液透析が可能で，心負荷の点で患者のQOLを損なわないことである．今回，血液透析導入時のバスキュラーアクセス選択について背景因子を検討した．2003年と2004年に当院で血液透析導入した94名において，プライマリーアクセスとして動静脈内シャント（以下AVF）は79例（85％）であった．AVF以外の15例は，心機能低下（10例），動静脈の問題（8例）のいずれかまたは両者を有していた．動脈表在化を選択した低心機能の患者は比較的長期にわたり安定した維持透析が可能であった．また，長期型バスキュラーカテーテルを選択した4例は心機能低下のほか，麻酔の侵襲が危惧される全身状態不良例であった．長期型バスキュラーカテーテル4例はいずれも，1～29か月で死亡していたが，その原因は感染ではなく，すべて原病の増悪あるいは突然死であった．アクセス選択に影響する患者因子は心機能，動脈硬化症の進行，前腕静脈の荒廃，加齢であった．

Patients with advanced chronic kidney disease are exposed to uremic toxins. In addition to causing uremic symptoms, uremic toxins accelerate the progression of renal failure. Indoxyl sulfate (IS) increases oxygen consumption in tubules, aggravating hypoxia of the kidney, and progression of the kidney disease. IS also induces endoplasmic reticulum stress and thereby contributes the progression of cellular damages in tubular epithelial cells. Hypoxia-inducible factor (HIF) is a master transcriptional regulator of adaptive responses against hypoxia and regulates expression of erythropoietin (EPO). IS suppresses EPO expression via HIF-dependent and HIF-independent manner. IS impedes the recruitment of transcriptional coactivators to HIF via upregulation of Cbp/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 through a mechanism of posttranscriptional messenger RNA stabilization. Furthermore, IS induces activating transcription factor 4 via endoplasmic reticulum stress, decreasing EPO expression. Although erythropoiesis-stimulating agent (ESA) resistance is generally defined as lack of responses to exogenous ESA administration, suppression of endogenous production of EPO under uremic conditions may aggravate ESA resistance. Uremia is associated with increased formation of advanced glycation end products (AGE). Studies of transgenic rats overexpressing glyoxalse 1 (GLO1), which detoxifies precursors of advanced glycation end products, demonstrated that glycative stress causes renal senescence and vascular endothelial dysfunction. Glycative stress also suppresses HIF activation making the kidney susceptible to hypoxia as a final common pathway to end-stage kidney disease.

Patients with long dialysis vintage have low cardiac output for various reasons. Although kidney transplantation is known to improve cardiac mortality, patients are sometimes evaluated as contraindicated for transplantation because of cardiac risk. We successfully performed kidney transplantation for a patient with a long dialysis vintage and dilated cardiomyopathy. Sequential (123)I-metaiodobenzylguanidine ((123)I-MIBG) scintigraphy suggested that amelioration of uraemia improved cardiac function. Kidney transplantation for patients with severely impaired cardiac function is safe and effective under careful perioperative monitoring irrespective of dialysis vintage. Sequential (123)I-MIBG scintigraphy can be used as an evaluation tool for the improvement in cardiac function.

Background: Although pegylated interferon (PEG-IFN) is now the standard treatment for chronic hepatitis C, there are few reports targeting dialysis patients and treatment protocol for hepatitis C virus (HCV) infection has not been determined, particularly in patients on peritoneal dialysis. Case: A 34-year-old woman with chronic hepatitis C started peritoneal dialysis because of progressive renal disease 2 years after peripheral blood stem cell transplantation for aplastic anaemia. The regimen was a single 6-h dwell of 2L glucose dialysate. Considering that her HCV genotype was 2a and that she was a candidate for cadaveric kidney transplant, we decided to treat her with PEG-IFN alpha-2a monotherapy 1 year after the beginning of peritoneal dialysis. We adopted a dose escalation strategy to minimize the total amount of PEG-IFN administration, thereby reducing the risk of adverse effects. Her HCV-RNA disappeared at the 17th week and sustained virus response was achieved thereafter. Only minor side effects were observed including flu-like symptoms and mild anaemia, and residual renal function remained stable during the treatment of 48 weeks (renal Kt/V; from 1.28 to 1.26). Conclusion: PEG-IFN monotherapy with dose modification may be a safe and effective treatment for HCV infection in patients undergoing peritoneal dialysis.

Chronic kidney disease (CKD) is characterized by irreversible pathological processes that result in the development of end-stage renal disease (ESRD). Accumulating evidence has emphasized the important role of chronic hypoxia in the tubulointerstitium in the final common pathway that leads to development of ESRD. The causes of chronic hypoxia in the tubulointerstitium are multifactorial and include mechanisms such as hemodynamic changes and disturbed oxygen metabolism of resident kidney cells. Epidemiological studies have revealed an association between CKD and systemically hypoxic conditions, such as chronic obstructive pulmonary disease and sleep apnea syndrome. In addition to tubulointerstitial hypoxia, glomerular hypoxia can occur and is a crucial factor in the development of glomerular disorders. Chemical compounds, polarographic sensors, and radiographical methods can be used to detect hypoxia. Therapeutic approaches that target chronic hypoxia in the kidney should be effective against a broad range of kidney diseases. Amelioration of hypoxia is one mechanism of inhibiting the renin-angiotensin system, the current gold standard of CKD therapy. Future therapeutic approaches include protection of the vascular endothelium and appropriate activation of hypoxia-inducible factor, a key transcription factor involved in adaptive responses against hypoxia.

Background/Aims: A significant number of uremic patients develop ischemic heart disease before hemodialysis (HD) is initiated. Recently, chronic cardiorenal syndrome among predialysis patients has been recognized. However, little is known about prognostic factors in this subgroup of incident HD patients. Methods: A total of 87 incident HD patients, who were classified into cardiorenal syndrome type 4 (chronic cardiorenal syndrome), were identified at Mitsui Memorial Hospital between 1984 and 2003. The survival and risk factors for mortality were examined. Results: 25 patients died and the 5-year survival rate amounted to approximately 75%. Both all-cause mortality and the adjusted mortality for age and sex were higher in patients with a lower serum albumin level (p = 0.03) or higher serum C-reactive protein level (p = 0.02). Conclusion: The poor survival rate of incident HD patients with a medical history of ischemic heart disease was predicted by malnutrition and inflammation at the start of HD.

IgA nephropathy can occur as a paraneoplastic syndrome of renal cell carcinoma. We report 3 cases of IgA nephropathy associated with renal cell carcinoma in the elderly patients and demonstrate that infiltrating lymphocytes and plasma cells around renal cell carcinoma produce IgA that likely contributed to mesangial IgA deposition.

A 72-year-old man was admitted with acute epididymis from methicillin-resistant Staphylococcus aureus. Minocycline and vancomycin were prescribed with control of symptoms. However, he subsequently developed acute renal failure and pancytopenia, and underwent hemodialysis on the twelfth day of admission. Urinalysis demonstrated 3+ protein and 3+ hemoglobin with dysmorphic erythrocytes in the urinary sediment. Renal biopsy showed endocapillary proliferation with crescents, capillary C3 deposition, and subepithelial electron dense deposits (humps), consistent with postinfectious acute glomerulonephritis. Azan staining showed erythrocytes in the tubular lumen as well as in the cytoplasm of the distal nephron without brush border (Figure 1a). Electron microscopy revealed erythrophagocytosis by intercalated cells (characterized by a large cell body, prominent mitochondria, and apical microplicae and vesicles) (Figure 1b and c). Erythrophagocytosis has also been demonstrated in the macrophages of the bone marrow, liver, and spleen; and epithelial cells in the small intestine, placenta, urinary bladder, and thyroid. Although erythrophagocytosis in the renal tubular cells has been first described by Tisher et al. over 20 years ago, its physiologic significance is uncertain.