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The relationship between cellular senescence and fibrosis in the kidney is being elucidated and we have identified it as therapeutic target in recent studies. Chronic kidney disease has also become a lifestyle disease, often developing on the background of hypertension and dyslipidemia. In this study, we clarify the effect of interaction between these two conditions on kidney fibrosis and senescence. Wild type mice (WT), apolipoprotein E-/- mice (ApoEKO), and endothelial nitric oxide synthase (eNOS)-/- ApoE-/- mice (DKO) were obtained by breeding. Unilateral ureteral obstruction (UUO) was performed on 8-10 week old male mice and the degree of renal tubular injury, fibrosis and kidney senescence were evaluated. DKO manifested elevated blood pressure, higher total cholesterol and lower HDL than WT. DKO showed sustained kidney injury molecule-1 protein expression. Kidney fibrosis was significantly higher in ApoEKO and DKO. mRNA expression of genes related to kidney fibrosis was the highest in DKO. The mRNA expression of Zinc-α2-Glycoprotein and heme oxygenase-1 were significantly decreased in DKO. Furthermore, mRNA expression of p53, p21 and p16 were increased both in ApoEKO and DKO, with DKO being the highest. Senescence associated β-gal positive tubule area was significantly increased in DKO. Increased DNA damage and target of rapamycin-autophagy spatial coupling compartments (TASCCs) formation was found in DKO. Mice with endothelial dysfunction and dyslipidemia developed kidney fibrosis and accelerated senescence even in young mice after injury. These data highlight the fact managing lifestyle-related diseases from a young age is important for CKD prevention.

Peritoneal dialysis (PD) is valuable for patients starting on renal replacement therapy because it preserves residual renal function, maintains hemodynamic stability, and affords higher quality of life than hemodialysis. Amyloid-related kidney disease is a rare condition and a cause of end-stage renal disease, the incidence of which appears to be rising in recent years. Hemoperitoneum is a common complication of PD. In some cases, it requires urgent treatment and careful monitoring for deterioration and potential complications. Although the kidney is a retroperitoneal organ, renal hemorrhage can cause bloody peritoneal dialysate. We encountered a rare case of amyloid light-chain amyloidosis where bilateral perirenal hematoma occurred shortly after initiation of PD. Amyloid angiopathy with increased blood vessel fragility and impaired vasoconstriction may promote bleeding. Therefore, hemoperitoneum in a patient on PD with disease causing fragile blood vessels, such as amyloidosis, should alert the physician to the possibility of underlying angiopathy.

Background Long-term exposure to bioincompatible peritoneal dialysate causes the loss of mesothelial cells and accumulation of matrix proteins, leading to an increase in the thickness of the submesothelial layer, thereby limiting the long-term effectiveness of peritoneal dialysis (PD). However, the detailed molecular mechanisms underlying the process of peritoneal fibrosis have not been clearly elucidated. Wnt/β-catenin signaling pathway activation has been suggested to play a pivotal role in the development of organ fibrosis. Moreover, Klotho protein can regulate Wnt/β-catenin signaling. We examined the role of Klotho protein in reducing peritoneal fibrosis by inhibiting Wnt/β-catenin signaling. Methods The β-catenin-activated transgenic (BAT) driving expression of nuclear β-galactosidase reporter transgenic (BAT-LacZ) mice, the alpha-Klotho gene under control of human elongation factor 1 alpha promoter [Klotho transgenic (KLTG) and C57BL/6 background] and C57BL/6 mice [wild-type (WT)] were used. The mice received daily intraperitoneal (i.p.) injections of 4.25% glucose with lactate (PD solution) or saline as a control for 4 weeks. Other mice received daily i.p. injections of the same volume of saline (normal control). Results After exposure to PD, Wnt signal activation was observed on the peritoneal mesothelial cells in WT-PD mice. The peritoneal fibrosis was also accelerated in WT-PD mice. The protein expression of β-catenin and Wnt-inducible genes were also remarkably increased in WT-PD mice. On the other hand, KLTG-PD mice attenuated activation of Wnt/β-catenin signaling after exposure to PD and ameliorated the progression of peritoneal fibrosis. Conclusions Overexpression of Klotho protein protects the peritoneal membrane through attenuation of the Wnt/β-catenin signaling pathway. The availability of recombinant Klotho protein would provide a novel potential therapeutic target in peritoneal fibrosis.

Tissue regeneration is limited in several organs including the kidney, contributing to the high prevalence of kidney disease globally. However, evolutionary and physiological adaptive responses and the presence of renal progenitor cells suggest existing remodeling capacity. This study uncovered a novel endogenous tissue remodeling mechanism in the kidney that is activated by the loss of body fluid and salt and involves a unique niche of chief cells called macula densa (MD) that control resident progenitor cells via secreted angiogenic, growth and extracellular matrix remodeling factors, cytokines and chemokines. Serial intravital imaging, MD Wnt mouse models and transcriptome analysis provide functional and molecular characterization of this newly identified MD program for kidney regeneration complemented with human and therapeutic translation. The concept that chief cells responding to organ-specific physiological inputs control local progenitors and direct them to remodel or repair tissues may be applicable to other organs and diverse tissue regenerative therapeutic strategies.

Endothelial cells are important in the maintenance of healthy blood vessels and in the development of vascular diseases. However, the origin and dynamics of endothelial precursors and remodeling at the single-cell level have been difficult to study in vivo owing to technical limitations. Therefore, we aimed to develop a direct visual approach to track the fate and function of single endothelial cells over several days and weeks in the same vascular bed in vivo using multiphoton microscopy (MPM) of transgenic Cdh5-Confetti mice and the kidney glomerulus as a model. Individual cells of the vascular endothelial lineage were identified and tracked owing to their unique color combination, based on the random expression of cyan/green/yellow/red fluorescent proteins. Experimental hypertension, hyperglycemia, and laser-induced endothelial cell ablation rapidly increased the number of new glomerular endothelial cells that appeared in clusters of the same color, suggesting clonal cell remodeling by local precursors at the vascular pole. Furthermore, intravital MPM allowed the detection of distinct structural and functional alterations of proliferating endothelial cells. No circulating Cdh5-Confetti+ cells were found in the renal cortex. Moreover, the heart, lung, and kidneys showed more significant clonal endothelial cell expansion compared with the brain, pancreas, liver, and spleen. In summary, we have demonstrated that serial MPM of Cdh5-Confetti mice in vivo is a powerful technical advance to study endothelial remodeling and repair in the kidney and other organs under physiological and disease conditions.

Lupus nephritis (LN) is a major organ complication and cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). There is an unmet medical need for developing more efficient and specific, mechanism-based therapies, which depends on improved understanding of the underlying LN pathogenesis. Here we present direct visual evidence from high-power intravital imaging of the local kidney tissue microenvironment in mouse models showing that activated memory T cells originated in immune organs and the LN-specific robust accumulation of the glomerular endothelial glycocalyx played central roles in LN development. The glomerular homing of T cells was mediated via the direct binding of their CD44 to the hyaluronic acid (HA) component of the endothelial glycocalyx, and glycocalyx-degrading enzymes efficiently disrupted homing. Short-course treatment with either hyaluronidase or heparinase III provided long-term organ protection as evidenced by vastly improved albuminuria and survival rate. This glycocalyx/HA/memory T cell interaction is present in multiple SLE-affected organs and may be therapeutically targeted for SLE complications, including LN., A combined immunology and renal pathophysiology study of the local kidney tissue microenvironment in lupus identifies a key role of glomerular endothelial glycocalyx in disease development.

Background and Aims In most developed countries, diabetic kidney disease (DKD) is the most common cause of chronic kidney disease, which can lead to end-stage renal disease. In recent clinical trials, sodium–glucose cotransporter 2 inhibitors (SGLT2is) slowed the progression of kidney disease as compared with a placebo in patients with type 2 diabetes. One of the main mechanisms of the renoprotective effects of SCLT2is in DKD is considered the ability of these inhibitors to improve glomerular hyperfiltration. We previously demonstrated that the adenosine/adenosine A1 receptor pathway played a pivotal role in the tubuloglomerular feedback(TGF) system in a type 1 diabetic model, Akita mice (Circulation, 2019). We also reported that increased oxidative stress was involved in the pathogenesis of diabetic vascular complications. Uncoupling of endothelial nitric oxide (NO) synthase (eNOS) via oxidation of tetrahydrobiopterin (BH4), a cofactor required for NO production, played a major role in generation of oxidative stress (AJPRP, 2005; JASN, 2013). In the present study, we explored the renal protective effects of SGLT2 inhibition, with a focus on glomerular hemodynamics and glomerular oxidative stress. Method This study used type 2 diabetic db/db mice and db/m+ mice as a control (male, 8wk old). We developed a novel method to measure the glomerular filtration rate of single nephrons (SNGFRs) in mice using multiphoton laser microscopy. In the first experiment, we measured the SNGFRs in 12 wk-old db/db and db/m+ mice to confirm glomerular hyperfiltration. Next, we evaluated the SNGFRs change before and after the administration of a single dose of canagliflozin (CANA) (10 mg/kg). The SNGFRs, glomerular permeability of macromolecules, glomerular reactive oxygen species (ROS) and NO production, and tetrahydrobiopterin (BH4) level in serum and kidney were evaluated after the CANA treatment for 8 wk. Finally, human glomerular endothelial cells (hGECs) were exposed to normal glucose (5 mmol/L), high glucose (30 mmol/L of D-glucose), or a hyperosmotic control (5 mmol/L of D-glucose plus 25 mmol/L of L-glucose) in the presence or absence of CANA (10 μmol/L). Results The CANA treatment ameliorated glomerular hyperfiltration in the db/db mice. In the db/db mice, glomerulus ROS production increased, and NO production decreased as compared with the levels in the control mice. CANA improved the imbalance between ROS and NO production. The serum and kidney concentrations of BH4 declined in the non-treated db/db mice, whereas the CANA treatment preserved the BH4 level. Leakage of 70-kD FITC-labeled albumin into the urinary space was observed in the db/db mice. The CANA treatment reduced the amount of FITC-labeled albumin in the urinary space of the db/db mice. The CANA treatment also alleviated vascular endothelial damage in glomeruli. BH4 levels decreased in the hGECs exposed to high glucose. CANA did not improved BH4 level in the hGECs exposed to high glucose. Conclusion SGLT2i ameliorated glomerular hyperfiltration, preserving BH4 levels and improving the glomerular ROS/NO imbalance in type 2 diabetic mice.

Background and Aims In recent clinical trials, the SGLT2 inhibitor (SGLT2i) slowed the progression of kidney disease compared with the placebo in patients with type 2 diabetes. Improvement of glomerular hyperfiltration via tubuloglomerular feedback (TGF) is considered to be one of the possible pathways for renal protection with SGLT2 inhibition (SGLT2i) in diabetic kidney disease (DKD). We have successfully developed the novel method to measure single-nephron GFR (SNGFR) in mice using multiphoton laser microscopy and demonstrated that the adenosine/adenosine A1 receptor (A1aR) pathway plays a pivotal role in the TGF mechanism in the type 1 diabetic model, Akita mice (Kengo Kidokoro, David Z. I. Cherney et al. Circulation. 2019). It has been suggested that the mechanism of improvement effects in glomerular hyperfiltration by SGLT2i is different in type 1 diabetes and type 2 diabetes. However, the detailed regulatory mechanism of GFR by SGLT2i is not fully understood in type 2 diabetes. This study aims to clarify the effects of SGLT2i on glomerular hemodynamics in type 2 diabetic rats. Method Zucker lean (ZL) rats and Zucker diabetic fatty (ZDF) rats were used. In the first experiment, SNGFR and diameters of glomerular afferent/efferent arterioles were measured in both groups. Next, we examined the change of SNGFR and diameters of glomerular afferent/efferent arterioles, as well as urinary excretions of glucose and sodium in ZDF after a single-dose administration of SGLT2i (luseogliflozin; 10mg/kg, gavage) for 120 minutes, which generated the following three groups: SGLT2i group, SGLT2i + adenosine A1 receptor (A1aR) antagonist (8-cyclopentyl-1,3-dipropylxanthine, 1mg/kg) group, and insulin group. Results SNGFR in the ZDF group was significantly higher than in the ZL group. The diameter of the afferent arteriole and efferent arteriole was also wider in ZDF rats than in ZL rats. The SNGFR and diameter of the afferent arteriole were significantly decreased after a single-dose administration of SGLT2i in ZDF. However, there was no significant diameter change in the efferent arteriole. Moreover, a decrease of SNGFR was not observed in the A1aR antagonist group after SGLT2i administration. Urinary excretions of glucose and sodium showed a similar pattern in the SGLT2i and SGLT2i+ A1aR antagonist groups. Conclusion The adenosine/A1aR pathway plays an important role in the regulation of the tonus of the afferent arteriole and is involved in the suppression of glomerular hyperfiltration by SGLT2 inhibition in type 2 diabetes.

A great variety of cell imaging technologies are used routinely every day for the investigation of kidney cell types in applications ranging from basic science research to drug development and pharmacology, clinical nephrology and pathology. Quantitative visualization of the identity, density and fate of both resident and non-resident cells in the kidney, and imaging-based analysis of their altered function, (patho)biology, metabolism, signaling in disease conditions can help to better define pathomechanism-based disease subgroups, identify critical cells and structures that play a role in the pathogenesis, critically needed biomarkers of disease progression, and cell and molecular pathways as targets for novel therapies. Overall, renal cell imaging has great potential for improving the precision of diagnostic and treatment paradigms for individual acute kidney injury (AKI) or chronic kidney disease (CKD) patients or patient populations. This review highlights and provides examples for some of the recently developed renal cell optical imaging approaches, mainly intravital multiphoton fluorescence microscopy, and the new knowledge they provided for our better understanding of renal pathologies.

Serum zinc (Zn) levels tend to be low in chronic kidney disease (CKD) patients. This cohort study was conducted to investigate the relationship between zinc deficiency and CKD progression. Patients were classified into two groups based on Zn levels < 60 μg/dl (low-Zn group, n = 160) and ≥ 60 μg/dl (high-Zn group, n = 152). The primary outcome was defined as end-stage kidney disease (ESKD) or death and was examined over a 1-year observation period. Overall, the mean Zn level was 59.6 μg/dl and the median eGFR was 20.3 ml/min/1.73 m2. The incidence of the primary outcome was higher in the low-Zn group (pp = 0.026). The results of this study indicate that zinc deficiency is a risk factor for CKD progression.

The present study aimed to assess the effects of colchicine, a known anti‑inflammatory agent, on renal fibrosis using a murine model of unilateral ureteral obstruction (UUO). Male C57BL/6 mice were divided into two groups, vehicle‑ and colchicine‑treated. Colchicine (0.5 mg/kg/day) was administered by osmotic pump, and the UUO procedure was performed on the left kidney 7 days later. The mice were sacrificed at 14 days following UUO. Colchicine treatment suppressed interstitial fibrosis of the UUO kidneys. In addition, fibrogenic gene expression in the UUO kidneys was decreased by colchicine administration. NRK‑49F normal rat kidney fibroblasts were cultured with or without colchicine under angiotensin II stimulation, following which a wound‑healing assay and actin fiber staining were performed to evaluate the effects of colchicine in vitro. Colchicine was demonstrated to inhibit angiotensin II‑induced fibroblast migration in vitro in a concentration‑dependent manner. Colchicine treatment also suppressed the angiotensin II‑induced activation of Ras homolog gene family member A in NRK‑49F cells. In conclusion, colchicine treatment significantly inhibited fibroblast activity in vitro and attenuated renal fibrosis in vivo in UUO‑operated mice. Therefore, the prevention of renal fibrosis following injury may represent a novel therapeutic application for colchicine.

Expression of klotho, the renoprotective anti-aging gene, is decreased in diabetic model kidneys. We hypothesized that klotho protein attenuates renal hypertrophy and glomerular injury in a mouse model of diabetic nephropathy. Klotho transgenic (KLTG) mice were crossed with spontaneously diabetic Ins2Akita (AKITA) mice. Glomerular morphology, macrophage infiltration, urinary albumin excretion and urinary 8-hydroxy-2-deoxy guanosine excretion were examined. In vitro, human glomerular endothelial cells were stimulated with high glucose with or without recombinant klotho, and calpain activity and proinflammatory cytokine expressions were measured. We found that klotho protein overexpression attenuates renal hypertrophy and glomerular injury in this mouse model of diabetic nephropathy. Klotho overexpression attenuated renal hypertrophy, albuminuria, glomerular mesangial expansion, and endothelial glycocalyx loss in the AKITA mice. AKITA mice exhibit high levels of urinary 8-hydroxy-2-deoxy guanosine excretion. In the presence of klotho overexpression, this effect was reversed. In addition, the glomerular macrophage infiltration characteristic of AKITA mice was attenuated in KLTG-AKITA mice. In human glomerular endothelial cells, high glucose induced calpain activity. This effect was suppressed by expression of recombinant klotho, which also suppressed the induction of proinflammatory cytokines. Our data suggest klotho protein protects against diabetic nephropathy through multiple pathways.

Aldosterone contributes to end-organ damage in heart failure and chronic kidney disease. Mineralocorticoid-receptor inhibitors limit activation of the receptor by aldosterone and slow disease progression, but side effects, including hyperkalemia, limit their clinical use. Damage to the endothelial glycocalyx (a luminal biopolymer layer) has been implicated in the pathogenesis of endothelial dysfunction and albuminuria, but to date no one has investigated whether the glomerular endothelial glycocalyx is affected by aldosterone. In vitro, human glomerular endothelial cells exposed to 0.1 nM aldosterone and 145 mMol NaCl exhibited reduced cell surface glycocalyx components (heparan sulfate and syndecan-4) and disrupted shear sensing consistent with damage of the glycocalyx. In vivo, administration of 0.6 μg/g/d of aldosterone (subcutaneous minipump) and 1% NaCl drinking water increased glomerular matrix metalloproteinase 2 activity, reduced syndecan 4 expression, and caused albuminuria. Intravital multiphoton imaging confirmed that aldosterone caused damage of the glomerular endothelial glycocalyx and increased the glomerular sieving coefficient for albumin. Targeting matrix metalloproteinases 2 and 9 with a specific gelatinase inhibitor preserved the glycocalyx, blocked the rise in glomerular sieving coefficient, and prevented albuminuria. Together these data suggest that preservation of the glomerular endothelial glycocalyx may represent a novel strategy for limiting the pathological effects of aldosterone.

The prevalence of gastroesophageal reflux disease (GERD) symptoms has not been investigated in patients on maintenance hemodialysis in Japan, and few studies have reported the effect of proton pump inhibitors (PPIs) in hemodialysis patients with GERD symptoms. Here, we investigated the prevalence of GERD symptoms and the effects of the PPI esomeprazole on the quality of life related to reflux and dyspepsia in patients on maintenance hemodialysis. This was a cross-sectional/cohort study of hemodialysis outpatients implemented in 10 Japanese medical facilities from October 2012 to March 2014. The trial was registered in the UMIN Clinical Trial Registry (UMIN000009124). Forty-one of 385 patients (11 %) reported GERD symptoms on the Global Overall Symptom (GOS) questionnaire. Multivariate logistic regression analysis identified the independent prognostic factors for GERD symptoms as a history of gastric ulcer and use of sevelamer hydrochloride or calcium polystyrene sulfonate. Participants with GERD symptoms completed the Quality of Life in Reflux and Dyspepsia, Japanese version (QOLRAD-J) questionnaire and were assigned to receive 4-week esomeprazole treatment (20 mg/day). This PPI therapy significantly improved all QOLRAD-J domains in the full analysis set (n = 28) and improved the GERD symptoms listed in the GOS questionnaire. Significantly impaired disease-specific quality of life (QOL) in the QOLRAD-J domains was observed in 44.4–74.1 % of patients who had symptoms before treatment. The mean GOS and QOLRAD-J scores correlated significantly. Therapy with 20 mg/day esomeprazole appears to be efficacious for improving disease-specific QOL and GERD symptoms in Japanese patients on maintenance hemodialysis.

Hypertensive patients have a higher incidence of new-onset diabetic mellitus than normotensive subjects, and we hypothesized that hypertension induces morphological changes in islets via vascular injury. To test our hypothesis, we administrated hydralazine or irbesartan to spontaneously hypertensive stroke-prone (SHRsp) rats. A greater islet fibrosis was observed in SHRsp rats compared with controls, and irbesartan significantly ameliorated the fibrosis. High fat diet induced glucose intorelance in SHRsp rats and irbesartan but not hydralazine improved glucose torelance. We demonstrate islet morphological changes in hypertensive rats, and our data suggest that angiotensin receptor blockers have the potential to prevent islet injury.

Proteinuria is an independent risk factor for progressive renal diseases because it initiates or aggravates tubulointerstitial injury. Clinically, females are less susceptible to progression of chronic kidney disease; however, the mechanisms underlying the renoprotective effect of estrogen receptor stimulation have yet to be clarified. Recently, inflammasome-dependent inflammatory responses were shown to be triggered by free fatty acids, and mitochondria-derived reactive oxygen species were shown to be required for this response. Albumin-bound free fatty acids trigger inflammasome activation through mitochondrial reactive oxygen species production in human proximal tubule epithelial cells in vitro, an effect inhibited by raloxifene. Female ICR-derived glomerulonephritic mice (mice with hereditary nephritic syndrome) were ovariectomized and treated with raloxifene, a selective estrogen receptor modulator. Ovariectomized mice showed activation of tubular inflammasomes and elevated levels of inflammasome-dependent cytokines. Raloxifene attenuated these changes ameliorating tubulointerstitial damage, reduced production of reactive oxygen species, averted morphological changes, and improved respiratory function in mitochondria. The expression of genes that encode rate-limiting enzymes in the mitochondrial β-oxidation pathway was reduced by ovariectomy but enhanced by raloxifene. Thus, inflammasomes may be a novel and promising therapeutic target for proteinuria-induced renal injury.

症例は79歳の男性．2009年9月発熱，全身倦怠感および食思不振を主訴に近医受診．炎症反応上昇に加え，血清クレアチニン（Cr）2.3mg/dLと腎機能低下を指摘．抗菌薬内服で症状改善なく，1週間後には腎機能が増悪（Cr＝14.9mg/dL）したため，精査加療目的に当科紹介．無尿が続き，連日血液透析を施行．右下肺に肺炎像を認め抗菌薬の点滴加療を継続していたが，炎症反応の改善に乏しく，自己免疫性疾患の合併が疑われた．抗好中球細胞質抗体や抗糸球体基底膜抗体などの各種自己抗体は陰性であった．造影CTにて腎動脈分枝の不整な狭小化を認め，腎実質の造影は減弱していた．また空腸動脈末梢の狭窄と同支配域の腸管壁肥厚を認めた．腎生検では糸球体や細・小血管に炎症を示唆する所見なく，高度な尿細管壊死を認めた．以上より古典的結節性多発動脈炎（polyarteritis nodosa：PN）による腎動脈分枝の血管炎により，虚血性の急性腎不全を呈したと考えられた．ステロイドパルス療法の後，プレドニゾロン（PSL）40mg/日の内服を開始したところ，全身状態は著明に改善し，炎症反応はほぼ陰性化した．透析離脱には至らなかったが，1年後にはPSL 10mg/日まで減量し再発を認めていない．古典的PNで透析を要する急激な腎機能低下をきたすことはまれであり，予後不良で生前診断に至らないことも多いが，本症例では早期診断と治療介入により救命することが可能となった．

A 76-year-old man developed fever and appetite loss, and then was referred to our hospital because of rapidly progressive renal insufficiency; his serum creatinine increased from 1.2 to 5.9 mg/dl within 1 month. On admission, his blood pressure was 166/92 mmHg, and laboratory findings showed signs of inflammation, anemia, proteinuria, and hematuria. Chest computed tomography (CT) suggested interstitial pneumonia, while a renal biopsy revealed that small arteries and arterioles were affected, and there was pauci-immune glomerulonephritis with cellular and fibrocellular crescents. In addition, an increased myeloperoxidase antineutrophil cytoplasmic antibody titer confirmed microscopic polyangiitis. Treatment with oral prednisolone was initiated and seemed to successfully resolve the vasculitis activity. On the 11th day of admission, a calcium channel blocker, azelnidipine, was added to treat hypertension. Two days later, the patient developed abdominal distension, and abdominal CT showed massive ascites. The ascitic fluid was a milky white transudate with a normal leukocyte count. Neither clinical manifestations nor laboratory findings suggestive of liver cirrhosis, malignancy, infectious peritonitis, or bowel perforation were observed. On the 18th day of admission, azelnidipine was discontinued in view of reports of calcium channel blocker-induced chyloperitoneum in patients undergoing peritoneal dialysis. Immediately, the abdominal distension disappeared, and the ascites appeared to decrease. Azelnidipine appears to have been responsible for the chyloperitoneum. Since a few cases of secondary vasculitis developing chyloperitoneum have been previously reported, vasculitis may have played a role in the development of chyloperitoneum.

High levels of aldosterone impair renal function by activating proinflammatory and profibrotic pathways. However, the molecular mechanism underlying aldosterone-induced inflammation and fibrosis is unknown. Inflammasome activation contributes to chronic kidney disease. We hypothesized that aldosterone induces renal tubulointerstitial inflammation and fibrosis by activating the inflammasome. Infusing wild-type mice with aldosterone (0.25 mg/kg/d) caused tubulointerstitial damage, increased expression of inflammasome components, caspase 1 activation, and overproduction of IL-1β and IL-18. These changes were suppressed by eplerenone treatment (100 mg/kg/d) in wild-type mice or in mice deficient in apoptosis-associated speck-like protein with a caspase-recruitment domain (ASC). Caspase 1-positive and F4/80-positive cells colocalized in the interstitium. Bone marrow transplantation using ASC-deficient mice indicated that inflammasome activation in macrophages mediated aldosterone-induced renal fibrosis. IL-18 was detected in culture supernatants of macrophages treated with aldosterone, and mitochondria-derived reactive oxygen species activated the inflammasome in these macrophages. Our results indicate that exposure of macrophages to high levels of aldosterone resulted in the activation of inflammasomes via the mitochondria-derived reactive oxygen species. Thus, inflammasome activation in macrophages may serve as a new therapeutic target for chronic kidney disease.

Background: Excessive urinary albumin excretion is associated with hypertension and diabetic nephropathy. Calcium channel blockers (CCBs) used as antihypertensives suppress such albuminuria with variable efficacy. While hypertension benefits from the addition of angiotensin receptor blockers (ARBs), it is unknown if ARBs alter the effects of CCBs on albuminuria. Objective: This study compared the efficacy of combined ARB irbesartan with either CCB amlodipine or CCB cilnidipine on albuminuria associated with experimental diabetic nephropathy. Methods: Male Sprague-Dawley rats with streptozotocin-induced diabetes were treated with a CCB alone (amlodipine 2.0 mg/kg/d or cilnidipine 2.0 mg/kg/d), an ARB alone (irbesartan 20.0 mg/kg/d), or combinations. In the acute protocol, changes in glomerular afferent and efferent arteriole diameters were examined by a charge-coupled device video microscope following single doses. In the chronic protocol, urinary albumin excretion, glomerular reactive oxygen species, and endothelial surface layer (ESL) condition were evaluated after 2 weeks of daily treatment. Results: In the acute protocol, cilnidipine mono therapy caused a greater dilation in glomerular efferent arterioles than amlodipine monotherapy, while combination therapy with irbesartan induced comparable efferent arteriole dilation. In the chronic protocol, cilnidipine mono therapy suppressed albuminuria, reduced glomerular oxidative stress, and protected the glomerular ESL against degeneration to a much greater extent that amlodipine monotherapy. However, addition of irbesartan reduced albumin excretion, oxidative stress, and ESL degeneration to the same extent in both groups. Conclusions: While cilnidipine is more effective alone, the combinations of irbesartan with cilnidipine or amlodipine are equally effective for reducing albuminuria and other pathological sequela of experimental diabetic nephropathy.

Podocyte depletion plays a major role in focal segmental glomerular sclerosis (FSGS). Because cells of the renin lineage (CoRL) serve as adult podocyte and parietal epithelial cell (PEC) progenitor candidates, we generated Ren1cCre/R26R-ConfettiTG/WT and Ren1dCre/R26R-ConfettiTG/WT mice to determine CoRL clonality during podocyte replacement. Four CoRL reporters (GFP, YFP, RFP, CFP) were restricted to cells in the juxtaglomerular compartment (JGC) at baseline. Following abrupt podocyte depletion in experimental FSGS, all four CoRL reporters were detected in a subset of glomeruli at day 28, where they co-expressed de novo four podocyte proteins (podocin, nephrin, WT-1 and p57) and two glomerular parietal epithelial cell (PEC) proteins (claudin-1, PAX8). To monitor the precise migration of a subset of CoRL over a 2w period following podocyte depletion, intravital multiphoton microscopy was used. Our findings demonstrate direct visual support for the migration of single CoRL from the JGC to the parietal Bowman's capsule, early proximal tubule, mesangium and glomerular tuft. In summary, these results suggest that following podocyte depletion, multi-clonal CoRL migrate to the glomerulus and replace podocyte and PECs in experimental FSGS.

Long-term peritoneal dialysis (PD) causes peritoneal dysfunction and structural alterations, eventually leading to peritoneal fibrosis. The endothelial nitric oxide synthase (eNOS)–NO signaling pathway contributes to the progression of organ fibrosis. However, it remains unknown whether NO signaling is involved in the process of peritoneal fibrosis. We evaluated the role of the eNOS–NO signaling pathway in the development of peritoneal fibrosis and whether stimulation of soluble guanylate cyclase (sGC), a downstream effector of NO, could attenuate peritoneal fibrosis. We used wild-type (WT) and eNOS-deficient mice (eNOSKO). The mice underwent mechanical peritoneal stripping-induced peritoneal fibrosis at day 0. At 3, 7, 14, and 28 days after peritoneal stripping, the mice were killed. In some eNOSKO mice, the sGC stimulator Bay 41-2272 was administered by intraperitoneal injection. In WT mice, granulomatous tissue formation was observed in the submesothelial area at days 3 and 7. After day 7, the peritoneal membrane thickness gradually decreased and peritoneal tissue was repaired with leaving only slight fibrosis at day 28. However, eNOSKO mice demonstrated more progression of peritoneal fibrosis than WT mice at 28 days after peritoneal stripping. Expression of vimentin in the thickened peritoneum was prolonged after day 7 in eNOSKO mice. Treatment with Bay 41-2272 significantly attenuated peritoneal vimentin expression and fibrosis in the eNOSKO mice. Disruption of the eNOS–NO signaling pathway exacerbates peritoneal fibrosis by delaying wound healing. sGC stimulation may be a useful therapy for prevention of peritoneal fibrosis.

In 2003, a 64-year-old woman was diagnosed with mixed connective tissue disease and treated with oral prednisolone (30 mg/day). The prednisolone dose was gradually decreased, and a dose of 5 mg/day had been maintained since 2004. In 2009, she gradually developed vision loss, malaise, anorexia, and throat pain due to hydrodipsia. She was noted to have iritis and vitreous opacity by an ophthalmologist, and was referred for further evaluation. Fine rales were audible throughout the entire lung field, and chest CT showed diffuse small nodules that were more prominent on the upper and middle lobes, and swelling of the mediastinal and hilar lymph nodes. Transbronchial lung biopsy showed many epithelioid granulomas with multinuclear giant cells, compatible with sarcoidosis. Polyuria was identified as a cause of hydrodipsia and a diagnosis of partial central diabetes insipidus was made. High-dose prednisolone (40 mg/day) together with intranasal administration of desmopressin resulted in improvement of all of her clinical symptoms. MCTD followed by sarcoidosis is rare. Furthermore, this is the first reported case of MCTD complicated by sarcoidosis and central diabetes insipidus.

In December 2008, a 69-year-old Japanese woman was admitted to the Department of Otorhinolaryngology because of hearing impairment due to bilateral exudative otitis media, and was discharged without complete recovery despite conventional treatment. Two weeks later, she was readmitted for worsened deafness, numbness, gait disturbance, and general fatigue. She was referred to our department for general investigation. On admission, laboratory examination revealed severe inflammatory signs and active nephritic urinary sediments. Cranial computed tomography (CT) revealed progressive exudative otitis media and sinusitis. Initially, Wegener’s granulomatosis was suspected. Nasal cavity biopsy, however, showed no granuloma formation or vasculitis. Serology revealed high titer of myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA), suggestive of microscopic polyangitis (MPA). However, contrast CT identified stenosis of a celiac artery, and renal biopsy showed tubulointerstitial changes with minor glomerular abnormalities. Therefore, polyarteritis nodosa (PAN) was suspected and treatment with intravenous methylprednisolone was initiated. However, a lacunar infarct developed followed by cerebral hemorrhage, and the patient died 19 days after readmission. Autopsy revealed fibrinoid necrosis, neutrophilic infiltration, and giant cell reaction in small to medium-sized arteries in multiple organs. These findings led to diagnosis of systemic vasculitis anatomically compatible with PAN. This was a rare case of a patient with MPO-ANCA-positive PAN who may have developed bilateral exudative otitis media and hearing loss as the initial manifestation of PAN.

AL amyloidosis is the most common form of systemic amyloidosis. Although kidney biopsy often is the method by which the disease is identified, small amounts of amyloid in kidney biopsy specimens may be missed on routine examination unless specifically investigated. We present here a previously healthy 60-year-oldmissed on routine examination unless specifically investigated. We present here a previously healthy 60-year-old man who developed nephrotic syndrome. His first renal biopsy showed minimal change nephrotic syndromeman who developed nephrotic syndrome. His first renal biopsy showed minimal change nephrotic syndromesuggesteda subtle depost ommon formsystemicamyloidfibrilhediminationof an early lesion of renal amyloido-s (MCNS). Proteinuria remained refractory to immunosuppressive treatments. Six months later, a repeat renal biopsy clearly showed AL amyloidosis. Re-examination of the first biopsy in the light of the final diagnosis again suggested a subtle deposition of amyloid fibrils. The discrimination of an early lesion of renal amyloidosis with MCNS may often be difficult. It is necessary to maintain a high level of alertness for amyloidosis especially in aged patients with nephrotic syndrome and to consider a repeat biopsy in steroid-resistant cases.

Although hypokalemia is a common clinical problem, symptoms generally do not become manifest unless the serum potassium (K) falls rapidly. We encountered five cases with symptomatic severe hypokalemia (K2.0 mEq/L) hospitalized for the past 15 months at our hospital. We examined the clinical characteristics and treatment of these patients. All five patients were women, and their mean age was 77.8 (73-82)years. They suffered from hypertension. Mean K level at admission was 1.66 (1.4-1.9) mEq/L and HCO3(-) was 48.3 (33.6-56.1) mmol/L. Plasma aldosterone level was low and plasma rennin activity was suppressed. All patients developed progressive muscle weakness with elevated creatinine phosphokinase. Three of the patients had received Chinese medicine which contained licorice, one received glycyrrhizin and the other one had received both. We diagnosed these cases as pseudoaldosteronism induced by glycyrrhizin. With discontinuation of the drugs and intravenous as well as oral K supplementation, serum K were normalized and clinical symptoms improved within 12 days. For one patient who developed cardiac dysfunction, concentrated K solution (230 mEq/L) was infused into the central vein. These findings show that glycyrrhizin ingestion should be kept in mind as a cause of an extreme degree of an hypokalemia, especially in elderly patients.

Henoch-Schönlein purpura (HSP) is a systemic disorder characterized by small vessel vasculitis with the deposition of IgA immune complexes. Renal involvement is the major cause of morbidity and mortality in patients with HSP. We report here a 37-year-old female patient with HSP nephritis (HSPN) associated with steroid-resistant nephrotic syndrome and renal dysfunction despite conventional therapy. The patient was successfully treated with intravenous cyclophosphamide following treatment with intravenous pulse methylprednisolone and oral prednisolone. The combination therapy resulted in a significant decrease in proteinuria, together with improvement of renal function. The patient finally reached a stage of clinical remission.

A 67-year-old, hepatitis C virus (HCV)-positive woman was admitted to our hospital because of proteinuria and leg edema. Laboratory examination showed decreased serum albumin and complement activity and positive cryoglobulin. The HCV RNA genotype was 1b with high viral load. Kidney biopsy showed membranoproliferative glomerulonephritis (MPGN) with capillary deposition of C3, IgM, and IgG, indicating HCV-associated glomerulonephritis. In addition to interferon (IFN) therapy, double-filtration plasmapheresis (DFPP) was performed to reduce HCV RNA blood levels in the early stage of IFN therapy. This treatment greatly reduced the viral load and induced clinical remission of MPGN, suggesting that DFPP plus IFN combination therapy may represent a potentially effective modality for refractory-type HCV-associated glomerulonephritis.