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Increased central venous pressure in congestive heart failure is responsible for renal dysfunction, which is mediated by renal venous congestion. Pericyte detachment from capillaries after renal congestion might trigger renal fibrogenesis via pericyte-myofibroblast transition (PMT). Platelet-derived growth factor receptors (PDGFRs), which are PMT indicators, were upregulated in our recently established renal congestion model. This study was designed to determine whether inhibition of the PDGFR pathway could suppress tubulointerstitial injury after renal congestion.The inferior vena cava between the renal veins was ligated in male Sprague-Dawley rats, inducing congestion only in the left kidney. Imatinib mesylate or vehicle were injected intraperitoneally daily from 1 day before the operation. Three days after the surgery, the effect of imatinib was assessed by physiological, morphological and molecular methods. The inhibition of PDGFRs against transforming growth factor-β1 (TGFB1)-induced fibrosis was also tested in human pericyte cell culture.Increased kidney weight and renal fibrosis were observed in the congested kidneys. Upstream inferior vena cava (IVC) pressure immediately increased to around 20 mmHg after IVC ligation in both the imatinib and saline groups. Although vasa recta dilatation and pericyte detachment under renal congestion were maintained, imatinib ameliorated the increased kidney weight and suppressed renal fibrosis around the vasa recta. TGFB1-induced elevation of fibrosis markers in human pericytes was suppressed by PDGFR inhibitors at the transcriptional level.The activation of the PDGFR pathway after renal congestion was responsible for renal congestion-induced fibrosis. This mechanism could be a candidate therapeutic target for renoprotection against renal congestion-induced tubulointerstitial injury.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a systemic autoimmune disease characterized by necrotizing inflammation of the small blood vessels. ANCA-associated vasculitis is subclassified into three variants: granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, and microscopic polyangiitis (MPA). Myeloperoxidase (MPO) ANCA is a marker antibody for MPA. Interstitial pneumonia (IP) is occasionally complicated with MPA. However, only a few cases of idiopathic IP develop MPO-ANCA-positive conversion and MPA. Therefore, we present a case of a 70-year-old Japanese man with idiopathic IP who developed MPO-ANCA-positive conversion and MPA. We performed renal biopsy, which revealed pauci-immune crescentic glomerulonephritis. The patient was treated with intravenous methylprednisolone pulse therapy and oral prednisone, and the patient's laboratory data gradually improved with steroid therapy. The association between the production of MPO-ANCA and IP remains unclear, and the present case suggests that IP plays a role in inducing MPO-ANCA production. Patients with idiopathic IP should be followed-up carefully for an examination of increased MPO-ANCA levels and MPA development. In addition, early gastric cancer was detected during upper gastrointestinal endoscopy in our case, and it could also be important not to miss malignancy in patients with ANCA-associated vasculitis.

Fabry disease (FD) is an X-linked disorder of the sphingolipid metabolism, caused by deficiency or decreased activity of α-galactosidase A. We report a rare case of Fabry nephropathy (FN) in a 21-year-old Japanese female patient presenting with only urinary mulberry bodies; she was treated with pharmacological chaperone therapy (PCT) after renal biopsy. The patient underwent a detailed examination because her mother was diagnosed with FD in the Division of Community Medicine of our hospital. She did not have renal dysfunction or proteinuria, and only mulberry bodies were detected in the urine. The activity of α-galactosidase A was low, and genetic analysis revealed the R301Q mutation. A percutaneous renal biopsy was performed, and the findings revealed enlargement and vacuolation of glomerular podocytes by light microscopy, and myelin and zebra bodies were detected in podocytes by electron microscopy. She was diagnosed with FN by renal biopsy and gene analysis. PCT was selected as the treatment to prevent cardiac events and renal dysfunction. The present case suggests that renal biopsy may be necessary even for young women with only mulberry bodies for the diagnosis of FN. It could be useful to evaluate the effect of treatment using the counts of mulberry bodies in the urine. In addition, due to its oral administration, PCT may be suitable for patients who are unable to visit the hospital frequently.

A 65-year-old woman was hospitalized for heart failure and pneumonia in a nearby hospital. She had been previously diagnosed as light chain (AL) amyloidosis and treated with melphalan plus dexamethasone (Mel-Dex), and lenalidomide plus dexamethasone (Len-Dex). She started treatment including antimicrobials and diuretics, but her renal function worsened progressively, and she was transferred to our hospital for nephrological care. She was treated with antimicrobials, noradrenaline, dobutamine, and continuous hemodiafiltration. Her general condition gradually stabilized, and she was switched to intermittent hemodialysis (HD). However, HD was discontinued due to intradialytic hypotension and the development of heparin-induced thrombocytopenia. Her renal replacement therapy was switched to peritoneal dialysis (PD), which enabled good volume control and stable cardiac function. She was discharged and is still in good condition, without serious complications and achieving a considerably better prognosis than was predicted. Our case suggests that PD is an effective modality for patients with AL amyloidosis with heart failure and renal dysfunction.

Peritoneal dialysis (PD) catheter malposition is one of the complications of renal replacement therapy. This study aimed to determine the preoperative factors that cause PD catheter malposition.The prospective cohort study included patients who underwent PD catheter insertion surgery and had preoperative and postoperative computed tomography scans. We compared preoperative and intraoperative factors between the lower depth catheter group (group L) and upper depth catheter group (group U), and preoperative and intraoperative factors between the posterior catheter group (group P) and anterior catheter group (group A). In addition, PD catheter obstruction requiring surgical intervention in each group was followed up for 1 year.A total of 150 patients were categorized into groups L (n = 77) and U (n = 73), or groups P (n = 107) and A (n = 43). Body mass index (BMI; P = 0.02), subcutaneous fat area (P = 0.02), and rate of previous abdominal surgery (P = 0.01) were significantly lower in group L than in group U. In terms of anterior catheter position, females had more-anterior catheter positions. The time to PD catheter obstruction requiring surgical intervention (P = 0.03) was significantly lower in group U than in group L.High BMI, high subcutaneous fat area, high subcutaneous fat thickness, and previous abdominal surgery were identified as preoperative factors that cause the PD catheter to have an upper depth. Female sex was a preoperative influencing factor for the anterior PD catheter position.

Renal venous congestion by increased central venous pressure in congestive heart failure is responsible for renal dysfunction. We have created a novel rat renal congestion model presenting increased renal interstitial hydrostatic pressure and vasa recta expansion, which leads to renal congestion-mediated fibrosis. Current clinical trials suggest the renoprotective effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors in heart failure patients; however, the underlying mechanisms are still discussing. Thus, we investigated the effect of phlorizin, a commercially available SGLT1/2 inhibitor, in our renal congestion model. All animal procedures were performed in accordance with the policies and guidelines of the “Position of the American Heart Association on Research Animal Use” and were approved by the Tohoku Medical and Pharmaceutical University Animal Experiment Committee (registration number: A18019-a, A19039-cn and A20005-cn). The inferior vena cava between the renal veins was ligated, which induced congestion only in the left kidney. Phlorizin (400 mg/kg body weight) or saline were injected subcutaneously daily from 1 day before the operation. Both the right control kidney and left congested kidney were collected 3 days after the surgery. Increased kidney weight and renal fibrosis were observed in the congested kidneys. Phlorizin attenuated the increased kidney weight and suppressed renal fibrosis staining. Molecules related to kidney injury (Kim1) and fibrosis (Fn1 and αSma) were also suppressed by Phlorizin in the congested kidney. Low-vacuum electron microscopy revealed the vasa recta dilatation in the congested kidney. This morphological change was alleviated by Phlorizin. These results suggest that SGLT1/2 inhibitor could suppress renal congestion-mediated fibrosis. This mechanism could be a potential therapeutic target for renoprotection against heart failure.

Tolvaptan is an effective treatment for polycystic kidney disease (PKD), but also causes unfortunate polyuria. Hydrochlorothiazide (HCTZ) has been shown to reduce urine volume in nephrogenic diabetes insipidus, raising the possibility that HCTZ could also be effective in reducing tolvaptan-induced polyuria. In this study, we examined the combined administration of HCTZ and tolvaptan. Male PCK rats were divided into four groups of normal chow (Cont), normal chow plus tolvaptan, gavage HCTZ treatment, and tolvaptan + HCTZ. Biochemical examinations of the plasma and urine were performed as well as histological and molecular (mRNA and protein expression) analyses. Groups treated with tolvaptan had significantly higher 24 h urine excretion, which was significantly reduced in the tolvaptan + HCTZ group after 2 weeks. Cyst size, pERK protein expression, and Cyclin D1 mRNA expression were all significantly reduced in both the tolvaptan and tolvaptan + HCTZ groups, indicating that HCTZ did not affect the beneficial functions of tolvaptan. Notably, aquaporin 2 redistribution from the apical to intracellular domains was observed in tolvaptan-treated rats and was partially reversed in the tolvaptan + HCTZ group. The renal glomerular filtration rate was reduced in the tolvaptan + HCTZ group. Significantly lowered mRNA expression of neuronal nitric oxide synthase, prostaglandin E synthase 2 and renin were also found in the medulla, but not in the cortex. HCTZ reduces tolvaptan-induced polyuria without altering its beneficial effects on PKD. This novel therapeutic combination could potentially lead to better PKD treatments and improved quality of life for the affected patients.

Background Inflammation, intrarenal renin-angiotensin system (RAS) activation, oxidative stress, and carbonyl stress have been postulated to play a fundamental role in controlling blood pressure. However, little is known about the association among renal RAS activation, carbonyl stress, and blood pressure elevation. Methods We evaluated the relationship between blood pressure elevation and either renal RAS activity or carbonyl stress in the general population (N = 355) in Japan. To minimize the effect of antihypertensive drug therapy, we divided participants into 3 groups (normotensive, hypertensive-with-non-medication, and hypertensive-with-medication). Intrarenal RAS activity and carbonyl stress were indicated by the urinary angiotensinogen (AGT) and carbonyl compound excretion levels, respectively. Results The urinary AGT and carbonyl compound excretion levels were significantly associated with blood pressure. Using a stepwise multiple regression analysis, we found that the urinary AGT excretion levels were strongly associated with blood pressure elevation, compared with inflammation, oxidative stress, and carbonyl stress markers, in all groups. Urinary carbonyl compound excretion was significantly associated with blood pressure in only the hypertensive-without-medication group. Furthermore, blood pressure was significantly increased in these participants, and both the urinary AGT and carbonyl compound levels were high. The urinary AGT excretion levels were strongly associated with elevated blood pressure in normotensive people, and inappropriate renal RAS activity and carbonyl stress independently contributed to the development of hypertension. Conclusions These findings suggest that RAS activation, particularly renal RAS activation exert a fundamental role in the pathogenesis of hypertension in the general population.

TGF-β1, which can cause renal tubular injury through a vacuolar-type H+-ATPase (V-ATPase)-mediated pathway, is induced by the glucose degradation product methylglyoxal to yield peritoneal injury and fibrosis. The present study investigated the roles of V-ATPase and its accessory protein, the (pro)renin receptor, in peritoneal fibrosis during peritoneal dialysis. Rats daily administered 20 mM methylglyoxal intraperitoneally developed significant peritoneal fibrosis after 7 days with increased expression of TGF-β and V-ATPase, which was reduced by the inhibition of V-ATPase with co-administration of 100 mM bafilomycin A1. The (pro)renin receptor and V-ATPase were expressed in acidic organelles and cell membranes of human peritoneal mesothelial cells. TGF-β1 upregulated the expression of collagens, α-SMA, and EDA-fibronectin, together with ERK1/2 phosphorylation, which was reduced by inhibition of V-ATPase, (pro)renin receptor, or the MAPK pathway. Fibronectin and the soluble (pro)renin receptor were excreted from cells by acidic organelle trafficking in response to TGF-β1; this excretion was also suppressed by inhibition of V-ATPase. Soluble (pro)renin receptor concentrations in effluents of patients undergoing peritoneal dialysis were associated with the dialysate-to-plasma ratio of creatinine. Together, these results demonstrate a novel fibrosis mechanism through the (pro)renin receptor and V-ATPase in the acidic organelles of peritoneal mesothelial cells.

Volume overload is common in liver cirrhosis, heart failure, and chronic kidney disease, being an independent risk factor for mortality. Loop diuretics have been widely used for treating volume overload in these patients. However, there is a tendency to increase the dose of loop diuretics partly because of diuresis resistance. Neurohormonal factors are also enhanced in these patients, which play a role in volume overload and organ ischemia. Loop diuretics cannot improve neurohormonal factors and could result in end-organ damage. The water diuretic tolvaptan has been approved for use for volume overload in heart failure and liver cirrhosis. Despite causing similar increases in urine volume, its characteristics differ from those of loop diuretics. Renal blood flow is maintained with tolvaptan but decreased with furosemide in heart failure patients. Neurohormonal factors and blood pressure are not markedly altered by tolvaptan administration. It is expected that these mechanisms of tolvaptan can protect against worsening renal function by volume overload diseases compared with loop diuretics. It has also been reported that some patients do not respond well to tolvaptan. Loop diuretics and tolvaptan share the same mechanism with regard to decreasing renal interstitial osmolality, which plays a fundamental role in water diuresis. Thus, a high dose of loop diuretics could result in resistance to tolvaptan, so tolvaptan should be administered before increasing the loop diuretic dose. Therefore, volume control without enhancing end-organ damage can be achieved by adding tolvaptan to a tolerable dose of Na-sparing diuretics.

Exit-site infection poses a risk for peritonitis and can shorten peritoneal dialysis (PD) vintage. A loose fit of the skin around the catheter at the exit site can push bacteria surrounding the catheter into the subcutaneous tunnel. Negative-pressure wound therapy (NPWT) has been used to hasten healing of the wound after an operation or to treat pressure ulcers. We hypothesized that NPWT could speed the healing of the exit site and tighten the fit of the skin around the catheter. Using a V.A.C. Therapy system [vacuum-assisted closure (KCI, San Antonio, TX, U.S.A.)], NPWT was therefore applied in 9 patients for 1 - 2 weeks after the PD catheter insertion operation. Results in those patients were compared with results in patients who did not receive NPWT.The healed exit site was classified as either tightly fitted (when the skin was tightly connected around the PD catheter) or loosely fitted (when the skin was not tightly connected around the catheter). The relevant data were retrieved from the medical record and analyzed retrospectively.Patients who received NPWT had a tight exit site after 1 - 2 weeks. Those who did not receive NPWT did not have a tight exit site after 1 - 2 weeks. No bleeding was observed in patients receiving NPWT. Bleeding from the exit site after the catheter insertion operation was observed in 3 patients not receiving NPWT.Because we use a fine trocar to make the subcutaneous catheter tunnel, bleeding from the vasculature can often be observed. That bleeding could be minimized with the application of NPWT. Negative pressure could also hasten wound healing and result in a tight fit of the skin around the catheter within in 1 - 2 weeks compared with the 1 month typically required with the use of conventional film dressings.Negative-pressure wound therapy is beneficial for creating a tight fit of the skin to the catheter within 1 - 2 weeks and might reduce the number of exit-site and tunnel infections, which could result in a reduction in the peritonitis rate.

In the present study, we assessed the effect of chronic tolvaptan treatment and compared it with the effect of conventional treatment without tolvaptan. In addition, changes in cardiac load and body fluid composition were compared.The study enrolled 22 patients undergoing peritoneal dialysis who had been receiving tolvaptan for more than 1 year and 10 patients undergoing peritoneal dialysis who had been treated with conventional diuretics. Left ventricular mass index (LVMI), left ventricular ejection fraction (LVEF), and E/e' index were measured by echocardiography at baseline and after 12 months of tolvaptan treatment (or an equivalent period). Body composition was analyzed by bioimpedance monitoring (BIM).In the tolvaptan group, LVMI was significantly reduced after 12 months of treatment; in the conventional-treatment group, it was significantly increased. The measured LVEF did not change in the tolvaptan group, but it increased significantly in the conventional-treatment group. The E/e' index was not altered in either group; however, it was reduced in patients receiving tolvaptan whose initial E/e' was greater than 15. Although urine volume was not significantly increased in either group, renal creatinine clearance increased significantly in tolvaptan group; no change was observed in the conventional-treatment group. Renal and peritoneal Kt/V did not significantly change during the study. In both groups, β

Neutral icodextrin peritoneal dialysis (PD) fluid (n-ICO) has become available for use in Japan. However, removal of water and solutes remains to be elucidated in detail. The present study was designed to determine removal of water, electrolytes, and small, middle, and large molecules in a period of 16 hours. In addition, biocompatibility with respect to peritoneal mesothelial cells was determined.Three stable patients undergoing PD at Tohoku University Hospital were administered n-ICO. Water removal was monitored every 2 hours. Sodium, urea nitrogen [molecular weight (MW): 28 Da], uric acid (MW: 168 Da), β

Sarcopenia is associated with increased morbidity and mortality in chronic kidney disease (CKD). Pathogenic mechanism of skeletal muscle loss in CKD, which is defined as uremic sarcopenia, remains unclear. We found that causative pathological mechanism of uremic sarcopenia is metabolic alterations by uremic toxin indoxyl sulfate. Imaging mass spectrometry revealed indoxyl sulfate accumulated in muscle tissue of a mouse model of CKD. Comprehensive metabolomics revealed that indoxyl sulfate induces metabolic alterations such as upregulation of glycolysis, including pentose phosphate pathway acceleration as antioxidative stress response, via nuclear factor (erythroid-2-related factor)-2. The altered metabolic flow to excess antioxidative response resulted in downregulation of TCA cycle and its effected mitochondrial dysfunction and ATP shortage in muscle cells. In clinical research, a significant inverse association between plasma indoxyl sulfate and skeletal muscle mass in CKD patients was observed. Our results indicate that indoxyl sulfate is a pathogenic factor for sarcopenia in CKD.