Yasuhiro Suzuki

Nagoya University, Nagoya, Aichi, Japan

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Publications (29)93.71 Total impact

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    ABSTRACT: Appropriate fluid balance is important for good clinical outcomes and survival in patients on peritoneal dialysis. We recently reported that lymphangiogenesis associated with fibrosis developed in the peritoneal cavity via the transforming growth factor-β1-vascular endothelial growth factor-C (VEGF-C) pathway. We investigated whether VEGF receptor-3 (VEGFR-3), the receptor for VEGF-C and -D, might be a new target to improve net ultrafiltration by using adenovirus-expressing soluble VEGFR-3 (Adeno-sVEGFR-3) in rodent models of peritoneal injury induced by methylglyoxal (MGO). We demonstrated that lymphangiogenesis developed in these MGO models, especially in the diaphragm, indicating that lymphangiogenesis is a common feature in the peritoneal cavity with inflammation and fibrosis. In MGO models, VEGF-D was significantly increased in the diaphragm; however, VEGF-C was not significantly upregulated. Adeno-sVEGFR-3, which was detected on day 50 after administration via tail vein injections, successfully suppressed lymphangiogenesis in the diaphragm and parietal peritoneum in mouse MGO models without significant effects on fibrosis, inflammation, or neoangiogenesis. Drained volume in the peritoneal equilibration test using a 7.5% icodextrin peritoneal dialysis solution (the 7.5% icodextrin peritoneal equilibration test) was improved by Adeno-sVEGFR-3 on day 22 (P<0.05) and day 50 after reduction of inflammation (P<0.01), indicating that the 7.5% icodextrin peritoneal equilibration test identifies changes in lymphangiogenesis. The solute transport rate was not affected by suppression of lymphangiogenesis. In human peritoneal dialysis patients, the dialysate to plasma ratio of creatinine positively correlated with the dialysate VEGF-D concentration (P<0.001). VEGF-D mRNA was significantly higher in the peritoneal membranes of patients with ultrafiltration failure, indicating that VEGF-D is involved in the development of lymphangiogenesis in peritoneal dialysis patients. These results indicate that VEGFR-3 is a new target to improve net ultrafiltration by suppressing lymphatic absorption and that the 7.5% icodextrin peritoneal equilibration test is useful for estimation of lymphatic absorption.Laboratory Investigation advance online publication, 29 June 2015; doi:10.1038/labinvest.2015.87.
    Laboratory Investigation 06/2015; DOI:10.1038/labinvest.2015.87 · 3.83 Impact Factor
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    ABSTRACT: Tolvaptan selectively binds to the vasopressin V2 receptor and inhibits reabsorption of free water. Although its efficacy for heart failure has been proven, its efficacy for chronic kidney disease (CKD) patients has not been assessed in detail. We examined 20 CKD patients (13 men and 7 women) who presented with volume overload and who were administered tolvaptan. We assessed urine volume (UV) and blood biochemistry before administration (dO), 1 day after administration (d1), and 7 to 14 days after administration (d7-14). The mean age was 74.0 +/- 13.1 years. Besides CKD, there were 9, 8, and 5 patients with heart failure, liver failure or liver cirrhosis, andsevere oedema, respectively. UV significantly increased from 959.0 +/- 503.8 mL/day at d0 to 1605.4 +/- 964.0 mL/day at d7-14 (P<0.01). Serum creatinine levels were not exacerbated (3.89 +/- 3.43 mg/dL at d0 and 3.66 +/- 3.02 mg/dL at d7-14). Serum albumin (ALB) levels and urinary protein creatinine ratio (uPCR) did not correlate with UV change. Estimated glomerular filtration rate (eGFR) correlated with UV change from d0 to d1 (r=0.6619, P<0.01). Serum sodium elevation correlated with increased UV (r=0.4951, P<0.05). Tolvaptan is useful to reduce volume overload without exacerbation of the renal function; its effect does not depend on ALB or uPCR. the eGFR correlated with the efficacy of tolvaptan. If UV increases drastically after tolvaptan administration, serum Na levels should be carefully monitored.
    Acta cardiologica 04/2015; 70(2):217-23. · 0.56 Impact Factor
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    ABSTRACT: We investigated the expression of membrane complement regulators (CRegs), CD46, CD55 and CD59 in human mesothelial cells, and correlated with clinical background and level of complement (C) activation products in peritoneal dialysis (PD) fluids (PDF) to clarify influence of the C activation system in PD patients. Expression of CRegs was assessed on primary cultures of mesothelial cells (HPMC) harvested from PD fluid of 31 PD patients. Because expression of CD55 but not CD46 and CD59 in mesothelial cells was significantly correlated to value of dialysate-to-plasma creatinine concentration ratio (D/P Cre) (p<0.005) as an indicator of peritoneal function, we focused on analysis of CD55 expression of HPMCs in comparison with levels of C activation products in the PDF of the PD patients, and their background factors. When comparing expression of the CRegs between systemic neutrophils and HPMC, no correlation was observed, supporting that change of CRegs' expression in HPMC was independently occurring in the peritoneum. Expression of CD55 protein in HPMC was closely correlated with expression at the mRNA level (p<0.0001) and was inversely correlated with levels of sC5b-9 (p<0.05), but not C3, C4, IL6 and CA125 in the PDF. Complications of diabetes, usage of icodextrin and residual renal function were not correlated with change of CD55 expression in HPMCs. Our data show that the process of PD therapy modifies expression of CD55 on peritoneal mesothelium and triggers local C activation. These findings support efforts to modify PD therapy to limit effects on activation and regulation of the C system. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Molecular Immunology 02/2015; 65(2):302-309. DOI:10.1016/j.molimm.2015.02.005 · 3.00 Impact Factor
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    ABSTRACT: A 66-year-old woman with an 11-year history of peritoneal dialysis (PD) for diabetic nephropathy and renal failure exhibited a movable tumor in the left atrium on echocardiography. Tumor resection was performed due to the difficulty in diagnosing the tumor and the future risk of heart failure and embolization. Light microscopy showed a calcified amorphous tumor (CAT), a rare intracardiac mass characterized by the presence of a pedicle and diffuse calcification. An increased calcium-phosphate product level was suspected as an etiology, although degeneration, inflammation and/or mineral balance disorders may also induce the development of CAT. We herein report the first known case of CAT in a PD patient.
    Internal Medicine 01/2015; 54(5):481-5. DOI:10.2169/internalmedicine.54.2967 · 0.97 Impact Factor
  • 25th International Complement Workshop; 10/2014
  • Masashi Mizuno, Yasuhiro Suzuki, Yasuhiko Ito
    Internal Medicine 01/2014; 53(6):647. DOI:10.2169/internalmedicine.53.1827 · 0.97 Impact Factor
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    ABSTRACT: In patients receiving peritoneal dialysis, fungal or yeast peritonitis has a poor prognosis. In rat peritoneum with mechanical scraping, severe peritonitis can be induced by zymosan, a component of yeast (Zy/scraping peritonitis). Administration of rat adipose tissue-derived stromal cells (ASCs) potentially can improve several tissue injuries. The present study investigated whether rat ASCs could improve peritoneal inflammation in Zy/scraping peritonitis. Rat ASCs were injected intraperitoneally on a daily basis in rats with Zy/scraping peritonitis. Peritoneal inflammation accompanied by accumulation of inflammatory cells and complement deposition was suppressed by day 5 after injection of rat ASCs. The peritoneal mesothelial layer in Zy/scraping peritonitis with rat ASC treatment was restored compared with the peritoneal mesothelial layer without rat ASC treatment. Injected rat ASCs co-existed with mesothelial cells in the sub-peritoneal layer. In vitro assays showed increased cellular proliferation of rat mesothelial cells combined with rat ASCs by co-culture assays, confirming that fluid factors from rat ASCs might play some role in facilitating the recovery of rat mesothelial cells. Hepatocyte growth factor was released from rat ASCs, and administration of recombinant hepatocyte growth factor increased rat mesothelial cell proliferation. Because the peritoneal mesothelium shows strong expression of membrane complement regulators such as Crry, CD55 and CD59, restoration of the mesothelial cell layer by rat ASCs might prevent deposition of complement activation products and ameliorate peritoneal injuries. This study suggests the therapeutic possibilities of intraperitoneal rat ASC injection to suppress peritoneal inflammation by restoring the mesothelial layer and decreasing complement activation in fungal or yeast peritonitis.
    Cytotherapy 12/2013; DOI:10.1016/j.jcyt.2013.10.011 · 3.10 Impact Factor
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    ABSTRACT: ESRD treated with dialysis is associated with increased left ventricular hypertrophy, which, in turn, is related to high mortality. Mineralocorticoid receptor antagonists improve survival in patients with chronic heart failure; however, the effects in patients undergoing dialysis remain uncertain. We conducted a multicenter, open-label, prospective, randomized trial with 158 patients receiving angiotensin-converting enzyme inhibitor or angiotensin type 1 receptor antagonist and undergoing peritoneal dialysis with and without (control group) spironolactone for 2 years. As a primary endpoint, rate of change in left ventricular mass index assessed by echocardiography improved significantly at 6 (P=0.03), 18 (P=0.004), and 24 (P=0.01) months in patients taking spironolactone compared with the control group. Rate of change in left ventricular ejection fraction improved significantly at 24 weeks with spironolactone compared with nontreatment (P=0.02). The benefits of spironolactone were clear in patients with reduced residual renal function. As secondary endpoints, renal Kt/V and dialysate-to-plasma creatinine ratio did not differ significantly between groups during the observation period. No serious adverse effects, such as hyperkalemia, occurred. In this trial, spironolactone prevented cardiac hypertrophy and decreases in left ventricular ejection fraction in patients undergoing peritoneal dialysis, without significant adverse effects. Further studies, including those to determine relative effectiveness in women and men and to evaluate additional secondary endpoints, should confirm these data in a larger cohort.
    Journal of the American Society of Nephrology 12/2013; 25(5). DOI:10.1681/ASN.2013030273 · 9.47 Impact Factor
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    ABSTRACT: Peritoneal fibrosis (PF) causes ultrafiltration failure (UFF) and is a complicating factor in long-term peritoneal dialysis. Lymphatic reabsorption also may contribute to UFF, but little is known about lymphangiogenesis in patients with UFF and peritonitis. We studied the role of the lymphangiogenesis mediator vascular endothelial growth factor-C (VEGF-C) in human dialysate effluents, peritoneal tissues, and peritoneal mesothelial cells (HPMCs). Dialysate VEGF-C concentration correlated positively with the dialysate-to-plasma ratio of creatinine (D/P Cr) and the dialysate TGF-β1 concentration. Peritoneal tissue from patients with UFF expressed higher levels of VEGF-C, lymphatic endothelial hyaluronan receptor-1 (LYVE-1), and podoplanin mRNA and contained more lymphatic vessels than tissue from patients without UFF. Furthermore, mesothelial cell and macrophage expression of VEGF-C increased in the peritoneal membranes of patients with UFF and peritonitis. In cultured mesothelial cells, TGF-β1 upregulated the expression of VEGF-C mRNA and protein, and this upregulation was suppressed by a TGF-β type I receptor (TGFβR-I) inhibitor. TGF-β1-induced upregulation of VEGF-C mRNA expression in cultured HPMCs correlated with the D/P Cr of the patient from whom the HPMCs were derived (P<0.001). Moreover, treatment with a TGFβR-I inhibitor suppressed the enhanced lymphangiogenesis and VEGF-C expression associated with fibrosis in a rat model of PF. These results suggest that lymphangiogenesis associates with fibrosis through the TGF-β-VEGF-C pathway.
    Journal of the American Society of Nephrology 08/2013; 24(10). DOI:10.1681/ASN.2012030226 · 9.47 Impact Factor
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    ABSTRACT: In peritoneal dialysis (PD) therapy, physical stresses such as exposure to peritoneal dialysate, catheter trauma and peritonitis induce peritoneal injuries which can prevent continued long-term PD therapy. Therefore, protection of the peritoneum is an important target to enable long-term PD therapy in patients with end-stage renal disease. We previously showed that neutralizations of membrane complement regulators (CRegs), Crry and CD59, in rat peritoneum provokes development of acute peritoneal injuries due to uncontrolled complement activation. C5a is a key effecter molecule of the complement system, released during acute inflammation. Control of C5a has been proposed as a strategy to suppress inflammatory reactions and, because peritoneal injuries are accompanied by inflammation, we hypothesized that C5a targeted therapy might be an effective way to suppress peritoneal injuries. In the present study, we have used the established acute peritonitis model induced by neutralization of CRegs to investigate effects on acute peritoneal injuries of inhibiting C5a. Intravenous administration of an anti-C5a complementary peptide (AcPepA) up to 4 h after induction of injury significantly and dose-dependently prevented accumulation of inflammatory cells and reduced tissue damage in the model, accompanied by decreased C3b deposition. Here we showed that C5a contributed to the development of peritoneal injuries. Our results suggest that C5a is a target to prevent or treat peritoneal injuries in PD patients on prolonged therapy or with infectious complications.
    AJP Renal Physiology 07/2013; 305(11). DOI:10.1152/ajprenal.00681.2012 · 4.42 Impact Factor
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    ABSTRACT: A 46-year-old man on peritoneal dialysis (PD) was hospitalized due to suspicious PD-related peritonitis. Because the patient's abdominal pain was unimproved by conventional antibiotics and multiple bacteria were identified in a smear-sample of PD fluid, endogenous peritonitis was suspected. Perforated appendicitis was finally diagnosed under exploratory laparotomy. In this patient, perforated appendicitis was difficult to diagnose due to the attenuated clinical symptoms and inconclusive results of abdominal computed tomography (CT), even though the positive predictive value of CT is >95% in non-PD patients. Quickly deciding to perform exploratory laparotomy in patients suspected of having endogenous peritonitis is thus important, even when the origin has not been clarified.
    Internal Medicine 01/2013; 52(11):1177-1181. DOI:10.2169/internalmedicine.52.9196 · 0.97 Impact Factor
  • Immunobiology 11/2012; 217(11):1144. DOI:10.1016/j.imbio.2012.08.046 · 3.18 Impact Factor
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    ABSTRACT: Non-steroidal anti-inflammatory drugs decrease the glomerular filtration rate. However, few studies have been conducted on renal function in patients treated with non-steroidal anti-inflammatory drugs during the first week after laparoscopic radical nephrectomy. The purpose of this study is to determine whether short-term administration of non-steroidal anti-inflammatory drugs during the first week after laparoscopic radical nephrectomy is a risk factor for impaired renal function. Renal carcinoma patients undergoing laparoscopic radical nephrectomy in Nagoya University Hospital from April 2004 to July 2010 were identified in a retrospective cohort study. The 164 patients were divided into non-non-steroidal anti-inflammatory drug-treated (n = 50) and non-steroidal anti-inflammatory drug-treated (n = 114) groups. Elderly patients (>60 years old) in the non-steroidal anti-inflammatory drug-treated group showed a significant correlation between the residual renal function ratio and the total dose of diclofenac sodium (r = -0.277, P < 0.05). There was no significant correlation between the residual renal function ratio and the total dose of loxoprofen sodium. The time to doubling of the serum creatinine level was significantly shorter in elderly patients treated with diclofenac sodium compared with that in patients treated with non-non-steroidal anti-inflammatory drugs (P = 0.034). These results suggest that renal ischemia induced by short-term administration of diclofenac sodium impairs renal function in elderly patients after laparoscopic radical nephrectomy. In the present study, we found the first evidence that short-term administration of diclofenac sodium is one risk factor for renal impairment after laparoscopic radical nephrectomy in elderly patients. To prevent renal impairment after laparoscopic radical nephrectomy in elderly patients, the use of loxoprofen sodium, which has a negligible effect on renal function compared with diclofenac sodium, is recommended.
    Japanese Journal of Clinical Oncology 09/2012; 42(11):1073-8. DOI:10.1093/jjco/hys145 · 1.75 Impact Factor
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    ABSTRACT: Protein-energy wasting and chronic inflammation are prevalent in patients with end-stage renal disease (ESRD). We investigated the combination of serum albumin, C-reactive protein (CRP) and body mass index (BMI) at initiation of hemodialysis therapy as a predictor of all-cause and cardiovascular disease (CVD) mortality in Japanese ESRD patients. A total of 1,228 consecutive Japanese ESRD patients on hemodialysis therapy were enrolled and followed for up to 10 years. Patients were divided into quartiles according to levels of albumin, CRP and BMI. Furthermore, to clarify the joint role of these factors, albumin <3.5 g/dl, CRP >4.0 mg/l and BMI <19.6 were defined as risk factors using receiver operating characteristic analysis; thereafter, patients were divided into groups according to the positive number of these factors. Adjusted hazard ratios (HRs) for lower serum albumin, elevated CRP and lower BMI for 10-year all-cause mortality were 1.97, 3.13 and 2.61, respectively. Regarding the combination of these variables, adjusted HRs for mortality were 2.31, 4.28 and 8.07, respectively, in patients having any one factor, any two factors and all three factors. The C-index for an established risk model with these three positive markers was the most accurate for predicting mortality (0.768), as compared to other models with one or two markers. Similar results were seen for CVD mortality. Serum albumin, CRP and BMI at the start of hemodialysis therapy were able to individually stratify the risk of long-term mortality in ESRD patients. Furthermore, a combination of these variables could more accurately predict mortality.
    American Journal of Nephrology 07/2012; 36(2):136-43. DOI:10.1159/000339940 · 2.65 Impact Factor
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    ABSTRACT: Oxaliplatin is effective in advanced colorectal cancer and is known to have relatively few side effects, such as hemolysis and renal toxicity. We report a case of acute kidney injury (AKI) after treatment with a combination of oxaliplatin, folinic acid and 5-fluorouracil or capecitabine. The patient developed acute renal failure, hemolytic anemia and thrombocytopenia after the 34th course of chemotherapy including oxaliplatin. A positive direct antiglobulin test and detection of immunoglobulin G and complement C3b and C3d on erythrocytes suggested the diagnosis of immune-related severe intravascular hemolytic anemia. She was successfully treated and recovered using plasma exchange, corticosteroids and hemodialysis therapy. Only seven other cases of AKI associated with oxaliplatin use have been reported to date. As in this case, acute hemolysis due to autoimmune mechanisms and subsequent AKI occurred suddenly after frequent use of oxaliplatin in four of those cases. We should be aware that oxaliplatin may cause sudden life-threatening hemolysis by drug-induced antibodies and subsequent AKI, even though oxaliplatin is frequently administered without side effects. This represents the first case report of AKI-related hemolysis due to oxaliplatin in Japan.
    Clinical and Experimental Nephrology 03/2012; 16(3):490-4. DOI:10.1007/s10157-012-0620-8 · 1.71 Impact Factor
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    ABSTRACT: Peritonitis and the rare sequela of encapsulating peritoneal sclerosis (EPS) are serious problems in patients on peritoneal dialysis therapy. Chronic and persistent peritoneal injuries may be a risk factor of EPS. We previously reported that a chronic, proliferative peritonitis developed when zymosan was administered intraperitoneally following scraping injury of rat peritoneum (Mizuno M, Ito Y, Hepburn N, Mizuno T, Noda Y, Yuzawa Y, Harris CL, Morgan BP, Matsuo S. J Immunol 183: 1403-1412, 2009). Peritoneal membrane complement regulators (CRegs), especially Crry and CD59, protected from injury by inhibiting local complement activation, suggesting that CRegs play important roles in maintaining homeostasis in rat peritoneum. Here, we investigated roles of complement in the development of EPS by neutralizing CReg function with monoclonal antibodies (MAbs). Proliferative peritonitis was induced by scraping the peritoneum, followed by daily intraperitoneal administration of zymosan. When either Crry or CD59 alone was neutralized by MAb, the tissue injuries were not significantly changed compared with rats without neutralizing MAb. When both Crry and CD59 were neutralized in this model, severe fibrin exudation was observed on the peritoneal surface on day 5, accompanied by inflammatory cell infiltration, resembling the early stages of development of EPS. Dense peritoneal deposition of C3 fragments and membrane attack complex were observed, along with the fibrin exudates. Intravenous administration of cobra venom factor, which profoundly activates complement, further enhanced these pathological changes. Our results show that complement activation in injured peritoneum drives peritoneal inflammation, and that enhancement of complement activation by inhibiting CReg and/or enhancing systemic activation contributes to the initiation of EPS; therefore, anti-complement agents might be of therapeutic value in humans for the treatment of EPS.
    AJP Renal Physiology 02/2012; 302(10):F1245-51. DOI:10.1152/ajprenal.00652.2011 · 4.42 Impact Factor
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    ABSTRACT: Inflammation is recognized as an important contributor to lymphangiogenesis; however, in tubulointerstitial lesions in human chronic kidney diseases, this process is better correlated with the presence of myofibroblasts rather than macrophages. As little is known about the interaction between lymphangiogenesis and renal fibrosis, we utilized the rat unilateral ureteral obstruction model to analyze inflammation, fibrosis, lymphangiogenesis, and growth factor expression. Additionally, we determined the relationship between vascular endothelial growth factor-C (VEGF-C), an inducer of lymphangiogenesis, and the profibrotic factor, transforming growth factor-β1 (TGF-β1). The expression of both TGF-β1 and VEGF-C was detected in tubular epithelial and mononuclear cells, and gradually increased, peaking 14 days after ureteral obstruction. The kinetics and localization of VEGF-C were similar to those of TGF-β1, and the expression of these growth factors and lymphangiogenesis were linked with the progression of fibrosis. VEGF-C expression was upregulated by TGF-β1 in cultured proximal tubular epithelial cells, collecting duct cells, and macrophages. Both in vitro and in vivo, the induction of VEGF-C along with the overall appearance of lymphatics in vivo was specifically suppressed by the TGF-β type I receptor inhibitor LY364947. Thus, TGF-β1 induces VEGF-C expression, which leads to lymphangiogenesis.
    Kidney International 01/2012; 81(9):865-79. DOI:10.1038/ki.2011.464 · 8.52 Impact Factor
  • Nihon Toseki Igakkai Zasshi 01/2012; 45(3):247-253. DOI:10.4009/jsdt.45.247
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    ABSTRACT: Colonic diverticulitis is an important cause of polymicrobial peritonitis, which requires surgical treatment and cessation of peritoneal dialysis (PD). The aim of this study was to examine whether plain abdominal computed tomography (CT) is useful for evaluating colonic diverticulosis in chronic kidney disease (CKD) patients and to explore whether colonic diverticulosis is a risk factor for enteric peritonitis. The subjects consisted of 137 consecutive CKD patients (Stage 4 or 5) who were candidates for PD from February 2005 to November 2009. Abdominal CT without contrast media was performed in all PD candidates. Diverticula of the colon were detected by plain CT in 57 cases (41.6%). The number of diverticula tended to increase with age. The most common site of involvement of diverticulosis was the ascending colon. In patients treated with PD, the incidence of peritonitis was higher in patients with diverticulosis than in those without diverticulosis (P = 0.004). However, only one episode of enteric peritonitis was observed among patients with diverticulosis. The presence of diverticulosis did not affect cumulative or technical survival. PD was not selected in four cases due to a high frequency of diverticula with episodes of abdominal pain. Two cases developed severe diverticulitis with peritonitis and underwent resection of the colon. Our study suggests that plain CT examination is useful for detecting diverticulosis in CKD patients. Silent diverticulosis is not a risk factor for enteric diverticulosis-related peritonitis. PD may be contraindicated in cases having frequent diverticulosis with episodes of lower abdominal pain.
    Nephrology Dialysis Transplantation 12/2011; 27(6):2511-6. DOI:10.1093/ndt/gfr685 · 3.49 Impact Factor
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    ABSTRACT: We report a case of peritonitis resulting from colon perforation caused by ingestion of a rare foreign body in a patient on peritoneal dialysis (PD). A 72-year-old woman on PD was hospitalized with abdominal pain and cloudy PD fluid (PDF). Although conventional antibiotic therapy was started because of a diagnosis of infectious peritonitis, low-grade fever, abdominal pain and a high number of white blood cells in PDF persisted. On day 3, anaerobic bacteria were recognized on bacterial culture of PDF, suggesting a gastrointestinal etiology. During exploratory laparotomy, sigmoidal perforation by a piece of bamboo, probably resulting from ingestion of contaminated food, was found.
    Clinical and Experimental Nephrology 09/2011; 15(6):962-5. DOI:10.1007/s10157-011-0529-7 · 1.71 Impact Factor