水野 智博

OBJECTIVES: We reported that the KDIGO (Kidney Disease: Improving Global Outcomes) criteria could stratify the risk of mortality in acute kidney injury (AKI) caused by cisplatin. The purpose of this study was to investigate risk factors of severe cisplatin-induced AKI (CIA). METHODS: From January 2006 to December 2012, we identified Japanese cancer patients who were treated with cisplatin as a first-line chemotherapy at Nagoya University Hospital. Serum creatinine levels were used to define CIA. RESULTS: We evaluated 1,721 patients treated with cisplatin. In multivariable analysis, cisplatin dosages/m(2) [odds ratio (OR) 1.019] or diagnosis of cancer stage 4 (OR 1.797) were risk factors of moderate CIA. History of diabetes mellitus (OR 3.454), history of cardiovascular disease (OR 3.612) or diagnosis of cancer stage 4 (OR 2.610) were risk factors of severe CIA. CONCLUSIONS: Diabetes mellitus, cardiovascular disease and advanced cancer increased the risk of severe CIA. As severe CIA shortens the survival period, we should consider whether the use of cisplatin benefits these patients.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

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.

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.

WHAT IS KNOWN AND OBJECTIVE: Renal impairment is unavoidable after laparoscopic radical nephrectomy (LRN) and is an important consideration for drug therapy. It is possible that the renal impairment after LRN causes adverse reactions following reduced elimination of some renally excreted drugs, such as hypoglycaemic drugs. However, there are few studies of renal function in patients with diabetes mellitus (DM) in the first week after LRN. The purpose of this study was to examine whether renal impairment after LRN affected glycaemic control. We assessed pre- and postoperative renal function of DM patients and examined whether re-administration of hypoglycaemic drugs in the first week after LRN causes episodes of hypoglycaemia. METHODS: Renal carcinoma patients undergoing LRN in Nagoya University Hospital from January 2007 to December 2009 were identified in a retrospective cohort study design. Patients were divided into non-DM (n = 60) and DM (n = 14) groups. RESULTS AND DISCUSSION: There were significant differences in postoperative estimated glomerular filtration rate values between the non-DM and DM groups. Four of nine patients (44%) experienced hypoglycaemia induced by re-administration of hypoglycaemic drugs, namely, sulfonylureas. WHAT IS NEW AND CONCLUSION: In the present study, we found the first evidence that renal impairment in the first week after LRN was a risk factor of hypoglycaemia. To prevent hypoglycaemia after LRN, assessment of renal function and the use of insulin therapy are important.

BACKGROUND: Atrial natriuretic peptide (ANP) was recently reported to ameliorate fibrosis in the heart and experimental renal diseases and vascular thickening after balloon injury. Peritoneal fibrosis is an important complication of long-term peritoneal dialysis, and peritonitis is a factor in its onset. In the present study, we investigated the effects of ANP in a rat peritonitis-induced peritoneal fibrosis model. METHODS: As pretreatment, an osmotic pump containing vehicle (saline) or ANP (0.15 or 0.3 μg/min) was inserted through the carotid vein in male Sprague-Dawley rats. ANP or saline was continuously infused using the osmotic pump. Three days after administration of ANP or saline, rats underwent peritoneal scraping in a blind manner and were sacrificed on Day 14. The effects of ANP were evaluated based on peritoneal thickness, immunohistochemistry and real-time polymerase chain reaction. In each experiment, we evaluated messenger RNA (mRNA) expression of the ANP receptor natriuretic peptide receptor A (NPR-A) in the peritoneum after scraping. The effects of ANP were also studied in cultured peritoneal fibroblasts and mesothelial cells. RESULTS: We observed a significant increase in NPR-A mRNA in the peritoneum. Peritoneal thickness increased with time and peaked on Day 14, but ANP significantly reduced peritoneal thickness. Parameters such as number of macrophages and CD-31-positive vessels and expression of type III collagen/transforming growth factor-β/plasminogen activator inhibitor-1 (PAI-1)/connective tissue growth factor (CTGF) were significantly suppressed by ANP. In cultured peritoneal fibroblasts and mesothelial cells, ANP suppressed angiotensin II-induced upregulation of CTGF and PAI-1. CONCLUSIONS: Our results suggest that ANP is useful in preventing inflammation-induced peritoneal fibrosis.

OBJECTIVES: The purpose of this study was to investigate if KDIGO (Kidney Disease: Improving Global Outcomes) criteria could be a useful outcome predictor of cisplatin-induced acute kidney injury (CIA). METHODS: In the period between January 2006 and December 2011, we identified Japanese patients who had been diagnosed with cancer and treated with cisplatin as a first-line chemotherapy at Nagoya University Hospital. The serum creatinine was used to define CIA and determine the KDIGO criteria of each patient after chemotherapy within 7 days. RESULTS: Eighty-nine patients (5.4%) were classified as having acute kidney injury (AKI) going by the KDIGO criteria, and the numbers of patients classified into AKI stages 1, 2 and 3 were 65 (3.9%), 18 (1.1%) and 6 (0.4%), respectively. Overall survival times were significantly shorter in AKI stages 2 and 3 than in stage 1. The area under the receiver operating characteristic curve with all patients was 0.68, and that of patients who were diagnosed with cancer stage 4 was 0.80. CONCLUSION: These results suggest that KDIGO criteria can be a predictor of CIA mortality in patients with different primary cancers.

BACKGROUND: The peritoneal cavity is isolated from the outside and is usually a sterile environment. Patients on peritoneal dialysis (PD) have PD fluid (PDF) infused into the peritoneal cavity. We previously showed that unregulated complement activation could contribute to the development of peritoneal inflammation in yeast peritonitis in PD therapy. In that situation, suppression of local complement activation is essential to protect the host from further injury. The membrane complement regulators (CRegs), Crry, CD55 and CD59, are expressed in the rat peritoneum, especially along the mesothelial cell layer. METHODS: We investigated CRegs' functional roles in the peritoneal cavity using blocking mAb against each CReg and complement activation in different PDFs. RESULTS: Blockade of any single CReg did not cause spontaneous peritoneal injury in rat. Combined blockade of Crry and CD59 induced focal peritoneal tissue injury and heavy accumulation of inflammatory cells with peritoneal edema at 24 h. Deposits of C3 and C5b-9 were found on the peritoneal surface after combined blocking of Crry and CD59. Systemic complement depletion by cobra venom factor abrogated these inflammatory changes. When combined blockade of Crry and CD59 was performed with PDF of different pH and glucose concentration in rats, the peritoneal injuries were enhanced with lower pH and higher glucose concentration. These results were confirmed by in vitro experiments using primary rat mesothelial cell culture. CONCLUSIONS: Rat CRegs, Crry and CD59, specifically collaborate to control complement activation in rat peritoneum. During PD, impairment of CReg might contribute to the development of severe peritoneal inflammation.

A 68-year-old man was admitted with acute renal failure caused by cholesterol embolization after undergoing carotid artery stenting. Hemodialysis therapy (HD) was immediately required because of uremia, using nafamostat mesilate as an anticoagulant for HD. However, blue toes and gangrene of the feet worsened. To prevent use of anticoagulants and stabilize BP, HD was changed to peritoneal dialysis (PD). After starting PD, blue toes and gangrene improved markedly. Residual renal function also partially recovered. Although BP was unstable during HD, stability of BP and avoidance of anticoagulants during PD therapy might have contributed to the good results.

Fungal peritonitis is an important complication in peritoneal dialysis patients; either continuous or recurrent peritonitis may enhance peritoneal damage. Even when the peritoneal dialysis catheter is removed in patients with fungal peritonitis, peritoneal fibrosis can progress and evolve into encapsular peritoneal sclerosis. It is unclear why fungal infections are worse than bacterial in these respects. Zymosan is a cell wall component of yeast that strongly activates the complement system. In this study, we compared the effects of zymosan and bacterial LPS on peritoneal inflammation in a rat peritoneal injury model induced by mechanical scraping. Intraperitoneal administration of zymosan, but not LPS or vehicle, caused markedly enhanced peritonitis with massive infiltration of cells and deposition of complement activation products C3b and membrane attack complex on day 5. In rats administered zymosan and sacrificed on days 18 or 36, peritoneal inflammation persisted with accumulation of ED-1-positive cells, small deposits of C3b and membrane attack complex, exudation of fibrinogen, and capillary proliferation in subperitoneal tissues. When zymosan was administered daily for 5 days after peritoneal scrape, there was even greater peritoneal inflammation with peritoneal thickening, inflammatory cell accumulation, and complement deposition. Inhibition of systemic complement by pretreatment with cobra venom factor or local inhibition by i.p. administration of the recombinant complement regulator Crry-Ig reduced peritoneal inflammation in zymosan-treated rats. Our results show that yeast components augment inflammation in the injured peritoneum by causing complement activation within the peritoneal cavity. Local anticomplement therapy may therefore protect from peritoneal damage during fungal infection of the peritoneum.