Peritoneal Dialysis and Malignancy: An Experience With a Patient Complicated by Gastric Carcinoma.

An 86-year-old man who had been treated with peritoneal dialysis for 14°months due to end-stage kidney disease secondary to hypertensive nephrosclerosis presented with a recent history of malaise, abdominal discomfort, and anorexia. An endoscopic evaluation revealed an elevated, ulcerated, and friable lesion around the lesser curvature of the stomach. The concurrent gastric biopsy specimens revealed moderately differentiated adenocarcinoma, while a cytological examination of the dialysis fluid revealed clusters of malignant cells. This is the first report illustrating a case of a Borrmann type 3 gastric cancer with synchronous peritoneal involvement in which the assessment of the disease state was aided by the cytological analysis of peritoneal effluent. Several concerns relating to this pathology are also discussed.

Multiple Sclerosis Drug Fingolimod Induces Thrombotic Microangiopathy in Deoxycorticosterone Acetate/Salt Hypertension.

We examined whether fingolimod (FTY720), an S1PR (sphingosine-1-phosphate receptor) modulator, has beneficial or harmful effects on mineralocorticoid/salt-induced renal injury. Uninephrectomized rats on 0.9% NaCl/0.3% KCl drinking solution were randomly divided into control, control+FTY720, deoxycorticosterone acetate (DOCA), and DOCA+FTY720 groups and administered vehicle, vehicle+FTY720, DOCA+vehicle, and DOCA+FTY720 for 4 weeks, respectively. Only the DOCA+FTY720 group had reduced survival rates and showed hemolysis because of intravascular mechanical fragmentation of erythrocytes and thrombocytopenia. Both the DOCA+FTY720 and DOCA groups developed malignant hypertension, which was more severe in the DOCA+FTY720 group. In the DOCA+FTY720 group only, thrombotic microangiopathy involving severe renal arteriole endothelial cell injury was observed and was characterized by fibrinoid necrosis and onion-skin lesions in arterioles. There were fewer circulating endothelial progenitor cells in the DOCA+FTY720 group but more in the DOCA group compared with the control group. Expression levels of VEGF (vascular endothelial growth factor), S1PR1, and S1PR3 in renal arteriole endothelial cells were significantly greater in the DOCA+FTY720 and DOCA groups compared with the control group, with levels being similar between the 2 groups. Expression levels of endothelial nitric oxide synthase in renal arteriole endothelial cells were significantly lower in the DOCA+FTY720 group only. The control+FTY720 group showed reduced circulating endothelial progenitor cells but no significant functional or pathological changes in kidneys or changes in blood pressure. Exposure of uninephrectomized rats to DOCA/salt+FTY720 for 4 weeks induced renal arteriolar endothelial cell injury, resulting in the development of thrombotic microangiopathy. Consideration of this possibility is recommended when prescribing FTY720.

Peritoneal Dialysis and Retroperitoneal Laparoscopic Radical Nephrectomy: A Favorable Experience With a Patient Complicated by Renal Cell Carcinoma.

Peritoneal dialysis (PD) is an accepted modality for managing end-stage kidney disease. We herein report a 75-year-old female patient on chronic PD who was complicated by renal cell carcinoma. She was successfully treated with retroperitoneal laparoscopic radical nephrectomy followed by a prompt resumption of the procedure. Various surgeries disturbing the abdominal wall integrity often disrupt the regular PD schedule, and using minimally invasive approaches is therefore an attractive therapeutic option. Our experience emphasizes the feasibility and safety of a retroperitoneal approach-based laparoscopic technique based on several empirical examples. However, systemic studies on this topic are obviously lacking, so we strongly recommend the accumulation of more cases similar to our own. Several surgical concerns that need to be dealt with among PD patients are also discussed.

Pleuroperitoneal Communication and Ovarian Cancer Complicating Peritoneal Dialysis: A Case Report of a Patient with End-Stage Kidney Disease.

Peritoneal dialysis has been a widely accepted modality for treating end-stage kidney disease, but a regular dialysis schedule can be seriously disrupted by various comorbid conditions requiring surgical intervention. A 40-year-old woman who had been receiving peritoneal dialysis was sequentially but separately complicated by pleuroperitoneal communication and ovarian cancer. Despite the need for temporary interruption of her peritoneal dialysis schedule, it was successfully resumed after the relevant surgeries for each disease. Several concerns regarding overall postoperative dialytic management strategies, including how to deal with the peritoneal dialysis catheter during the postoperative period as well as how long peritoneal dialysis should be interrupted, which remain an unresolved issue in the field of nephrology, are also discussed.

Nephrotic Syndrome and a Retroperitoneal Mass: A Case Report of a Patient with Recurrent Invasive Thymoma.

A 68-year-old man was admitted to our hospital to undergo an examination for nephrotic syndrome while concurrently complicated with recurrent thymoma in the parietal pleura and retroperitoneum. He had been diagnosed with invasive thymoma and had undergone thymo-thymectomy seven years previously. Based on the renal biopsy findings, his nephrotic syndrome was ascribed to minimal change disease. He was treated with corticosteroid monotherapy, which resulted in complete remission six months later, despite the fact that the recurrent thymoma remained. The role of thymoma in the pathogenesis of paraneoplastic glomerulopathy and the therapeutic concerns that emerged in this case are also discussed.

Acute Kidney Injury Associated with Renal Cell Carcinoma Complicated by Renal Vein and Inferior Vena Cava Involvement.

Acute kidney injury (AKI) is caused by diverse pathologies, although it may occasionally result from concurrent renal efflux disturbances. We herein describe a case of AKI in a patient complicated by renal cell carcinoma (RCC) with renal vein and inferior vena cava (IVC) involvement. A neoplastic thrombus which disrupted the blood flow in the renal vein appeared to play a role in the rapid decline in the renal function. Such a scenario has rarely been mentioned in the previous literature describing the cases of RCC complicated by AKI. Concerns regarding the diagnostic and therapeutic strategies for RCC are also discussed.

A Supraglottic Pseudotumor in an Immunocompromised Patient with Nephrotic Syndrome, Herpes Zoster, and a Cytomegalovirus Infection.

Several viral infections may occasionally induce supraglottic mass lesions, resulting in an obstructive airway emergency. We herein report one such case in a 63-year-old male immunocompromised patient with nephrotic syndrome due to membranous nephropathy who also had ophthalmic herpes zoster with a laryngeal mass, which required urgent intubation and mechanical ventilation. The patient was initially treated with acyclovir; however, because a serological analysis revealed a concurrent cytomegalovirus infection, we discontinued the administration of acyclovir and gave priority to the simultaneous treatment of the cytomegalovirus and varicella-zoster virus infections with ganciclovir. The clinical course was favorable, and he was weaned from the ventilator 10 days later when a serial imaging analysis revealed no signs of the supraglottic mass, leading us to conclude that these two viral infections could have additively or synergistically contributed to the development of the local pseudotumor. The diagnostic and therapeutic concerns arising in the current case are also discussed.

Bowel Obstruction and Peritoneal Dialysis: A Case Report of a Patient with Complications from a Broad Ligament Hernia.

Abdominal hernias are a common cause of bowel obstruction. The major types of abdominal hernias are external or abdominal wall hernias, which occur at areas of congenital or acquired weakness in the abdominal wall. An alternative entity is internal hernias, which are characterized by a protrusion of viscera through the peritoneum or mesentery. We herein present the case of a female peritoneal dialysis patient with bowel obstruction due to an internal hernia. Although an initial work-up did not lead to a correct diagnosis, an exploratory laparotomy revealed that she had intestinal herniation due to a defect in the broad ligament of the uterus, which was promptly corrected by surgery. The concerns about the perioperative dialytic management as well as the diagnostic problems regarding the disease that arose in our experience with the present patient are also discussed.

Sarcoidosis during etanercept treatment for rheumatoid arthritis in women with a history of bilateral oophorectomy.

nd in immune-mediated inflammatory diseases, such as rheumatoid arthritis (RA). Paradoxically, this treatment induces sarcoidosis in a small population of RA patients as a class effect. A safer anti-TNF therapeutic strategy requires understanding of the risk factors for sarcoidosis. In Japan, TNF inhibitor was introduced in 2003. We reviewed 226 consecutive patients (65 men and 161 women) who were newly diagnosed with sarcoidosis between 2003 and 2012 at Jichi Medical University Hospital, Japan. We detected 3 cases in which sarcoidosis developed during etanercept treatment for RA. All 3 cases were women who had undergone bilateral oophorectomy more than 20 years earlier. Taken together with our previous epidemiologic findings of a consistently maintained second peak after menopause in the age-specific distribution of sarcoidosis in women over four decades, long-term insidious ovarian dysfunction was a possible risk factor for sarcoidosis under certain conditions, especially during etanercept treatment.

Tubulointerstitial Nephritis and Uveitis Syndrome: Are Drugs Offenders or Bystanders?

A 16-year-old female patient was admitted to our hospital due to progressive renal dysfunction with an increased serum creatinine (sCr) level of 1.7 mg/dL. Her clinical course without any ocular manifestations and results of drug-induced, lymphocyte-stimulating tests, in addition to a renal histological assessment, initially encouraged us to ascribe the patient's renal abnormalities to drug-induced acute interstitial nephritis (AIN). Four months later, she started to complain about reduced visual acuity when she was found to have anterior bilateral uveitis despite the recovered renal function with almost constant sCr levels around 0.7 mg/dL. Thus, a diagnosis of tubulointerstitial nephritis and uveitis (TINU) syndrome was finally made. Our case illustrates the difficulties in distinguishing late-onset uveitis TINU syndrome from drug-induced AIN at the time of the renal biopsy, thereby suggesting the importance of a longitudinal follow-up to overcome the potential underdiagnosis of the disease. Several diagnostic conundrums that emerged in this case are also discussed.

Matrix metalloproteinase-2 as a superior biomarker for peritoneal deterioration in peritoneal dialysis.

AIM: To investigate the efficacy of effluent biomarkers for peritoneal deterioration with functional decline in peritoneal dialysis (PD). METHODS: From January 2005 to March 2013, the subjects included 218 PD patients with end-stage renal disease at 18 centers. Matrix metalloproteinase-2 (MMP-2), interleukin-6 (IL-6), hyaluronan, and cancer antigen 125 (CA125) in peritoneal effluent were quantified with enzyme-linked immunosorbent assay. Peritoneal solute transport rate was assessed by peritoneal equilibration test (PET) to estimate peritoneal deterioration. RESULTS: The ratio of the effluent level of creatinine (Cr) obtained 4 h after injection (D) to that of plasma was correlated with the effluent levels of MMP-2 (ρ = 0.74, P < 0.001), IL-6 (ρ = 0.46, P < 0.001), and hyaluronan (ρ = 0.27, P < 0.001), but not CA125 (ρ = 0.13, P = 0.051). The area under receiver operating characteristic curve for the effluent levels of MMP-2, IL-6, and hyaluronan against high PET category were 0.90, 0.78, 0.62, and 0.51, respectively. No patient developed new-onset encapsulating peritoneal sclerosis for at least 1.5 years after peritoneal effluent sampling. CONCLUSION: The effluent MMP-2 level most closely reflected peritoneal solute transport rate. MMP-2 can be a reliable indicator of peritoneal deterioration with functional decline.

HIF-1α mediates Hypoxia-induced epithelial-mesenchymal transition in peritoneal mesothelial cells.

The epithelial-to-mesenchymal transition (EMT) of peritoneal mesothelial cells plays a pivotal role in the development of peritoneal fibrosis. The pathological effects of hypoxia on mesothelial cell EMT have not been fully elucidated. In this study, we, therefore, investigated the effects of hypoxia on EMT in mesothelial cells. Human mesothelial (MeT-5A) cells and primary-cultured rat mesothelial cells were cultured under hypoxic conditions (1% O(2)) for up to 72 h. Changes in cell type were then determined by investigating changes in morphology and in expression of epithelial (E-cadherin and occludin) and mesenchymal (fibronectin-1, vimentin and α-smooth muscle actin) cell markers. In some cases, MeT-5A cells were cultured under hypoxic conditions with a HIF-1α inhibitor and then assessed for changes in morphology and for altered expression of signaling molecules, such as HIF-1α, Snail-1, vascular endothelial growth factor (VEGF), and matrix metalloproteinase-2 (MMP-2). Levels of HIF-1α, Snail-1, VEGF, and MMP-2 in Met-5A cells were increased by hypoxia. Levels of epithelial cell markers were decreased and those of mesenchymal cell markers were increased. Cell morphology also changed from a cobblestone-like monolayer to spindle-shaped fibroblast-like cells in response to hypoxia. Inhibition of HIF-1α signaling by a HIF-1α inhibitor abrogated these changes. The cell marker and morphological changes induced by hypoxia were also observed in primary-cultured rat mesothelial cells. We can conclude that hypoxia induces EMT in mesothelial cells by activating HIF-1α. This finding indicates that hypoxia has pivotal roles in the development of peritoneal fibrosis in peritoneal dialysis patients.

Attenuation of methylglyoxal-induced peritoneal fibrosis: immunomodulation by interleukin-10.

Peritoneal fibrosis (PF), a serious pathophysiology of peritoneal dialysis (PD), is implicated in various types of chronic inflammation. In the present study, we examined the benefits of interleukin (IL)-10, which exerts anti-inflammatory effects, in an experimental rat model of methylglyoxal (MGO)-induced PF. We injected an adeno-associated virus (AAV) vector encoding rat IL-10 or enhanced green fluorescent protein (GFP) into male Sprague-Dawley rats at 6 weeks of age. Four weeks later, the rats received continuous peritoneal injections of conventional PD fluid (PDF) with MGO for 3 weeks. Then, the peritoneal histology and the expression levels of fibrogenic mediators and proinflammatory cytokines were analyzed. The rats demonstrating persistent IL-10 expression showed significantly reduced fibrous peritoneal thickening compared with those with GFP expression. The infiltration of macrophages, the expression of tumor necrosis factor-α, IL-1ß, IL-6, transforming growth factor-ß1, Snail, and matrix metalloproteinase 2 genes as well as the proliferation of mesenchymal-like mesothelial cells augmented by MGO were all significantly suppressed by IL-10 expression. IL-10 also abrogated the extent of MGO-induced bowel adhesions mimicking a cocoon-like mass. Our findings provide valuable insight into the potential benefit of immunomodulation with IL-10 as one potentially effective therapeutic strategy for preventing the onset of peritoneal injury resulting in PF.

Methylglyoxal Induced Basophilic Spindle Cells with Podoplanin at the Surface of Peritoneum in Rat Peritoneal Dialysis Model.

Peritoneal dialysis (PD) is a common treatment for patients with reduced or absent renal function. Long-term PD leads to peritoneal injury with structural changes and functional decline. At worst, peritoneal injury leads to encapsulating peritoneal sclerosis (EPS), which is a serious complication of PD. In order to carry out PD safely, it is important to define the mechanism of progression of peritoneal injury and EPS. We prepared rat models of peritoneal injury by intraperitoneal administration of glucose degradation products, such as methylglyoxal (MGO) or formaldehyde (FA), chlorhexidine gluconate (CG), and talc. In rats treated with MGO, peritoneal fibrous thickening with the appearance of basophilic spindle cells with podoplanin, cytokeratin, and α-smooth muscle actin at the surface of the peritoneum was observed. These cells may have been derived from mesothelial cells by epithelial-to-mesenchymal transition. In FA- or CG-treated rats, the peritoneum was thickened, and mesothelial cells were absent at the surface of the peritoneum. The CG- or MGO-treated rats presented with a so-called abdominal cocoon. In the talc-treated rats, extensive peritoneal adhesion and peritoneal thickening were observed. MGO-induced peritoneal injury model may reflect human histopathology and be suitable to analyze the mechanism of progression of peritoneal injury and EPS.

Delivery of microRNA-146a with polyethylenimine nanoparticles inhibits renal fibrosis in vivo.

Renal fibrosis is the final common pathway leading to end-stage renal disease. Although microRNA (miR) was recently shown to be involved in the development of renal fibrosis, few studies have focused on the effects on renal fibrosis of exogenous miR delivered in an in vivo therapeutic setting. The study reported here investigated the effects of miR-146a delivery using polyethylenimine nanoparticles (PEI-NPs) on renal fibrosis in vivo. PEI-NPs bearing miR-146 or control-miR (nitrogen/phosphate ratio: 6) were injected into the tail vein of a mouse model of renal fibrosis induced by unilateral ureteral obstruction. PEI-NPs bearing miR-146 significantly enhanced miR-146a expression in the obstructed kidney compared with the control group, while inhibiting the renal fibrosis area, expression of alpha-smooth muscle actin, and infiltration of F4/80-positive macrophages into the obstructed kidney. In addition, PEI-NPs bearing miR-146a inhibited the transforming growth factor beta 1-Smad and tumor necrosis factor receptor-associated factor 6-nuclear factor kappa B signaling pathways. Control-miR-PEI-NPs did not show any of these effects. These results suggest that the delivery of miR-146a attenuated renal fibrosis by inhibiting pro-fibrotic and inflammatory signaling pathways and that the delivery of appropriate miRs may be a therapeutic option for preventing renal fibrosis in vivo.

Low-dose corticosteroid and gallium-67 scintigraphy and acute interstitial nephritis.

We describe a 19-year-old male who developed diclofenac-induced acute interstitial nephritis (AIN). Diffuse mononuclear cell infiltration was confirmed by renal biopsy and a Gallium (Ga)-67 scintigraphy revealed diffuse uptake of the isotope in both kidneys. His renal function had gradually and promptly recovered after initiation of low-dose prednisolone (0.5 mg/kg/day). There are no established criteria for the administration of corticosteroids in the treatment of drug-induced AIN. Moreover, no clear recommendations regarding the optimal dose and duration of steroid administration in the treatment for drug-induced AIN has been established. In addition, we discuss the clinical benefit of steroid treatment and the diagnostic impact of Ga scanning on the management of drug-induced AIN.

ASC in renal collecting duct epithelial cells contributes to inflammation and injury after unilateral ureteral obstruction.

Inflammation plays a crucial role in the pathophysiological characteristics of chronic kidney disease; however, the inflammatory mechanisms underlying the chronic kidney disease process remain unclear. Recent evidence indicates that sterile inflammation triggered by tissue injury is mediated through a multiprotein complex called the inflammasome. Therefore, we investigated the role of the inflammasome in the development of chronic kidney disease using a murine unilateral ureteral obstruction (UUO) model. Inflammasome-related molecules were up-regulated in the kidney after UUO. Apoptosis-associated speck-like protein containing a caspase recruitment domain deficiency significantly reduced inflammatory responses, such as inflammatory cell infiltration and cytokine expression, and improved subsequent renal injury and fibrosis. Furthermore, apoptosis-associated speck-like protein containing a caspase recruitment domain was specifically up-regulated in collecting duct (CD) epithelial cells of the UUO-treated kidney. In vitro experiments showed that extracellular adenosine triphosphate (ATP) induced inflammasome activation in CD epithelial cells through P2X7-potassium efflux and reactive oxygen species-dependent pathways. These results demonstrate the molecular basis for the inflammatory response in the process of chronic kidney disease and suggest the CD inflammasome as a potential therapeutic target for preventing chronic kidney disease progression.

Increased antiangiogenetic factors in severe proteinuria without hypertension in pregnancy: is kidney biopsy necessary?

Acute onset of severe proteinuria during pregnancy obliges physicians to clinically discriminate between gestational proteinuria (GP) and new onset of nephritis. A multiparous woman developed severe proteinuria (5.8 g/day) without hypertension at 32 weeks of gestation. We measured the maternal level of soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEng), which were extremely high (41.3 and 54.8 ng/ml, respectively), leading us to consider this condition as GP rather than acute onset of nephritis. Thus, we did not perform a kidney biopsy and did not administer a steroid agent. Non-reassuring fetal status required emergency Cesarean section at 33 weeks. Proteinuria decreased to 0.36 g/day at 12 weeks after delivery, and finally disappeared 26 weeks postpartum. Measurement of sFlt-1 and sEng in a pregnant woman with severe proteinuria without hypertension may assist in differential diagnosis of GP from acute onset of nephritis, and thus help to decide whether to perform kidney biopsy during pregnancy.

Delayed development of pulmonary hemorrhage in a patient with positive circulating anti-neutrophil cytoplasmic antibody: a clinical dilemma.

Detection of circulating anti-neutrophil cytoplasmic antibody (ANCA) provides a powerful clue in the diagnosis of vasculitis, but the clinical interpretation of the results is difficult in some cases. Here, we describe the case of a 65-year-old man who underwent hemodialysis due to focal segmental glomerulosclerosis and abruptly developed hemoptysis 14 years after a renal biopsy. At the time of the biopsy, computed tomography (CT) showed interstitial shadows in the lungs and pleural thickening, indicating pneumoconiosis that was accompanied by tuberculosis. Circulating myeloperoxidase-ANCA (10.5-32.5 U/ml) was subsequently noted, but the significance of this observation was unclear due to the preexisting disorders in the lungs and kidneys. Potent immunosuppressive therapies were avoided because of the pulmonary lesions and decreased renal function. There were few changes noted on follow-up CT, but infiltrative shadows emerged in the bilateral lungs, consistent with hemoptysis. The hemorrhagic shadows completely disappeared shortly after initiation of steroid therapy, with normalization of the serum ANCA level. Herein, we report this case, with an emphasis on the clinical dilemma faced in deciding the appropriate treatment. The findings in the case provide deep insights into clinical management of ANCA-positive patients.