Glomerular lipidosis as a feature of renal-limited macrophage activation syndrome in a transplanted kidney: a case report.

BACKGROUND: Glomerular lipidosis is a rare histological feature presenting the extensive glomerular accumulation of lipids with or without histiocytic infiltration, which develops under various conditions. Among its various etiologies, macrophage activation syndrome (MAS) is a condition reported to be associated with histiocytic glomerular lipidosis. Here we describe the first case of glomerular lipidosis observed in a renal allograft that histologically mimicked histiocytic glomerulopathy owing to MAS. CASE PRESENTATION: A 42-year-old man underwent successful living-donor kidney transplantation. However, middle-grade proteinuria and increased serum triglyceride levels indicative of type V hyperlipidemia developed rapidly thereafter. An allograft biopsy performed 6 months after the transplantation showed extensive glomerular infiltration of CD68+ foam cells (histiocytes) intermingled with many CD3+ T-cells (predominantly CD8+ cells). Furthermore, frequent contact between glomerular T-cells and histiocytes, and the existence of activated CD8+ cells (CD8+, HLA-DR+ cells) were observed by double immunostaining. There was no clinicopathological data suggesting lipoprotein glomerulopathy or lecithin cholesterol acyltransferase deficiency, both of which are well-known causes of glomerular lipidosis. The histological findings were relatively similar to those of histiocytic glomerulopathy caused by MAS. As systemic manifestations of MAS, such as fever, pancytopenia, coagulation abnormalities, hyperferritinemia, increased liver enzyme levels, hepatosplenomegaly, and lymphadenopathy were minimal, this patient was clinicopathologically diagnosed as having renal-limited MAS. Although optimal treatment strategies for MAS in kidney transplant patients remains unclear, we strengthened lipid-lowering therapy using pemafibrate, without modifying the amount of immunosuppressants. Serum triglyceride levels were normalized with this treatment; however, the patient's extensive proteinuria and renal dysfunction did not improve. Biopsy analysis at 1 year after the transplantation demonstrated the disappearance of glomerular foamy changes, but the number of glomerular infiltrating cells remained similar. CONCLUSION: To our knowledge, this is the first reported case of glomerular lipidosis in a transplanted kidney. Increased interaction-activation of histiocytes (macrophages) and CD8+ T-cells, the key pathogenic feature of MAS, was observed in the glomeruli of this patient, who did not demonstrate overt systemic manifestations, suggesting a pathological condition of renal-limited MAS. The clinical effects of triglyceride-lowering therapy were limited, suggesting that hypertriglyceridemia was not the cause of but rather may be a consequence of renal-limited MAS.

Cytokine modulation in abdominal septic shock via the crucial role of IL-6 signaling in endothelial dysfunction.

Background: Early recovery from shock improves prognosis in septic shock patients. We determined whether cytokine modulation by Continuous Renal Replacement Therapy (CRRT) following acute care surgery resulted in stable hemodynamics in them. To investigate our hypothesis, we measured proinflammatory cytokines IL-6, IL-1ra and the coagulation cascade activator plasminogen activator inhibitor-1 (PAI-1) following CRRT with polymyxin B immobilized fiber (PMX-DHP) which has been utilized as an adjuvant treatment option for patients with severe septic shock. Methods: 66 septic shock patients requiring 2 h direct hemoperfusion therapy PMX-DHP were included. 36 patients of them also received continuous hemodiafiltration (CHDF) after performing PMX-DHP. Circulatory dynamics and levels of inflammatory mediators, namely IL-6, IL-1ra, and PAI-1 were assessed before, immediately after, and 24 h initiation of PMX-DHP. Results: Mean Arterial Pressure (MAP) rose intentionally by PMX-DHP just after enforcement 24 h later (p < 0.01). Levels of IL-6, IL-1ra, and PAI-1 significantly decreased after PMX-DHP (p < 0.05) and this trend was observed up to 24 h post initiation of PMX-DHP (p < 0.05). IL-6 modulation by PMX-DHP was enhanced with using CHDF and there was a significant correlation between IL-6 and MAP (p < 0.0001). In addition, levels of Il-6 and PAI-1 showed a significant correlation. Conclusion: Our data showed employing CRRT as cytokine modulators could be an additional therapeutic strategy to improve septic shock outcomes via the crucial role of IL-6 signaling in endothelial dysfunction.

Metabolomic Profiling of Plasma, Urine, and Saliva of Kidney Transplantation Recipients.

Kidney biopsy is commonly used to diagnose kidney transplant dysfunction after transplantation. Therefore, the development of minimally invasive and quantitative methods to evaluate kidney function in transplant recipients is necessary. Here, we used capillary electrophoresis-mass spectrometry to analyze the biofluids collected from transplant recipients with impaired (Group I, n = 31) and stable (Group S, n = 19) kidney function and from donors (Group D, n = 9). Metabolomics analyses identified and quantified 97 metabolites in plasma, 133 metabolites in urine, and 108 metabolites in saliva. Multivariate analyses revealed apparent differences in the metabolomic profiles of the three groups. In plasma samples, arginine biosynthesis and purine metabolism between the I and S Groups differed. In addition, considerable differences in metabolomic profiles were observed between samples collected from participants with T cell-mediated rejection (TCR), antibody-mediated rejection, and other kidney disorders (KD). The metabolomic profiles in the three types of biofluids showed different patterns between TCR and KD, wherein 3-indoxyl sulfate showed a significant increase in TCR consistently in both plasma and urine samples. These results suggest that each biofluid has different metabolite features to evaluate kidney function after transplantation and that 3-indoxyl sulfate could predict acute rejection.

Photoresponsive Gelation of Four-Armed Poly(ethylene glycol) with Photodimerizable Groups.

Standard hydrogels prepared by free radical polymerization (FRP) have heterogeneous structures with a wide mesh size distribution, which affect their mechanical and separation properties. Recent research has identified four-armed poly(ethylene glycol) (tetra-PEG) as a solution to this problem. tetra-PEG gels with a homogeneous network can be prepared and applied as high-strength gels and cell-culture substrates by reacting two types of tetra-PEG with different reactive groups at the ends. In this study, we report a photoresponsive tetra-PEG that undergoes a phase transition from a sol to a gel state in response to light. tetra-PEGs containing cinnamoyl and maleimide groups at the ends of the four-armed chains were found to gel when exposed to light. The effects of polymer concentration and light irradiation time on the gelation of tetra-PEG containing photodimerization groups were investigated. The results showed that the elastic modulus of the gel increased with the increase in the light irradiation time.

Individual Lymphocyte Sensitivity to Steroids as a Reliable Biomarker for Clinical Outcome after Steroid Withdrawal in Japanese Renal Transplantation.

Recently, steroid reduction/withdrawal regimens have been attempted to minimize the side effects of steroids in renal transplantation. However, some recipients have experienced an increase/resumption of steroid administrations and acute graft rejection (AR). Therefore, we investigated the relationship between the individual lymphocyte sensitivity to steroids and the clinical outcome after steroid reduction/withdrawal. We cultured peripheral blood mononuclear cells (PBMCs) isolated from 24 recipients with concanavalin A (Con A) in the presence of methylprednisolone (MPSL) or cortisol (COR) for four days, and the 50% of PBMC proliferation (IC50) values and the PBMC sensitivity to steroids were calculated. Regarding the experience of steroid increase/resumption and incidence of AR within one year of steroid reduction/withdrawal, the IC50 values of these drugs before transplantation in the clinical event group were significantly higher than those in the event-free group. The cumulative incidence of steroid increase/resumption and AR in the PBMC high-sensitivity groups to these drugs before transplantation were significantly lower than those in the low-sensitivity groups. These observations suggested that an individual's lymphocyte sensitivity to steroids could be a reliable biomarker to predict the clinical outcome after steroid reduction/withdrawal and to select the patients whose dose of steroids can be decreased and/or withdrawn after transplantation.

Pharmacodynamic Drug-Drug Interaction on Human Peripheral Blood Mononuclear Cells Between Everolimus and Tacrolimus at the Therapeutic Concentration Range in Renal Transplantation.

BACKGROUND Everolimus (EVL) plus tacrolimus (TAC) therapy is effective and safe in renal transplantation. However, the pharmacokinetic and pharmacodynamic information for EVL combined with TAC is limited. We investigated the pharmacodynamic drug-drug interaction between EVL and TAC at their therapeutic concentration range. MATERIAL AND METHODS Isolated peripheral blood mononuclear cells (PBMCs) from 22 healthy participants aged 22 to 24 years were cultured with concanavalin A (Con A) in the presence of EVL and/or TAC for 4 days, and the proliferation rate of the PBMCs was calculated. RESULTS TAC promoted the inhibitory efficacy of EVL against the mitogen-activated proliferation of PBMCs at the EVL therapeutic concentration range. When 0.175 ng/mL or more of TAC was combined with 30 ng/mL or more of EVL, the antagonistic effect of TAC on the inhibitory efficacy of EVL against the mitogen-activated proliferation of PBMCs was observed. Conversely, when 0.4 ng/mL TAC and 10 ng/mL or more of EVL were combined, the antagonistic effect of EVL on the inhibitory efficacy of TAC against the mitogen-activated proliferation of PBMCs was observed. CONCLUSIONS The pharmacodynamic synergistic efficacy of EVL and TAC in combination on mitogen-activated PBMCs was evident at the therapeutic concentration range, which is used in renal transplantation. However, these drugs antagonize each other to suppress the proliferation of activated PBMCs at concentrations higher than those clinically used.

Development of pure red cell aplasia by transmission and persistent infection of parvovirus B19 through a kidney allograft.

We report a case of pure red cell aplasia (PRCA) caused by parvovirus B19 (PVB19) infection, which was transmitted through a kidney allograft. The patient underwent a living-donor kidney transplant from his wife at the age of 60. Despite successful engraftment with a normal creatinine level, he developed severe anemia that required frequent blood transfusions 2 months after transplantation. Renal anemia was unlikely as his serum erythropoietin level was extremely high. A bone marrow aspiration test demonstrated the existence of large proerythroblasts. Although anti-PVB19 IgM antibody levels were not increased, polymerase chain reaction (PCR) detected PVB19 DNA in his serum. Thus, he was diagnosed as having PRCA induced by PVB19 infection. PCR analysis of total DNA isolated from 0-hour biopsy sections showed the existence of PVB19 DNA. Furthermore, PVB19 proteins was detected on renal tubules of 0-hour allograft by immunoperoxidase staining. Thus, transmission of PVB19 through the allograft was confirmed. A single course of intravenous immunoglobulin (IVIG) therapy resulted in substantial improvement; however, the effect was limited, and severe anemia relapsed after 5-6 months. Several courses of IVIG with adjustment of immunosuppressive drugs resulted in long-term remission. Our case demonstrates that donor-transmitted PVB19 infection should be suspected in kidney transplant recipients who develop refractory anemia during the early post-operative phase.

Overexpression of hydroxyproline via EGLN/HIF1A is associated with distant metastasis in pancreatic cancer.

For pancreatic cancer, the probability of distant metastasis can help choose the best course of treatment. The aim of this study is to establish the efficacy of hydroxyproline as a biomarker for distant metastasis for pancreatic cancer and to clarify the mechanism of EGLN/HIF1A axis that controls the invasion and metastasis. Metabolites (hydroxyproline) and genes (EGLN2 and EGLN3) were identified by metabolome analysis of the serum with pancreatic cancers with and without distant metastasis. The mechanism of EGLN/HIF1A axis including angiogenesis was examined in pancreatic cancer cells. Hydroxyproline associated with these mechanisms was evaluated to suggest the association with overall survival in pancreatic cancer. Decreased expression of EGLN2 and EGLN3 in pancreatic cancer, via the HIF1A and TGF ß1 pathway, was associated with the induction of angiogenic factors, increased vascular invasion, and poor overall patient survival. Hydroxyproline concentrations were regulated via the HIF1A pathway by EGLN2 and EGLN3, and that increased concentrations of hydroxyproline promote the invasion and metastasis of pancreatic cancer cells. These results suggested that the expression of hydroxyproline through the HIF1A pathway induced by EGLN2 and EGLN3 could be a surrogate marker for treatment and might predict distant metastasis in pancreatic cancer.

[Efficacy of 89Sr as Pain Relief for Gastric Cancer Bone Metastasis].

We experienced 2 cases in which strontium chloride was used for pain associated with gastric cancer bone metastasis. Case 1 was of a 69-year-old woman. In 2015, she underwent surgery for advanced gastric cancer followed by adjuvant chemotherapy with S-1 for 1 year. Multiple bone metastases were confirmed 2 years and 3 months after surgery. Obvious pain relief was obtained after 89Sr was administered, and SOX therapy was started. Case 2 was of a 62-year-old man. In 2016, he underwent curative surgery for stomach cancer. Chemotherapy with S-1 was performed for approximately 6 months, but 9 months after surgery multiple LN metastases, liver metastasis, and multiple bone metastases were observed . In case 2, 89Sr was administered, but good pain control was not obtained. The use of 89Sr for pain relief against multiple bone metastases should be based on the previous literature.

Efficacy of Enteral Nutrition by Double Elementary Diet Tube after Pylorus-Preserving Pancreatoduodenectomy.

Nutritional support after pylorus-preserving pancreaticoduodenectomy (PpPD) is still controversial. This study aimed to evaluate the efficacy of enteral nutrition (EN) via the double elementary diet (W-ED) tube after PpPD. One hundred two patients who received EN by the W-ED tube were compared with 52 patients who received total parental nutrition (TPN) previously. Clinicopathological and postoperative features were analyzed among the two groups. Patients with EN by the W-ED tube after PpPD had a lower incidence of postoperative pancreatic fistula than those with TPN. The total protein and albumin levels on discharge in the EN group were significantly higher than those in the TPN group. In the case without complication, decreasing rate of the third lumbar vertebra skeletal muscle area was significantly lower in the EN group. In the cases of soft pancreas, drainage volume by the W-ED tube until four postoperative day was significantly larger in the case without postoperative pancreatic fistula. The W-ED tube offers the advantages of reducing gastrointestinal pressure and enabling reduction of complications after PpPD surgery.

Resection of Hepatic Lesions Perfused by the Cholecystic Vein Using Indocyanine Green Navigation in Patients with cT2 Gallbladder Cancer.

BACKGROUND: Various approaches to hepatectomy have been proposed for cT2 gallbladder cancers (GBC), but the optimal management strategy remains unclear. The aim of this study is to assess the effectiveness of using an indocyanine green (ICG)-based intraoperative navigation system during hepatic resection for cT2 GBC. METHODS: From September 2007 to December 2017, 24 consecutive patients diagnosed with cT2 GBC underwent hepatic resection using ICG navigation. After cannulation of the cholecystic artery, ICG diluted with dissolution liquid was injected and ICG fluorescence illumination was visualized with the HyperEye Medical System. And additional histopathological examination was performed on the most recent 15 of the 24 patients for detection of microscopic liver metastasis. RESULTS: For all patients, the disease-free survival rate was 59.1% at 5 years and overall survival rate was 86.2% at 5 years. Microscopic liver metastasis was detected in the resected liver in 3 (20%) of 15 patients, whose site of liver was S6, S5, and S5, respectively. The weight of the liver resected using ICG navigation was significantly smaller than that of S4a/S5 segmentectomy (P < 0.0001). CONCLUSION: Resected hepatic lesion using ICG imaging was possible to perform hepatectomy including liver micro-metastasis without excess or deficiency. This procedure might be novel intraoperative imaging method to provide valuable information on the optimal surgical approach to cT2 GBC.

The diagnostic value of 99m-Tc GSA scintigraphy for liver function and remnant liver volume in hepatic surgery: a retrospective observational cohort study in 27 patients.

BACKGROUND: The aim was to analyze hepatic hypertrophy after portal vein embolization (PVE) and Associating Liver Partition with Portal vein ligation for Staged hepatectomy (ALPPS) to determine whether clinical circumstances associated with major hepatic resections correlated with remnant growth. METHODS: Data was abstracted from a retrospectively maintained database on 27 patients undergoing hepatic resection followed by PVE and the ALPPS procedure between October 1, 2007 and December 31, 2016. The increasing rate of liver volume and remnant liver LU15 was defined as the percentage-point difference between the liver volume and remnant liver LU15 before and after the intervention or surgery. And correlation between kinetic growth rate (KGR) of liver and future remnant liver volume or remnant liver LU15 was analyzed. RESULTS: The degree of hypertrophy (DH) of volume and LU15 was significantly greater after ALPPS (volume: 40.3% and LU15: 65.0%) than after PVE (volume: 22.7% and LU15: 48.8%) (P < 0.05). KGR of volume and LU15 was significantly greater after ALPPS (volume: 19.0 cm3/day and 2.00%/day) (LU15: 0.61 /day and 1.82%/day) than after PVE (volume: 3.89 cm3/day and 0.42%/day) (LU15: 0.19 /day and 0.63%/day) (P < 0.001). An inverse correlation between KGR and initial remnant liver volume was observed. And a positive correlation between KGR and LU15 was observed. CONCLUSION: Future remnant liver volume and KGR was greater after the ALPPS procedure than after PVE. Liver hypertrophy is related to the expected remnant liver volume and total liver function. This study suggested that total liver function and initial remnant liver volume might be a new indication of hepatectomy after PVE and ALPPS in the case of insufficient remnant liver volume.

Superficial Surgical Site Infection in Hepatobiliary-Pancreatic Surgery: Subcuticular Suture Versus Skin Staples.

PURPOSE: Postoperative superficial surgical site infection is a major complication in hepatobiliary-pancreatic surgery. We aimed to compare the efficacy of subcuticular sutures versus staples for skin closure in preventing superficial surgical site infection in hepatobiliary-pancreatic surgery. METHODS: Consecutive patients who underwent hepatobiliary-pancreatic surgery at our hospital from October 2006 to March 2011 and from April 2012 to March 2015 were reviewed retrospectively. Superficial surgical site infection incidence was evaluated in patients who received subcuticular sutures and those who received staples for skin closure. Propensity score matching analysis was used to adjust bias from confounding factors. RESULTS: A total of 691 patients were included. Patients with skin staple closures (n = 346) were compared with patients with subcuticular suture closures (n = 345). After a propensity score matching analysis, a significant difference in superficial surgical site infection incidence was found between the skin stapler group (11.3%) and subcuticular sutures group (2.6%). The same comparison was performed by a subgroup analysis and supported this finding in patients after hepatectomy without biliary reconstruction, pancreatoduodenectomy, or open laparotomy surgeries and in patients with body mass index < 25. CONCLUSIONS: Subcuticular suturing after hepatobiliary-pancreatic surgery was more efficacious in reducing postoperative superficial surgical site infection incidence than staples for skin closure.

Predicting hepatic failure with a new diagnostic technique by preoperative liver scintigraphy and computed tomography: a pilot study in 123 patients undergoing liver resection.

BACKGROUND: A novel index, total liver LU15, has been identified as a surrogate marker for liver function. We evaluated the ability of preoperative remnant liver LU15 values to predict postoperative hepatic failure. METHODS: Preoperative risk factors for postoperative hepatic failure and remnant liver LU15 were evaluated in 123 patients undergoing liver resection for several diseases from September 1st, 2007 to December 1st, 2016. We calculated the remnant liver LU15 value from the total liver LU15 value and the functional remnant liver ratio. Risk factors for postoperative hepatic failure was determined by univariate and multivariate analysis. RESULTS: Hepatic failure grade B/C developed postoperatively in six patients of seven patients within Makuuchi criteria / without criteria for remnant liver LU15. Operative time (p = 0.0242) and criteria for remnant liver LU15 (p = 0.0001) were prognostic factors for hepatic failure according to the univariate analysis. And criteria for remnant liver LU15 (p = 0.0009) was only prognostic factor by multivariate analysis. CONCLUSION: Based on the findings form this pilot study, it appears that patients with a remnant liver LU15 value of 13 or less may have a high risk of postoperative hepatic failure.

[Long-Term Survival of a Gastric Neuroendocrine Carcinoma Patient with Extra-Regional Lymph Node Metastases].

A 56-year-old man with advanced gastric tumor in the pyloric antrum had multiple lymph node metastases(lymph nodes #5, 6, 8, and 13), as revealed by abdominal computed tomography(CT).The patient was diagnosed with coexisting clinical Stage III A gastric cancer(cT2[SS], cN2, cM0)with concomitant malignant lymphoma.Distal gastrectomy, D2 lymph node dissection, and resection of lymph node #13 were performed.Histopathological findings indicated that both the primary tumor and lymph node metastases were neuroendocrine carcinomas.Adjuvant chemotherapy with S-1 was administered; however, follow-up CT after 6 months revealed local recurrence around the celiac artery.Therefore , the chemotherapy regimen was changed to irinotecan and cisplatin.A clinical complete response was obtained after 6 chemotherapy courses and maintained for up to 45 months.The patient is alive at 60 months after the operation.

Increased expression of HOXB9 in hepatocellular carcinoma predicts poor overall survival but a beneficial response to sorafenib.

At advanced stages of hepatocellular carcinoma (HCC), the multikinase inhibitor sorafenib is the only effective treatment. Surrogate markers that predict the biological and clinical efficacy of sorafenib may help tailor treatment on an individual patient basis. In the present study, the clinical significance of the expression of HOXB9, a transcriptional factor, in HCC was assessed. Increased HOXB9 expression in HCC was found to be positively correlated with the expression of angiogenic factors, increased vascular invasion and was found to be associated with poor overall patient survival. Sorafenib treatment effectively suppressed the expression of angiogenic factors and activation of the Raf/MEK/ERK pathway in HOXB9-expressing HCC cell lines. Consistent with these findings, HCC patients, whose cancer expressed high levels of HOXB9, exhibited increased overall survival upon sorafenib treatment. Collectively, these results suggest that HOXB9 expression in HCC could be a surrogate marker for a beneficial response to sorafenib treatment.

Long-term survival of a recurrent gallbladder carcinoma patient with lymph node and peritoneal metastases after multidisciplinary treatments: a case report.

BACKGROUND: Gallbladder carcinoma with peritoneal metastasis has a poor prognosis, with a median survival time of 4.8 months. We report the survival of a patient with gallbladder carcinoma with peritoneal metastasis for 7.6 months owing to treatment with tumor resection after chemoradiotherapy. CASE PRESENTATION: A 69-year-old man was referred to our hospital for gallbladder carcinoma with hepatic invasion. Cholecystectomy was performed along with S4a and S5 hepatectomy and extrahepatic bile duct resection with lymph node dissection. The postoperative pathological diagnosis was moderately differentiated adenocarcinoma, T3, N0, M0, stage IIIA by the International Union Against Cancer TNM classification. Despite treatment with gemcitabine, the common hepatic artery and para-aortic lymph nodes showed metastases after 3 months from surgery. Although a combination of cisplatin, gemcitabine, and radiotherapy reduced the size of the lymph node metastasis, the peritoneal metastasis persisted. The peritoneal metastasis responded to chemoradiotherapy using tegafur-uracil and leucovorin, but it recurred. The metastasis was resected after 3 years and 9 months from the first surgery, and chemotherapy was discontinued. Seven years and 6 months after the initial surgery, the patient exhibited no signs of tumor recurrence or metastasis. CONCLUSIONS: Multidisciplinary treatment including resection without residual tumors could achieve complete remission of gallbladder carcinoma with lymph node and peritoneal metastases in the selected patient.