Dysbiosis of Gut Microbiota in Patients with Chronic Kidney Disease.

Objective The gut bacterial microbiota is altered in patients with chronic kidney disease (CKD). However, the bacterial composition at each stage of CKD is unclear in these patients, including those receiving renal replacement therapy. We herein report the changes in the gut microbiota among patients with CKD. Methods A total of 93 individuals were recruited for the study. Seventy-three patients had stage 3-5 CKD, including those receiving renal replacement therapy (CKD group), and 20 were age- and sex-matched controls (CKD stage 1-2). The gut microbiome composition was analyzed using a 16S ribosomal RNA gene-based sequencing protocol. Results At the genus level, the butyrate-producing bacteria Lachnospira, Blautia, Coprococcus, Anaerostipes, and Roseburia were more abundant in the control group (linear discriminant analysis score of >3) than in the CKD group. Lachnospira was more abundant in the control group than in patients with CKD stage 3a. Compared to the control group, multiplex butyrate-producing bacteria were deficient in patients with CKD stage 3b-5D, including in patients receiving renal replacement therapy. Conclusion Our findings highlight the fact that the gut bacterial composition, including butyrate-producing bacteria, deteriorates from CKD stage 3b. Even after renal replacement therapy, the bacterial composition did not change.

Associations among preoperative transthoracic echocardiography variables and cerebral near-infrared spectroscopy values at baseline before anesthesia in patients undergoing cardiac surgery: a retrospective observational study.

Cerebral tissue oximetry with near-infrared spectroscopy (NIRS) is used to monitor cerebral oxygenation during cardiac surgery. To date, reduced baseline cerebral NIRS values have been attributed to reduced cerebral blood flow primarily based on a significant positive correlation between left ventricular ejection fraction (LVEF) and baseline rSO2 measured with the INVOS 5100C oximeter. Reportedly, however, rSO2, but not StO2 measured with the FORESIGHT Elite oximeter, correlated with LVEF. We, thus, investigated associations among baseline NIRS values measured with three different oximeters before anesthesia for cardiac surgery and preoperative transthoracic echocardiography (TTE) variables, including LVEF, to examine whether there are inter-device differences in associations among baseline NIRS values and TTE variables. Using Spearman's correlation coefficient, we retrospectively investigated associations among 15 preoperative TTE variables, including LVEF, and baseline NIRS values, including rSO2, StO2, and TOI with the NIRO-200NX oximeter in 1346, 515, and 301 patients, respectively. Only rSO2 (p < 0.00001), but not TOI or StO2 (p > 0.05), positively correlated with LVEF. On the other hand, baseline rSO2, TOI, and StO2 consistently, negatively correlated with the left atrial diameter index (LADI), early diastolic transmitral flow velocity (E), E-to-early diastolic mitral annular velocity ratio (E/e'), estimated right ventricular systolic pressure (eRVP), and inferior vena cava diameter index (IVCDI) (p < 0.0005 to p < 0.00001). Because all of these five TTE variables could be positively associated with right as well as left ventricular filling pressure, our results indicated that reduced baseline NIRS values were consistently associated not with reduced LVEF but with TTE findings indicative of elevated biventricular filling pressure. Our data suggest that regional venous congestion greatly contributes to reduced baseline NIRS values in patients undergoing cardiac surgery.

A case of crescentic glomerulonephritis induced by afatinib for lung adenocarcinoma.

Afatinib is a second-generation, oral, epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). One of the most common adverse effects of affatinib is diarrhea, which may lead to acute kidney injury (AKI) due to severe plasma volume loss; however, no case of glomerular injury directly induced by afatinib has been reported to date. Here, we describe the case of a 53-year-old Japanese male patient with advanced lung adenocarcinoma who twice developed AKI requiring dialysis, once after starting and once after increasing the dose of afatinib. Although serum anti-neutrophil cytoplasmic antibodies were negative, crescentic glomerulonephritis with no immune deposits was confirmed on kidney biopsy. No vasculitis-like signs were observed in other organs, such as lung, skin, or peripheral nerves. Afatinib was considered the cause of glomerular damage and was immediately discontinued; corticosteroids were administered. Renal function gradually recovered thereafter, with serum creatinine levels at ~ 2.3 mg/dL after second-line therapy with bevacizumab and atezolizumab. Several cases of cutaneous leukocytoclastic vasculitis have been reported in patients treated with other EGFR-TKIs; therefore, afatinib-induced vasculitis may lead to crescentic glomerulonephritis. Although afatinib-induced glomerular injury is extremely rare and has an unclear mechanism, renal function and urinary findings need to be closely monitored.

Suppressed expression of ErbB3-binding protein 1 (EBP1) genes compromised the hypersensitive response cell death in Nicotiana benthamiana.

Target of rapamycin (TOR) regulates essential processes associated with plant growth, development, and cell death by modulating metabolic activities and translation in response to environmental signals. The ATP-competitive TOR inhibitor AZD8055 suppressed the hypersensitive response (HR) cell death in Nicotiana benthamiana infected with the incompatible Ralstonia solanacearum. The induced expression of the HR marker gene hin1 was also inhibited by the AZD8055 treatment. To further clarify the mechanisms underlying TOR-regulated HR cell death, we focused on TOR-related ErbB3-binding protein 1 (EBP1) in N. benthamiana (NbEBP1). We found four EBP1 orthologs in the N. benthamiana genome. The expression levels of all four EBP1 orthologs in N. benthamiana were up-regulated by the R. solanacearum infection. The silencing of the four NbEBP1 orthologs suppressed the induction of HR cell death, hin1 expression, and the production of reactive oxygen species. These results suggest that the TOR signaling pathway helps regulate HR cell death along with reactive oxygen species-related signaling in N. benthamiana.

Continuing versus withholding angiotensin receptor blocker (ARB)/calcium channel blocker (CCB) combination tablets during perioperative periods in patients undergoing minor surgery: a single-blinded randomized controlled trial.

PURPOSE: This trial was conducted to compare effects of continuing versus withholding single-pill combination tablets consisting of angiotensin receptor blockers (ARBs) and calcium channel blockers (CCBs) on perioperative hemodynamics and clinical outcomes. METHODS: Patients undergoing minor abdominal or urological surgery (n = 106) were randomly assigned to Group C, in which ARB/CCB combination tablets were continued until surgery, or Group W, in which they were withheld within 24 h of surgery. Perioperative hemodynamics and clinical outcomes were compared between the Groups. RESULTS: The incidence of hypotension during anesthesia requiring repeated treatment with vasoconstrictors was higher in Group C than Group W (p = 0.0052). Blood pressure during anesthesia was generally lower in Group C than Group W (p < 0.05) despite significantly more doses of ephedrine and phenylephrine administrated in Group C (p = 0.0246 and p = 0.0327, respectively). The incidence of postoperative hypertension did not differ between Groups (p = 0.3793). Estimated glomerular filtration rate (eGFR) on the preoperative day did not differ between Groups (p = 0.7045), while eGFR was slightly lower in Group C than Group W on the first and third postoperative days (p = 0.0400 and p = 0.0088, respectively), although clinically relevant acute kidney injury did not develop. CONCLUSIONS: Continuing ARB/CCB combination tablets preoperatively in patients undergoing minor surgery increased the incidence of hypotension during anesthesia, increased requirements of vasoconstrictors to treat hypotension, and might deteriorate postoperative renal function, albeit slightly. These results suggest that withholding ARB/CCB tablets preoperatively is preferable to continuing them. CLINICAL TRIAL REGISTRATION: This trial is registered with the Japan Registry of Clinical Trials (jRCT) at Japanese Ministry of Health, Labour, and Welfare (Trial ID: jRCT1031190027).

Focal segmental glomerulosclerosis and concurrent glomerular microangiopathy after long-term imatinib administration.

A 79-year-old Japanese man was admitted to our hospital because of proteinuria and kidney dysfunction. He was diagnosed with chronic myeloid leukemia 13 years before and was treated with imatinib. Deep molecular response was achieved but he developed 1+ proteinuria in the first year, which gradually worsened thereafter. Imatinib was discontinued 12 years later but proteinuria and kidney dysfunction were progressive. Percutaneous kidney biopsy revealed mild mesangial hyper-cellularity and matrix increase, swelling of endothelial cells, and partial double contours of glomerular tufts. Subendothelial edema in the interlobular artery was also noted. Immunofluorescence was not remarkable. Electron microscopy revealed endothelial injury with severe sub-endothelial edema. Since imatinib had already been discontinued, conservative therapy with maximal dose of azilsartan was administered. A second biopsy was performed 1 year later because of further deterioration of kidney function, which revealed markedly increased global glomerulosclerosis and severe interstitial fibrosis and tubular atrophy. Segmental glomerulosclerosis with podocyte hyperplasia was also observed. Electron microscopy revealed glomerulosclerotic changes and partially attenuated endothelial injury. Two and a half years later, proteinuria reduced, progression of kidney dysfunction slowed, and he was independent on dialysis therapy. Molecular response of chronic myeloid leukemia was also maintained. The clinical course suggested that endothelial and podocyte injuries were induced by imatinib, and that the nephrotoxic effects lasted for a few years after discontinuation.

Cerebral oxygen saturation (rSO2) during cardiopulmonary bypass (CPB) measured using the INVOS oximeter closely correlates with baseline rSO2.

Baseline cerebral regional saturation (rSO2) measured using the INVOS 5100C (Medtronic, MN, USA) varies widely among patients with cardiac and/or renal diseases. To identify significant correlates of baseline rSO2 and to investigate intraoperative rSO2 changes, we conducted a retrospective study in 494 patients undergoing on-pump cardiovascular surgery. Correlations between preoperative blood laboratory test variables and baseline rSO2 before anesthesia were examined. Intraoperative rSO2 changes were analyzed. Of all the variables examined, log-transformed B-type natriuretic peptide (BNP) most significantly and negatively correlated with baseline rSO2 (r = - 0.652, p < 0.0001). Intraoperatively, rSO2 showed the lowest value during cardiopulmonary bypass (CPB) (median rSO2: 56.2% during CPB vs. 63.9% at baseline, p < 0.0001). Although rSO2 during CPB correlated positively with hemoglobin concentration and oxygen delivery during CPB (r = 0.192, p < 0.0001; and r = 0.172, p = 0.0001, respectively), it correlated much more closely with baseline rSO2 (r = - 0.589, p < 0.0001). Thus, patients showing low baseline rSO2 primarily associated with preoperatively high BNP continued to show low rSO2 even during CPB independent of hemodynamics artificially controlled by CPB. Our findings suggest that low baseline rSO2 in patients with high BNP due to cardiac and/or renal diseases is more likely to result from tissue edema causing alterations in optical pathlength and thus in calculated rSO2 values, not readily modifiable with CPB, rather than actual cerebral hemodynamic alterations readily modifiable with CPB. These may partly explain why the INVOS oximeter is a trend monitor requiring baseline measures.

Concurrent minimal change disease and retroperitoneal liposarcoma successfully treated by tumor resection and steroid therapy.

A 54-year-old Japanese woman developed simultaneous abdominal distension and bilateral leg edema. Her medical history and results of periodic medical check-up were unremarkable. Blood tests revealed severe hypoproteinemia and acute kidney injury, and urinalysis revealed 4+ proteinuria and 2+ hematuria. Abdominal computed tomography revealed a large intra-abdominal mass with fat tissue density. She underwent emergency tumor excision, splenectomy, and distal pancreatectomy. However, hypoproteinemia and acute kidney injury worsened. Therefore, she was transferred to the nephrology division for confirmation of diagnosis and for treatment of acute kidney injury and nephrotic syndrome. We conducted percutaneous kidney biopsy and diagnosed minimal change disease (MCD). Intravenous prednisolone was started, and heavy proteinuria and systemic edema were gradually alleviated. She achieved complete remission 2 months later, and oral prednisolone was tapered. Histopathological diagnosis of abdominal tumor was dedifferentiated liposarcoma of retroperitoneal origin. Immunohistochemical staining revealed strong expression of vascular endothelial growth factor in the tumor cells in the dedifferentiated component. Currently, her clinical course is stable without recurrence of liposarcoma and nephrotic syndrome. MCD develops in patients with Hodgkin's lymphoma, solid organ cancers, hematological malignancies, and thymoma, whereas concurrent MCD and liposarcoma are rare. Remission of nephrotic syndrome and normalized kidney function induced by steroid therapy are important for better management of patients with malignancy.

Anemia in Diabetic Patients Reflects Severe Tubulointerstitial Injury and Aids in Clinically Predicting a Diagnosis of Diabetic Nephropathy.

Objective A kidney biopsy is generally performed in diabetic patients to discriminate between diabetic nephropathy (DN) and non-diabetic kidney disease (NDKD) and to provide more specific treatments. This study investigated the impact of anemia on the renal pathology and the clinical course in patients who underwent a kidney biopsy. Methods We reviewed 81 patients with type 2 diabetes who underwent a percutaneous kidney biopsy. Patients were classified into two groups: isolated DN (DN group, n=30) and NDKD alone or concurrent DN (NDKD group, n=51) groups. The laboratory and pathological findings and clinical courses were investigated. Results In the NDKD group, membranous nephropathy was the most common finding (23.5%), followed by IgA nephropathy (17.6%) and crescentic glomerulonephritis (13.7%). In the logistic regression analysis, the absence of severe hematuria and presence of anemia were significantly associated with a diagnosis of DN. Akaike's information criterion (AIC) and net reclassification improvement (NRI) analyses revealed improved predictive performance by adding anemia to the conventional factors (AIC 100.152 to 91.844; NRI 27.0%). The tissues of patients in the DN group demonstrated more severe interstitial fibrosis and tubular atrophy (IF/TA) than those in the NDKD group (p<0.05) regardless of the rate of global glomerulosclerosis, and IF/TA was related to the prevalence of anemia (odds ratio: 7.31, 95% confidence interval: 2.33-23.00, p<0.01) according to a multivariable regression analysis. Furthermore, the isolated DN group demonstrated a poorer prognosis than the NDKD group. Conclusion DN is associated with anemia because of severe IF/TA regardless of the renal function, and anemia helps clinician discriminate clinically between isolated DN and NDKD.

Secondary renal amyloidosis associated with asbestos-related pleuropulmonary diseases.

Here, we present a 67-year-old Japanese man who developed insidious-onset nephrotic syndrome. He had a history of occupational asbestos exposure for about 8 years during his 30s, and was found to have pleural effusion 3 years before his present illness. At that time, repeated cytology testing of his pleural effusion found no malignant cells, and pleural biopsy found fibrous pleuritis without evidence of malignant mesothelioma. Percutaneous kidney biopsy found massive deposits of AA-type amyloid in the glomeruli, small arteries, and medulla. Computed tomography showed a calcified mass in the right lower lung that was positive for 67Ga uptake, but transbronchial lung biopsy and bronchoalveolar lavage found no evidence of malignancy. He was diagnosed with rounded atelectasis and diffuse pleural thickening. As these benign asbestos-related diseases have no standard treatment, we administered low-dose angiotensin II receptor blocker to preserve kidney function. Unfortunately, his nephrotic syndrome persists, with progressive chronic kidney failure. Kidney involvement in patients with asbestos-related disease is rare. To our knowledge, this is the first case to present with secondary amyloidosis. Kidney biopsy should be considered for patients with existing asbestos-related pleuropulmonary diseases who have urinary abnormalities or renal dysfunction, to clarify the incidence and pathophysiology of renal manifestations.

B-Type Natriuretic Peptide and Hemoglobin are Two Major Factors Significantly Associated With Baseline Cerebral Oxygen Saturation Measured Using the INVOS Oximeter in Patients Undergoing Off-Pump Coronary Artery Bypass Graft Surgery.

OBJECTIVES: To investigate an association between the preoperative plasma B-type natriuretic peptide (BNP) concentration and cerebral regional saturation (rSO2) measured using the INVOS oximeter (Medtronic, Minneapolis, MN). DESIGN: A retrospective data analysis. SETTING: Single university hospital. PARTICIPANTS: Patients undergoing off-pump coronary artery bypass (OPCAB) surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Associations of variables obtained from preoperative blood laboratory tests and transthoracic echocardiography with baseline rSO2 before induction of general anesthesia were investigated using bivariate and multivariate regression analyses in 330 OPCAB patients. With bivariate analyses, age; body size-related variables such as weight and body surface area; hematologic function-related variables such as blood hemoglobin (Hb) concentration and arterial oxygen saturation; renal function-related variables including estimated glomerular filtration rate, creatinine, and blood urea nitrogen; hepatic function-related variables including cholinesterase, albumin, total bilirubin, and alanine aminotransferase; serum electrolytes including sodium, chloride, and phosphorus; BNP or log-transformed BNP; and 13 transthoracic echocardiography variables such as left ventricular ejection fraction highly significantly correlated with baseline rSO2 (p < 0.0001). However, the multiple regression analysis revealed that only BNP and Hb remained major factors significantly associated with baseline rSO2 (p < 0.0001), while estimated glomerular filtration rate, arterial oxygen saturation, and body surface area remained minor factors (p < 0.05). Baseline rSO2 correlated better with log-transformed BNP than with BNP, indicating that rSO2 correlated with BNP in an exponential fashion. CONCLUSIONS: Preoperative BNP and Hb concentrations were 2 major factors associated with INVOS rSO2 in patients undergoing OPCAB.

Tubulointerstitial nephritis as adverse effect of programmed cell death 1 inhibitor, nivolumab, showed distinct histological findings.

Immune-checkpoint inhibitor nivolumab (anti-PD-1 antibody) blocks T cell inhibition and stimulate immunologic response toward cancer cells. It was also revealed that PD-1/PD-L1 interaction crucially controls the effector differentiation of auto-reactive T cells to maintain self-tolerance. Therefore, potential autoimmunological side-effect can occur in any organ. Here, we report a case of 67-year-old Japanese male with lung adenocarcinoma treated with nivolumab who developed acute tubulointerstitial nephritis after the third infusion of nivolumab. Kidney biopsy showed distinct histological findings: Proliferation of CD38 positive and IgG positive plasma cells, and affluent infiltration of FoxP3+ regulatory T cells. Herein, we do pathological discussion concerning acute tubulointerstitial nephritis occurred in this case based on these histological findings.

High serum level of methylglyoxal-derived AGE, Nδ-(5-hydro-5-methyl-4-imidazolone-2-yl)-ornithine, independently relates to renal dysfunction.

BACKGROUND: The dicarbonyl methylglyoxal reacts primarily with arginine residues to form advanced glycation end products, including Nδ-(5-hydro-5-methyl-4 -imidazolone-2-yl)-ornithine (MG-H1), which are risk factors for not only diabetic complications but also lifestyle-related disease including renal dysfunction. However, the data on serum level and clinical significance of this substance in chronic kidney disease are limited. METHODS: Serum levels of MG-H1 and Nε-(carboxymethyl) lysine (CML) in 50 patients with renal dysfunction were measured by liquid chromatography/triple-quadruple mass spectrometry. RESULTS: The median serum MG-H1 levels in patients with estimated glomerular filtration rate (eGFR) of ≥30, 15-30, and <15 ml/min/1.73 m2 was 4.16, 12.58, and 14.66 mmol/mol Lys, respectively (p > 0.05). On the other hand, MG-H1 levels in patients with HbA1c of <6 and ≥6 % was 12.85 and 10.45 mmol/mol Lys, respectively, the difference between which is not significant. In logistic regression analysis, decreased renal function (eGFR <15 ml/min/1.73 m2) significantly associated with high serum levels of MG-H1 [odds ratio: 9.39 (95 % confidence interval 1.528-57.76), p = 0.015; Spearman rank correlation: MG-H1 vs. eGFR, r = -0.691, p < 0.01]. In contrast, the serum level of CML did not correlate with eGFR, but correlated with systolic blood pressure [odds ratio 16.17 (95 % confidence interval 1.973-132.5), p = 0.010; Spearman rank correlation coefficient: CML vs. eGFR, r = 0.454, p < 0.01]. CONCLUSION: These results showed that the serum concentration of MG-H1 was strongly related to renal function rather than to DM.

IL-1ß promotes tubulointerstitial injury in MPO-ANCA-associated glomerulonephritis
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BACKGROUND: It is widely accepted that tubulointerstitial injury (TII) is caused by glomerular injury (GI) in glomerular diseases. Glomerular endocapillary inflammation may result in crescent formation and exuded protein leakage, which may induce TII in antineutrophil cytoplasmic antibody-associated glomerulonephritis (ANCAGN). However, some reports have indicated a glomerulonephritis-independent mechanism of TII in ANCAGN. The aim of this study was to determine the principle cytokines correlated with TII severity and to elucidate a characteristic mechanism for TII in ANCAGN. METHODS: 28 myeloperoxidase-ANCA-positive ANCAGN patients were enrolled, and their kidney biopsy specimens were histologically evaluated with regard to GI and TII. The mRNA expression of various cytokines was examined in 28 specimens. RESULTS: Interleukin (IL)-1ß was significantly correlated with the severity of TII. The mRNA expression of Toll-like receptor 4 (TLR4) and Nod-like receptor family pyrin domain-containing-3 (NLRP3) also correlated with TII severity. Immunohistochemical analysis demonstrated that TLR4 protein was positively stained in the tubulointerstitial infiltrating cells. NRLP3 protein was detected in macrophages in the severe infiltrating area but was absent or only very faintly expressed in the glomeruli. These results indicated that NLRP3 inflammasome-dependent processing in macrophages releases the mature active form of IL-1ß, which may lead to the development and deterioration of TII. CONCLUSIONS: Sterile inflammation leads to the formation of ANCA-mediated neutrophil extracellular traps (NETs), which may stimulate macrophages and dendritic cells via TLR4 and induce NF-κB-dependent mRNA expression and translation of pro-IL-1ß. Simultaneously, damage-associated molecular pattern signals resulting from NETs promote NLRP3 inflammasome-dependent processing and release mature active IL-1ß. Sterile inflammation utilizing the NLRP3 inflammasome might be a characteristic reaction limited to the tubulointerstitium. Thus, neutralizing IL-1ß may be a promising strategy to suspend the progress of TII and improve the prognosis of chronic kidney disease resulting from ANCAGN.
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Parasites alter the pathological phenotype of lupus nephritis.

Lupus nephritis is one of the most serious complications of systemic lupus erythematosus and manifests with considerable phenotypic and histological heterogeneity. In particular, diffuse proliferative lupus nephritis (DPLN) and membranous lupus nephritis (MLN) represent morphologic forms that are polar opposites. DPLN is associated with autoimmune responses dominated by Th1 immune response associated with high levels of interferon (IFN)-γ. In contrast, a Th2 cytokine response is associated with the pathogenesis of MLN. MRL/lpr mice develop human LN-like immune complex-associated nephritis and provide a suitable histological model for human DPLN. Infection with Schistosoma mansoni skewed a Th2-type immune response induction and IL-10 in MRL/lpr mice, drastically changing the pathophysiology of glomerulonephritis from DPLN to MLN accompanied by increased IgG1 and IgE in the sera. T cells in 32-week-old MRL/lpr mice infected with S. mansoni expressed significantly more IL-4 and IL-10 than T cells of uninfected mice; T cells with IFN-γ were comparable between infected and uninfected MR/lpr mice. Thus, the helminthic infection modified the cytokine microenvironment and altered the pathological phenotype of autoimmune nephritis.

Total and HMW adiponectin is independently associated with B-type natriuretic peptide and anemia in chronic hemodialysis patients.

OBJECTIVE: A number of vasculo-protective roles have been reported for adiponectin. In contrast, higher, rather than lower, plasma adiponectin levels are associated with an increased risk of cardiovascular disease and mortality in patients undergoing hemodialysis (HD). The mechanisms by which high adiponectin levels are associated with adverse outcome are unclear. METHODS: This study measured the level of total and high molecular weight (HMW) adiponectins in 70 patients with HD patients (age: 65.2±8.6 years, man/woman: 30/40), and examined the association between adiponectins, metabolic and echocardiographic parameters. RESULTS: Women had a significantly higher total, HMW levels and HMW to total ratio than men. The levels of total and HMW adiponectin were positively correlated with those of HDL-cholesterol and B-type natriuretic peptide (BNP) levels, and negatively associated with body mass index (BMI), triglyceride, high sensitive-C reactive protein (CRP) and hemoglobin levels. A multiple linear regression analysis showed that HMW adiponectin had an independent association with BMI (ß=-0.270, p=0.003), HDL-cholesterol (ß=0.356, p<0.001), hemoglobin (ß=-0.180, p=0.034) and BNP (ß=0.200, p=0.014) as total did adiponectin. CONCLUSION: Anemia and BNP levels had independent influence on the total and HMW adiponectin levels in chronic HD patients.

Macrophage impairment produced by Fc receptor gamma deficiency plays a principal role in the development of lipoprotein glomerulopathy in concert with apoE abnormalities.

BACKGROUND: To obtain a clear understanding of the pathogenesis of lipoprotein glomerulopathy (LPG), we studied the role of the deficiency of Fc receptor gamma chain (FcRγ) for the development of LPG in concert with apolipoprotein E (apoE) abnormalities. METHODS: We generated apoE and FcRγ double-knockout (FcRγ/apoE-KO) mice, and subsequently introduced several kinds of human recombinant apoE genes. At 21 days after infection, the mice were sacrificed and histologically examined. Peritoneal macrophages were evaluated for their response to modified lipids. RESULTS: In the FcRγ/apoE-KO mice, the human apoE3-injected mice showed the most drastic LPG-like changes, as well as prominent hypertriglyceridemia. Meanwhile, relative to the human apoE3-injected mice, the FcRγ/apoE-KO mice showed greater lipoprotein deposition and less macrophage infiltration into the mesangial area. Moreover, the peritoneal macrophages in the apoE/FcRγ-KO mice were impaired in lipid uptake and secretion of the cytokines monocyte chemotactic protein-1 and regulated upon activation, normal T-cell expressed and secreted, after the uptake of oxidized low-density lipoprotein. CONCLUSIONS: These results suggest that the impairment of macrophage function resulting from FcRγ deficiency plays a principal role in the development of LPG in the presence of apoE abnormalities.

Scavenger receptor expressions in the kidneys of mice with lipoprotein glomerulopathy.

BACKGROUND: To clarify whether dysfunction of the scavenger receptor (SR) participates in the development of lipoprotein glomerulopathy (LPG) in immunoglobulin F(c) receptor γ chain (F(c)Rγ)-deficient mice [F(c)Rγ knock-out (KO) mice] with induced chronic graft-versus-host disease (cGVHD). METHOD: In wild-type (WT) and F(c)Rγ KO C57BL/6 mice, cGVHD was induced by injection of lymphoid cells from donor Bm12 mice. At 6 months after injection, the mice were sacrificed and histologically examined. Total RNA was extracted from the kidneys and cytokine, chemokine, and SR transcript expressions were evaluated by reverse transcription-polymerase chain reaction. RESULTS: Three of 4 female cGVHD(+)/F(c)Rγ KO mice presented LPG in >60% of glomeruli. cGVHD(-) and cGVHD(+)/WT mice did not show LPG. The SRs CD36, CD68, and CXCL16 showed a significant difference in the values of their transcripts between cGVHD(+)/WT and cGVHD(+)/F(c)Rγ KO mice. Among them, only CD36 showed a drastic decline of mRNA expressions in cGVHD(+)/F(c)Rγ KO mice. CONCLUSION: CD36 may play a crucial role in the development of LPG in F(c)Rγ KO mice with cGVHD. In addition to the apolipoprotein E mutation, dysfunction of lipid clearance in the kidney might be one of the factors for the development of LPG.

Aggravation of diabetic nephropathy in OLETF rats by Thy-1.1 nephritis.

OBJECTIVE: To clarify whether the induction of Thy-1.1 nephritis aggravates diabetic nephropathy in the Otsuka Long-Evans Tokushima Fatty (OLETF) rat, which is a model of diabetes mellitus. METHOD: Forty-week-old OLETF rats were divided into 2 groups according to treatment: (1) 1 mg/kg body weight of OX7, an anti-Thy1.1 antibody (administered intravenously) (Group T, n = 14); (2) 0.9% saline (Group C, n = 14). The histological findings for the kidneys and the index of glomerulosclerosis (IGS) were determined 20 weeks after administration, and urine and serum chemistry were also assessed. The same procedure was performed as a control in 2 groups of Long-Evans Tokushima Otsuka (LETO) rats (i.e., nondiabetic OLETF rats). RESULTS: The urinary protein excretion values and the levels of serum albumin in the OX7-treated OLETF rats were significantly higher and lower than those in the untreated OLETF rats, respectively. Total cholesterol was significantly increased in the OX7-treated OLETF rats compared with the untreated OLETF rats. In the histological analysis, IGS was significantly higher in the OX7-treated OLETF rats than in the untreated OLETF rats. Neither deteriorations in the laboratory assessment values nor histological alterations were seen in the LETO rats. CONCLUSION: These findings indicate that an anti-Thy-1.1 antibody irreversibly aggravates diabetic nephropathy in the OLETF rat.

The proportion and metabolic effects of adiponectin multimeric isoforms in patients with chronic kidney disease on maintenance hemodialysis.

Adiponectin circulates at least in three major forms of oligomeric complexes in plasma: a low-molecular-weight (LMW) trimer, a middle-molecular-weight (MMW) hexamer, and high-molecular-weight (HMW) adiponectin. Although it has been reported that adiponectin has the favorable metabolic properties for humans, the roles of these multimers in the patients with the end-stage renal disease (ESRD) were unidentified. We determined the level of total and multimeric adiponectin in 71 patients with nondiabetic ESRD treated with hemodialysis (HD) using a commercially available kit of enzyme-linked immunosorbent assay (ELISA). Correlations between metabolic variables and total and multimeric adiponectin were examined by Spearman's correlations analysis. Forward stepwise multiple linear regression analysis was also performed to determine the factors independently associated with them. Female patients had significantly higher total, HMW, and MMW levels than male patients did. According to homeostasis model of assessment of insulin resistance (HOMA-IR), value was associated not only with HMW but also with MMW and LMW. In multivariate analyses, HMW showed independently and positively associated with high-density lipoprotein cholesterol (HDL-C), body mass index (BMI), and sex as total adiponectin did. Unexpectedly, LMW adiponectin was independently and negatively correlated with TG and high-sensitive C-reactive protein (hs-CRP). Not only HMW adiponectin but also LMW adiponectin track with favorable metabolic effects in the patient with the ESRD.