Matrix metalloproteinase-10 deficiency has protective effects against peritoneal inflammation and fibrosis via transcription factor NFκΒ pathway inhibition.

One of the most common causes of discontinued peritoneal dialysis is impaired peritoneal function. However, its molecular mechanisms remain unclear. Previously, by microarray analysis of mouse peritoneum, we showed that MMP (matrix metalloproteinase)-10 expression is significantly increased in mice with peritoneal fibrosis, but its function remains unknown. Chlorhexidine gluconate (CG) was intraperitoneally injected to wild-type and MMP-10 knockout mice to induce fibrosis to elucidate the role of MMP-10 on peritoneal injury. We also examined function of peritoneal macrophages and mesothelial cells obtained from wild-type and MMP-10 knockout mice, MMP-10-overexpressing macrophage-like RAW 264.7 cells and MeT-5A mesothelial cells, investigated MMP-10 expression on peritoneal biopsy specimens, and the association between serum proMMP-10 and peritoneal solute transfer rates determined by peritoneal equilibration test on patients. MMP-10 was expressed in cells positive for WT1, a mesothelial marker, and for MAC-2, a macrophage marker, in the thickened peritoneum of both mice and patients. Serum proMMP-10 levels were well correlated with peritoneal solute transfer rates. Peritoneal fibrosis, inflammation, and high peritoneal solute transfer rates induced by CG were all ameliorated by MMP-10 deletion, with reduction of CD31-positive vessels and VEGF-A-positive cells. Expression of inflammatory mediators and phosphorylation of NFκΒ subunit p65 at S536 were suppressed in both MMP-10 knockout macrophages and mesothelial cells in response to lipopolysaccharide stimulation. Overexpression of MMP-10 in RAW 264.7 and MeT-5A cells upregulated pro-inflammatory cytokines with phosphorylation of NFκΒ subunit p65. Thus, our results suggest that inflammatory responses induced by MMP-10 are mediated through the NFκΒ pathway, and that systemic deletion of MMP-10 ameliorates peritoneal inflammation and fibrosis caused by NFκΒ activation of peritoneal macrophages and mesothelial cells.

Sacubitril/valsartan ameliorates renal tubulointerstitial injury through increasing renal plasma flow in a mouse model of type 2 diabetes with aldosterone excess.

BACKGROUND: Aldosterone has been assumed to be one of aggravating factors in diabetic kidney disease (DKD). Natriuretic peptides/guanylyl cyclase-A/cGMP signalling has been shown to ameliorate aldosterone-induced renal injury in mice. Sacubitril/valsartan (SAC/VAL) is used clinically for chronic heart failure and hypertension, in part by augmenting natriuretic peptide bioavailability. The effects of SAC/VAL on renal pathophysiology including in DKD, however, have remained unclarified. METHODS: Eight-week-old male db/db mice fed on a high-salt diet (HSD) were treated with vehicle or aldosterone (0.2 µg/kg/min), and divided into four groups: HSD control, ALDO (aldosterone), ALDO + VAL (valsartan), and ALDO + SAC/VAL group. After 4 weeks, they were analysed for plasma atrial natriuretic peptide (ANP) levels, renal histology, and haemodynamic parameters including glomerular filtration rate (GFR) by FITC-inulin and renal plasma flow (RPF) by para-amino hippuric acid. RESULTS: The ALDO + SAC/VAL group showed significantly increased plasma ANP concentration and creatinine clearance, and decreased tubulointerstitial fibrosis and neutrophil gelatinase-associated lipocalin expression compared to ALDO and ALDO + VAL groups. SAC/VAL treatment increased GFR and RPF, and suppressed expression of Tgfb1, Il1b, Ccl2, and Lcn2 genes compared to the ALDO group. The percentage of tubulointerstitial fibrotic areas negatively correlated with the RPF and GFR. CONCLUSION: In a mouse model of type 2 diabetes with aldosterone excess, SAC/VAL increased RPF and GFR, and ameliorated tubulointerstitial fibrosis. Furthermore, RPF negatively correlated well with tubulointerstitial injury, suggesting that the beneficial effects of SAC/VAL could be through increased renal plasma flow with enhanced natriuretic peptide bioavailability.

Long-Term Prognosis of Hyperferritinemia Induced by Intravenous Iron Therapy in Patients Undergoing Maintenance Hemodialysis: A 10-Year, Single-Center Study.

Optimal ferritin level in hemodialysis patients between Japan and other countries is controversial. Long-term side effects of iron supplementation in these patients remain unclear. We aimed to elucidate whether past hyperferritinemia in hemodialysis patients was associated with high risk of death and cerebrovascular and cardiovascular diseases (CCVDs). This small retrospective cohort study included approximately 44 patients unintentionally supplemented with excessive intravenous iron. A significantly higher risk of CCVDs was observed in patients with initial serum ferritin levels ≥1000 ng/mL than in the remaining patients. High ferritin levels slowly decreased to <300 ng/mL in a median of 24.2 (10.5-46.5) months without treatment. However, compared with the remaining patients, only patients whose ferritin levels did not decrease to <300 ng/mL steadily had a significantly higher risk of all-cause death (hazard ratio, 9.6). Long-term hyperferritinemia due to intravenous iron therapy is a risk factor for death in maintenance hemodialysis patients. For a prolonged better prognosis, intravenous iron should be carefully administered so as to avoid hyperferritinemia in patients with hemodialysis.

Kidney allograft pyelonephritis caused by Salmonella enterica serovar Schwarzengrund.

Kidney transplant recipients (KTRs) taking immunosuppressive drugs have a 20-fold greater risk of nontyphoidal Salmonella (NTS) infection than the healthy adult population. Among KTRs, the urinary tract is the most common site of infection. However, few cases of urinary tract infection caused by NTS have been documented in KTRs, and only one in Japan. Furthermore, it frequently induces acute allograft rejection with high mortality. Salmonella enterica subsp. enterica serovar Schwarzengrund (S. Schwarzengrund) is now among the more common Salmonella serovars isolated in Japan and is likely to be invasive. We present a case of a 45-year old female with vesicoureteral reflux to her transplanted kidney who developed kidney allograft pyelonephritis caused by S. Schwarzengrund. She was admitted to our hospital with fever, urodynia, lower abdominal pain, gross hematuria, and cloudy urine. Urine cultures were positive for S. Schwarzengrund. Exposure to cats, especially stray cats, were identified as the most likely source. We administered antibiotics for 4 weeks (ceftriaxone then amoxicillin, each for 2 weeks) and educated her about pet safety. She experienced no recurrence of infection or clinical kidney allograft rejection for 3 months post-treatment. NTS should be considered as a possible pathogen of urinary tract infection among KTRs, especially in cases with animal exposure or structural urologic abnormalities. When the pathogen is NTS, appropriate antibiotics and treatment periods are essential for preventing recurrence and allograft rejection after the completion of treatment.

Bacteremic kidney cyst infection caused by Helicobacter cinaedi.

Cyst infection is one of the major complications in patients with autosomal dominant polycystic kidney disease (ADPKD). The causative pathogen in kidney cyst infection frequently goes undetected. Although only one case report of kidney cyst infection caused by Helicobacter cinaedi (H. cinaedi) is published in English literature, it may be an important pathogen in kidney cyst infection. Kidney cyst infection and H. cinaedi infection share the common characteristic of tendency to relapse and chronic kidney disease is a major risk factor for H. cinaedi infection. Moreover, a long period is required to detect H. cinaedi in blood cultures, potentially causing false-negative results. After the identification of H. cinaedi, we must carefully select antibiotics and the antibiotic treatment period should be extended to prevent recurrence. Here we present a case of a 58-year-old male with ADPKD who developed bacteremic kidney cyst infection caused by H. cinaedi. He was admitted to our hospital because of fever, lower left back pain, vomiting, and feeling of abdominal enlargement. H. cinaedi was detected from the blood cultures obtained at admission after 4 days of culture. Antibiotics were administered for 8 weeks after confirming negative blood cultures. There was no evidence of kidney cyst infection relapse at 3 months after treatment completion. Nephrologists should regard H. cinaedi as a challenging but important pathogen in kidney cyst infection, particularly when the causative organism is unknown or kidney cyst infection is recurrent.

Thrombotic microangiopathy caused by interferon ß-1b for multiple sclerosis: a case report.

A 41-year-old man with a history of multiple sclerosis (MS) developed thrombotic microangiopathy after taking interferon ß-1b for 10 years. Although the relapse of his MS was well controlled under normal blood pressure, he had persistent nausea, anorexia, gait disturbance and visual disorder 1 month before admission. He showed lethargy and high blood pressure (180/102 mmHg). Laboratory test results revealed anemia and thrombocytopenia, elevated LDH and renal dysfunction. Urinary dipstick showed a 2+ result for proteinuria and 3+ for hematuria. Schizocyte were present and haptoglobin decreased, and we diagnosed him with possible thrombotic microangiopathy (TMA). Magnetic resonance image indicated posterior reversible encephalopathy syndrome (PRES), which could be accelerated by TMA. After discontinuing interferon ß-1b, high dose intravenous methylpredonisolone, anti-hypertension therapy and plasma exchange was started. Because a mild decrease in ADAMTS13 activity and absence of ADAMTS 13 inhibitor could not cause thrombotic thrombocytopenic purpura, plasma exchange was stopped. The patient's renal function recovered and PRES resolved, and he was discharged with slightly decrease of visual acuity. We suggest that his TMA was likely caused by interferon ß-1b, resulting in PRES in a patient with multiple sclerosis. We report this rare case and also review the literature.