U-KIM-1 as a predictor of treatment response in lupus nephritis.

OBJECTIVE: Biomarkers of disease activity in lupus nephritis (LN) are in demand. This is because they may be useful in patients who are unable to undergo invasive kidney biopsy, as predictors of renal function, and for early detection of LN recurrence. The focus is on the measurement of urinary chemokines and cytokines, especially in urinary biomarkers, which are non-invasive and simple. In our previous report, we reported that kidney injury molecule-1 (KIM-1) is expressed in injured tubules and that the number of tubular-KIM-expressing positive cells correlates with renal pathology findings and also with urinary (u)-KIM-1 levels. However, there have been no reports examining the effect of u-KIM-1 levels on response to therapy, correlation with renal pathology, and usefulness as a predictor of renal function. METHODS: U-KIM-1 levels were measured by ELISA in 61 SLE patients. In 38 active LN who underwent renal biopsy, we also examined whether u-KIM-1 levels affected LN disease activity, renal histological findings, and predictors of renal function. RESULTS: In SLE patients, proteinuria and u-KIM-1 levels were elevated in active LN compared to inactive LN. U-KIM-1 and proteinuria decreased with intensified treatment. U-KIM-1 levels also correlated with the percentage of glomerular crescent formation in renal pathology. In addition, patients with higher baseline u-KIM-1 levels had significantly higher eGFR and lower LN disease activity at 12 months after treatment intensification. CONCLUSIONS: These data suggest that u-KIM-1 levels correlate with LN disease activity and renal histopathology findings and may be used as a predictor of treatment response.

[Two Cases of Advanced Recurrent Breast Cancer with Severe Heart Failure Caused By Anthracycline].

Case 1: A 48-year-old woman, had right breast cancer with multiple liver metastases. Seven courses of paclitaxel plus bevacizumab were administered, but due to disease progression, 12 courses of FEC 75(total epirubicin 900 mg/m2)were administered. 2 months after the last FEC administration, the patient developed heart failure and died about 3 months later. Case 2: A 58-year-old woman, was on endocrine therapy after surgery for left breast cancer. Recurrence of lung and bone metastases were appeared 5 years after surgery, 10 courses of FEC 75(total epirubicin 750 mg/m2)were administered due to disease progression. Eight months after the last administration of FEC, the patient developed heart failure and died about 8 months later. Anthracycline induced cardiotoxicity is irreversible and has a severe course. Therefore, anthracycline should be administered with caution.

Deletion of Antigen-Presenting Cells in Lipopolysaccharide-Induced Acute Kidney Injury (AKI) Affects the Exacerbation and Repair in AKI.

The pathogenesis of acute kidney injury (AKI) is complex and involves various immune and inflammatory responses. Antigen-presenting cells such as macrophages and dendritic cells (DCs) were recently reported to have diverse functions in AKI depending on the pathogenesis and disease phase. Herein, we intraperitoneally administered liposomal clodronate (LC) to lipopoly-saccharide (LPS)-induced AKI model mice in order to deplete antigen-presenting cells (e.g., macrophages and DCs). After the LPS injection, the mice were divided into LC-treated (LPS + LC) and saline-treated groups (LPS), and the immune responses of macrophages and DCs in the acute and recovery phases were evaluated. The LPS + LC-treated group exhibited significantly suppressed renal macrophages and DC infiltration at 18 h and improved survival at 120 h after LPS injection. Via the depletion of macrophages and DC infiltrations, the serum and renal tissue inflammatory cytokines/chemokines were suppressed at 18 h and reversed at 120 h. Tubular kidney injury molecule-1 expression was decreased at 18 h and increased at 120 h. These findings indicate that LC administration suppressed tubular and interstitial injury in the acute phase of AKI and affected delayed tissue repair in the recovery phase. They are important for understanding innate and acquired immune responses in the therapeutic strategy for LPS-induced AKI.

Lymph Node Metastasis Location and Postoperative Adjuvant Chemotherapy in Patients With pN1 Stage IIB Non-small Cell Lung Cancer.

BACKGROUND/AIM: The benefit of adjuvant chemotherapy for patients with pN1 non-small cell lung cancer (NSCLC) according to the location of lymph node (LN) metastases remains unclear. In this study, we examined the location of LN metastasis and prognosis to identify the significance of adjuvant chemotherapy. PATIENTS AND METHODS: Thirty-five patients with pathological T1a-2bN1M0 NSCLC who underwent curative resection between 2010 and 2016 were enrolled in the study. We defined patients with LN metastasis extending in stations 10-12 as the hilar group (n=22), and only in stations 13-14 as the intralobar group (n=13). RESULTS: There was a significant difference in the overall survival (OS) (p=0.042) and disease-free survival (DFS) rates (p=0.021) between the intralobar and hilar groups. In the intralobar group, there were no significant differences in the OS and DFS rates according to adjuvant chemotherapy. However, patients without adjuvant chemotherapy had a poorer OS (p<0.001) and DFS rates (p<0.001) in the hilar group. CONCLUSION: Prognosis significantly differed according to adjuvant chemotherapy in the hilar group.

Usefulness of Interleukin-18 as a Diagnostic Biomarker to Differentiate Adult-Onset Still's Disease With/Without Macrophage Activation Syndrome From Other Secondary Hemophagocytic Lymphohistiocytosis in Adults.

Background: Interleukin (IL)-18 is markedly elevated in systemic inflammatory diseases that cause the 'cytokine storm' such as adult-onset Still's disease (AOSD) and hemophagocytic lymphohistiocytosis (HLH). The differences in IL-18 between AOSD and HLH, especially in adults, is uncertain. Macrophage activation syndrome (MAS), a form of secondary HLH, is often difficult to differentiate cases of AOSD that include MAS from other secondary HLH. In this case-control study, we investigated whether serum IL-18 levels could be a useful biomarker for the differential diagnosis of AOSD with or without MAS (AOSD group) and other secondary HLH in adults (adult HLH group). Patients and Methods: We enrolled 46 patients diagnosed with AOSD including 9 patients with MAS and 31 patients in the adult HLH group, which excluded AOSD-associated MAS. The clinical features and laboratory data were compared between the AOSD and adult HLH groups. In addition, we subdivided the AOSD group (with or without MAS) and the adult HLH group (whether lymphoma-associated or not) and compared the four groups. A logistic regression analysis was used to identify factors with high efficacy in differentiating the two groups, followed by a receiver operating characteristic (ROC) curve analysis to evaluate the differential diagnostic ability of IL-18. We analyzed the correlation between IL-18 and various laboratory parameters in the AOSD group. Results: Serum IL-18 levels of patients in the AOSD groups were significantly higher than those of the adult HLH groups, and were closely correlated with ferritin, soluble interleukin-2 receptor (sIL-2R), and other laboratory data. Univariate and multivariate logistic regression analyses revealed that IL-18, sIL-2R, and 'arthralgia or arthritis' are independent factors useful in the differential diagnosis of AOSD from adult HLH. In the differential diagnosis of both groups, the area under the curve obtained from the ROC curve of IL-18 with a cutoff value of 18,550 pg/mL was 0.91 (95% confidence interval 0.83-1.00; sensitivity 90.3%, specificity 93.5%), and the differential diagnosis ability of IL-18 was superior to that of other laboratory data. Conclusions: IL-18 could be a useful biomarker for the differential diagnosis of AOSD and adult HLH.

Takayasu's Arteritis Diagnosed in an Adolescent Patient with Crohn's Disease: Management of Biologicals.

We report a 14-year-old man with Crohn's disease (CD) who developed right upper arm pain while being treated with the anti-tumor necrosis factor (TNF)-alpha monoclonal antibody, infliximab. There were no symptoms suggestive of active CD, but the inflammatory response was high, and a contrast-enhanced CT showed the occlusion of the right brachial artery. We diagnosed the patient as having Takayasu's arteritis (TA) and started treatment with corticosteroids, then tapered off the steroids as the symptoms of TA resolved. Later, TA flared up, and his treatment was changed from infliximab to an anti-IL-6 receptor antibody, tocilizumab. The change to TCZ stabilized TA, but exacerbated CD. It is difficult to control both diseases at the same time, and the choice of biologics for treatment must be carefully considered.

Effects of denosumab versus teriparatide in glucocorticoid-induced osteoporosis patients with prior bisphosphonate treatment.

INTRODUCTION: Osteoporosis is one of the serious adverse effects associated with glucocorticoid therapy. Although bisphosphonates have been used for glucocorticoid-induced osteoporosis (GIO), some patients have shown an inadequate response. In such cases, denosumab or teriparatide are used. However, there is no consensus on which of these two drugs is superior. We prospectively compared denosumab's and teriparatide's effects on the bone mineral density (BMD) in GIO patients with prior bisphosphonate treatment. MATERIALS AND METHODS: After receiving oral bisphosphonates for ≥2 years, GIO patients with low T-score BMD (<-2.5) were switched from bisphosphonates to denosumab (n = 20) or daily teriparatide (n = 21). We measured the BMD (lumbar spine, femoral neck, and total hip) in both groups every 6 months for 24 months. RESULTS: At 24 months of treatment, the lumbar spine BMD increased significantly from baseline in both the denosumab and teriparatide groups (baseline vs. denosumab and teriparatide; 5.9 ± 5.6%, P < 0.001 and 7.9 ± 5.4%, P < 0.001). A significant increase in femoral neck BMD from baseline occurred only in the teriparatide group (6.6 ± 10.8%, P < 0.05); denosumab (1.5 ± 5.0%). No significant changes occurred in the total hip BMD from baseline in either group (-0.1 ± 5.6% and 3.3 ± 7.5%, respectively). There was no significant difference between the denosumab and teriparatide groups at 24 months in lumbar spine and femoral neck BMD, but was significantly higher in the teriparatide group at 12 months (P < 0.01 and P < 0.05 in the lumbar spine and femoral neck, respectively). CONCLUSION: Teriparatide might have some advantages over denosumab and be a good alternative for treating GIO patients with prior bisphosphonate treatment.

Signaling Rho-kinase mediates inflammation and apoptosis in T cells and renal tubules in cisplatin nephrotoxicity.

Nephrotoxicity is a frequent complication of cisplatin-induced chemotherapy, in which T cells are known to promote acute kidney injury (AKI). Apoptosis and necrosis of tubules and inflammatory events also contribute to the nephrotoxicity. A delineation of the mechanisms that underlie the inappropriate renal and tubular inflammation can thus provide important insights into potential therapies for cisplatin-induced AKI. Rho-kinases are known to act as molecular switches controlling several critical cellular functions, including cell migration, cytokine production, and apoptosis. Here, we show that the Rho-kinase inhibitor fasudil attenuated cisplatin nephrotoxicity, resulting in less histological damage, improved renal function, and the infiltration of fewer leukocytes into the kidney. Renal nuclear factor-κB activation and apoptosis were reduced, and the expressions of proinflammatory renal cytokine and chemokine mRNA were decreased. Urinary and renal kidney injury molecule-1 (Kim-1) expression was also reduced, a finding that is consistent with diminished kidney injury. In the current study, we also showed that fasudil could be protective of the impaired tubules. In vitro, fasudil reduced the apoptosis (annexin-V+PI cells) and cytokine production (tumor necrosis factor+ cells) in T cells and the apoptosis (annexin-V+PI cells) and tubular damage (Kim-1+ cells) in proximal tubular cells by flow cytometric analysis. As Rho-kinase plays an important role in promoting cisplatin nephrotoxicity, inhibiting Rho-kinase may be a therapeutic strategy for preventing cisplatin-induced AKI.

The pathological role of IL-18Rα in renal ischemia/reperfusion injury.

Interleukin (IL)-18 is a proinflammatory cytokine produced by leukocytes and parenchymal cells (eg, tubular epithelial cells (TECs), mesangial cells, and podocytes). IL-18 receptor (IL-18R) is expressed on these cells in the kidney during ischemia/reperfusion injury (IRI), but its role in this injury is unknown. Fas/Fas ligand (FasL) is also involved in the pathogenesis of renal IRI via tubular apoptosis. In addition, IL-18 enhances the expression of FasL on TECs, but the mechanism underlying this enhancement is not known. Here we used IL-18Rα-deficient mice to explore the pathological role of IL-18Rα in renal IRI. We found that compared to wild-type (WT) mice with renal IRI as an acute kidney injury (AKI), the IL-18Rα-deficient mice demonstrated decreased renal function (as represented by blood urea nitrogen), tubular damage, an increased accumulation of leukocytes (CD4+ T cells, neutrophils, and macrophages), upregulated early AKI biomarkers (ie, urinary kidney injury molecule-1 levels), and increased mRNA expressions of proinflammatory cytokines (IL-1ß, IL-12p40, and IL-18) and chemokines (intercellular adhesion molecule-1 and CCL2/monocyte chemoattractant protein-1). The mRNA expression of FasL in the kidney was increased in the IL-18Rα-deficient mice compared to the WT mice. The adoptive transfer of splenocytes by WT mice led to decreased renal IRI compared to the IL-18Rα-deficient mice. In vitro, the mRNA expression of FasL on TECs was promoted in the presence of recombinant IL-18. These data reveal that IL-18Rα has an anti-inflammatory effect in IRI-induced AKI. Above all, IL-18 enhanced the inflammatory mechanisms and the apoptosis of TECs through the Fas/FasL pathway by blocking IL-18Rα.

Signaling through the interleukin-18 receptor α attenuates inflammation in cisplatin-induced acute kidney injury.

Interleukin (IL)-18 is produced by leukocytes and renal parenchymal cells (tubular epithelial cells, podocytes, and mesangial cells). The IL-18 receptor (IL-18R) is expressed on these cells in cisplatin-induced acute kidney injury, but the role of IL-18R is unknown. To help define this, we compared IL-18Rα knockout with wild-type mice in cisplatin-induced acute kidney injury and found deteriorated kidney function, tubular damage, increased accumulation of leukocytes (CD4(+) and CD8(+) T-cells, macrophages, and neutrophils), upregulation of early kidney injury biomarkers (serum TNF, urinary IL-18, and KIM-1 levels), and increased expression of pro-inflammatory molecules downstream of IL-18. In vitro, leukocytes from the spleen and kidneys of the knockout mice produced greater amounts of pro-inflammatory cytokines upon stimulation with concanavalin A compared to that in wild-type mice. Levels of the suppressor of cytokine signaling 1 and 3 (negative regulators of cytokine signaling) were reduced in the spleen and kidneys of IL-18Rα-deficient compared to wild-type mice. Adoptive transfer of wild-type splenocytes by IL-18Rα-deficient mice led to decreased cisplatin nephrotoxicity compared to control IL-18Rα-deficient mice. In contrast, anti-IL-18Rα and anti-IL-18Rß antibody treatment tended to increase cisplatin nephrotoxicity in wild-type mice. Thus, signaling through IL-18Rα activates both inflammation-suppressing and pro-injury pathways in cisplatin-induced acute kidney injury.

Therapeutic effect of retinoic acid on unilateral ureteral obstruction model.

BACKGROUND: Retinoic acids, a group of natural and synthetic vitamin A derivatives, have potent anti-proliferative, anti-inflammatory and anti-fibrotic properties. We investigated the therapeutic effect of all-trans-retinoic acid (ATRA) on unilateral ureteral obstruction (UUO) model mice. METHODS: First, to evaluate the prophylactic effect, we administered 0.5 mg of ATRA for 3 days before UUO (UUO ATRA). Then, to evaluate the therapeutic effects, we administered 0.5 mg of ATRA 3 days after UUO (Day 3 ATRA). We compared the histological changes and immunostaining of macrophages, α-smooth muscle actin (α-SMA) and collagen I, and mRNA expression of monocyte chemotactic protein-1 (MCP-1), transforming growth factor (TGF)-ß(1) and TGF-ß R-II by RT-PCR 7 days after UUO. RESULTS: In the UUO ATRA and Day 3 ATRA groups, we observed a significant improvement in histological and immunological findings, including macrophage infiltration and improved expression of MCP-1, TGF-ß(1), α-SMA and collagen I compared with the UUO Day 7 group. CONCLUSION: ATRA treatment is not only an effective prophylactic strategy, but also a therapeutic strategy for the treatment of progressive renal fibrosis in diseased kidneys.

Therapeutic strategy and significance of serum rheumatoid factor in patients with rheumatoid arthritis during infliximab treatment.

To predict the response of patients with rheumatoid arthritis (RA) to infliximab, patient profile and laboratory findings were compared to determine whether there was any association with the clinical course of the disease, and the clinical significance of serum rheumatoid factor (RF) in the response to this treatment was considered. Sixty-two RA patients were treated with infliximab, 87.9% of whom were positive for RF. At baseline and 12 months after the start of treatment, RF titers were significantly lower in the low-CRP group (CRP at 12 months<0.3 mg/dl) compared with that in the high-CRP group (CRP at 12 months >1.5 mg/dl). Furthermore, at baseline and 12 months, RF titers were significantly lower in the good-CRP-response group (DeltaCRP>or=1.5 mg/d) compared with the poor-CRP-response group (DeltaCRP

Effect of combining ACE inhibitor and statin in lupus-prone mice.

MRL-Fas(lpr) mice spontaneously develop a systemic autoimmune disease resembling human systemic lupus erythematosus. The glomerulonephritis in MRL-Fas(lpr) mice is mediated by autoantibodies and autoreactive lymphocytes. To investigate the effect of combination therapy by angiotensin-converting enzyme inhibitor (ACEI) and hydroxymethylglutaryl-coenzyme A reductase inhibitor (statin) for lupus nephritis, we treated MRL-Fas(lpr) mice with imidapril, pravastatin or both agents. Compared with other groups, the mice treated by combination therapy survived longer and showed a significant reduction in proteinuria, renal pathology, including glomerular IgG deposit, and serum anti-DNA Ab. Furthermore, monocyte chemoattractant protein-1 (MCP-1) in the kidney was reduced significantly in the combination therapy group, compared with that in the control group. We conclude that combination therapy with ACEI and statin for MRL-Fas(lpr) mice significantly alleviates autoimmune renal disorder and prolongs survival. These results suggest that combination therapy by ACEI and statin may represent a new approach to the treatment of patients with lupus.

Successful treatment with retinoids in patients with lupus nephritis.

Lupus nephritis is a major manifestation of systemic lupus erythematosus. Treatment with such immunosuppressive agents as corticosteroids or cyclophosphamide can decrease the progression of lupus nephritis; however, these agents have potentially severe adverse reactions. Therefore, the development of new drugs with fewer side effects is needed. Here, we report 2 patients with lupus that were treated successfully with retinoids. Initially, both patients were treated with 60 mg/d of prednisolone. However, nephrotic syndrome was not improved. Subsequently, treatment with 10 mg/d of all-trans-retinoic acid was started orally and elicited a good response, showing a decrease in proteinuria. Although additional controlled clinical studies are needed to confirm these findings, we suggest that therapy using retinoids may represent a novel approach to the treatment of patients with lupus nephritis.

[Early diagnosis of connective tissue disease-related pulmonary hypertension].

It is known that prognosis of pulmonary hypertension (PH), especially connective tissue disease related PH (CTD-PH), is serious. CTD-PH is caused by not only pulmonary arterial hypertension, but also interstitial pneumonitis, hypoxia, chronic thromboembolism of pulmonary artery, or left heart diseases. Recently, prognosis of PH is improved by progress of diagnostic measures including echocardiography and development of effective vasodilators. However, early diagnosis of PH is necessary for further improvement of the prognosis. Previous reports have shown that diffusion lung capacity for carbon monoxide (DLco) is reduced in the early phase of PH, and we have shown that serum lactate dehydrogenase level is also elevated in this phase. Furthermore, we have been studying significance of stress echocardiography. Therefore, if reduced DLco or LDH elevation are recognized, follow up of laboratory data such as blood levels of KL-6, NT-proBNP, D-dimer, echocardiography, high resolution CT of the lung, in addition to clinical findings are important for prediction of PH.

Two cases of lupus cystitis with no bladder irritation symptoms.

Lupus cystitis is a rare manifestation in systemic lupus erythematosus (SLE); it usually occurs in association with gastrointestinal manifestations. We report two cases of lupus cystitis without bladder irritation symptoms. Both cases developed severe abdominal pain, nausea, and diarrhea and showed no bladder irritation symptoms. The diagnosis of lupus cystitis was made by abdominal ultrasonography and bladder biopsy. The patients were treated with intravenous methylprednisolone pulse therapy followed by oral prednisolone. Their symptoms were ameliorated, and hydroureteronephrosis improved. Thus, when a patient with SLE shows gastrointestinal symptoms, further examinations are required to determine whether the patient has lupus cystitis.

Deletion of IL-18 receptor ameliorates renal injury in bovine serum albumin-induced glomerulonephritis.

Bovine serum albumin (BSA) glomerulonephritis is a type of immune complex glomerulonephritis that is characterized by a large number of leukocytes infiltrating the kidney. Interleukin (IL)-18, which has potent interferon (IFN)-gamma-inducing activities, may play an important role in lymphocyte-mediated inflammatory responses. To investigate the role of IL-18 in BSA glomerulonephritis, we used IL-18R-deficient C57BL/6 mice. Compared with control mice, IL-18R-deficient mice showed a significant reduction of proteinuria, renal pathological findings including glomerular IgG and C3 deposits, and leukocyte infiltrates. Transcripts encoding IFN-gamma and tumor necrosis factor (TNF)-alpha in the kidney were significantly reduced in IL-18R-deficient mice compared with those in control mice. On the other hand, serum anti-BSA Ab was not reduced in IL-18R-deficient mice. We conclude that the blockading of IL-18 signaling in BSA nephritis mice significantly alleviates immune complex renal disorder; this may thus represent a novel approach to the treatment of patients with immune complex nephritis.

A case of adult onset Still's disease showing marked accumulation in the liver and spleen, on positron emission tomography-CT images.

A 35-year-old woman was admitted to our hospital because of high fever and skin rash, and subsequently diagnosed as having adult onset Still's disease (AOSD). Because of resistance to the steroid hormones, high levels of the serum-soluble form of the interleukin-2 receptor and splenomegaly, we suspected a possible diagnosis of malignant lymphoma and performed positron emission tomography (PET), which disclosed an intense accumulation of 2-deoxy-2 [F18] fluoro-D-glucose (FDG) in the liver and spleen. However, bone marrow aspiration and liver biopsy did not reveal any malignant cells. After the treatment of high-dose adrenocorticosteroids and plasma exchange, her symptoms and laboratory data, including PET findings, gradually improved. This is a rare case of severe AOSD in which an intense accumulation of FDG was detected by PET, and a differential diagnosis from malignant lymphoma may be difficult by FDG-PET alone, so that careful evaluation by techniques including histopathological examination may be necessary.

Olopatadine suppresses the migration of THP-1 monocytes induced by S100A12 protein.

Olopatadine hydrochloride (olopatadine) is an antiallergic drug with histamine H(1) receptor antagonistic activity. Recently, olopatadine has been shown to bind to S100A12 which is a member of the S100 family of calcium-binding proteins, and exerts multiple proinflammatory activities including chemotaxis for monocytes and neutrophils. In this study, we examined the possibility that the interaction of olopatadine with S100A12 inhibits the proinflammatory effects of S100A12. Pretreatment of olopatadine with S100A12 reduced migration of THP-1, a monocyte cell line, induced by S100A12 alone, but did not affect recombinant human regulated upon activation, normal T cell expressed and secreted (RANTES)-induced migration. Amlexanox, which also binds to S100A12, inhibited the THP-1 migration induced by S100A12. However, ketotifen, another histamine H(1) receptor antagonist, had little effect on the activity of S100A12. These results suggest that olopatadine has a new mechanism of action, that is, suppression of the function of S100A12, in addition to histamine H(1) receptor antagonistic activity.