Characterization of urinary exosomal release of aquaporin-1 and -2 after renal ischemia-reperfusion in rats.

Acute kidney injury (AKI) is an important risk factor for the development of chronic kidney disease (CKD), and an alteration in renal water handling has been observed during the transition of AKI to CKD. Urinary exosomal release of aquaporin-1 (AQP1) and AQP2, important proteins for renal water handling, has recently been reported to predict their levels of renal expression. Therefore, we examined the patterns of urinary exosomal release of AQP1 and AQP2, and the exosomal marker proteins tumor susceptibility 101 protein (TSG101) and ALG-2 interacting protein X (Alix), in the acute and chronic phases following induction of AKI by renal bilateral ischemia/reperfusion (I/R) in rats. Blood tests and histological examinations indicated that AKI occurred before at 7 days after renal I/R ( day 7) and that renal fibrosis developed progressively thereafter. Immunoblotting demonstrated significant decreases in the urinary exosomal release of AQP1 and AQP2 during severe AKI. Urinary exosomal release of Alix and TSG101 was significantly increased on day 7. These data were also confirmed in rats with unilateral renal I/R causing more serious AKI. Urinary exosomal release of either the Ser-256- or Ser-269-phosphorylated form of AQP2, both of which are involved in apical trafficking of AQP2, was positively correlated with that of total AQP2. These results suggest that urinary exosomal release of AQP1 and AQP2 is reduced in I/R-induced AKI, whereas that of Alix and TSG101 is increased in the initial phase of renal fibrosis. Furthermore, apical trafficking of AQP2 appears to be related to urinary exosomal release of AQP2.

Clinical Features and Treatment Outcomes of 81 Patients with Aggressive Type Adult T-cell Leukemia-lymphoma at a Single Institution over a 7-year Period (2006-2012).

OBJECTIVE: Despite the remarkable advances in chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT), adult T-cell leukemia-lymphoma (ATL) is still associated with a high mortality rate. It is therefore essential to elucidate the current features of ATL. METHODS: We retrospectively analyzed 81 patients with aggressive type ATL at our institution over a 7-year period based on Shimoyama's diagnostic criteria. RESULTS: Eighty-one patients with a median age of 67.5 years were classified as having acute (n=47), lymphoma (n=32), or chronic type (n=2) ATL. They were initially treated by either palliative therapy (n=25) or systemic chemotherapy [n=56; cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy (n=25)/vincristine, cyclophosphamide, doxorubicin, and prednisone (VCAP)-doxorubicin, ranimustine, and prednisone (AMP)-vindesine, etoposide, carboplatin, and prednisone (VECP) therapy (VCAP-AMP-VECP) or CHOP-VMMV therapy (n=31)], and showed median survival durations of 16 and 277 days, respectively. Subsequent to the initial treatment, HSCT (n=6) was performed for certain patients, thus revealing that two-thirds (n=4) relapsed, and one-third (n=2) survived for 131 days and 203 days, respectively. The relapsed ATL patients were treated with conventional salvage therapy (n=29) or anti-CC chemokine receptor 4 antibody (mogamulizumab) (n=3). The patients treated with mogamulizumab demonstrated complete response (2) and partical response (1) with short duration periods of 82 days, 83 days, and 192 days, respectively. Among the five long-term survivors (>5 years) who received chemotherapy, most showed a low and intermediate risk according to the ATL prognostic index. CONCLUSION: In our study, the overall survival of ATL remains poor due to the advanced age of the patients at diagnosis, a high proportion of patients receiving palliative therapy, and a small proportion of long-term survivors receiving chemotherapy and undergoing HSCT. This study illustrates the current clinical features, treatment strategies, and outcomes in clinical practice.

Successful treatment of bortezomib-refractory multiple myeloma derived from monoclonal gammopathy of undetermined significance with dose-adjusted lenalidomide therapy in a patient with concomitant end-stage renal disease due to diabetic nephropathy requiring haemodialysis.

Malignancy is a fatal complication of end-stage renal disease (ESRD) requiring haemodialysis. However, the successful treatment of haematological malignancies has been rarely reported. We describe the case of a 63-year-old man who presented with IgA-type multiple myeloma (MM; Durie-Salmon stage IIIB) derived from monoclonal gammopathy of undetermined significance concomitant with ESRD due to diabetic nephropathy. First, haemodialysis was initiated before chemotherapy, and bortezomib and dexamethasone were found to be ineffective. Subsequently, 8 courses of dose-adjusted lenalidomide therapy were administered according to the degree of haematological and renal functions. The patient remained in partial remission without disease progression for 21 months. Thus, lenalidomide therapy is effective for bortezomib-refractory MM concomitant with ESRD.

Clinical characteristics and outcomes of 11 patients with pure red cell aplasia at a single institution over a 13-year period.

OBJECTIVE: Pure red cell aplasia (PRCA) is a rare clinical entity characterized by anemia due to severe suppression of erythroid precursors, where the other cell lineages in the bone marrow remain morphologically normal. A standard treatment has not yet been established for PRCA due to the rarity of this condition. Recently, however, the administration of either cyclosporine (CSP) or prednisolone (PSL) has been reported to be an effective treatment for PRCA. METHODS: To clarify the clinical characteristics of PRCA, 11 PRCA cases were retrospectively analyzed over a 13-year period at our institution. Since acute PRCA was found to be self-limiting, we administered the immunosuppressive treatment of CSP or PSL after providing supportive care for 4 weeks. RESULTS: The causes of PRCA were as follows: idiopathic (3), acute parvovirus infection (1), chronic parvovirus infection (3), thymic tumor (3), and end-stage renal disease with hemodialysis (1). Complete remission (CR) was achieved for 4 of the 5 patients treated with CSP, for 2 of the 3 patients with chronic parvovirus infection treated by immunoglobulin (Ig), and for all 3 patients treated with PSL. During the follow-up periods, 4 of the 11 patients relapsed. Complete remission was achieved a second time in all 4 cases by therapies that were more intensive and had longer administration periods than those provided during initial treatment. Consequently, 9 of the 11 patients were still alive (80%) after 5 years. CONCLUSION: Depending on the cause of the PRCA, treatment with CSP, PSL, or Ig was found to be effective in most PRCA cases.

Therapeutic modality of 11 patients with TTP in a single institution in Miyazaki from 2000 to 2011.

OBJECTIVE: Thrombotic thrombocytopenic purpura (TTP) is a life-threatening generalized disease with pathological features that are termed thrombotic microangiopathies. Since the discovery of the von Willebrand factor-cleaving protease [a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13)], it is widely known that approximately two-thirds of TTP patients have a severe deficiency of ADAMTS13 activity due to gene mutations or acquired autoantibodies to this enzyme. However, the remaining one-third of TTP patients have only moderately reduced or almost normal ADAMTS13 activity. To elucidate the clinical characteristics and outcomes of these two types of TTP, we have retrospectively analyzed the cases of acquired TTP patients treated in a single institution from 2000 to 2011. METHODS: Our case studies include 11 TTP patients, of which 5 were considered idiopathic and 6 had cases of TTP associated with underlying diseases such as non-Hodgkin lymphoma or connective tissue diseases. RESULTS: These patients were treated with a combination therapy of plasma exchange and steroids and with several adjunctive therapeutic regimens including the on-label use of cyclophosphamide and cyclosporine and the off-label use of high-dose steroid or immunoglobulin with rituximab. Splenectomies were not performed. As a result of these treatments, 6 out of the 7 patients with ADAMTS13 activity deficient TTP achieved a complete remission without relapse, but the remaining 4 patients with non-ADAMTS13 activity deficient TTP all died without complete remission. CONCLUSION: We present herein the detailed clinical courses of 11 patients with TTP and address our experiences with the efficacy of various therapeutic regimens. This case-oriented study should be helpful to the physicians who directly care for TTP patients, and may provide a future direction for developing a more efficient treatment modality.

Successful treatment of non-Hodgkin's lymphoma with rituximab and dose-adjusted CHOP therapy in a patient with concomitant end-stage renal disease requiring haemodialysis.

Although malignancy is a fatal complication of end-stage renal disease (ESRD) requiring haemodialysis, successful treatment of haematological malignancies has been rarely reported. We describe the case of a 64-year-old man who presented with non-Hodgkin's lymphoma (NHL; clinical stage, IVB) concomitant with ESRD. Before chemotherapy, haemodialysis was initiated, and one course of dose-adjusted CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) therapy followed by eight courses of rituximab therapy were administered according to the performance status and degree of organ dysfunction. Consequently, the patient was disease free for 27 months. Thus, rituximab plus CHOP combination therapy was effective for NHL concomitant with ESRD.

Decreased abundance of urinary exosomal aquaporin-1 in renal ischemia-reperfusion injury.

Urinary exosomes, secreted into urine from renal epithelial cells, are known to contain many types of renal functional membrane proteins. Here, we studied whether renal ischemia-reperfusion (I/R) affects urinary exosomal aquaporin-1 (AQP1) excretion in rats subjected to renal I/R and patients who underwent renal transplantation. Immunoblotting studies demonstrated reduction of the urinary exosomal AQP1 level even at 6 h after renal I/R, and the level continued to be low over 96 h after I/R. Renal AQP1 mRNA and protein analyses revealed that the decreased excretion of urinary exosomal AQP1 is associated with renal AQP1 protein retention in the early phase and with a decreased expression level of renal AQP1 in the later phase of renal I/R injury. Decreased abundance of urinary exosomal AQP1 in a recipient patient was also observed at 48 h after renal allograft transplantation. No significant decrease in urinary exosomal AQP1 was observed in a rat model of nephropathy or in patients with proteinuria. Our studies suggest that the renal AQP1 expression level is possibly controlled by its urinary exosomal excretion and indicate that urinary exosomal AQP1 is a novel urinary biomarker for renal I/R injury.

Amelioration of renal ischemia-reperfusion injury by inhibition of IL-6 production in the poloxamer 407-induced mouse model of hyperlipidemia.

It is largely unknown whether hyperlipidemia is involved in the pathobiology of renal ischemia-reperfusion (I/R) injury that is an important cause of acute kidney injury. Here we studied the effect of experimental dyslipidemia on renal I/R injury. Renal I/R injury was less severe in hyperlipidemic mice treated with poloxamer 407 than in the control mice. Cytokine analyses revealed decreased levels of renal and serum IL-6 in the hyperlipidemic mice after renal I/R. Protection from renal I/R injury in the hyperlipidemic mice was diminished by administration of recombinant IL-6. Concanavalin A-induced IL-6 release from cultured splenocytes derived from the hyperlipidemic mice was lower than that from splenocytes of normal mice. In hypercholesterolemic apolipoprotein E-knockout mice, in which renal I/R injury is less severe than in control mice, renal I/R-induced IL-6 production was also less than that in controls. In angiopoietin-like 3-deficient mice, which were hypolipidemic, renal dysfunction and renal IL-6 level after I/R were similar to those of control mice. Our data indicate that the presence of experimental hyperlipidemia may be associated with a decreased risk of renal I/R injury, possibly mediated by reduced renal IL-6 production after the insult and extend the notion that an anti-IL6 agent would be useful for the treatment of acute kidney injury.