A MAP1B-cortactin-Tks5 axis regulates TNBC invasion and tumorigenesis.

The microtubule-associated protein MAP1B has been implicated in axonal growth and brain development. We found that MAP1B is highly expressed in the most aggressive and deadliest breast cancer subtype, triple-negative breast cancer (TNBC), but not in other subtypes. Expression of MAP1B was found to be highly correlated with poor prognosis. Depletion of MAP1B in TNBC cells impairs cell migration and invasion concomitant with a defect in tumorigenesis. We found that MAP1B interacts with key components for invadopodia formation, cortactin, and Tks5, the latter of which is a PtdIns(3,4)P2-binding and scaffold protein that localizes to invadopodia. We also found that Tks5 associates with microtubules and supports the association between MAP1B and α-tubulin. In accordance with their interaction, depletion of MAP1B leads to Tks5 destabilization, leading to its degradation via the autophagic pathway. Collectively, these findings suggest that MAP1B is a convergence point of the cytoskeleton to promote malignancy in TNBC and thereby a potential diagnostic and therapeutic target for TNBC.

The Normalized Protein Catabolic Rate and Mortality Risk of Patients on Hemodialysis by Frailty Status: The Japanese Dialysis Outcomes and Practice Pattern Study.

OBJECTIVE: The appropriate protein intake for patients on hemodialysis complicated with frailty remains highly controversial. METHODS: We conducted a prospective cohort study using data from Japanese Dialysis Outcomes and Practice Pattern Study. The patients were separated by their baseline of normalized protein catabolic rate (nPCR) into 3 categories: low (nPCR < 1.0), medium (1.0 ≤ nPCR <1.2), and high (nPCR ≥1.2). The frailty score was calculated based on the 12-item Short Form, and frailty was defined in cases with a total score of ≥2 points. The all-cause mortality was compared between groups using a Cox proportional hazard model. RESULTS: A total of 2,404 patients were included in the longitudinal analysis, 1,096 (45.6%) of whom had frailty. Patients in the low-nPCR group showed a higher prevalence of frailty than those in the other groups. In the Cox proportional hazard model, no significant differences in the all-cause mortality were noted between the low-nPCR and medium-nPCR groups or the high-nPCR and medium-nPCR groups. Furthermore, no significant differences were noted among any groups when subjects were limited to patients with frailty. CONCLUSIONS: Patients with a low nPCR have a higher prevalence of frailty and incidence of mortality than those with a medium nPCR. Patients with a high nPCR did not show a lower survival rate than those with a medium nPCR in this study. To clarify the appropriate protein intake for patients on hemodialysis with frailty, an intervention study or large-scale, long-term cohort study will be needed.

An Autopsy Case of Myeloperoxidase-anti-neutrophil Cytoplasmic Antibody (MPO-ANCA)-associated Vasculitis Accompanied by Cryoglobulinemic Vasculitis Affecting the Kidneys, Skin, and Gastrointestinal Tract.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and cryoglobulinemic vasculitis (CV) rarely coexist. An 83-year-old woman was admitted with rapidly progressive renal failure, gastrointestinal hemorrhage and purpura with myeloperoxidase (MPO)-ANCA positivity and cryoglobulinemia. Despite intensive immunosuppressive treatment, she died of aspergillus pneumonia. Autopsy revealed necrotizing crescentic glomerulitis in the majority of the glomeruli, accompanied by partially membranoproliferative-like glomerular changes. Immunofluorescence staining revealed the presence of neutrophil extracellular trap (NET) formation in the glomeruli and cutaneous arteries. These pathological findings suggested that MPO-AAV and/or CV caused NET formation, leading to lethal systemic vasculitis.

Clinical and histological features of antineutrophil cytoplasmic antibody-associated vasculitis related to antithyroid drugs
.

BACKGROUND: Antithyroid drugs such as propylthiouracil and methimazole have been reported to cause antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), but little is known about long-term outcomes. MATERIALS AND METHODS: We identified AAV patients who underwent renal biopsy and retrospectively assessed their clinical and histological findings. Patients with AAV who had received propylthiouracil or methimazole were defined as having antithyroid drug-associated AAV (ATD-AAV), and the other patients were defined as having primary AAV. RESULTS: Seven patients with ATD-AAV and 83 patients with primary AAV were identified. Compared with the primary AAV group, the patients with ATD-AAV were significantly younger (mean ± standard deviation; 45.4 ± 21.4 years vs. 65.9 ± 13.8 years, p < 0.01), and had lower serum creatinine (median [interquartile range]; 0.7 mg/dL [0.6 - 1.5] vs. 2.3 mg/dL [1.0 - 4.0], p = 0.02), as well as a higher frequency of positivity for MPO--ANCA/PR3-ANCA (42.9 vs. 4.8%, p < 0.01). While glomerular crescents varied, interstitial fibrosis and tubular atrophy were milder in ATD-AAV patients. Kaplan-Meier analysis showed a significantly higher kidney survival rate in patients with ATD-AAV than in those with primary AAV (p = 0.05). CONCLUSION: Patients with ATD-AAV were younger and had milder kidney involvement, resulting in a better long-term outcome compared with primary AAV.
.

Clinical and Pathological Features of Plasma Cell-Rich Acute Rejection After Kidney Transplantation.

BACKGROUND: Plasma cell-rich acute rejection (PCAR) is a rare type of allograft rejection characterized by the presence of mature plasma cells. In general, the prognosis of PCAR is poor, and its clinical and pathological features remain unclear. METHODS: We performed a retrospective observational study and compared allograft survival between kidney transplant recipients who developed PCAR and those who did not develop PCAR. We further analyzed clinical and pathological risk factors for allograft failure in PCAR patients. RESULTS: Of 1956 recipients, 40 developed PCAR. There was a higher prevalence of deceased donor transplants (27.5% vs 11.7%, P = 0.0059), longer median total ischemia time (99 minutes; interquartile range, 71-144 vs 77 minutes; interquartile range, 59-111; P = 0.0309), and lower prevalence of ABO-incompatible transplantation (7.5% vs 22.5%; P = 0.0206) in patients with PCAR than in those without PCAR.Multivariate Cox regression analysis showed that development of PCAR was associated with allograft loss (hazard ratio, 8.03; 95% confidence interval, 3.89-14.80; P < 0.0001).We classified PCAR according to the Banff 2015 criteria into a borderline change group, a T cell-mediated rejection (TCMR) group, an antibody-mediated rejection (AMR) or suspected of having AMR (AMR/sAMR) group, and a mixed rejection (TCMR/AMR) group. The AMR/sAMR group was associated with a lower rate of allograft survival without significant difference (log-rank test, P = 0.1692). CONCLUSIONS: The results indicated that PCAR was an independent risk factor for allograft loss. PCAR presented with all types of rejection in the Banff 2015 criteria, and AMR/sAMR was associated with poor allograft survival.

Cryoglobulinemic vasculitis with primary Sjögren's syndrome: A case report.

A 63-year-old Japanese woman with Sjögren's syndrome and peripheral neuropathy was admitted for evaluation of purpura on her lower extremities. Skin biopsy revealed leukocytoclastic vasculitis with the deposition of IgM, and serum cryoglobulin was positive. Accordingly, cryoglobulinemic vasculitis was diagnosed. There was no response to high-dose steroid therapy and plasmapheresis, but intravenous cyclophosphamide pulse therapy was effective for 4 years. Thereafter, proteinuria and hematuria developed, with cryoglobulinemic glomerulopathy being diagnosed by renal biopsy. Because the total dose of cyclophosphamide had reached 8000 mg, treatment with rituximab was selected. While rituximab was initially effective for her skin lesions and nephropathy, relapse occurred within 2 years and additional administration of this agent was required. The long-term efficacy of treatment for cryoglobulinemic vasculitis remains uncertain in patients with Sjögren's syndrome.

Clinical and pathological features of anti-neutrophil cytoplasmic antibody-associated vasculitis in patients with minor urinary abnormalities.

AIM: Kidney biopsy is the gold standard for diagnosis of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), but it is unknown whether vasculitis can be detected from AAV patients with minor urinary abnormalities. METHODS: Ninety ANCA-positive patients undergoing kidney biopsy were evaluated retrospectively after being divided into two groups, which were group A (minor urinary abnormalities with both proteinuria <0.5 g/day and red blood cells ≤5/high power field) and group B (major urinary abnormalities except group A). RESULTS: Thirteen patients were included in group A and 77 patients were in group B. Crescentic glomeruli were detected less frequently in group A than in group B (61.5% vs. 92.2%, P < 0.01). The percentage of crescentic glomeruli relative to total glomeruli was significantly lower in group A than in group B (median [interquartile range]; 2.7% [0-5.2%] vs. 27.3% [8.1-56.1%], P < 0.01). Vasculitis of the small renal arteries was detected more frequently in group A than in group B without significant difference (30.8% vs. 19.5%, P = 0.46). Overall renal vasculitis (crescentic glomeruli and/or small renal artery vasculitis) was detected less frequently in group A than in group B (69.2% vs. 92.2%, P = 0.03). CONCLUSIONS: These findings indicate that renal biopsy can be a useful tool for histological diagnosis of ANCA-associated vasculitis in ANCA-positive patients with minor urinary abnormalities, even though the rate of renal vasculitis to the total number of glomeruli sampled is lower in patients with minor urinary abnormalities than patients with major abnormalities.

False Elevation of the Blood Tacrolimus Concentration, as Assessed by an Affinity Column-mediated Immunoassay (ACMIA), Led to Acute T Cell-mediated Rejection after Kidney Transplantation.

Tacrolimus is the most commonly used immunosuppressant. Because of its narrow therapeutic range, it is necessary to frequently monitor its concentration. We report the case of a 25-year-old man who underwent kidney transplantation whose tacrolimus concentrations, as measured by an affinity column-mediated immunoassay, were falsely elevated. As we reduced the dose of tacrolimus, the recipient developed T cell-mediated rejection. Using the same blood samples, an enzyme-multiplied immunoassay technique showed that the patient's levels of tacrolimus were extremely low. A further examination indicated that the false increase in the tacrolimus concentration was likely due to an unknown interfering substance. We administered methylprednisolone and antithymocyte-globulin. The patient's serum creatinine level decreased and remained stable after these treatments.

Preemptive anti-cytomegalovirus therapy in high-risk (donor-positive, recipient-negative cytomegalovirus serostatus) kidney transplant recipients.

OBJECTIVES: Universal prophylaxis and preemptive therapy are used to prevent cytomegalovirus (CMV) disease post-transplantation. Data regarding which strategy is superior are sparse, especially in high-risk recipients (donor CMV seropositive (D+) and recipient CMV seronegative (R-)). METHODS: This retrospective, single-center cohort study included recipients who underwent kidney transplantation between 2009 and 2015. The incidence of CMV infection/disease and patient and graft outcomes were analyzed and compared between high-risk recipients (D+/R-) and intermediate-risk recipients (D+/R+ or D-/R+), all managed with preemptive therapy. RESULTS: Of 118 kidney transplant recipients, 21 were high-risk and 97 were intermediate-risk. Over a median follow-up period of 3 years, asymptomatic CMV infection developed significantly more frequently in high-risk patients than in intermediate-risk patients (38.1% vs. 16.5%, p=0.04), and CMV disease developed in a similar manner (28.6% vs. 3.1%, p<0.01). Among high-risk patients, CMV infection developed within the first 3 months post-transplantation and CMV disease within the first 9 months post-transplantation. Kaplan-Meier analysis showed no difference in the probability of mortality (log-rank p=0.63) or graft loss (log-rank p=0.50) between the patient groups. Graft rejection occurred more frequently in high-risk than in intermediate-risk patients, but the difference was not significant (log-rank p=0.24). CONCLUSIONS: These results suggest that further studies on universal prophylaxis in high-risk patients are needed to elucidate whether preventing CMV infection/disease during the early post-transplant period leads to better outcomes, especially in terms of reducing graft rejection.

Cardiovascular and Stroke Risk in Japanese Hemodialysis Patients With Atrial Fibrillation.

Atrial fibrillation is one of the most common arrhythmias in hemodialysis patients. We evaluated its clinical outcomes among hemodialysis patients with atrial fibrillation in Japan. Using data derived from the Japanese Dialysis Outcomes and Practice Patterns Study, we analyzed backgrounds and outcomes among hemodialysis patients with and without atrial fibrillation in Japan. Among 7002 hemodialysis patients, the prevalence of atrial fibrillation was 5.7% and the incidence was 0.2 per 100 patient-years. Atrial fibrillation was independently associated with all-cause mortality (hazard ratio, 1.32; 95% confidence interval, 1.02-1.71) and cardiovascular events (hazard ratio, 1.39; 95% confidence interval, 1.15-1.68), but not with stroke events (hazard ratio, 0.77; 95% confidence interval, 0.55-1.06) after adjustment for other variables. We conclude that patients with atrial fibrillation experienced higher mortality and more cardiovascular events than did patients without atrial fibrillation, although the risk of stroke was lower than expected.

Prognostic Value of Tubulointerstitial Lesions, Urinary N-Acetyl-ß-d-Glucosaminidase, and Urinary ß2-Microglobulin in Patients with Type 2 Diabetes and Biopsy-Proven Diabetic Nephropathy.

BACKGROUND AND OBJECTIVES: Some biomarkers of renal tubular injury are reported to be useful for predicting renal prognosis in the early stage of diabetic nephropathy (DN). Our study compared predictions of the renal prognosis by such biomarkers and by histologic tubulointerstitial damage. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Among 210 patients with type 2 diabetes and biopsy-proven DN managed from 1985 to 2011, 149 patients with urinary N-acetyl-ß-d-glucosaminidase (NAG) and urinary ß2-microglobulin (ß2-MG) data at the time of renal biopsy were enrolled. The primary outcome was a decline in eGFR of ≥50% from baseline or commencement of dialysis for ESRD. RESULTS: The median follow-up period was 2.3 years (interquartile range, 1.1-5.3), and the primary outcome was noted in 94 patients. Mean eGFR was 46.3±23.2 ml/min per 1.73 m(2), and 132 patients (89%) had overt proteinuria at baseline. Cox proportional hazards analysis revealed that the association of urinary NAG and ß2-MG with the outcome was attenuated after adjustment for known promoters of progression (+1 SD for log NAG: hazard ratio [HR], 1.14; 95% confidence interval [95% CI], 0.84 to 1.55; +1 SD for log ß2-MG: HR, 1.23; 95% CI, 0.94 to 1.62). In contrast, the interstitial fibrosis and tubular atrophy (IFTA) score was still significantly correlated with the outcome after adjustment for the same covariates (+1 for IFTA score: HR, 2.31; 95% CI, 1.56 to 3.43). Moreover, adding the IFTA score to a model containing known progression indicators improved prediction of the outcome (increase of concordance index by 0.02; 95% CI, 0.00 to 0.05; category-free net reclassification improvement by 0.54; 95% CI, 0.03 to 1.05; and relative integrated discrimination improvement by 0.07; 95% CI, -0.08 to 0.22). CONCLUSIONS: Adding urinary NAG and ß2-MG excretion to known promoters of progression did not improve prognostication, whereas adding the IFTA score did. The IFTA score may be superior to these tubulointerstitial markers for predicting the renal prognosis in advanced DN.

Characteristics of Intravascular Large B-Cell Lymphoma Limited to the Glomerular Capillaries: A Case Report.

A 65-year-old woman was admitted to our hospital for the evaluation of rapidly progressive renal dysfunction with serum creatinine of 2.7 mg/dl and urinary protein of 1.5 g daily. C-reactive protein (CRP) was 0.1 mg/dl. Kidney-limited intravascular large B-cell lymphoma (IVL) localized to the glomerular capillaries was diagnosed because the intraglomerular cells were positive for CD20 and CD79a, while there was no positivity in the extraglomerular kidney and extrarenal organs. Treatment with rituximab, cyclophosphamide, hydroxydaunomycin, vincristine, and prednisolone was started, and the patient has since been doing well. When IVL is limited to the intraglomerular capillaries, CRP may not be elevated.

Simultaneous nephrotic syndrome and hepatitis in secondary syphilis: case report and review of the literature.

A 66-year-old man presented with a penile ulcer, an acute clinical onset of nephrotic syndrome and hepatitis. Secondary syphilis was diagnosed on the basis of the history of rash and the result of strongly positive serological test for syphilis. A renal biopsy demonstrated membranous glomerulonephritis with subepithelial electron-dense deposits. After treatment with amoxicillin for 2 weeks, he achieved clinical recovery. It is important to recognize syphilis as a reversible cause of nephrotic syndrome and acute hepatitis because antibiotic therapy can result in complete remission.

A case of immunoglobulin A nephropathy treated successfully with tonsillectomy and steroid pulse therapy 20 years after onset.

A 46-year-old male was found to have proteinuria on a routine medical examination in 1985 at the age of 22 years and was diagnosed with immunoglobulin A (IgA) nephropathy by renal biopsy. He regularly visited a hospital, but 3 years later made the decision to stop. In 2000, his serum creatinine level was 1.3 mg/dl. His renal function then deteriorated, with persistent proteinuria and hematuria, following which he visited our hospital in December 2008. A further renal biopsy was performed. Active and chronic IgA nephropathy was confirmed histologically, with sclerosing lesions also being found. He was treated with three courses of steroid pulse therapy in February and tonsillectomy in April 2009. During the follow-up period at the outpatient clinic, results for proteinuria and hematuria were negative, suggesting that progression of renal impairment had been prevented. The efficacy of tonsillectomy plus steroid pulse therapy for early IgA nephropathy has been demonstrated, and this treatment was effective in our patient 20 years after the onset of the disease.

A case of disseminated tuberculosis after the initiation of hemodialysis.

A 67-year-old man with diabetes mellitus, chronic kidney disease, chronic heart failure, and amputation of the left lower limb was admitted to our hospital with decreasing renal function. On admission, he was started on hemodialysis. He simultaneously developed a urinary tract infection, infected necrotic wound of the right lower limb, and pneumonia, and was treated with broad-spectrum antibiotics. Although his general condition improved, fever and anorexia persisted and jaundice worsened. He died 138 days after admission. Autopsy revealed granulomas in the lungs, liver, and spleen. Cultures revealed Mycobacterium tuberculosis, leading to the diagnosis of disseminated tuberculosis.