Mototsugu Tanaka

Aberrantly Glycosylated IgA1 as a Factor in the Pathogenesis of IgA Nephropathy

Predominant or codominant immunoglobulin (Ig) A deposition in the glomerular mesangium characterizes IgA nephropathy (IgAN). Accumulated glomerular IgA is limited to the IgA1 subclass and usually galactose-deficient. This underglycosylated IgA may play an important role in the pathogenesis of IgAN. Recently, antibodies against galactose-deficient IgA1 were found to be well associated with the development of IgAN. Several therapeutic strategies based on corticosteroids or other immunosuppressive agents have been shown to at least partially suppress the progression of IgAN. On the other hand, several case reports of kidney transplantation or acquired IgA deficiency uncovered a remarkable ability of human kidney to remove mesangial IgA deposition, resulting in the long-term stabilization of kidney function. Continuous exposure to circulating immune complexes containing aberrantly glycosylated IgA1 and sequential immune response seems to be essential in the disease progression of IgAN. Removal of mesangial IgA deposition may be a challenging, but fundamental approach in the treatment of IgAN.

Lactoferrin Suppresses Neutrophil Extracellular Traps Release in Inflammation

Neutrophils are central players in the innate immune system. They generate neutrophil extracellular traps (NETs), which protect against invading pathogens but are also associated with the development of autoimmune and/or inflammatory diseases and thrombosis. Here, we report that lactoferrin, one of the components of NETs, translocated from the cytoplasm to the plasma membrane and markedly suppressed NETs release. Furthermore, exogenous lactoferrin shrunk the chromatin fibers found in released NETs, without affecting the generation of oxygen radicals, but this failed after chemical removal of the positive charge of lactoferrin, suggesting that charge-charge interactions between lactoferrin and NETs were required for this function. In a model of immune complex-induced NET formation in vivo, intravenous lactoferrin injection markedly reduced the extent of NET formation. These observations suggest that lactoferrin serves as an intrinsic inhibitor of NETs release into the circulation. Thus, lactoferrin may represent a therapeutic lead for controlling NETs release in autoimmune and/or inflammatory diseases.

Arteriovenous access closure in hemodialysis patients with refractory heart failure: a single center experience.

Arteriovenous dialysis access may impose a burden on the cardiac system. The objective of this study is to examine the usefulness of access closure in hemodialysis patients with refractory heart failure and to identify possible factors associated with symptomatic improvements. The study population comprised 33 hemodialysis patients with symptomatic heart failure (New York Heart Association [NYHA] class ≥II), who underwent arteriovenous access closure (30 fistulas and three grafts) between 1991 and 2008. In all patients, heart failure was refractory to all possible medical and surgical treatments, and persisted after optimal dry weight control. First, short‐term changes in hemodynamics, clinical symptoms and echocardiographic morphology were examined. Second, clinical and echocardiographic parameters were compared between responders (N = 23), who demonstrated NYHA class improvement after access closure, and non‐responders (N = 10). After access closure, systolic blood pressure rose and the heart rate decreased significantly. Body weight and echocardiographic parameters did not change significantly. Twenty‐three patients (70%) demonstrated NYHA class improvement and were designated as responders. In responders, the duration from access creation to closure was significantly shorter and fewer had ischemic heart disease, compared with non‐responders. Access flow, cardiac output and ejection fraction were comparable between the two groups. Although the five‐year survival was 20.2% in all patients, responders showed better early survival than non‐responders. Arteriovenous access closure improved clinical symptoms in 70% of patients with refractory heart failure. This improvement was especially likely to be achieved in patients without ischemic heart disease and those who developed heart failure within a relatively short time after access creation.

Immunomodulation with eicosapentaenoic acid supports the treatment of autoimmune small-vessel vasculitis

Small-vessel vasculitis is a life-threatening autoimmune disease that is frequently associated with anti-neutrophil cytoplasmic antibodies (ANCAs). Conventional immunotherapy including steroids and cyclophosphamide can cause serious adverse events, limiting the efficacy and safety of treatment. Eicosapentaenoic acid (EPA), a key component of fish oil, is an omega-3 polyunsaturated fatty acid widely known to be cardioprotective and beneficial for vascular function. We report two elderly patients with systemic ANCA-associated vasculitis (AAV) in whom the administration of EPA in concert with steroids safely induced and maintained remission, without the use of additioal immunosuppressants. To explore the mechanisms by which EPA enhances the treatment of AAV, we employed SCG/Kj mice as a spontaneous murine model of AAV. Dietary enrichment with EPA significantly delayed the onset of crescentic glomerulonephritis and prolonged the overall survival. EPA-derived anti-inflammatory lipid mediators and their precursors were present in the kidney, plasma, spleen, and lungs in the EPA-treated mice. Furthermore, a decrease in ANCA production and CD4/CD8-double negative T cells, and an increase in Foxp3+ regulatory T cells in the lymph nodes of the kidney were observed in the EPA-treated mice. These clinical and experimental observations suggest that EPA can safely support and augment conventional therapy for treating autoimmune small-vessel vasculitis.

AA amyloid nephropathy with predominant vascular deposition in Crohns disease

A 44-year-old man with a 17-year history of Crohns disease (CD) was referred to our nephrology department on suspicion of drug-induced nephrotoxicity. Over the preceding 18 months, he had slowly progressive renal insufficiency with slight urinary abnormalities. His disease activity had been well controlled up to that point with 5-aminosalicylic acid and azathiopurine. Laboratory examination revealed slight proteinuria without hematuria and an elevated serum creatinine level of 1.4 mg/dl. Pathological examination revealed amyloid A (AA) deposition in the kidney, predominantly in the arterial and arteriolar walls with little to none in the glomerular capillaries. AA amyloidosis is typically accompanied by glomerular amyloid deposition and massive proteinuria. In the present case, however, vascular amyloid deposition was predominant, and the renal function was deteriorated with slight urinary abnormalities. The present case confirmed the importance of conducting a definitive pathological diagnosis of renal insufficiency in CD patients.

Resolution of Henoch-Schönlein purpura nephritis after acquired IgA deficiency

We report a case of Henoch-Schönlein purpura nephritis (HSPN) with acquired IgA deficiency due to parvovirus B19 infection. The patient was diagnosed as having Henoch-Schönlein purpura (HSP) at 6 years old, and subsequently developed macrohematuria and massive proteinuria of 7.4 g/day with decreased creatinine clearance of 70.2 ml/min/1.73 m2 and significantly elevated serum IgA level of 449 mg/dl. The first kidney biopsy yielded the diagnosis of severe HSPN. After the initiation of the immunosuppressive therapy, the patient was infected with parvovirus B19 and developed virus-associated hemophagocytic syndrome (VAHS). Thereafter, the serum level of IgA selectively decreased and remained undetectable until the present time. Repeated kidney biopsies performed over a period of 14 years revealed a remarkable histological improvement in association with stabilization of the patients kidney function. Considering the severity of initial kidney injury, persistent acquired IgA deficiency was likely to add favorable effects to the immunosuppressive therapy in this patient with HSPN.

A multicenter, randomized controlled trial comparing the identification rate of stigmata of recent hemorrhage and rebleeding rate between early and elective colonoscopy in outpatient-onset acute lower gastrointestinal bleeding: study protocol for a randomized controlled trial

BackgroundThe clinical benefit of early colonoscopy within 24 h of arrival in patients with severe acute lower gastrointestinal bleeding (ALGIB) remains controversial. This trial will compare early colonoscopy (performed within 24 h) versus elective colonoscopy (performed between 24 and 96 h) to examine the identification rate of stigmata of recent hemorrhage (SRH) in ALGIB patients. We hypothesize that, compared with elective colonoscopy, early colonoscopy increases the identification of SRH and subsequently improves clinical outcomes.MethodsThis trial is an investigator-initiated, multicenter, randomized, open-label, parallel-group trial examining the superiority of early colonoscopy over elective colonoscopy (standard therapy) in ALGIB patients. The primary outcome measure is the identification of SRH. Secondary outcomes include 30-day rebleeding, success of endoscopic treatment, need for additional endoscopic examination, need for interventional radiology, need for surgery, need for transfusion during hospitalization, length of stay, 30-day thrombotic events, 30-day mortality, preparation-related adverse events, and colonoscopy-related adverse events. The sample size will enable detection of a 9% SRH rate in elective colonoscopy patients and a SRH rate of ≥ 26% in early colonoscopy patients with a risk of type I error of 5% and a power of 80%.DiscussionThis trial will provide high-quality data on the benefits and risks of early colonoscopy in ALGIB patients.Trial registrationUMIN-CTR Identifier, UMIN000021129. Registered on 21 February 2016; ClinicalTrials.gov Identifier, NCT03098173. Registered on 24 March 2017.

Age-Related Differences of Organism-Specific Peritonitis Rates: A Single-Center Experience

Peritonitis remains an important cause of morbidity and mortality in peritoneal dialysis (PD) patients, but its incidence and the distribution of causative organisms vary widely between institutions and age groups. This study was performed to investigate the recent status and risk factors of PD‐related peritonitis and to clarify differences between age groups. We retrospectively reviewed the medical records of 119 PD patients treated at our department between January 2002 and January 2013. We calculated both overall and organism‐specific peritonitis rates and also analyzed risk factors. Sixty‐three episodes of peritonitis occurred during 261.5 patient‐years for an incident rate of 0.24 episodes/patient‐year. Multivariate analysis showed that older age (≥65 years) and hypoalbuminemia (<3.0 g/dL) were associated with an increased risk of peritonitis (P = 0.035 and P = 0.029, respectively). In elderly patients (≥65 years old), the rate of peritonitis due to Gram‐positive and Gram‐negative bacteria was 0.17 and 0.08 episodes/patient‐year, respectively, and Gram‐positive peritonitis was markedly more frequent than in younger patients (<65 years old). In particular, there was a high frequency of Staphylococcus aureus peritonitis in elderly patients (0.09 episodes/patient‐year) and it had a poor outcome. At our department, the risk of peritonitis was increased in older patients and patients with hypoalbuminemia. The distribution of causative organisms was markedly different between age groups and analysis of organism‐specific peritonitis rates helped to identify current problems with our PD program.

Acute kidney injury after a pelvic surgery

A 69-year-old Japanese woman, who underwent a radical surgery with para-aortic and pelvic lymphadenectomy for stage IC ovarian clear cell carcinoma, was referred to our department because of postoperative acute kidney injury (AKI). The patient had no history of diabetes, hypertension or renal diseases. Her serum creatinine was 0.56 mg/dL (normal range: 0.6–1.2) on the 7th postoperative day. However, she gradually developed anuric renal failure, despite normal urinalysis, with a serum creatinine of 4.01 mg/dL by the 16th postoperative day. The patient presented no signs of infection or progressive anaemia. Abdominal ultrasound test showed bilateral hydronephrosis and hydroureter and also multilocular echo-free mass that looked like ‘two bladders’ in the pelvic space. Transurethral bladder catheter did not resolve the situation. A computed tomography scan revealed bilateral hydronephrosis with ureteral obstruction due to symmetric large cysts in the pouch of Douglas (Fig. 1A). Percutaneous puncture of bilateral cysts and antegrade placement of the double J catheter were thus undertaken. A total of 2 L of lymphatic drainage, which was similar to the plasma in composition, was obtained (Fig. 1B). Her kidney function had almost recovered soon after these procedures. Since the drainage persisted for more than 3 weeks and further exacerbated hydronephrosis, we decided to treat the patient with sclerotherapy using OK-432 (Picibanil, Chugai Pharmaceuticals, Tokyo, Japan). All tubes could be finally removed after two episodes of successful sclerotherapy with no complication. Although the differential diagnosis of a postoperative fluid collection in the pelvis includes lymphocele, urinoma, haematoma, seroma or abscess, bilateral lesions like this case are rare. In the present case, percutaneous puncture clarified the diagnosis of lymphoceles. Pelvic lymphocele occurs at an incidence rate of 22–48.5% after lymphadenectomy in patients with gynaecologic malignancies. Postrenal AKI due to pelvic lymphocele was repeatedly reported especially in kidney transplant recipients who have only a single functioning ureter. However, pelvic lymphocele rarely causes postrenal AKI in patients with normal kidney function because it is usually described as a unilateral form. The present case demonstrated the possibility of severe postrenal AKI by the bilateral pelvic lymphoceles through the obstruction of both ureters. A small uninfected lymphocele is often asymptomatic and can be managed with conservative therapy; however, a rapidly growing or infected one requires more invasive approaches. Percutaneous catheter drainage is the first choice to attempt in the management of lymphoceles in general, but in the refractory cases, sclerotherapy would be a good alternative. OK-432 sclerotherapy may be a safe and effective treatment modality for lymphoceles and there has been only some minor complications reported, such as mild fever, flank pain and leukocytosis.