Efficacy and Safety of Esaxerenone in Hypertensive Patients with Diabetes Mellitus Undergoing Treatment with Sodium-Glucose Cotransporter 2 Inhibitors (EAGLE-DH).

INTRODUCTION: The EAGLE-DH study assessed the efficacy and safety of esaxerenone in hypertensive patients with diabetes mellitus receiving sodium-glucose cotransporter 2 (SGLT2) inhibitors. METHODS: In this multicenter, open-label, prospective, interventional study, esaxerenone was started at 1.25 or 2.5 mg/day and could be gradually increased to 5 mg/day on the basis of blood pressure (BP) and serum potassium levels. Oral hypoglycemic or antihypertensive medications prior to obtaining consent was continued. Data were evaluated in the total population and creatinine-based estimated glomerular filtration rate (eGFR) subcohorts (eGFR ≥ 60 mL/min/1.73 m2 [G1-G2 subcohort] and 30 to < 60 mL/min/1.73 m2 [G3 subcohort]). RESULTS: In total, 93 patients were evaluated (G1-G2, n = 49; G3, n = 44). Morning home systolic/diastolic BP values (SBP/DBP) were significantly reduced from baseline to week 12 (- 11.8 ± 10.8/- 5.1 ± 6.3 mmHg, both P < 0.001) and week 24 (- 12.9 ± 10.5/- 5.7 ± 6.3 mmHg, both P < 0.001). Similar results were observed in both eGFR subcohorts. The urinary albumin-to-creatinine ratio significantly decreased from baseline to week 24 in the total population (geometric percentage change, - 49.1%, P < 0.001) and in both eGFR subcohorts. The incidences of treatment-emergent adverse events (TEAEs) and drug-related TEAEs were 45.2% and 12.9%, respectively; most were mild or moderate. Serum potassium levels increased over the first 2 weeks of esaxerenone treatment, gradually decreased by week 12, and remained constant to week 24. One patient in the G1-G2 subcohort had serum potassium levels ≥ 5.5 mEq/L. No patients had serum potassium ≥ 6.0 mEq/L. CONCLUSION: Esaxerenone effectively lowered BP, was safe, and showed renoprotective effects in hypertensive patients with diabetes mellitus receiving treatment with SGLT2 inhibitors. Esaxerenone and SGLT2 inhibitors did not interfere with either drug's efficacy and may reduce the frequency of serum potassium elevations, suggesting they are a compatible combination. CLINICAL TRIAL REGISTRATION: jRCTs031200273.

Efficacy and Safety of Esaxerenone in Hypertensive Patients with Diabetic Kidney Disease: A Multicenter, Open-Label, Prospective Study.

INTRODUCTION: Clinical data of esaxerenone in hypertensive patients with diabetic kidney disease (DKD) are lacking. We evaluated the efficacy and safety of esaxerenone in patients with DKD and an inadequate response to blood pressure (BP)-lowering treatment. METHODS: In this multicenter, open-label, prospective study, patients were divided into urinary albumin-to-creatinine ratio subcohorts (UACR < 30, 30 to < 300, and 300 to < 1000 mg/gCr). Esaxerenone was initiated at 1.25 mg/day and followed by incremental dose escalation based on BP and serum potassium level monitoring. The treatment period was 12 weeks. The primary endpoint was change in morning home systolic BP/diastolic BP (SBP/DBP) from baseline to end of treatment (EOT). Secondary endpoints included achievement rate of target BP, change in UACR from baseline, and safety. RESULTS: In total, 113 patients were enrolled. Morning home SBP/DBP significantly decreased from baseline to EOT in the total population (- 11.6/- 5.2 mmHg, both p < 0.001) and in all UACR subcohorts (all p < 0.001). The target BP achievement rate was 38.5%. Significant reductions in bedtime home and office BPs were also shown in the total population and all UACR subcohorts. UACR significantly improved from baseline to EOT in the total (- 50.9%, p < 0.001) and all UACR subcohorts (all p < 0.001). Incidence of serum potassium elevation as drug-related treatment emergent adverse events was 2.7%. The change from baseline in estimated glomerular filtration rate (eGFR) was - 4.8 mL/min/1.73 m2. CONCLUSION: Esaxerenone demonstrated a BP-lowering effect and improved albuminuria. The effects were consistent regardless of the severity of albuminuria without clinically relevant serum potassium elevation and eGFR reduction. CLINICAL TRIAL REGISTRATION: jRCTs06119002.

Feline Adipose Derived Multipotent Stromal Cell Transdifferentiation Into Functional Insulin Producing Cell Clusters.

Diabetes mellitus (DM) is one of the most prevalent feline endocrinopathies, affecting up to 1% of pet cats. De novo generation of functional insulin producing cell (IPC) clusters via transdifferentiation of feline adipose-derived multipotent stromal cells (ASCs) may not only provide a viable, functional cell therapy for feline DM, but may also serve as a platform for developing a comparable human treatment given feline and human DM similarities. Cells were induced to form IPCs with a novel, three-stage culture process with stromal or differentiation medium under static and dynamic conditions. Clusters were evaluated for intracellular zinc, viability, intracellular insulin, glucagon, and somatostatin, ultrastructure, glucose stimulated insulin secretion in the presence or absence of theophylline, and protein and gene expression. Isolated cells were multipotent, and cell clusters cultured in both media had robust cell viability. Those cultured in differentiation medium contained zinc and mono- or polyhormonal α-, ß-, and δ-like cells based on immunohistochemical labeling and Mallory-Heidenhan Azan-Gomori's staining. Ultrastructurally, cell clusters cultured in differentiation medium contained insulin granules within vesicles, and clusters had a concentration-dependent insulin response to glucose in the presence and absence of theophylline which increased both insulin secretion and intracellular content. Expression of NK6.1, Pax6, Isl1, Glut2, RAB3A, glucagon, insulin, and somatostatin increased with differentiation stage for both sexes, and expression of nestin at stages 1 and 2 and Neurod1 at stage 2 was higher in cells from female donors. The cluster insulin secretion responses and endocrine and oncogene gene expression profiles were inconsistent with insulinoma characteristics. A total of 180 proteins were upregulated in differentiated clusters, and the majority were associated with biological regulation, metabolic processes, or stimulus response. Dynamic culture of IPC clusters resulted in clusters composed of cells primarily expressing insulin that released higher insulin with glucose stimulation than those in static culture. Collectively, the results of this study support generation of functional IPC clusters using feline ASCs isolated from tissues removed during routine sterilization. Further, cluster functionality is enhanced with dynamic, motion-driven shear stress. This work establishes a foundation for development of strategies for IPC therapy for short or long-term diabetes treatment and may represent an option to study prevention and treatment of diabetes across species.

Association of Chronic Myelogenous (Basophilic) Leukemia and the BCR/ABL Mutation in a Yucatan Barrow (Sus scrofa domestica).

Background: Chronic myelogenous leukemia (CML) is a clonal proliferative disorder of the myeloid, megakaryocyte, and erythroid lineages. The onset and subsequent progression of CML is well-described in humans. There is comparably little information surrounding CML progression in veterinary species, including Yucatan miniature swine that are common for preclinical pharmaceutical and device testing. In humans, more than 90% of CML cases are associated with a chromosomal translocation that results in the Philadelphia gene (BCR/ABL mutation). In this report, the presence of the Philadelphia gene in a Yucatan burrow was confirmed in white blood cells collected prior to onset of clinical signs with primers designed from the human BCR/ABL sequence. Case Presentation: A 24 month old, 70 kg, Yucatan barrow received a prefabricated bovine cortical bone xenograft following a unilateral zygomatic ostectomy for a preclinical study. Complete blood count and serum chemistries were performed prior to and 28, 53, 106, and 129 days after facial surgery. Fifty three days after surgery, a bone marrow biopsy was performed due to anorexia, severe basophilia, and mild anemia. A finding of a moderate increase in basophilic precursors in bone marrow cytology was followed by lymphocyte immunophenotyping via flow cytometry and RT-PCR amplification of the Philadelphia gene in white blood cell samples from the affected barrow and an unaffected barrow in the same treatment group. Bone marrow, lymph node, liver, spleen, lung, kidney, and adrenal gland lesions of mostly myeloblasts were identified after the affected barrow died 146 days after surgery. Flow cytometry confirmed lymphopenia and suggested basophilia, and RT-PCR established the presence of the BCR/ABL gene. Conclusions: The information in this report confirms the presence of the BCR/ABL mutation and documents progression of chronic myelogenous (basophilic) leukemia from a chronic phase to a terminal blast crisis in an adult Yucatan barrow. The natural occurrence and progression of CML associated with the BCR/ABL mutation in miniature swine establishes potential for future porcine models of human CML. The information also establishes a genetic test to confirm porcine CML to prevent inadvertent attribution of clinical signs to treatment complications during preclinical testing.

Biocompatibility of allogenic canine fascia lata: In vitro evaluation and small case series.

OBJECTIVE: To evaluate the biocompatibility of canine fascia lata (FL) in vitro and after FL allograft implantation in dogs with clinical disease. STUDY DESIGN: In vitro experiment and small case series. SAMPLE POPULATION: Six dogs treated with allogenic freeze-dried FL. METHODS: Fibroblasts were cultured on disks of FL, polypropylene mesh (PM; negative control), and porcine small intestinal submucosa (SIS; positive control). Constructs were compared at 3, 7, and 14 days for water content, DNA amounts, scanning electron microscopy, and histology. Records of dogs treated with FL allografts with follow-up examination were reviewed for signalment, indication for surgery, surgical procedure, and outcomes. All owners were invited to complete a standardized questionnaire for long-term follow-up. RESULTS: Water content was greater in FL and SIS than in PM (P = .03). Fascia lata constructs contained more DNA compared with PM constructs at days 7 and 14 (P < .05), whereas SIS constructs did not differ from FL or PM. Fibroblasts appeared spherical and distributed throughout FL constructs, whereas they appeared stellate and remained on the surface of SIS and PM. Fascia lata allografts were implanted in six dogs with surgical conditions. No incisional complications were noted. All dogs had good to excellent long-term outcomes, except one that experienced recurrence of a perineal hernia 2 years after repair. CONCLUSION: In vitro, canine FL allowed attachment and proliferation of fibroblasts throughout layers of the graft. Canine allogenic FL was clinically well tolerated in this small population of dogs. CLINICAL SIGNIFICANCE: Allogenic FL is biocompatible and can be considered an alternative to SIS for soft tissue augmentation in dogs.

Influence of Donor's Age on Immunomodulatory Properties of Canine Adipose Tissue-Derived Mesenchymal Stem Cells.

Osteoarthritis challenges traditional therapies and remains a leading cause of lameness in older dogs. Regenerative medicine offers new strategies, typically involving the injection of autologous adipose-derived mesenchymal stem cells (MSCs). Conversely, allogenic MSCs are appealing candidates to palliate patient morbidity and cell preparation time. Regardless of the source of cells, identifying critical donor characteristics, such as age, is essential to obtain the most competent MSCs. The objectives of this study were to determine the influence of donor's age on proliferation, gene expression, and immunomodulatory properties of MSCs in dogs. Canine adipose tissue-derived MSCs (cAD-MSCs) were isolated from the falciform-ligament adipose tissues of nine pairs of gender-matched young (<2 years) or old (>7 years) client-owned dogs undergoing abdominal surgery. Growth kinetics, transcriptome before and after stimulation by tumor necrosis factor alpha and interferon gamma, MSC-induced lymphocyte suppression assay, and secretion of prostaglandin E2 (PGE2) and indoleamine 2,3-dioxygenase (IDO) were compared between cells obtained from young or old dogs. The doubling times at passages 2 and 3 were shorter when MSCs were isolated from young (34.8 ± 1.8 h and 46.3 ± 2.3 h) rather than old dogs (56.5 ± 8.0 h and 123.8 ± 46.7 h, P < 0.05). The MSC transcriptomes from both populations were similar without stimulation, while stimulation resulted in a 3-fold greater expression of osteogenic gene, fibroblast growth factor 10, in cells from old dogs. cAD-MSCs from young dogs suppressed proliferation of activated T cells more strongly (P < 0.05), although secretion of PGE2 and IDO did not differ between groups. In conclusion, donors' age affected proliferation, immunomodulatory properties of cAD-MSCs, and increased expression of osteogenic gene under proinflammatory conditions in our population of dogs. Collectively, our results provide evidence to support further evaluation of allogenic MSC therapies derived from young donors as alternatives to autologous MSC therapy in older dogs.

Evaluation of Stem Cell Therapies in a Bilateral Patellar Tendon Injury Model in Rats.

Regenerative medicine provides novel alternatives to conditions that challenge traditional treatments. The prevalence and morbidity of tendinopathy across species, combined with the limited healing properties of this tissue, have prompted the search for cellular therapies and propelled the development of experimental models to study their efficacy. Umbilical cord matrix-derived mesenchymal stem cells (UCM-MSC) are appealing candidates because they are abundant, easy to collect, circumvent the ethical concerns and risk of teratoma formation, yet resemble primitive embryonic stem cells more closely than adult tissue-derived MSCs. Significant interest has focused on chitosan as a strategy to enhance the properties of MSCs through spheroid formation. This paper details techniques to isolate UCM-MSCs, prepare spheroids on chitosan film, and analyze the effect of spheroid formation on surface marker expression. Consequently, creation of a bilateral patellar tendon injury model in rats is described for in vivo implantation of UCM-MSC spheroids formed on chitosan film. No complication was observed in the study with respect to morbidity, stress rising effects, or tissue infection. The total functional score of the operated rats at 7 days was lower than that of normal rats, but returned to normal within 28 days after surgery. Histological scores of tissue-healing confirmed the presence of a clot in treated defects evaluated at 7 days, absence of foreign body reaction, and progressing healing at 28 days. This bilateral patella tendon defect model controls inter-individual variation via creation of an internal control in each rat, was associated with acceptable morbidity, and allowed detection of differences between untreated tendons and treatments.

Agmatine for Pain Management in Dogs With Coxofemoral Joint Osteoarthritis: A Pilot Study.

Background: Pain from coxofemoral joint (CFJ) osteoarthritis (OA) characteristic of canine hip dysplasia (CHD) afflicts many dogs. Intervertebral disc (IVD) degeneration is a common CFJ OA comorbidity. Non-steroidal anti-inflammatory drug (NSAID) administration is standard for treatment of pain from degenerative joint disease. Potential side effects and tolerance from prolonged administration drive efforts to identify compounds that may be alternatives to or combined with NSAIDs. Agmatine, decarboxylated arginine, reportedly alleviates neuropathic pain, a likely component of OA pain. The objective of this study was to compare treatment response to agmatine and carprofen in dogs with varying degrees of CFJ OA with or without IVD degeneration and to test the hypothesis that agmatine improves hindlimb use comparably to carprofen and more than placebo. Methods: Nine hound-type dogs received oral carprofen (4.4 mg/kg, sid) for 7 days. Six months later, oral agmatine sulfate (25 mg/kg, bid) or placebo (hydroxypropyl methylcellulose, bid) was administered to the same dogs for 28 days with a 2 week washout period between treatments. Validated pain assessment scores were measured before treatment and every seven days throughout the treatment periods. Serum chemistry levels and ground reaction forces (GRF) were quantified before and after each treatment period. A board-certified radiologist quantified radiographic CFJ OA based on Orthopedic Foundation for Animals criteria and IVD degeneration on magnetic resonance images. GRFs were compared among treatments at each time point and among time points for each treatment. Results: There were no detectable adverse effects with any treatment. Significant results included improved GRFs in dogs with mild CFJ OA (N = 3) following agmatine administration compared to carprofen or placebo and a trend for improved GRFs in dogs with moderate CFJ OA (N = 2) following carprofen vs. agmatine or placebo. Neither agmatine nor carprofen improved GRFs in dogs with severe CFJ OA (N = 4). The GRFs improved in dogs with IVD degeneration (N = 3) following carprofen treatment compared to agmatine or placebo regardless of CFJ OA score, but no effect was observed in dogs with normal lumbar spines (N = 6). Conclusions: Results support agmatine over carprofen treatment to improve limb use in dogs with early or mild CFJ OA, while carprofen may be the better choice for dogs with moderate CFJ OA or IVD degeneration regardless of CFJ OA severity.

Influence of hypoxia on the stemness of umbilical cord matrix-derived mesenchymal stem cells cultured on chitosan films.

Chitosan is attractive as a substrate for stem cell expansion because it improves stemness through formation of spheroids. Hypoxia has also been proposed as a strategy to enhance stemness and survival of stem cells after in vivo implantation. This study was therefore designed to evaluate the influence of hypoxia on chitosan-induced behavior of stem cells. Umbilical cord matrix-derived stem cells were cultured on chitosan film or standard plate under normoxia and hypoxia, for 3 and 7 days. Based on immunophenotyping, chitosan strongly suppresses the expression of CD90 and CD105 cell surface markers, changes partially reversed by combined exposure to hypoxia. Hypoxia generally increased the volume and number of spheroids formed on chitosan, but the cellularity of cultures on chitosan films remained lower than that of standard plates. After 7 days of culture, the expression of stemness related genes (Oct4, Sox2, and Nanog) was best stimulated by combined exposure to chitosan and hypoxia. Based on our results, conditioning stem cells for 7 days on chitosan films under hypoxic conditions is recommended to enhance the stemness of stem cells, and minimize cell loss due to lack of attachment on chitosan. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 501-511, 2018.

Successful Management of Lupus Nephritis with High Titers of Myeloperoxidase Anti-Neutrophil Cytoplasmic Antibodies Using Tacrolimus.

A 63-year-old Japanese woman with a 30-year history of systemic lupus erythematosus developed macrohematuria and massive proteinuria after seroconversion of myeloperoxidase anti-neutrophil cytoplasmic antibodies (MPO-ANCA). A renal biopsy indicated focal proliferative lupus nephritis (class III A/C) with a fibrous crescent formation. Methylprednisolone pulse therapy (500 mg, 3 successive days) was administered because of progressive proteinuria. Steroid therapy did not suppress the progressive proteinuria; therefore, tacrolimus was added as an alternative immunosuppressive therapy, resulting in the improvement of proteinuria and renal impairment. This case report suggests that MPO-ANCA might play a pathogenic role in the exacerbation of immune-complex-type lupus nephritis.

A new variant of cytolethal distending toxin in a clinical isolate of Campylobacter hyointestinalis.

Increasing numbers of Campylobacter hyointestinalis have been isolated from humans and animals with gastroenteritis, although the virulence mechanism of this species remains largely unknown. Here, we show that C. hyointestinalis isolated from a patient with diarrhoea in Thailand produced a novel variant of cytolethal distending toxin (CDT). Sequencing of a 13 965 bp genomic region of C. hyointestinalis carrying the genes coding for Ch-CDT revealed three ORFs of 798, 804 and 537 bp, which code for the Ch-CdtA, Ch-CdtB and Ch-CdtC subunits, respectively. The deduced amino acid sequence of Ch-CdtA showed ∼38.9 % homology with the CdtA of Campylobacter coli, but sequences of Ch-CdtB and Ch-CdtC were homologous to CdtB (65.7 %) and CdtC (33.1 %) of Campylobacter upsaliensis, respectively. Filter-sterilized sonic lysate of C. hyointestinalis demonstrated distension and death of HeLa cells by arresting the cell cycle at the G(2)/M phase and phosphorylation of host histone H2AX, a sensitive marker of DNA double-strand breaks. Rabbit antiserum raised against recombinant Ch-CdtB was not reactive against the recombinant CdtB protein of Campylobacter jejuni. A reconstituted Ch-CDT holotoxin prepared using each of the recombinant subunit proteins demonstrated distension and death of HeLa cells, suggesting that the C. hyointestinalis isolate indeed produced functionally active Ch-CDT. Furthermore, the immunological distinctiveness of the Ch-CDT produced by C. hyointestinalis and the increasing prevalence of the species in patients and animals with gastroenteritis suggest that this species may be an important emerging zoonotic pathogen.

A case of membranoproliferative glomerulonephritis and AA amyloidosis complicated with pulmonary nontuberculous mycobacterial infection.

A 75-year-old man was diagnosed with pulmonary nontuberculous mycobacterial (NTM) infection in February 2005 and was treated with rifampicin, ethambutol, and clarithromycin. However, the infection was resistant to treatment, and his chest radiograph showed an abnormality that gradually seemed to aggravate. The patient's sputum was positive for Mycobacteria. Moreover, the patient had dyspnea and an underlying chronic inflammation in the lungs. He visited our hospital because of dyspnea and leg edema in June 2011. Laboratory evaluation on admission revealed proteinuria (6 g/day) and decreased serum total protein (5.8 g/dL) and albumin (1.6 g/dL) levels, indicating nephrotic syndrome. Percutaneous renal biopsy revealed membranoproliferative glomerulonephritis (MPGN) in the acute stage and AA amyloidosis of mild degree. AA amyloidosis was also diagnosed histologically on gastric and colonic biopsy, in addition to renal biopsy. His renal function decreased gradually, and therefore, he underwent hemodialysis therapy in January 2012. However, his gastrointestinal-related symptoms persisted, and his appetite diminished, because of which he had become severely malnourished; he died 8 months later. This is a rare case of a patient with two different renal lesions (MPGN and AA amyloidosis) complicated with NTM. Our case suggests that MPGN and amyloidosis should be considered in elderly patients with nephrotic syndrome onset and chronic inflammation.

Continuous inflammation and ascites 10 months after the initiation of peritoneal dialysis.

A 38-year-old man underwent peritoneal dialysis (PD) in May 2011 due to chronic renal failure with chronic glomerulonephritis. In early February 2012, he underwent laparoscopy to salvage and correct a malpositioned PD catheter. The laparoscopic intra-abdominal findings revealed turbid ascites and multiple fibrin lumps, despite the patient's lack of history of peritonitis. Based on these findings, in addition to the presence of continuous inflammation and ascites, a diagnosis of pre-encapsulating peritoneal sclerosis was suspected, and the treatment was switched from PD to hemodialysis. The administration of prednisolone at a dose of 20 mg/day and peritoneal lavage resulted in a decrease in the ascites and fibrin lumps.

Chaga mushroom-induced oxalate nephropathy.

Chaga mushrooms have been used in folk and botanical medicine as a remedy for cancer, gastritis, ulcers, and tuberculosis of the bones. A 72-year-old Japanese female had been diagnosed with liver cancer 1 year prior to presenting at our department. She underwent hepatectomy of the left lobe 3 months later. Chaga mushroom powder (4 - 5 teaspoons per day) had been ingested for the past 6 months for liver cancer. Renal function decreased and hemodialysis was initiated. Renal biopsy specimens showed diffuse tubular atrophy and interstitial fibrosis. Oxalate crystals were detected in the tubular lumina and urinary sediment and oxalate nephropathy was diagnosed. Chaga mushrooms contain extremely high oxalate concentrations. This is the first report of a case of oxalate nephropathy associated with ingestion of Chaga mushrooms.

Japan Renal Biopsy Registry and Japan Kidney Disease Registry: Committee Report for 2009 and 2010.

The Japan Renal Biopsy Registry (J-RBR) was started in 2007 and the Japan Kidney Disease Registry (J-KDR) was then started in 2009 by the Committee for Standardization of Renal Pathological Diagnosis and the Committee for the Kidney Disease Registry of the Japanese Society of Nephrology. The purpose of this report is to describe and summarize the registered data from 2009 and 2010. For the J-KDR, data were collected from 4,016 cases, including 3,336 (83.1 %) by the J-RBR and 680 (16.9 %) other cases from 59 centers in 2009, and from 4,681 cases including 4,106 J-RBR cases (87.7 %) and 575 other cases (12.3 %) from 94 centers in 2010, including the affiliate hospitals. In the J-RBR, 3,165 native kidneys (94.9 %) and 171 renal grafts (5.1 %) and 3,869 native kidneys (94.2 %) and 237 renal grafts (5.8 %) were registered in 2009 and 2010, respectively. Patients younger than 20 years of age comprised 12.1 % of the registered cases, and those 65 years and over comprised 24.5 % of the cases with native kidneys in 2009 and 2010. The most common clinical diagnosis was chronic nephritic syndrome (55.4 % and 50.0 % in 2009 and 2010, respectively), followed by nephrotic syndrome (22.4 % and 27.0 %); the most frequent pathological diagnosis as classified by the pathogenesis was IgA nephropathy (31.6 % and 30.4 %), followed by primary glomerular diseases (except IgA nephropathy) (27.2 % and 28.1 %). Among the primary glomerular diseases (except IgA nephropathy) in the patients with nephrotic syndrome, membranous nephropathy was the most common histopathology in 2009 (40.3 %) and minor glomerular abnormalities (50.0 %) were the most common in 2010 in native kidneys in the J-RBR. Five new secondary and longitudinal research studies by the J-KDR were started in 2009 and one was started in 2010.

Renal thrombotic microangiopathies/thrombotic thrombocytopenic purpura in a patient with primary Sjögren's syndrome complicated with IgM monoclonal gammopathy of undetermined significance.

Thrombotic microangiopathy (TMA)/thrombotic thrombocytopenic purpura (TTP) is a rare but potentially lethal condition requiring rapid recognition, diagnosis, and initiation of therapy. We experienced a case of a 61-year-old woman with primary Sjögren's syndrome (pSS) complicated with severe renal TMA/TTP following IgM monoclonal gammopathy of undetermined significance (MGUS). She was admitted to our hospital for further evaluation of hypergammaglobulinema, acute renal failure, and severe thrombocytopenia. She had been diagnosed with pSS 13 years prior to admission. Histological examination of her kidney revealed fibrin thrombi in the glomeruli and arterioles, a finding that is consistent with TMA/TTP. The patient was subsequently treated with plasma exchange, which resulted in a successful outcome without any complications. This rare case suggests that it is important to make a therapeutic decision based on appropriate and prompt pathological diagnosis.

Renal disease in the elderly and the very elderly Japanese: analysis of the Japan Renal Biopsy Registry (J-RBR).

BACKGROUND AND OBJECTIVES: Data regarding renal disease in the elderly (age ≥65 years old) and very elderly (age ≥80 years old) Japanese are extremely limited. The aim of this study was to examine the causes of renal disease and their clinical presentations in elderly patients who underwent renal biopsy. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: From July 2007 to November 2011, all of the elderly native renal biopsy patients who had been registered in the Japan Renal Biopsy Registry (J-RBR; 2802 including 1596 males and 1206 females) were identified. Their data were compared with a control group of 7416 patients who ranged in age from 20 to 64 years old and were registered on the J-RBR over the same period. In addition, the clinical and pathological classifications of 276 very elderly patients were also analyzed. RESULTS: The indications for biopsy were nephrotic syndrome (NS) in 36.2 and 50.7 % of the elderly and the very elderly patients, chronic nephritic syndrome in 31.8 and 17.4 %, and acute kidney injury including rapidly progressive glomerulonephritis in 18.6 and 22.5 %, respectively. Primary glomerular disease was the most frequent diagnosis, followed by MPO-ANCA-positive nephritis, IgA nephropathy (IgAN), and diabetic nephropathy. In primary GN including IgAN, membranous nephropathy (MN) was the most frequent histological type, followed by IgAN and minor glomerular abnormalities. A comparison with the control group showed that MN, MPO-ANCA-positive nephritis, and amyloid nephropathy were more common in the elderly (P < 0.001), and IgAN was less common (P < 0.001). As for nephrotic syndrome in the elderly, MN was the most common histological type, followed by minimal change NS, diabetic nephropathy, amyloid nephropathy, and focal segmental glomerulosclerosis. There was a significant discrepancy between the urinary protein/creatinine ratio and daily proteinuria after the 7th decade of life. CONCLUSIONS: Renal biopsy is a valuable diagnostic tool, even in elderly and very elderly Japanese patients. In the future, modified clinical guidelines for elderly renal disease should be developed.

De novo minimal change disease after ABO-incompatible kidney transplantation.

We report the clinical and pathological findings of a case of de novo minimal change disease (MCD) after ABO-incompatible living kidney transplantation. A 62-yr-old man with end-stage renal disease associated with type I diabetes received ABO-incompatible kidney transplantation from his 58-yr-old wife. Although allograft function was excellent immediately after surgery, massive proteinuria (35 g/d) appeared on post-transplantation day 5. After the allograft biopsy taken on post-transplantation day 6, he was treated with 12 cycles of plasma exchange, but the nephrotic-range proteinuria showed no remission. The biopsy specimen showed no significant pathological findings on light microscopy, but electron microscopy showed diffuse effacement of podocyte foot processes. Based on the diagnosis of de novo MCD, the patient received intravenous methylprednisolone pulse therapy, followed by high-dose steroid maintenance therapy. The steroid therapy induced complete remission of nephrotic syndrome and stable allograft function immediately, which was also maintained at one yr after the transplantation.

An elderly patient with diabetic nephropathy complicated by ANCA-associated nephritis.

A 67-year-old man, on oral therapy for type 2 diabetes mellitus since 1990, had sustained proteinuria since 2005. When hematuria was first discovered in 2008, renal dysfunction [creatinine (Cr), 1.2 mg/dL], inflammation [C-reactive protein (CRP), 12 mg/dL] and high myeloperoxidase anti-neutrophil cytoplasmic antibodies (MPO-ANCA) levels [546 ELISA units (EU)] were observed. Renal biopsy showed the diagnosis of ANCA-associated nephritis combined with diabetic nephropathy. For this patient, there was pathological proof of the combination of diabetic nephropathy and ANCA-associated vasculitis.

Membranous nephropathy in Japan: analysis of the Japan Renal Biopsy Registry (J-RBR).

Membranous nephropathy (MN) is one of the most common causes of nephrotic syndrome in adults. The J-RBR/J-KDR registry developed by the Japanese Society of Nephrology provides nationwide cohort data for epidemiological studies of MN. MN was present in 36.8% of 1,203 primary nephrotic syndrome patients in Japan. In addition, 633 (77.9%) out of 813 MN patients were referred to as "idiopathic," whereas 22.1% were classified as "secondary" and involved conditions such as systemic lupus erythematosus, drug exposure, infections, cancer, and various collagen diseases. The mean age of the MN patients was 62.2 (2-88) years old, their mean eGFR was 76.7 (7.6-154.6) ml/min/1.73 m(2), and 63.3% had hypertension at the time of renal biopsy. On the basis of these findings, half of Japanese idiopathic MN patients have risk factors (age >60, male, or lower eGFR) for end-stage renal failure, and 10% belong to the high-risk group (daily proteinuria of over 8.0 g). Further studies with high-grade evidence should resolve the natural history and therapeutic problems of idiopathic MN in elderly Japanese.