Novel function of transglutaminase 2 in extracellular histone-induced acute lung injury.

Extracellular histones induce endothelial damage, resulting in lung haemorrhage; however, the underlying mechanism remains unclear. Factor XIII, as a Ca2+-dependent cross-linking enzyme in blood, mediates fibrin deposition. As another isozyme, transglutaminase 2 (TG2) has a catalytic activity distributing in most tissues. Herein, we investigated whether TG2 promotes fibrin deposition and mediates the adhesion of platelets to ECs in histone-induced acute lung injury (ALI). We evaluated the lung histology and the adhesion of platelets to endothelial cells (ECs) after injecting histones to wild-type (WT) C57BL/6J and TG2 knockout (TG2-/-) mice, and administered a TG2 inhibitor (NC9) to WT mice. Pulmonary haemorrhage was more severe in TG2-/- mice than that in WT mice. The area of fibrin deposition and the proportion of CD41+CD31+ cells were lower in TG2-/- mice than in WT mice. Pre-treatment of NC9 decreased the area of fibrin deposition and the proportion of CD41+CD31+ cells in WT mice. These results suggest that TG2 prevents from pulmonary haemorrhage in ALI by promoting the adhesion of platelets to ECs and the fibrin deposition.

Lower Blood Pressure-Induced Renal Hypoperfusion Promotes Cisplatin-Induced Nephrotoxicity.

BACKGROUND AND AIMS: Cisplatin-induced nephrotoxicity primarily occurs in the proximal tubules, and tubular injuries reduce glomerular filtration rates. Lower blood pressure causes renal hypoperfusion, which promotes ischemic acute kidney injury (AKI). Our study examined the relationship between lower blood pressure-induced renal hypoperfusion and cisplatin-induced nephrotoxicity. METHODS: The relationship between cisplatin use and hypoalbuminemia is not clear. This study consisted of Japanese patients who received cisplatin as the first-line chemotherapy at Fujita Health University Hospital from April 2006 to December 2012. Hypoalbuminemia was defined as serum albumin levels ≤3.5 mg/dl. RESULTS: Patients who experienced lower blood pressure during chemotherapy were included in the lower blood pressure group (n = 229), and those who did not were included in the normal blood pressure group (n = 743). Total cisplatin dose in the normal blood pressure and lower blood pressure groups was 58.9 ± 23.8 and 55.0 ± 20.4 mg/m2, respectively. The rate of severe nephrotoxicity was higher and overall survival was shorter in the lower blood pressure group than in the normal blood pressure group. In a multivariable analysis, lower blood pressure significantly correlated with hypoalbuminemia. CONCLUSIONS: To prevent ischemic AKI, nutrition and cachexia controlling are important parts of cancer treatment.

Cancer Stem Cells: The Potential Targets of Chinese Medicines and Their Active Compounds.

The pivotal role of cancer stem cells (CSCs) in the initiation and progression of malignancies has been rigorously validated, and the specific methods for identifying and isolating the CSCs from the parental cancer population have also been rapidly developed in recent years. This review aims to provide an overview of recent research progress of Chinese medicines (CMs) and their active compounds in inhibiting tumor progression by targeting CSCs. A great deal of CMs and their active compounds, such as Antrodia camphorate, berberine, resveratrol, and curcumin have been shown to regress CSCs, in terms of reversing drug resistance, inducing cell death and inhibiting cell proliferation as well as metastasis. Furthermore, one of the active compounds in coptis, berbamine may inhibit tumor progression by modulating microRNAs to regulate CSCs. The underlying molecular mechanisms and related signaling pathways involved in these processes were also discussed and concluded in this paper. Overall, the use of CMs and their active compounds may be a promising therapeutic strategy to eradicate cancer by targeting CSCs. However, further studies are needed to clarify the potential of clinical application of CMs and their active compounds as complementary and alternative therapy in this field.

Comparison between Long- and Short-Acting Erythropoiesis-Stimulating Agents in the Period Required for Haemoglobin Stabilisation in Treatment of Anaemia in Patients with Chronic Kidney Disease.

Comparative studies of the potency of long- and short-acting erythropoiesis-stimulating agents (L-ESAs and S-ESAs) on erythropoietic activity in patients with chronic kidney disease without dialysis have not been performed, although L-ESAs are used in many countries. We performed a retrospective analysis of non-dialysis (ND) patients who had received L-ESA or S-ESA. More days were needed for the S-ESA-treated group (368 d) to reach the haemoglobin (Hb) reference range than for the L-ESA-treated group (126 d). Therefore, we investigated risk factors that influence the period until the Hb level reaches the reference range. Patients were classified into two groups by the period until the Hb level was stabilised within the reference range: the short- and long-term group. Two risk factors for delayed Hb stabilisation were identified: age ≥60 years; and administration of an S-ESA for initial treatment. These findings suggest that the Hb level should be carefully monitored during ESA therapy in elderly ND patients, and that the ESA dose should be increased or L-ESA therapy should be utilised to treat renal anaemia.

Myoclonus after dextromethorphan administration in peritoneal dialysis.

OBJECTIVE: To report a case of myoclonus that developed after administration of dextromethorphan. CASE SUMMARY: A 64-year-old man was diagnosed with chronic renal failure due to diabetic nephropathy. The patient started on peritoneal dialysis 6 months before he was hospitalized. Two days before hospitalization, he developed cough and sputum and he visited an outpatient clinic, where dextromethorphan was prescribed. After taking a total of 30 mg of dextromethorphan, the patient developed myoclonus, tremor, agitation, slurred speech, and diaphoresis, which continued after he stopped taking the prescribed medicine. He visited an emergency department and was hospitalized for examination and treatment of myoclonus. DISCUSSION: As the patient's dialysis schedule was adequate, these symptoms were likely not due to uremia. The blood concentration of dextromethorphan (2.68 ng/mL) 60 hours after the 30-mg dose was higher than expected, and the blood concentration of dextrorphan, a metabolite, was lower than expected. We suspected that myoclonus was due to dextromethorphan-related symptoms induced by CYP2D6, which primarily metabolizes dextromethorphan. We analyzed the CYP2D6 gene for polymorphisms and identified CYP2D6 (*)1/(*)10. The patient had been taking metoprolol 40 mg/day for 2 years. The blood concentration of metoprolol 6 hours after administration was 13 ng/mL, which suggests that it was metabolized normally. Metoprolol has another metabolic pathway, via CYP2C19, and this may have led to its lack of accumulation. Moreover, metoprolol may have bound to active CYP2D6. Thus, affinity for CYP2D6, protein-binding rate, and lipid solubility may influence these drug interactions. Total scores for the Adverse Drug Reaction (ADR) probability scale and the Drug Interaction Probability Scale (DIPS) were 9 (highly probable) and 3 (possible), respectively. CONCLUSIONS: Myoclonus and other symptoms in this patient may have been caused by a prolonged high concentration of dextromethorphan due to CYP2D6 polymorphisms and drug interactions.

[Development of new problem-based learning to promote problem-solving ability in therapeutics at Meijo University].

Pharmacy students in the six-year education system are expected to combine their knowledge obtained from many lectures and to develop problem-solving abilities in therapeutics. These two expectations are considered to be difficult in the conventional education system. Therefore we introduced a new problem-based learning (PBL) method in the class on "pharmacotherapeutics," which was held in the first semester of the fourth year. In the PBL modules, students studied the etiology, pathology, and appropriate drug therapeutics of a given disease and obtained the knowledge and skills necessary for monitoring patients during treatment. We conducted 12 PBL modules, and students studied one case per module, each lasting a week. To encourage constructive group work and to generate original input formats to provide students with a problem-solving road map, we developed new systems including a class review and portfolio. The new PBL method also included lectures on the overview of each disease and the therapeutic agents (action mechanism, physical properties, pharmacokinetics, and monitoring of the efficacy and adverse reactions). By integrating their knowledge and skills, we hope that the students will be able to acquire problem-solving abilities in therapeutics when they become pharmacists.

CD140b and CD73 are markers for human induced pluripotent stem cell-derived erythropoietin-producing cells.

Renal anemia in chronic kidney disease is treated with recombinant human erythropoietin (rhEPO). However, some patients with anemia do not respond well to rhEPO, emphasizing the need for a more biocompatible EPO. Differentiation protocols for hepatic lineages have been modified to enable production from human induced pluripotent stem cell (hiPSC)-derived EPO-producing cells (EPO cells). However, markers for hiPSC-EPO cells are lacking, making it difficult to purify hiPSC-EPO cells and therefore to optimize EPO production and cell counts for transplantation. To address these issues, we investigated whether CD140b and CD73 could be used as markers for hiPSC-EPO cells. We measured the expression of EPO, CD140b, and CD73 in hiPSC-EPO cells and the EPO concentration in the cell supernatant by immunohistochemistry and enzyme-linked immunosorbent assays on culture day 13, revealing that expression levels of CD140b and CD73 are correlated with the level of EPO. In addition, rates of CD140b+ CD73+ cells were observed to be correlated with the concentration of EPO. Thus, our results suggest that CD140b and CD73 may be markers for hiPSC-EPO cells.

Effects of kynurenine metabolites on mesangial cell proliferation and gene expression.

In the present study, we examined the effects of kynurenine metabolites on cultured mesangial cells (MCs) and demonstrated for the first time that they affect MC proliferation and gene expression. Anthranilic acid and 3-hydroxy-DL-kynurenine suppressed MC proliferation by 32% and 43%, respectively at 10(-6) M compared to the control. In contrast, quinolinic acid and l-kynurenine promoted MC proliferation by 49% and 35% at 10(-8) M respectively, although promoting activities declined at higher concentrations. In addition, quinolinic acid upregulated the gene expression of platelet-derived growth factor-B, collagen type-Ialpha1, and collagen type-IValpha1. However, the gene expression of hepatocyte growth factor (HGF) was downregulated. We further examined the gene expressions in the glomeruli of high serum IgA (HIGA) mice with IgA nephropathy using microarray technology and found that the gene expression of insulin-like growth factor-1 was higher, but that of HGF was lower at 40 weeks of age compared to 8 weeks of age. In Balb/c mice, the gene expression of three kynurenine pathway enzymes (kynurenine aminotransferase I, kynurenine aminotransferase II, and quinolinate phospho-ribosyltransferase) increased 2- to 3.5-fold, whereas those in HIGA mice did not change significantly. These results suggest that abnormalities in the kynurenine pathway are associated with the dysfunction of MCs and progression of chronic kidney diseases.

Clinical medication review type III of polypharmacy reduced unplanned hospitalizations in older adults: A meta-analysis of randomized clinical trials.

AIM: To analyze the impact of clinical medication reviews (CMR) on reducing unplanned hospitalizations owing to polypharmacy among older adults using an intervention. METHODS: Our meta-analysis complied with PRISMA guidelines. The literature review comprised a search for articles published between January 1972 and March 2017 on MEDLINE and Google Scholar. We identified randomized controlled trials focusing on CMR that evaluated unplanned hospitalization and re-hospitalization among older adults as a primary outcome. The keywords used were "CMR" or "medication review" in their titles, and the phrases "elderly" or "older adults" or "geriatric" and "polypharmacy." The randomized controlled trials selected were divided according to the three types of CMR to analyze the characteristics of each review. RESULTS: We included nine randomized controlled trials that examined the impact of CMR of polypharmacy in older patients. Five trials corresponded to CMR type I (prescription only review) or II (adherence review), whereas four corresponded to type III (comprehensive clinical evaluation for disease management). Type I/II increased the number of unplanned hospitalizations (RR 1.22, 95% CI 1.07-1.38, P = 0.002), whereas type III decreased hospital admissions (RR 0.86, 95% CI 0.79-0.95, P = 0.001). CONCLUSIONS: The present findings show the need for an intervention standardization for CMR, particularly for type III in older adults with polypharmacy, to decrease hospitalizations. Geriatr Gerontol Int 2019; 19: 1275-1281.

Downregulated expression in high IgA (HIGA) mice and the renal protective role of meprinbeta.

This study discusses the critical role of the metalloproteinase meprinbeta in the progression of glomerulonephritis. Using a microarray technique, the gene expression profiles in glomeruli isolated from high serum IgA (HIGA) mice with a purity of 97% or greater were examined. HIGA mice are a valid model of human IgA nephropathy (IgAN), with the typical pathological features of this condition, including a consistently high serum IgA level as well as dominant mesangial IgA deposition and mesangial enlargement. Among the many upregulated/downregulated genes after the development of IgAN, the downregulation of meprinbeta was intriguing. The expression level of the meprinbeta gene at 40 weeks of age was 52% of that observed at 8 weeks of age (prior to the development of IgAN), although in the control BALB/c mice, a 2.19-fold elevation was seen. These results were also confirmed by semi-quantitative RT-PCR and immunostaining analyses. As meprinbeta is a subunit of metalloproteinase meprins (meprin A, meprin B) and meprins are capable of proteolytically degrading extracellular matrix (ECM) components and proteolytically processing bioactive peptides, the downregulation of meprinbeta may contribute to the progression of glomerulonephritis and the eventual glomerular scarring. This working hypothesis was examined using an in vivo meprinbeta inhibition study. The inhibition of meprins by actinonin exacerbated some parameters of renal injury in mice afflicted with anti-glomerular basement membrane (anti-GBM) antibody-associated nephritis. These in vitro and in vivo results suggest that meprinbeta may play a protective role against the progression of renal injury through the degradation of ECM and bioactive peptides.

Pioglitazone improves obesity type diabetic nephropathy: relation to the mitigation of renal oxidative reaction.

Medications to treat hyperglycemia and hyperinsulinemia are expected to inhibit the accumulation of advanced glycation end-products in the diabetic kidney and improve renal function by inhibiting oxidative reactions. In this study, we examined the effect of pioglitazone, an insulin sensitizer, on diabetic nephropathy. Feed containing pioglitazone at 0.01 or 0.02% was given to Zucker-fatty rats for 27 weeks. Pioglitazone reduced plasma glucose, plasma insulin, and blood HbAlc levels. It also decreased plasma total cholesterol, triglyceride, phospholipid and cystatin C levels and inhibited the increase in urine of 8-hydroxydeoxyguanosine and in plasma of malondialdehyde. In the histopathological examinations, pioglitazone inhibited diffusive or nodular thickening of the mesangial matrix, atrophy of the proximal convoluted tubule, thickening of the basement membrane of the tubule, and mild cellular infiltration (mostly small lymphocytes) in the stroma. Furthermore, pioglitazone inhibited the mRNA expression of the receptor for advanced glycation end-products (RAGE) and that of transforming growth factor-beta. Long-term administration of pioglitazone improved hyperglycemia lipid profiles, hypercholesterolemia, and hyperinsulinemia and had a protective effect on diabetic nephropathy in Zucker-fatty rats.

Chondroitin sulfate protects vascular endothelial cells from toxicities of extracellular histones.

Extracellular histones induce lethal thrombosis by promoting platelet aggregation, neutrophil migration, and cell injuries. Heparin, which has negative charges, can bind to extracellular histones; however, heparin strongly inhibits the activation of coagulation. Since chondroitin sulfate (CS) shows less effect on the coagulation system than heparin does, CS has the potential to become an effective drug for lethal thrombosis with high risk of bleeding. To elucidate the therapeutic mechanisms of CS in lethal thrombosis, we investigated the interaction between CS and extracellular histones. Mouse vascular endothelial cells were incubated with histones in the presence of heparin or CS, and the expression of caspase-3/7 was measured. The interactions between histones and heparin or CS were measured by surface plasmon resonance analysis. Vascular permeability, platelet counts, liver and renal functions, and coagulation times were evaluated in an in vivo assay. The apoptosis induced by histones was inhibited by treatment with heparin or CS. Heparin and CS showed strong binding to histones and inhibited vascular hyperpermeability. The platelet counts as well as liver and renal functions were not decreased by the treatment with heparin or CS. Moreover, CS showed less effect on the coagulation system than heparin did. These results suggested that CS can be a novel agent for lethal thrombosis with the risk for hemorrhage. Since vascular endothelial cell injuries occur at an early stage of lethal thrombosis, administration of CS might be a useful approach.

Clinical medication review tool for polypharmacy: Mapping approach for pharmacotherapeutic classifications.

AIM: Polypharmacy is an extremely important problem, because it increases the risk of adverse drug reactions. The aim of the current study was to create a clinical medication review tool to detect inappropriate medication use, and assess this new method with elderly Japanese patients. METHODS: The new method involves optimizing prescription drugs from indications, based on the chronic disease-anatomical therapeutic class code list. The present study investigated the prevalence of potentially inappropriate medications in 5667 Japanese patients aged ≥65 years with polypharmacy (≥5 drugs) in comparison with the Beers criteria 2012. RESULTS: We propose a new method called the Mapping Approach for Pharmacotherapeutic Classifications: (i) identify the chronic disease-anatomical therapeutic class code assigned to the prescription drugs; (ii) identify the chronic disease-anatomical therapeutic class code corresponding to the patient's chronic disease; (iii) compare the prescription drug and patient's chronic disease chronic disease-anatomical therapeutic class codes; and (iv) identify the appropriateness of medication use based on the comparison (appropriate use is defined as matching codes). The mean number of potentially inappropriate medications detected was significantly different between the mapping approach and Beers criteria 2012 (3.1 ± 2.6 vs 0.6 ± 0.8 drugs, respectively; P < 0.001). CONCLUSIONS: The Mapping Approach for Pharmacotherapeutic Classifications is highly dependent on the chronic condition. Pharmacists should confirm the chronic condition with the treating physician before reducing a patient's medications. We hope this process will further influence prescribing patterns, and decrease the inappropriate use of medications and associated adverse drug reactions in older adults. Geriatr Gerontol Int 2017; 17: 2025-2033.

Complement component 5 promotes lethal thrombosis.

Extracellular histones promote platelet aggregation and thrombosis; this is followed by induction of coagulation disorder, which results in exhaustion of coagulation factors. Complement component 5 (C5) is known to be associated with platelet aggregation and coagulation system activation. To date, the pathological mechanism underlying liver injury has remained unclear. Here, we investigated whether C5 promotes liver injury associated with histone-induced lethal thrombosis. C5-sufficient and C5-deficient mice received single tail vein injections of purified, unfractionated histones obtained from calf thymus (45-75 µg/g). Subsequently, the mice were monitored for survival for up to 72 h. Based on the survival data, the 45 µg/g dose was used for analysis of blood cell count, liver function, blood coagulation ability, and promotion of platelet aggregation and platelet/leukocyte aggregate (PLA) production by extracellular histones. C5-deficient mice were protected from lethal thrombosis and had milder thrombocytopenia, consumptive coagulopathy, and liver injury with embolism and lower PLA production than C5-sufficient mice. These results indicate that C5 is associated with coagulation disorders, PLA production, and embolism-induced liver injury. In conclusion, C5 promotes liver injury associated with histone-induced lethal thrombosis.

[The Synergistic Effect of Problem-based Learning Combined with the Jigsaw Method in a Pharmacotherapy Course].

To promote problem-solving ability within a pharmacotherapy course, we developed new problem-based learning (PBL) and information and communication technologies (ICT) support systems, and introduced the "Jigsaw Method," an active learning method in which, similar to parts of a jigsaw puzzle, students are dependent on each other to create the full picture, to succeed. We conducted 10 PBL modules (one case per module), each lasting one week. To encourage constructive group work, information sharing, and student understanding in the individual modules, we implemented a Jigsaw Method-based wiki worksheet system in which students were to identify patient problems and check each other's work on an e-portfolio system. After completing this new curriculum, students were able to create comprehensive therapeutic care plans. A significant correlation was observed between the students' care plan evaluation scores and their module test results, suggesting that constructive group work can enhance problem-solving ability in therapeutics. These results clearly indicate the benefit of combining our new PBL-ICT support system with the Jigsaw Method.

Pharmacist blood pressure management programs using telemonitoring systems are useful for monitoring side effects of antihypertensive drugs in a community pharmacy.

We previously started pharmacist blood pressure (BP) management programs using telemonitoring systems for monitoring side effects of antihypertensive drugs in a community pharmacy. The present case demonstrates that pharmacist BP management programs using telemonitoring systems are useful for monitoring side effects of antihypertensive drugs in a community pharmacy.

Significance of downregulation of renal organic cation transporter (SLC47A1) in cisplatin-induced proximal tubular injury.

BACKGROUND/AIM: To elucidate the mechanism responsible for developing acute kidney injury in patients with diabetes mellitus, we also evaluated the issue of whether advanced glycation endproducts (AGEs) influence the expressions of multi antimicrobial extrusion protein (MATE1/SLC47A1) in tubular cells. MATERIALS AND METHODS: To detect changing expression of MATE1/SLC47A1 in dose- and time-dependent manners, human proximal tubular epithelial cells were incubated with AGE-aggregated-human serum albumin. As a function assay for MATE1/SLC47A1, human proximal tubular epithelial cells were incubated with cisplatin or carboplatin. RESULTS: On incubation with AGEs, the expressions of MATE1/SLC47A1 were decreased in tubular cells. In addition, the toxicities of cisplatin were increased in tubular cells that had been pretreated with AGEs. However, the toxicities of carboplatin were smaller than that of cisplatin in proximal tubular epithelial cells. CONCLUSION: The expression of the MATE1/SLC47A1 is decreased by AGEs, which increases the risk for proximal tubular injury.

Inhibition of eukaryotic elongation factor-2 confers to tumor suppression by a herbal formulation Huanglian-Jiedu decoction in human hepatocellular carcinoma.

ETHNOPHARMACOLOGICAL RELEVANCE: An oriental medicinal formulation, Huanglian Jiedu Decoction (HLJDD), has been well documented in few Traditional Chinese Medicine Classics 1300 years ago for treatment of heat and dampness-related diseases. Its effect is well accepted in Asian community, including China, Japan and Korea. Recent studies have postulated HLJDD as a regimen for cancer treatment, especially liver cancer, but the underlying mechanism is unknown. The aim of this study was to examine the suppressive effect of HLJDD on the growth of hepatocellular carcinoma (HCC) and its possible underlying mechanism. METHODS: Chemical composition of HLJDD was analyzed by high performance liquid chromatography. The tumor suppressive effect of HLJDD was determined on both HCC cells and xenograft model. Nascent protein synthesis was detected with Click-IT protein labeling technology; protein expression was determined by immunoblotting and imunnohistochemical analysis. RESULTS: Quality analysis revealed that HLJDD of different batches is consistent in both chemical composition and bioactivities. HLJDD inhibited HCC cell proliferation at its non-toxic doses, and suppressed growth and angiogenesis in xenografted murine model. HLJDD suppressed the synthesis of nascent protein via inactivation of eEF2 without deregulating the translation initiation factors. The major components in HLJDD, geniposide, berberine and baicalin, additively act on eEF2, and contributed to the responsible activity. HLJDD-activated eEF2 kinase (eEF2K) led to eEF2 inactivation, and activation of AMPK signaling may be responsible for the eEF2K induction. Blocked AMPK activity in HLJDD-treated HCC cells attenuated eEF2K activation as well as the inhibitory effect of the formula. In nutrient deprived HCC cells with inactivated eEF2, the inhibitory effect of HLJDD in tumor cell expansion was interfered. CONCLUSION: Our results indicate that HLJDD has potential in blocking HCC progression with involvement of eEF2 inhibition.

Adenosine 3', 5' cyclic monophosphate attenuates the production of fibronectin in the glomeruli of anti-glomerular basement membrane antibody-associated nephritic rats.

1. Excessive production of extracellular matrix is thought to be involved in the progression of glomerulonephritis and glomerulosclerosis. In chronic glomerulonephritis, fibronectin has been shown to accumulate in the glomeruli, accompanied by cell proliferation. 2. Glomerulonephritis was induced in rats by the injection of anti-glomerular basement membrane antibody. The rats showed proteinuria and histological alterations in the glomeruli. An increase in fibronectin levels in the culture medium of isolated nephritic glomeruli was confirmed, and was associated with the development of nephritis. Immunohistochemical staining demonstrated a marked accumulation of fibronectin in the glomeruli of nephritic rats. 3. Attenuated generation of cyclic AMP was also observed in the nephritic glomeruli treated with forskolin, prostaglandin E1 or adenosine. 4. Forskolin, prostaglandin E2 and 8-bromo-cyclic AMP markedly reduced the production of fibronectin by the nephritic glomeruli compared with controls in a dose-dependent manner. 8-Bromo-cyclic AMP suppressed the production of fibronectin by cultured mesangial cells. 5. These findings suggest that the attenuated generation of cyclic AMP in response to ligands is connected to the augmented accumulation of fibronectin in nephritic glomeruli, and may facilitate the development of methods for treating glomerulonephritis and glomerulosclerosis.

Risk factors for an early dialysis start in patients with diabetic nephropathy end-stage renal disease.

BACKGROUND: Patients with end-stage renal disease (ESRD) have symptoms related to severe anemia, edema, and heart failure. Although dialysis improves ESRD syndromes, the optimum timing for initiation of dialysis is unclear. Recent observational studies have suggested that early commencement of dialysis can be harmful. Given that early dialysis may increase the risk of death, avoiding an early start to dialysis is recommended. Patients with diabetic nephropathy (DN) may have risk factors for early dialysis. However, the risk factors for early dialysis are unclear in ESRD patients with DN. The aim of this study was to elucidate the risk factors for early initiation of dialysis in patients with DN and ESRD. METHODS: From April 2009 to December 2012, we identified Japanese DN patients with an estimated glomerular filtration rate of less than 15 mL/minute/1.73 m(2). The patients were divided into late or early dialysis groups based on the timing of start of dialysis. RESULTS: We evaluated 52 patients who commenced dialysis during the observation period, including 33 in the late dialysis group and 19 in the early dialysis group. There was a significant association between early dialysis and age ≥65 years (odds ratio 4.59). The incidence of pneumonia before starting dialysis was significantly higher in elderly patients than in nonelderly patients. CONCLUSION: Our findings suggest that elderly patients with DN and ESRD have an increased risk of early initiation of dialysis, and occurrence of pneumonia is also associated with early dialysis. To avoid early commencement of dialysis, booster pneumococcal vaccination could be useful in elderly DN patients with ESRD.