Objectives We aimed to examine the validity of the quick Sequential Organ Failure Assessment (qSOFA) score for mortality and bacteraemia risk assessment in Japanese haemodialysis patients.Design This is a retrospective multicentre cohort study.Setting The six participating hospitals are tertiary-care institutions that receive patients on an emergency basis and provide primary, secondary and tertiary care. The other participating hospital is a secondary-care institution that receives patients on an emergency basis and provides both primary and secondary care.Participants This study included haemodialysis outpatients admitted for bacteraemia suspicion, who had blood drawn for cultures within 48 hours of their initial admission.Primary and secondary outcome measures The primary outcome measure was overall in-hospital mortality. Secondary outcomes included 28-day in-hospital mortality and the incidence of bacteraemia diagnosed based on blood culture findings. The discrimination, calibration and test performance of the qSOFA score were assessed. Missing data were handled using multiple imputation.Results Among the 507 haemodialysis patients admitted with bacteraemia suspicion between August 2011 and July 2013, the overall in-hospital mortality was 14.6% (74/507), the 28-day in-hospital mortality was 11.1% (56/507) and the incidence of bacteraemia, defined as a positive blood culture, was 13.4% (68/507). For predicting in-hospital mortality among haemodialysis patients, the area under the receiver operating characteristic curve was 0.61 (95% CI 0.56–0.67) for a qSOFA score ≥2. The Hosmer-Lemeshow χ2 statistics for the qSOFA score as a predictor of overall and 28-day in-hospital mortality were 5.72 (p=0.02) and 7.40 (p<0.01), respectively.Conclusion On external validation, the qSOFA score exhibited low diagnostic accuracy and miscalibration for in-hospital mortality and bacteraemia among haemodialysis patients.

Focal segmental glomerulosclerosis (FSGS) is a leading cause of end-stage renal disease in children and adults. Genetic factors significantly contribute to early-onset FSGS, but the etiologies of most adult cases remain unknown. Genetic studies of monogenic syndromic FSGS exhibiting extra-renal manifestations have uncovered an unexpected biological role for genes in the development of both podocytes and other cellular lineages. To help define these roles, we studied two unrelated families with FSGS associated with Duane Retraction Syndrome, characterized by impaired horizontal eye movement due to cranial nerve malformation. All four affected individuals developed FSGS and Duane Retraction Syndrome in their first to second decade of life, manifested as restricted abduction together with globe retraction and narrowed palpebral fissure on attempted adduction. Hypoplasia of the abducens nerves and hearing impairment occurred in severely affected individuals. Genetic analyses revealed that affected individuals harbor a rare heterozygous substitution (p.Leu239Pro) in MAFB, a leucine zipper transcription factor. Luciferase assays with cultured monocytes indicated that the substitution significantly reduced transactivation of the F4/80 promoter, the known MAFB recognition element. Additionally, immunohistochemistry indicated reduced MAFB expression in the podocytes of patients. Structural modeling suggested that the p.Leu239Pro substitution in the DNA-binding domain possibly interferes with the stability of the adjacent zinc finger. Lastly, podocytes in neonatal mice with p.Leu239Pro displayed impaired differentiation. Thus, MAFB mutations impair development and/or maintenance of podocytes, abducens neurons and the inner ear. The interactions between MAFB and regulatory elements in these developing organs are likely highly specific based on spatiotemporal requirements.

Metabolic acidosis, which reduces serum bicarbonate levels, contributes to the progression of chronic kidney disease (CKD). The difference between sodium and chloride (Na–Cl) may theoretically predict serum bicarbonate levels. This study aimed to evaluate serum Na–Cl level as a risk factor for renal function decline among patients who participated in the chronic kidney disease Japan cohort (CKD-JAC) study.

The role of IL-6 signaling in renal diseases remains controversial, with data describing both anti-inflammatory and proinflammatory effects. IL-6 can act via classic signaling, engaging its two membrane receptors gp130 and IL-6 receptor (IL-6R). Alternatively, IL-6 trans-signaling requires soluble IL-6R (sIL-6R) to act on IL-6R-negative cells that express gp130. Here, we characterize the role of both pathways in crescentic nephritis. Patients with crescentic nephritis had significantly elevated levels of IL-6 in both serum and urine. Similarly, nephrotoxic serum-induced nephritis (NTN) in BALB/c mice was associated with elevated serum IL-6 levels. Levels of serum sIL-6R and renal downstream signals of IL-6 (phosphorylated signal transducer and activator of transcription 3, suppressor of cytokine signaling 3) increased over time in this model. Simultaneous inhibition of both IL-6 signaling pathways using anti-IL-6 antibody did not have a significant impact on NTN severity. In contrast, specific inhibition of trans-signaling using recombinant sgp130Fc resulted in milder disease. Vice versa, specific activation of trans-signaling using a recombinant IL-6-sIL-6R fusion molecule (Hyper-IL-6) significantly aggravated NTN and led to increased systolic BP in NTN mice. This correlated with increased renal mRNA synthesis of the Th17 cell cytokine IL-17A and decreased synthesis of resistin-like alpha (RELMalpha)-encoding mRNA, a surrogate marker of lesion-mitigating M2 macrophage subtypes. Collectively, our data suggest a central role for IL-6 trans-signaling in crescentic nephritis and offer options for more effective and specific therapeutic interventions in the IL-6 system.

Anti-cytokine therapies have substantially improved the treatment of inflammatory and autoimmune diseases. Cytokine-targeting drugs are usually biologics such as antibodies or other engineered proteins. Production of biologics, however, is complex and intricate and therefore expensive which might limit therapeutic application. To overcome this limitation we developed a strategy that involves the design of an optimized, monogenic cytokine inhibitor and the protein producing capacity of the host. Here, we engineered and characterized a receptor fusion protein, mIL-6-RFP-Fc, for the inhibition of interleukin-6 (IL-6), a well-established target in anti-cytokine therapy. Upon application in mice mIL-6-RFP-Fc inhibited IL-6-induced activation of the transcription factor STAT3 and ERK1/2 kinases in liver and kidney. mIL-6-RFP-Fc is encoded by a single gene and therefore most relevant for gene transfer approaches. Gene transfer through hydrodynamic plasmid delivery in mice resulted in hepatic production and secretion of mIL-6-RFP-Fc into the blood in considerable amounts, blocked hepatic acute phase protein synthesis and improved kidney function in an ischemia and reperfusion injury model. Our study establishes receptor fusion proteins as promising agents in anti-cytokine therapies through gene therapeutic approaches for future targeted and cost-effective treatments. The strategy described here is applicable for many cytokines involved in inflammatory and other diseases.

Renal inflammation, in particular glomerular, is often characterized by increased IL-6 levels. The in vivo relevance of IL-6 signaling in glomerular podocytes, which play central roles in most glomerular diseases, is unknown. Here, we show that in normal mice, podocytes express gp130, the common signal-transducing receptor subunit of the IL-6 family of cytokines. Following systemic IL-6 or LPS injection in mice, podocyte IL-6 signaling was evidenced by downstream STAT3 phosphorylation. Next, we generated mice deficient for gp130 in podocytes. Expectedly, these mice exhibited abrogated IL-6 downstream signaling in podocytes. At the age of 40 wk, they did not show spontaneous renal pathology or abnormal renal function. The mice were then challenged using two LPS injury models as well as nephrotoxic serum to induce crescentic nephritis. Under all conditions, circulating IL-6 levels increased markedly and the mice developed the pathological hallmarks of the corresponding injury models such as proteinuria and development of glomerular crescents, respectively. However, despite the capacity of normal podocytes to transduce IL-6 family signals downstream, there were no significant differences between mice bearing the podocyte-specific gp130 deletion and their control littermates in any of these models. In conclusion, under the different conditions tested, gp130 signaling was not a critical component of the (patho-)biology of the podocyte in vivo.

A 55-year-old woman with end-stage renal disease from IgA nephropathy started continuous ambulatory peritoneal dialysis (CAPD). Three months later, she was admitted with sudden onset of right flank pain. She had undergone total hysterectomy 2 years ago and PD catheter placement 8 months ago. On admission she was afebrile and abdominal examination showed no sign of peritoneal irritation. Chest X-ray revealed air under the right diaphragm with haustrations suggestive of colonic air (Figure 1). CAPD fluid and blood test detected no sign of peritonitis. Abdominal computed tomographic (CT) scan revealed interposed colon between the liver and the diaphragm (Figure 2). Analgesics did not relieve her pain. Given a possibility of volvulus, laparoscopic enteropexy was planned. However, the pain was abruptly relieved after drainage of CAPD fluid and the subsequent chest X-ray showed that the interposed colon was no longer present. She has not experienced relapse since the last 6 months. Chilaiditi sign is asymptomatic appearance of interposed bowl between the liver and the diaphragm. It is found with an incidence of 0.025–0.28% in X-ray and of 1.2–2.4% in abdominal CT. With the presence of clinical symptoms, the condition is referred to as ‘Chilaiditi syndrome’. This condition is usually treated conservatively but rarely surgery is indicated in case of ileus, perforation, and ischemia. The predisposing factors include ascites, pregnancy, and any other conditions leading to an enlarged space under the right diaphragm or hypermobility of intestines.Figure 2Computed tomographic (CT) scan shows the interposed colon between the liver and the diaphragm (arrows).View Large Image Figure ViewerDownload (PPT)

Cinacalcet, a calcium receptor modulator, reduces serum phosphate levels as well as parathyroid hormone (PTH) and serum calcium levels, and improve the control of mineral metabolic disorder, which is a major problem by the active vitamin D sterols in the treatment of secondary hyperparathyroidism. In addition, cinacalcet could improve achievement of the biochemical targets for chronic kidney disease, bone and mineral disorder (CKD-MBD) recommended by K/DOQI and Japanese society for dialysis and therapy (JSDT) guidelines. Some clinical studies clarified the improvement of reduction in PTH levels and achievement targets for serum calcium and phosphate levels by the combined therapy with cinacalcet and vitamin D sterols, such as OPTIMA or ACHIEVE study. However, the effect of therapy may be different which medicine would be used mainly, further examination about the way to combine these two medicines is required. From the results of some experimental and clinical examinations, cinacalcet may have some efficiency on the prevention or regression of the parathyroid hyperplasia, onset of cardiovascular disease and ectopic calcification, prevention of bone fracture, and improvement of bone metabolism or mortality. Various efficient role of cinacalcet in the treatment of CKD-MBD would be elucidated if results of the clinical studies ongoing now, such as EVOLVE and ADVANCE or MBD-5D planning in Japan, will be published in the near future.