tion’, implying that most patients ‘should’ receive a particular action. In contrast, level 2 guidelines are essentially ‘suggestions’ and are deemed to be ‘weak’ or discretionary, recognising that management decisions may vary in different clinical contexts. Each recommendation was further graded from A to D by the quality of evidence underpinning them, with grade A referring to a high quality of evidence whilst grade D recognised a ‘very low’ evidence base. The overall strength and quality of the supporting evidence is summarised in table 1 . The guidelines focused on 4 key domains: (1) AKI definition, (2) prevention and treatment of AKI, (3) contrastinduced AKI (CI-AKI) and (4) dialysis interventions for the treatment of AKI. The full summary of clinical practice statements is available at www.kdigo.org, but a few key recommendation statements will be highlighted here.

/pdf/kdigo-clinical-practice-guidelines-for-acute-kidney-injury-27tybolw7l.pdf

KDIGO clinical practice guidelines for acute kidney injury.

Sepsis is the leading cause of death in critically ill patients in the United States. Yet the individual host response to septicemia is variable, depending on the patient's immune response, age, nutritional status, and coexisting conditions, as well as on the virulence of the organism and the size of the inoculum. This review examines evolving concepts of sepsis and discusses new and potential therapies. Recent clinical advances include therapy with activated protein C, stringent control of blood glucose, and early goal-directed therapy to treat cellular oxygen deficit. Future therapies may be focused on modulating the immune response in the light of the characteristics of the specific pathogen, the genetic profile of the patient, and the duration of the disease.

https://www.nejm.org/doi/pdf/10.1056/NEJMra021333

The pathophysiology and treatment of sepsis.

The neonatal Fc receptor for IgG (FcRn) has been well characterized in the transfer of passive humoral immunity from a mother to her fetus. In addition, throughout life, FcRn protects IgG from degradation, thereby explaining the long half-life of this class of antibody in the serum. In recent years, it has become clear that FcRn is expressed in various sites in adults, where its potential function is now beginning to emerge. In addition, recent studies have examined the interaction between FcRn and the Fc portion of IgG with the aim of either improving the serum half-life of therapeutic monoclonal antibodies or reducing the half-life of pathogenic antibodies. This Review summarizes these two areas of FcRn biology.

FcRn: the neonatal Fc receptor comes of age

The role of macrophages in tumour growth and development is complex and multifaceted. Whilst there is limited evidence that tumour-associated macrophages (TAMs) can be directly tumouricidal and stimulate the anti-tumour activity of T cells, there is now contrasting evidence that tumour cells are able to block or evade the activity of TAMs at the tumour site. In some cases, tumour-derived molecules even redirect TAM activities to promote tumour survival and growth. Indeed, evidence has emerged for a symbiotic relationship between tumour cells and TAMs, in which tumour cells attract TAMs and sustain their survival, with TAMs then responding to micro-environmental factors in tumours such as hypoxia (low oxygen tension) by producing important mitogens as well as various growth factors and enzymes that stimulate tumour angiogenesis. This review presents evidence for the number and/or distribution of TAMs being linked to prognosis in different types of human malignancy. It also outlines the range of pro- and anti-tumour functions performed by TAMs, and the novel therapies recently devised using TAMs to stimulate host immune responses or deliver therapeutic gene constructs to solid tumours.

The role of tumour‐associated macrophages in tumour progression: implications for new anticancer therapies

It is increasingly apparent that not only is a cure for the current worldwide diabetes epidemic required, but also for its major complications, affecting both small and large blood vessels. These complications occur in the majority of individuals with both type 1 and type 2 diabetes. Among the most prevalent microvascular complications are kidney disease, blindness, and amputations, with current therapies only slowing disease progression. Impaired kidney function, exhibited as a reduced glomerular filtration rate, is also a major risk factor for macrovascular complications, such as heart attacks and strokes. There have been a large number of new therapies tested in clinical trials for diabetic complications, with, in general, rather disappointing results. Indeed, it remains to be fully defined as to which pathways in diabetic complications are essentially protective rather than pathological, in terms of their effects on the underlying disease process. Furthermore, seemingly independent pathways are also showing significant interactions with each other to exacerbate pathology. Interestingly, some of these pathways may not only play key roles in complications but also in the development of diabetes per se. This review aims to comprehensively discuss the well validated, as well as putative mechanisms involved in the development of diabetic complications. In addition, new fields of research, which warrant further investigation as potential therapeutic targets of the future, will be highlighted.

Mechanisms of Diabetic Complications

Renin is an aspartyl protease essential for the control of blood pressure and was long suspected to have cellular receptors We report the expression cloning of the human renin receptor complementary DNA encoding a 350-amino acid protein with a single transmembrane domain and no homology with any known membrane protein Transfected cells stably expressing the receptor showed renin- and prorenin-specific binding The binding of renin induced a fourfold increase of the catalytic efficiency of angiotensinogen conversion to angiotensin I and induced an intracellular signal with phosphorylation of serine and tyrosine residues associated to an activation of MAP kinases ERK1 and ERK2 High levels of the receptor mRNA are detected in the heart, brain, placenta, and lower levels in the kidney and liver By confocal microscopy the receptor is localized in the mesangium of glomeruli and in the subendothelium of coronary and kidney artery, associated to smooth muscle cells and colocalized with renin The renin receptor is the first described for an aspartyl protease This discovery emphasizes the role of the cell surface in angiotensin II generation and opens new perspectives on the tissue renin-angiotensin system and on renin effects independent of angiotensin II

/pdf/pivotal-role-of-the-renin-prorenin-receptor-in-angiotensin-k0vsk59f6p.pdf

Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin

The morphology of "acute tubular necrosis" in man: analysis of 57 renal biopsies and a comparison with the glycerol model.

Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (HRIs) have been recently shown to prevent atherosclerosis progression. Clinical benefit results from combined actions on various components of the atherosclerotic lesion. This study was designed to identify the effects of HRI on one of these components, the endothelial fibrinolytic system. Aortas isolated from rats treated for 2 days with lovastatin (4 mg/kg body wt per day) showed a 3-fold increase in tissue plasminogen activator (tPA) activity. In a rat aortic endothelial cell line (SVARECs) and in human nontransformed endothelial cells (HUVECs), HRI induced an increase in tPA activity and antigen in a time- and concentration-dependent manner. In SVARECs, the maximal response was observed when cells were incubated for 48 hours with 50 mmol/L HRI. An increase of tPA mRNA was also in evidence. In contrast, HRI inhibited plasminogen activator inhibitor-1 activity and mRNA. The effects of HRI were reversed by mevalonate and geranylgeranyl pyrophosphate, but not by LDL cholesterol and farnesyl pyrophosphate, and were not induced by a-hydroxyfarnesyl phosphonic acid, an inhibitor of protein farnesyl transferase. C3 exoenzyme, an inhibitor of the geranylgeranylated- activated Rho protein, reproduced the effect of lovastatin on tPA and plasminogen activator inhibitor-1 activity and blocked its reversal by geranylgeranyl pyrophosphate. The effect of HRI was associated with a disruption of cellular actin filaments without modification of microtubules. A disrupter of actin filaments, cytochalasin D, induced the same effect as lovastatin on tPA, whereas a disrupter of microtubules, nocodazole, did not. In conclusion, HRI can modify the fibrinolytic potential of endothelial cells, likely via inhibition of geranylgeranylated Rho protein and disruption of the actin filaments. The resulting increase of fibrinolytic activity of endothelial cells may contribute to the beneficial effects of HRI in the progression of atherosclerosis. (Circ Res. 1998;83:683-690.)

3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors Increase Fibrinolytic Activity in Rat Aortic Endothelial Cells Role of Geranylgeranylation and Rho Proteins

https://www.kidney-international.org/article/S0085-2538(15)59805-0/pdf

Specific receptor binding of renin on human mesangial cells in culture increases plasminogen activator inhibitor-1 antigen

https://www.kidney-international.org/article/S0085-2538(15)47291-6/pdf

Jean-Daniel Sraer

Papers

Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin

The morphology of "acute tubular necrosis" in man: analysis of 57 renal biopsies and a comparison with the glycerol model.

3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors Increase Fibrinolytic Activity in Rat Aortic Endothelial Cells Role of Geranylgeranylation and Rho Proteins

Specific receptor binding of renin on human mesangial cells in culture increases plasminogen activator inhibitor-1 antigen

Plasminogen activator inhibitor type 1 is a potential target in renal fibrogenesis.