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Scleroderma renal crisis (SRC) is an important complication of scleroderma associated with significant morbidity and mortality. Current treatment of patients with SRC focuses on renin-angiotensin-aldosterone system (RAAS) blockade, ideally using angiotensin-converting enzyme inhibitors. We present a case of SRC in a patient established on maximal tolerable RAAS-blocking treatment. Introduction of a selective endothelin-A receptor antagonist followed by a direct renin inhibitor provided excellent blood pressure control and complete abrogation of heavy proteinuria. This was associated with a decrease in kidney function, with serum creatinine level increasing by approximately 30%. This increase is considered acceptable after the introduction of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, is regarded as an indicator of drug efficacy, and confers longer term renal protection. Both endothelin receptor antagonism and direct renin inhibition offer alternate novel therapies for patients with SRC. Their ability to preserve or improve kidney function is unclear.

A key role of the kidney is to eliminate many of the waste products generated by cellular metabolism and to maintain biochemical and acid base homeostasis of the organism. Kidneys contain spherical microvascular capillary networks called glomeruli that filter the plasma through a highly specialised filtration barrier (Fig. 1). Glomeruli are composed of three main cell types: mesangial cells, endothelial cells and glomerular epithelial cells (podocytes). The contractile mesangial cells are located within the centre of the glomerulus and support the delicate glomerular capillary network. The outermost podocytes are key components of the glomerular filtration barrier. The glomerular filtrate passes into Bowman’s space and the composition of this fluid is altered by tubular epithelial cells as it passes along the lumen of the nephrons. A more detailed description of renal physiology is outside the scope of the chapter but it should be noted that end stage renal failure is uniformly fatal if patients do not undergo dialysis or receive a functioning kidney transplant. It is therefore apparent that strategies that promote the resolution of glomerular inflammation would be predicted to be of great therapeutic benefit.

Acute kidney injury (AKI) is a significant complication of cardiac surgery and is associated with increased morbidity and mortality [1]. Despite much research, there is no specific therapy available. Although AKI can be multifactorial, ischaemia reperfusion injury (IRI) often plays a key role. Thus, cardiac surgery offers an attractive opportunity for translational AKI research given the predictive haemodynamic challenge to renal perfusion. Hemeoxygenase-1 (HO-1) is a key inducible anti-inflammatory enzyme that catalyses the breakdown of the pro-oxidant protein heme ubiquitously found at inflamed sites. The drug heme arginate has been in use for over 20 years in the treatment of porphyria but also upregulates HO-1 in peripheral blood mononuclear cells (PBMCs) [2] and ameliorates calf muscle ischaemia [3]. In addition, treatment of mice with heme arginate prior to renal IRI strongly upregulates renal HO-1 expression and protects from AKI [4]. We therefore hypothesise that HA may offer a prophylactic therapy for human renal IRI via the upregulation of HO-1.

770 www.thelancet.com Vol 385 February 28, 2015 basiliximab to 7% with alemtuzumab in a randomised trial of 852 renal transplant recipients. Despite its rather high rate and standardised detection, BPAR nowadays should no longer guide treatment decisions. Early BPAR without effect on graft function is well known to have no eff ect on long-term outcomes. Hence, for trials of renal transplantation, both the European Medicines Agency and US Food and Drug Administration have suggested use of combined primary endpoints that include patient and graft survival, and graft function besides acute rejection. In this trial, despite the reported advantage of BPAR, graft loss summed to 4% and patient death summed to 3% with alemtuzumab, with graft loss summing to 3% and patient death summing to 1% with basiliximab at 1 year. Therefore, the authors should provide numbers of non-death-censored graft loss (sum of death and graft loss) in both groups (these would theoretically sum to 6·3% [alemtuzumab] vs 4·5% [basiliximab] if only one event is assumed to occur in any given patient). Furthermore, BK virus infection occurred twice as often with alemtuzumab than with basiliximab, and leucopenia was 3·6 times more frequent, both of which might reduce graft survival long term. Some evidence suggests that long-term outcomes might be inferior with alemtuzumab compared with conventional induction treatment. Finally, clinical use of alemtuzumab might be severely hampered because the drug (MabCampath) has been withdrawn from the market in the European Union since Aug 8, 2012.

Rationale: The role played by resident pleural macrophages in the initiation of pleural inflammation is currently unclear.Objective: To evaluate the role of resident pleural macrophages in the initiation of inflammation.Methods: We have used a conditional macrophage ablation strategy to determine the role of resident pleural macrophages in the regulation of neutrophil recruitment in a murine model of experimental pleurisy induced by the administration of carrageenan and formalin- fixed Staphylococcus aureus.Measurements and Main Results: Conditional macrophage ablation mice express the human diphtheria toxin receptor under the control of the CD11b promoter such that the administration of diphtheria toxin induces ablation of nearly 97% of resident macrophages. Ablation of resident pleural macrophages before the administration of carrageenan or S. aureus dramatically reduced neutrophil influx into the pleural cavity. In the carrageenan model, the reduction in neutrophil infiltration was associated with marked early reduction in the level of macrophage inflammatory protein 2 as well as reduced levels of various cytokines, including tumor necrosis factor α, interleukin 6, and interleukin 10. Adoptive transfer of nontransgenic macrophages partially restored neutrophil infiltration. We also stimulated macrophage-depleted and nondepleted pleural cell populations with carrageenan in vitro and determined the production of chemokines and cytokines. Chemokine and cytokine production was markedly reduced by macrophage depletion, reinforcing the role of resident pleural macrophages in the generation of mediators that initiate acute inflammation.Conclusion: These studies indicate a critical role for resident pleural macrophages in sensing perturbation to the local microenvironment and orchestrating subsequent neutrophil infiltration.Read More: http://www.atsjournals.org/doi/abs/10.1164/rccm.200504-538OC

A sequential model involving chemokines has been proposed for leukocyte extravasation into areas of inflammation; however, site-specific aspects remain to be elucidated. Hence, we studied the role of chemokines produced by mesangial (MC) or glomerular endothelial cells (GEC) and their receptors in glomerular recruitment of monocytes. Stimulation of MC with TNF-α up-regulated mRNA and protein of CC and CXC chemokines but not constitutive expression of the CX3C chemokine fractalkine. While growth-related activity (GRO)-α was immobilized to MC proteoglycans, monocyte chemotactic protein (MCP)-1 was secreted into the soluble phase. Firm adhesion and sequestration of monocytes on activated MC was supported by the GRO-α receptor CXCR2 and to a lesser extent by CX3CR, whereas the MCP-1 receptor CCR2 contributed to their transendothelial chemotaxis toward activated MC. In contrast, fractalkine mRNA and protein was induced by TNF-α in transformed rat GEC, and both CXCR2 and CX3CR mediated monocyte arrest on GEC in shear flow. The relevance of these mechanisms was confirmed in a rat nephrotoxic nephritis model where acute glomerular macrophage recruitment was profoundly inhibited by blocking CXCR2 or CCR2. In conclusion, our results epitomize a combinatorial model in which chemokines play specialized roles in driving glomerular monocyte recruitment and emphasize an important role for CXCR2 in macrophage infiltration during early phases of nephrotoxic nephritis.

Amelioration of rodent type 2 diabetes by hemin has been linked to increased heme oxygenase (HO) activity, however alternative mechanisms have recently been proposed for its anti-diabetic effect. We sought to determine the anti-diabetic efficacy of heme arginate (HA), a clinically licensed preparation of heme, and whether its predominant mode of action is via increased HO activity. Intravenous administration of HA reduced hyperglycemia in diabetic (db/db) mice. Co-administration of the HO inhibitor stannous (IV) mesoporphyrin IX dichloride (SM) resulted unexpectedly in a further improvement in glycaemic control despite restoring HO activity to baseline levels. The anti-diabetic effects of HA±SM were associated with increased adiposity, increased serum adiponectin levels, reduced adipose tissue and islet inflammation and preservation of islet β-cell function. HO activity independent effects of HA on adipogenesis and β-cell inflammation were further confirmed in cell culture models using the 3T3-L1 pre-adipocyte and MIN6 β-cell lines, respectively. In conclusion, our work demonstrates that the heme component of HA ameliorates experimental type 2 diabetes by promoting metabolically favourable adipogenesis and preserving islet β-cell function, but this is not mediated via increased HO activity.

Macrophages function as sentinel, cell-regulatory hubs capable of initiating, perpetuating and contributing to the resolution of an inflammatory response, following their activation from a resting state. Highly complex and varied gene expression programs within the macrophage enable such functional diversity. To investigate how programs of gene expression relate to the phenotypic attributes of the macrophage, the development of in silico modeling methods is needed. Such models need to cover multiple scales, from molecular pathways in cell-autonomous immunity and intercellular communication pathways in tissue inflammation to whole organism response pathways in systemic disease. Here, we highlight the potential of in silico macrophage modeling as an amenable and important yet under-exploited tool in aiding in our understanding of the immune inflammatory response. We also discuss how in silico macrophage modeling can help in future therapeutic strategies for modulating both the acute protective effects of inflammation (such as host defense and tissue repair) and the harmful chronic effects (such as autoimmune diseases)., 7 pages plus 1 figure

Macrophages are inflammatory cells with important roles in the propagation of renal injury. More recently they have also been shown to be important in the resolution of inflammation. Wang et al. show that macrophages can be modulated ex vivo by cytokine stimulation, localize to renal tissue, and slow progression of experimental glomerular inflammation. Thus strategies targeting macrophage function have considerable therapeutic potential.

Gandolfo et al. report the key role played by regulatory T cells in modulating recovery from ischemic renal injury. The role of regulatory T cells in modulating ischemia-reperfusion injury in the kidney and other organs is discussed in this commentary.