Correction to: Late-onset Pneumocystis jirovecii pneumonia (PJP) in patients with ANCA-associated vasculitis.

The family name of the corresponding author on the original version of this article was incorrectly spelled as "Mariana Philipos".

The impact of age on patient tolerance of mycophenolate following kidney transplantation.

BACKGROUND: In Scotland, standard maintenance immunosuppression following kidney transplantation consists of mycophenolate (MPA), tacrolimus and prednisolone irrespective of recipient age. We analyzed the tolerability of this immunosuppression regimen and the association with transplant outcomes. METHODS: A national, multicentre retrospective analysis of patients transplanted in 2015 and 2016, comparing graft function, acute rejection, significant infection rates and immunosuppression dosing between patients aged 18 and 59 years (Group 1) and ≥60 years (Group 2). RESULTS: Of the 490 patients, 26% were aged ≥60 years. Acute rejection (AR) rates at 1 year were 15% and 11% in Groups 1 and 2, respectively. Full-dose MPA was poorly tolerated with 53% in Group 1 and 77% in Group 2 requiring dose reduction or cessation. Female gender and age ≥60 years were independent predictors for MPA dose changes. One year following MPA dose reduction, AR risk was low (5%) in Group 2, however, those remaining on full dose MPA had a 79% increased rate of serious infections. CONCLUSION: The majority of renal transplant recipients aged ≥60 fail to tolerate full-dose MPA. In this group, MPA dose reduction is associated with low rejection rates, but full-dose MPA is associated with high infection rates. We suggest that a tailored approach to immunosuppression in elderly recipients incorporating lower doses of MPA may be appropriate.

Correction to: Late-onset Pneumocystis jirovecii pneumonia (PJP) in patients with ANCA-associated vasculitis.

The family name of the corresponding author on this article was incorrectly spelled as "El Hakem Matraiah". The correct spelling should have been "El Hakem Metraiah". This is now presented correctly in this article.

Late-onset Pneumocystis jirovecii pneumonia (PJP) in patients with ANCA-associated vasculitis.

Immunosuppression in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is complicated by increasing risk of infections including opportunistic infections like Pneumocystis jirovecii pneumonia (PJP). Available evidence on risk factors and indications for prophylaxis in AAV is derived from PJP occurring early in the course of AAV. In this retrospective study, we characterized the profile of PJP in patients with AAV. PJP cases were identified retrospectively based on positive polymerase chain reaction test from electronic record followed by confirmation from medical records over a 10-year period. AAV patients without PJP over the same period were used as control group. Sixteen PJP+AAV+ were identified; in 14 of them, we were able to confirm they received PJP prophylaxis during induction therapy, while in two cases, data were missing. The onset of the infection was after 6 months from AAV diagnosis in 80% of cases. Escalations in immunosuppression prior to PJP were observed in six cases within 3 months prior to PJP onset. Overall mortality was 12.5%. By univariate analysis, renal involvement at AAV diagnosis was associated with PJP. These results indicate that PJP is not limited to the first 6 months following AAV diagnosis. Late-onset infection can occur in context of augmented immunotherapy, particularly with concurrent lymphopenia. Other risk factors that can independently predict late-onset PJP remain to be identified.

Nitric oxide is an important mediator of renal tubular epithelial cell death in vitro and in murine experimental hydronephrosis.

Macrophages play a pivotal role in tissue injury and fibrosis during renal inflammation. Although macrophages may induce apoptosis of renal tubular epithelial cells, the mechanisms involved are unclear. We used a microscopically quantifiable co-culture assay to dissect the cytotoxic interaction between murine bone marrow-derived macrophages and Madin-Darby canine kidney cells and primary murine renal tubular epithelial cells. The induction of tubular cell apoptosis by cytokine-activated macrophages was reduced by inhibitors of nitric oxide synthase whereas tubular cell proliferation was unaffected. Furthermore, cytokine-activated macrophages derived from mice targeted for the deletion of inducible nitric oxide synthase were noncytotoxic. We then examined the role of nitric oxide in vivo by inhibiting inducible nitric oxide synthase in the model of murine experimental hydronephrosis. l-N(6)-(1-iminoethyl)-lysine was administered in the drinking water between days 5 and 7 after ureteric obstruction. Macrophage infiltration was comparable between groups, but treatment significantly inhibited tubular cell apoptosis at day 7. Tubular cell proliferation was unaffected. Inducible nitric oxide synthase blockade also reduced interstitial cell apoptosis and increased collagen III deposition. These data indicate that nitric oxide is a key mediator of macrophage-directed tubular cell apoptosis in vitro and in vivo and also modulates tubulointerstitial fibrosis.

Inhibition of macrophage nuclear factor-kappaB leads to a dominant anti-inflammatory phenotype that attenuates glomerular inflammation in vivo.

Infiltrating macrophages (mphi) can cause injury or facilitate repair, depending on how they are activated by the microenvironment. Studies in vitro have defined the roles of individual cytokines and signaling pathways in activation, but little is known about how macrophages integrate the multiple signals they receive in vivo. We inhibited nuclear factor-kappaB in bone marrow-derived macrophages (BMDMs) by using a recombinant adenovirus expressing dominant-negative IkappaB (Ad-IkappaB). This re-orientated macrophage activation so they became profoundly anti-inflammatory in settings where they would normally be classically activated. In vitro, the lipopolysaccharide-induced nitric oxide, interleukin-12, and tumor necrosis factor-alpha synthesis was abrogated while interleukin-10 synthesis increased. In vivo, fluorescently labeled BMDMs transduced with Ad-IkappaB and injected into the renal artery significantly reduced inducible nitric oxide synthase and MHC class II expression when activated naturally in glomeruli of rats with nephrotoxic nephritis. Furthermore, although they only comprised 15% of glomerular macrophages, their presence significantly reduced glomerular infiltration and activation of host macrophages. Injury in nephrotoxic nephritis was also decreased when assessed morphologically and by severity of albuminuria. The results demonstrate the power of Ad-IkappaB-transduced BMDMs to inhibit injury when activated by acute immune-mediated inflammation within the glomerulus.

Macrophages and the kidney.

PURPOSE OF REVIEW: Macrophage infiltration is a hallmark of all forms of inflammatory and non-inflammatory renal injury. However, the classical view of macrophages as cells that cause injury has been superseded with evidence of their heterogeneous role, i.e. with involvement in all stages of the inflammatory process including tissue repair and healing. This review summarizes the major advances in macrophage biology achieved in the last year, highlighting the different activation states, how these are regulated, and their relevance in renal disease. RECENT FINDINGS: New concepts have emerged concerning the factors controlling monocyte recruitment into inflamed tissue and their subsequent differentiation into activated macrophages. There is now compelling evidence for the heterogeneity of macrophages in clinical disease, i.e. they appear to be able to both promote and downregulate inflammation. An increased understanding of the factors regulating the expression of pro-inflammatory or reparative characteristics by macrophages is establishing how their function can be manipulated to attenuate renal inflammation in experimental models. SUMMARY: An understanding of the role of macrophages at different time-points in renal inflammation, and the development of techniques for modulating macrophage activation in vivo, will provide a powerful method for exploiting the reparative attributes of these cells in clinical settings, restoring regulation to the inflammatory process and promoting healing.