Upregulation of Monocyte/Macrophage HGFIN (Gpnmb/Osteoactivin) Expression in End-Stage Renal Disease

Background and objectives: Hematopoietic growth factor–inducible neurokinin 1 (HGFIN), also known as Gpnmb and osteoactivin, is a transmembrane glycoprotein that is expressed in numerous cells, including osteoclasts, macrophages, and dendritic cells. It serves as an osteoblast differentiation factor, participates in bone mineralization, and functions as a negative regulator of inflammation in macrophages. Although measurable at low levels in monocytes, monocyte-to-macrophage transformation causes substantial increase in HGFIN expression. HGFIN is involved in systemic inflammation, bone demineralization, and soft tissue vascular calcification.Design, setting, participants, & measurements: We explored HGFIN expression in monocytes and monocyte-derived macrophages in 21 stable hemodialysis patients and 22 control subjects.Results: Dialysis patients exhibited marked upregulation of colony-stimulating factor and IL-6 and significant downregulation of IL-10 in intact monocytes and transformed macrophages. HGFIN expression in intact monocytes was negligible in control subjects but conspicuously elevated (8.6-fold) in dialysis patients. As expected, in vitro monocyte-to-macrophage transformation resulted in marked upregulation of HGFIN in cells obtained from both groups but much more so in dialysis patients (17.5-fold higher). Upregulation of HGFIN and inflammatory cytokines in the uremic monocyte-derived macrophages occurred when grown in the presence of either normal or uremic serum, suggesting the enduring effect of the in vivo uremic milieu on monocyte/macrophage phenotype and function.Conclusions: Uremic macrophages exhibit increased HGFIN gene and protein expression and heightened expression of proinflammatory and a suppressed expression of anti-inflammatory cytokines. Further studies are needed to determine the role of heightened monocyte/macrophage HGFIN expression in the pathogenesis of ESRD-induced inflammation and vascular and soft tissue calcification.Hematopoietic growth factor–inducible neurokinin 1 (HGFIN; also known as glycoprotein nonmetastatic melanoma protein b [gpnmb], dendritic cell–associated heparan sulfate proteoglycan integrin ligand [DC-HIL], and osteoactivin) is a type 1 transmembrane glycoprotein (1). Its extracellular domains include a heparin-binding domain, an integrin-binding arginine-glycine-aspartic acid motif, and a polycystic kidney disease sequence (1–4). It is expressed in many cells and tissues, including embryonic nervous system, developing nephrons, basal layer of skin, germinal cells of hair follicles, osteoblasts, osteoclasts, myocytes, retinal pigment epithelium, renal tubules, macrophages, and dendritic cells (1,5–9). In bone, it plays an essential role in terminal osteoblast differentiation and bone mineralization (6,10,11).HGFIN expression is enriched in monocytes and is strongly upregulated during macrophage differentiation. Upon macrophage activation, increased HGFIN is associated with a reduction of the proinflammatory cytokine IL-6, suggesting that it may play a role in mitigating inflammatory responses (12). In fact, mice with an inactivation mutation in HGFIN exhibit elevated numbers of peritoneal macrophages and higher levels of proinflammatory cytokines in response to LPS (12). HGFIN has also been shown to inhibit T cell activation by antigen-presenting cells by binding syndecan 4 (a heparan sulfate proteoglycan) (13,14). Thus, it seems that HGFIN functions as a negative regulator of inflammation.ESRD is associated with systemic inflammation, arteriosclerosis, bone demineralization, and soft tissue vascular calcification/ossification (15–19). Vascular calcification in ESRD is not a passive process but an active one that resembles bone mineralization (20). Because HGFIN is involved in inflammation and mineralization, processes that are upregulated in ESRD, we explored its expression in circulating monocytes and monocyte-derived macrophages in a group of hemodialysis-dependent patients and age-matched control subjects.     

Analysis of poor outcomes after laparoscopic adjustable gastric banding

Background  

Recent studies document excess weight loss (EWL) of more than 50% with the laparoscopic adjustable gastric band (LGB). This study reviews the LGB experience at an urban academic center in terms of complications, reoperative rates, and comorbidities.     

Liver transplant listing for hepatitis C‐associated cirrhosis and hepatocellular carcinoma has fallen in the United Kingdom since the introduction of direct‐acting antiviral therapy

Following the introduction of direct‐acting antivirals (DAA), there have been reports of declining incidence of hepatitis C (HCV)‐related liver disease as a liver transplantation indication. In this study, we assessed the impact of DAA on liver transplant indications in the UK and waiting list outcomes for patients with HCV. We assessed UK adult elective liver transplant registrants between 2006 and 2017. The aetiology of liver disease at registration was reclassified using an accepted hierarchical system and changes were assessed over time and compared before and after the introduction of DAA. Registration UKELD scores and 1‐year waiting list outcomes were also compared. The proportion of waiting list patients registered with HCV‐related cirrhosis reduced after the introduction of DAA from 10.5% in 2013 to 4.7% in 2016 (P < 0.001). Alcohol‐related liver disease (ARLD) was the leading indication for liver transplantation followed by liver cancer (26.1% and 18.4% in 2016, respectively). The proportion of registrations with Hepatocellular carcinoma (HCC) associated with HCV reduced from 46.4% in 2013 to 33.7% in 2016 (P = 0.002). For patients with HCV‐related cirrhosis at one year the outcomes of death, transplantation, delisting due to improvement or deterioration and awaiting a graft at 1 year were similar. For patients with HCV‐related HCC, the proportion dying at 1 year reduced significantly from 2.9% to 0.0% (P = 0.04). These data demonstrate an association between DAA and reduced listing rates for HCV‐related cirrhosis and HCC, but no significant changes in waiting list outcomes other than reduced mortality in the HCC group.     

Laparoscopic resection of a retroperitoneal schwannoma

Schwannomas or neurilemomas are rare, benign tumors that originate from the neural sheath. A 54-year-old man presented with left flank discomfort and lumbar pain for 6 months. A computed tomographic scan confirmed the existence of a 12 × 9 cm heterogeneous retroperitoneal mass adherent to the left psoas muscle that displaced the left kidney anteriorly. Total laparoscopic removal of the tumor was performed and pathologic examination revealed a benign schwannoma.     

Retrograde migration and endovascular retrieval of a venous bullet embolus

Venous bullet embolism is a rare and complicated occurrence reported in approximately 0.3% of penetrating trauma. The management of bullet emboli is decided on a case-by-case basis, balancing the risk of the embolus itself against those associated with extraction. We report a case of a 19-year-old man who sustained a gunshot wound to the anterior chest, which migrated to the left internal iliac vein in a retrograde fashion. We were able to successfully retrieve the missile using an endovascular approach, thereby minimizing the morbidity associated with an open procedure.     

The aging kidney

Renal aging, by itself, is associated with alterations in renal morphology and a decline in renal function, which is accelerated and/or accentuated by diseases such as diabetes mellitus and hypertension. The aging-related renal insufficiency has important implications with regards to body homeostasis, drug toxicity, and renal transplantation. An understanding of renal aging and its distinction from renal insufficiency secondary to diseases is essential for individualized care of the elderly. Toward this end, investigations are underway to elucidate the molecular mechanisms of renal aging. This review summarizes the structural and functional changes of the aging kidney and highlights the advances made in our understanding of the renal aging process.     

Chronic inflammatory disorders and accelerated atherosclerosis: chronic kidney disease

Increasing evidence points to the fact that plasma HDL cholesterol levels do not always accurately predict HDL function including reverse cholesterol transport and modulation of inflammation. These functions appear to have evolved as part of our innate immune system. HDL is anti inflammatory in healthy individuals in the absence of systemic oxidative stress and inflammation. In those with chronic illnesses such as renal failure however, HDL may become dysfunctional and actually promote inflammation. HDL may be thought of as a shuttle whose size can be estimated by HDL cholesterol levels. The content of the shuttle however, is what determines the anti inflammatory potential of HDL and can change from one, supporting reverse cholesterol transport to one that is less efficient in carrying out this function. Chronic kidney disease (CKD), and inflammatory disorder, is associated with development of accelerated atherosclerosis and premature death from coronary artery disease (CAD). Patients with CKD present with dyslipidemia, oxidative stress and systemic inflammation. Among the abnormalities in lipid metabolism in these patients is reduced levels and protective capacity of HDL. Recent studies have shown that HDL from patients with end stage renal disease is not capable of preventing LDL oxidation and that it induces monocyte migration in artery wall model systems. Treatment of plasma from these patients, with an HDL mimetic peptide improved the anti inflammatory properties of patient's HDL and made LDL more resistant to oxidative modification. Animal models of kidney disease also had proinflammatory HDL and treatment with the peptide mimetic improved markers of inflammation and anti inflammatory capacity of HDL. Whether HDL mimetic peptides will have therapeutic benefit in patients with renal failure will have to be determined in clinical studies.     

Analysis of machine perfusion benefits in kidney grafts: a preclinical study

Background  

Machine perfusion (MP) has potential benefits for marginal organs such as from deceased from cardiac death donors (DCD). However, there is still no consensus on MP benefits. We aimed to determine machine perfusion benefits on kidney grafts.