Iris Lee

Growth arrest-specific gene 6 (Gas6) levels are elevated in patients with chronic renal failure

BACKGROUND The TAM receptors (tyro3, axl and mer) and their ligands (vitamin K-dependent proteins-Gas6 and Protein S) are crucial modulators of inflammation, which may be relevant in chronic kidney disease (CKD). Gas6 and axl have multiple roles in mediating vascular atherosclerosis and injury, thrombosis and inflammation, yet nothing is known about the Gas6-axl pathway in humans with CKD. Given the prevalence of chronic inflammation and vascular disease in this population, we measured TAM ligands in patients with various levels of renal function. METHODS Gas6 and protein S were quantified in the plasma by ELISA in three patient groups: end-stage renal disease on chronic hemodialysis (HD), CKD and normal controls. RESULTS Significantly increased levels of Gas6 and protein S were found in CKD patients compared with normal controls (P < 0.01 and <0.001, respectively). In HD patients, Gas6 levels were elevated compared with controls (P < 0.001) and positively associated with low albumin (r = 0.33; P = 0.01), dialysis vintage (r = 0.36; P = 0.008) and IV iron administration (r = 0.33; P = 0.01). The levels of Gas6 rose with CKD stage and were inversely associated with estimated GFR (P < 0.0001). CONCLUSIONS Dysregulation of circulating Gas6 is associated with renal disease and inversely proportional to renal function. Low albumin and higher IV iron administration were associated with higher Gas6 levels, suggesting a possible connection between inflammation and oxidative stress mediated by iron. Protein S levels were also elevated in CKD patients, but the relevance of this finding needs to be further investigated.

Chronic kidney disease alters vascular smooth muscle cell phenotype

Vascular access dysfunction associated with arteriovenous grafts and fistulas contributes to the morbidity and mortality of chronic kidney disease (CKD) patients receiving hemodialysis. We hypothesized that the uremic conditions associated with CKD promote a pathophysiological vascular smooth muscle cell (VSMC) phenotype that contributes to neointimal hyperplasia. We analyzed the effect of culturing human VSMC with uremic serum. Expression of VSMC contractile marker genes was reduced 50-80% in cells exposed to uremic serum and the decreased expression was accompanied by changes in histone marks. There was an increase in proliferation in cells exposed to uremic conditions, with no change in the levels of apoptosis. Interestingly, we found that uremic serum inhibited PDGF-induced migration of VSMC. Histomorphometric analysis revealed venous neointimal hyperplasia in veins from chronic kidney disease (CKD) patients prior to any surgical manipulation as compared to veins from patients with no kidney disease. We conclude that uremia associated with CKD alters VSMC phenotype in vitro and contributes to neointimal hyperplasia formation in vivo contributing to the pathogenesis of vascular access dysfunction in CKD patients.

Monocyte and plasma expression of TAM ligand and receptor in renal failure: Links to unregulated immunity and chronic inflammation

Chronic inflammation is increased in patients with chronic kidney disease (CKD) and contributes to cardiovascular morbidity and mortality. Specific immune mechanisms and pathways that drive and maintain chronic inflammation in CKD are not well described. The TAM ligands (Gas6 and protein S) and receptors (Axl and Mer) have been recently recognized as playing a prominent role in immune regulation. The receptors exist in both soluble and cell-bound forms; the soluble receptors (sAxl and sMer) are believed to compete with the bound receptors and thus inhibit their function. In this study, we determined the expression of cell-bound and soluble TAM proteins in patients with CKD. CKD patients had significantly lower expression of Mer in monocytes, yet increased expression of soluble TAM receptors sAxl and sMer in plasma compared to controls. The metalloproteinase ADAM 17, responsible for cleavage of Mer to its soluble form, was increased in patient monocytes. Elevated levels of soluble TAM receptors were more evident in patients with progressive renal failure. These observations suggest that functional deficiency of TAM receptor-mediated regulation of inflammation may contribute to chronic inflammation in patients with CKD.

Biomarkers in renal transplantation

Identifying surrogate markers of renal allograft outcome and biomarkers of acute and chronic graft injury is a critical issue for the transplant community. Measurement of serum creatinine and biopsy remain the current gold standards for the evaluation of renal allografts. These tests have significant limitations in predicting which patients are destined for immune tolerance or immune-mediated graft loss, and aiding in the management of long-term immunosuppression. The goal of biomarkers is to diagnose rejection early, determine prognosis and tailor immunosuppressive therapy in a noninvasive, cost-effective manner. Biomarker research has focused on primary areas of kidney injury, the tubules and the cells that infiltrate them. This article reviews biomarkers currently under investigation in the setting of renal allograft transplantation.

Search for useful tools: biomarkers in lupus nephritis

Iris J Lee† & Michael P Madaio †Author for correspondence Temple University School of Medicine, Section of Nephrology & Kidney Transplantation, 3322 North Broad Street, MOB, 1st Floor, Philadelphia, PA 19140, USA Tel.: +1 215 707 9171; Fax: +1 215 707 9697; iris.lee@tuhs.temple.edu ‘For lupus nephritis, the critical issues at stake include identifying those patients at risk for flare, progressive nephritis and development of end-stage renal disease’

Post-Kidney Transplant Modification of Cardiovascular Risk

Kidney transplantation (KT) offers a survival advantage compared to remaining on dialysis in patients with end stage renal disease. Excellent short-term graft survival is achieved in kidney recipients as a result of improvement in immunosuppressive protocols. Unfortunately, there has been minimal improvement in long-term graft survival mainly due to recipient death from cardiovascular disease (CVD) with a functioning transplant. Both traditional as well as transplant specific risk factors contribute to CVD risk in KT. Graft dysfunction and adverse effects of immunosuppressive agents are the predominant transplant-specific risk factors. Measures to address traditional risk factors as well as modification of immunosuppressive regimens may lower the CVD risk post-KT. General cardio-protective strategies such as lifestyle modifications to minimize weight gain, use of aspirin, aggressive control of dyslipidemia, hypertension, and diabetes need to be optimized in kidney recipients. Evolving protocols with corticosteroid avoidance, calcineurin inhibitor minimization, and use of newer agents such as belatacept have better metabolic risk profile for CVD in kidney recipients. Minimizing time spent on dialysis pre-KT also improves cardiovascular outcomes.