Biomarkers in native and transplant kidneys: opportunities to improve prediction of outcomes in chronic kidney disease.

PURPOSE OF REVIEW: Predicting the outcomes of patients with chronic kidney disease (CKD) is important from both patient and healthcare system perspectives. This review examines the current state of conventional and nonconventional biomarkers as noninvasive tools to improve risk-stratification and outcome prediction in CKD. RECENT FINDINGS: Conventional biomarkers (serum creatinine, urine albumin, and clinical variables such as sex, age, and diabetes) have been the cornerstone of most prediction models for CKD progression to end-stage renal disease (ESRD), and adverse cardiovascular outcomes including death. With better understanding of the pathophysiology of CKD and the evolution of molecular diagnostics, numerous novel or nonconventional markers have emerged. They have been examined individually and in combination to predict specific outcomes. We highlight these markers and studies, conducted primarily in patients with native kidneys. In those with transplant kidneys, markers of both acute and chronic kidney dysfunction have been examined, although to a lesser extent. Similarities and differences in knowledge derived from these two populations are highlighted. SUMMARY: Improving prediction of outcomes in CKD patients with either native or transplant kidneys remains an important goal. Increasingly sophisticated biomarkers may potentially identify targets for clinical research, improve the nature and timing of therapeutic interventions, and guide resource allocation.

TCR complex-activated CD8 adhesion function by human T cells.

The CD8 receptor plays a central role in the recognition and elimination of virally infected and malignant cells by cytolytic CD8(+) T cells. In conjunction with the TCR, the CD8 coreceptor binds Ag-specific class I MHC (MHC-I) molecules expressed by target cells, initiating signaling events that result in T cell activation. Whether CD8 can further function as an adhesion molecule for non-Ag MHC-I is currently unclear in humans. In this study, we show that in human CD8(+) T cells, TCR complex signaling activates CD8 adhesion molecule function, resulting in a CD8 interaction with MHC-I that is sufficient to maintain firm T cell adhesion under shear conditions. Secondly, we found that while CD8 adhesive function was triggered by TCR complex activation in differentiated cells, including in vitro generated CTL and ex vivo effector/memory phenotype CD8(+) T cells, naive CD8(+) T cells were incapable of activated CD8 adhesion. Lastly, we examine the kinetics of, and signaling for, activated CD8 adhesion in humans and identify notable differences from the equivalent CD8 function in mouse. Activated CD8 adhesion induced by TCR signaling may contribute to the more rapid and robust elimination of pathogen-infected cells by differentiated CD8(+) T cells.

Epitope mapping of Ly-49G and G-like receptors: CK-1 antibody defines a polymorphic site of functional interaction with class I ligand.

Ly-49 receptors regulate mouse natural killer cell functions. Members of the polymorphic Ly-49 multigene family recognize specific alleles of major histocompatibility complex class I (MHC I) or MHC I-like proteins. Previous studies have provided insight into the nature of Ly-49A and -C interaction with their high-affinity MHC I ligands, H-2Dd and Kb, respectively. Unlike Ly-49C, recognition of MHC I by Ly-49A is regulated in part by residues within the beta4-beta5 loop of its ectodomain. Ly-49A and -G are within the same Ly-49 subfamily, and both receptors recognize Dd. However, there have been no studies that define specific sites on Ly-49G that mediate class I MHC recognition. The Ly-49G receptors of different inbred mouse strains can differ as a result of amino acid polymorphisms within their ectodomains. In this report, we have generated a novel antibody, CK-1, which recognizes Ly-49G(B6) and a Ly-49G(B6)-like receptor, Ly-49M(nonobese diabetic), but not Ly-49G(BALB/c). By exploiting the differences within ectodomains of C57BL/6 and BALB/c Ly-49G allele products, we identified epitopes recognized by the Ly-49G-specific antibodies CK-1 and Cwy-3, whose epitopes mapped within the beta4-beta5 loop and the beta1 strand, respectively, and were nonoverlapping. Although both antibodies specifically recognized the Ly-49G(B6) ectodomain, Cwy-3 was unable to block its interaction with MHC I, and CK-1 significantly inhibited it. The importance of residues within the beta4-beta5 loop in Ly-49G recognition demonstrates that its interaction with MHC I is similar to that of Ly-49A but not Ly-49C.

Requirement for Q226, but not multiple charged residues, in the class I MHC CD loop/D strand for TCR-activated CD8 accessory function.

Activation of CD8+ cytotoxic T lymphocytes typically begins with recognition of class I MHC-peptide complexes by the TCR and CD8 as a coreceptor. In its coreceptor role, CD8 binds thesame class I-peptide antigen complex as the TCR, enhancing the strength of TCR-class I interaction. Subsequent to initial TCR engagement, CD8 acts as an accessory molecule by binding any properly conformed class I molecules on the target cell surface, leading to CD8-mediated adhesion and cosignaling functions. We expressed and isolated a number of mutant class I molecules in which one or moreacidic or polar residues in the class I alpha3 domain CD loop and D strand region, or alpha2 domain were altered. Using solid phase CTL adhesion and degranulation assays with isolated class I molecules, we demonstrate that multiple acidic residues in the alpha3 domain, although involved in CD8 coreceptor interaction, are not required for TCR-activated CD8 accessory interactions. Instead, we show that Q226, a polar group on the end of the CD loop, is required for TCR-activated CD8 accessory functions. These results indicate that CD8 coreceptor and accessory interactions differ substantially and suggest that TCR activation results in changes that alter the structural constraints for CD8 accessory interactions.