There is currently an unmet need for better biomarkers across the spectrum of renal diseases. In this paper, we revisit the role of beta-2 microglobulin (β2M) as a biomarker in patients with chronic kidney disease and end-stage renal disease. Prior to reviewing the numerous clinical studies in the area, we describe the basic biology of β2M, focusing in particular on its role in maintaining the serum albumin levels and reclaiming the albumin in tubular fluid through the actions of the neonatal Fc receptor. Disorders of abnormal β2M function arise as a result of altered binding of β2M to its protein cofactors and the clinical manifestations are exemplified by rare human genetic conditions and mice knockouts. We highlight the utility of β2M as a predictor of renal function and clinical outcomes in recent large database studies against predictions made by recently developed whole body population kinetic models. Furthermore, we discuss recent animal data suggesting that contrary to textbook dogma urinary β2M may be a marker for glomerular rather than tubular pathology. We review the existing literature about β2M as a biomarker in patients receiving renal replacement therapy, with particular emphasis on large outcome trials. We note emerging proteomic data suggesting that β2M is a promising marker of chronic allograft nephropathy. Finally, we present data about the role of β2M as a biomarker in a number of non-renal diseases. The goal of this comprehensive review is to direct attention to the multifaceted role of β2M as a biomarker, and its exciting biology in order to propose the next steps required to bring this recently rediscovered biomarker into the twenty-first century.

Objective: There are few detailed data on cognition in patients undergoing dialysis. We evaluated the frequency of and risk factors for poor cognitive performance using detailed neurocognitive testing.Methods: In this cross-sectional cohort study, 314 hemodialysis patients from 6 Boston-area hemodialysis units underwent detailed cognitive assessment. The neuropsychological battery assessed a broad range of functions, with established age-, sex-, and education-matched normative scores. Principal component analysis was used to derive composite scores for memory and executive function domains. Risk factors for each domain were evaluated using linear regression adjusting for age, sex, race, and education status. Analyses were repeated in those with Mini-Mental State Examination (MMSE) score $24.Results: Compared with population norms, patients on dialysis had significantly poorer executive function but not memory performance, a finding that persisted in the subgroup with MMSE score $24. In adjusted analyses, vascular risk factors and vascular disease were associated with lower executive function (p , 0.01).Conclusions: There is a high frequency of poor cognitive performance in hemodialysis patients, primar- Cognitive impairment in dialysis is an increasingly important public health problem given the aging end-stage renal disease (ESRD) population and the increasing prevalence of diabetes and vascular disease. In older studies in hemodialysis patients, cognitive impairment, defined by poor performance on the Mini-Mental State Examination (MMSE), was present in 40% to 60%. 1-3 Despite the fact that the MMSE remains the most frequently used screening tool for cognitive impairment, it focuses on memory and largely neglects other cognitive domains such as executive function; accordingly, the MMSE may not be sufficient to detect more subtle degrees of cognitive impairment.The major causes of dementia in the general population are Alzheimer disease, which initially manifests with memory loss with later involvement of other cognitive domains, and vascular dementia, which primarily manifests with impairment in executive function. [4][5][6][7] Although it is likely that patients undergoing dialysis have similar causes for cognitive impairment as the general population, there are few studies that have attempted to distinguish the prevalence of and risk factors for each type of cognitive impairment in this population.The goals of this study were therefore to evaluate the frequency of and risk factors for poor cognitive performance in hemodialysis patients using detailed measures of multiple cognitive domains, From the Division of Nephrology (M.J.S., K

Background Although dialysis patients are at high risk for stroke and have a high burden of cognitive impairment, there are few reports on anatomic brain findings in the hemodialysis population. Using brain magnetic resonance imaging (MRI), we compared the prevalence of brain abnormalities in hemodialysis patients to a control population without known kidney disease. Study Design Cross-sectional cohort. Setting & Participants 45 maintenance hemodialysis patients and 67 controls without reported kidney disease, both without prior history of known stroke. Predictor The primary predictor was dialysis status. Covariates included demographics (age, race, sex), vascular risk factors (diabetes and hypertension) and cardiovascular disease (coronary artery disease, congestive heart failure). Outcomes Brain MRI features including severity of white matter disease and cerebral atrophy (sulcal prominence and ventricular atrophy), hippocampal size, and small/large vessel infarcts. Measurements Semi-quantitative scale (0-9 for white matter disease and cerebral atrophy, 0-3 for hippocampal size) and infarct prevalence. Results The mean age of hemodialysis patients and controls was 55 ± 17 (SD) and 53 ± 13 years, respectively. In comparison with controls, hemodialysis patients had more severe white matter disease (1.6 v 0.7) and cerebral atrophy (sulcal prominence = 2.3 v 0.6; ventricular enlargement = 2.3 v 0.9; hippocampal size = 1.3 v 1.0) with all p-values <0.001. In multivariable analyses, hemodialysis status was independently associated with worse white matter disease and atrophy grades. Hemodialysis patients also had a higher prevalence of small (17.8%) and large (7.8%) vessel infarcts than controls (combined 22% vs 0%, p<0.001). Limitations The dialysis cohort is likely healthier than the overall US hemodialysis population, partly limiting generalizability. Conclusions Hemodialysis patients have more white matter disease and cerebral atrophy compared to controls without known kidney disease. Hemodialysis patients also have a high prevalence of unrecognized infarcts.

Background Accurate assessment of kidney function is important for management of solid organ transplant recipients. In other clinical populations, glomerular filtration rate (GFR) is most commonly estimated using the CKD-EPI (Chronic Kidney Disease–Epidemiology Collaboration) creatinine or the 4-variable MDRD (Modification of Diet in Renal Disease) Study equation. The accuracy of these equations compared to other GFR estimating equations in transplant recipients has not been carefully studied. Study Design Diagnostic test study. Setting & Participants Solid organ transplant recipients >6 months post-transplantation from 5 clinical populations [N=3,622, including recipients of kidney (53%), liver (35%) and other or multiple organs (12%)] Index Test Estimated GFR (eGFR) using creatinine-based GFR estimating equations identified from a systematic review of the literature. Performance of the CKD-EPI creatinine and MDRD Study equations was compared to alternative equations. Reference Test Measured GFR (mGFR) from urinary clearance of iothalamate or plasma clearance of iohexol. Measurements Error (difference between the mGFR and eGFR) expressed as P30 (proportion of absolute percent error <30%) and mean absolute error. Results We identified 26 GFR estimating equations. Mean mGFR was 55.1 ± 22.7 (SD) ml/min/1.73 m2. P30 and mean absolute error for the CKD-EPI and MDRD Study equations were 78.9% (99.6% CI, 76.9%–80.8%) for both and 10.6 (99.6% CI, 10.1–11.1) vs. 11.0 (99.6% CI, 10.5–11.5) ml/min/1.73 m2, respectively; these equations were more accurate than any of the alternative equations (p<0.001 for all pair-wise comparisons for both measures). They performed better than or as well as the alternative equations in most subgroups defined by demographic and clinical characteristics, including the type of transplanted organ. Limitations Study population included few non-whites and people with solid organ transplants other than liver and kidneys. Conclusions The CKD-EPI creatinine and MDRD Study equations perform better than the alternative creatinine-based estimating equations in solid organ transplant recipients. They can be used for clinical management.

Background: There are limited data regarding the relationship between depression and mortality in hemodialysis (HD) patients. Methods: Among 323 patients receiving maintenance HD, depression symptoms were assessed using the Center for Epidemiologic Studies Depression (CES-D) scale, with a score of ≥16 consistent with depression. Adjusted Cox proportional-hazards models with additional analyses incorporating antidepressant medication use were used to evaluate the association between depression and mortality. Baseline CES-D scores were used for the primary analyses, while secondary time-dependent analyses incorporated subsequent CES-D results. Results: The mean age was 62.9 ± 16.5 years, 46% of the subjects were women and 22% were African-American. The mean baseline CES-D score was 10.7± 8.3, and 83 (26%) participants had CES-D scores ≥16. During a median (25th, 75th) follow-up of 25 (13, 43) months, 154 participants died. After adjusting for age, sex, race, primary cause of kidney failure, dialysis vintage and access, baseline depression was associated with an increased risk of all-cause mortality (HR 1.51 and 95% CI 1.06-2.17). This attenuated with further adjustment for cardiovascular disease, smoking, Kt/V, serum albumin, log C-reactive protein and use of antidepressants (HR 1.21 and 95% CI 0.82-1.80). When evaluating time-dependent CES-D, depression remained associated with increased mortality risk in the fully adjusted model (HR 1.44 and 95% CI 1.00-2.06). Conclusions: Greater symptoms of depression are associated with an increased risk of mortality in HD patients, particularly when accounting for the most proximate assessment. This relationship was attenuated with adjustment for comorbid conditions, suggesting a complex relationship between clinical characteristics and depression symptoms. Future studies should evaluate whether treatment for depression impacts mortality among HD patients.