Table 1.
Research studies on biomarkers of renal function and main outcomes in CKD patients.
| Year | Study Type | Study Population | Biomarker (s) | Study Outcomes | Reference |
|---|---|---|---|---|---|
| 2015 | Prospective cohort | 9703 participants from the ARIC | serum B2M | Greater than 30% decline in B2M may be less common, but appears to be more specific for ESRD than equivalent changes in eGFR based on serum creatinine | [24] |
| 2015 | Prospective cohort | 250 Pima Indians with T2D | serum BTP, B2M | BTP and to a lesser extent B2M were associated with ESRD; only higher serum concentrations of B2M were associated with increased mortality risk in this population | [22] |
| 2015 | Cross-sectional | 93 CKD patients at stages 1–5 | urinary klotho | Decreased tubular phosphate reabsorption was associated with decreased eGFR, but it was not associated with urinary klotho levels | [39] |
| 2016 | Cross-sectional | 355 CKD patients, classified in the different stages of CKD | urinary BTP | BTP is present in the urine of patients with normal GFR, and its urinary excretion progressively increases along with the reduction of GFR; clearance of BTP progressively increases with the reduction of GFR | [16] |
| 2016 | Cross-sectional | 109 CKD patients with T2D and 32 healthy controls | serum klotho | Serum klotho levels were significantly elevated in diabetic patients; klotho levels decreased with increasing albumin excretion | [33] |
| 2016 | Retrospective cohort | 3551 participants with CKD from MDRD, AASK and CRIC studies | serum BTP, B2M | BTP and B2M are less influenced by age, sex and race than creatinine and less influenced by race than cystatin C, but provide less accurate GFR estimates | [10] |
| 2016 | Prospective cohort | 3613 adults from the CRIC study | serum BTP, B2M | BTP and B2M were independent predictors of ESRD and all-cause mortality, but only B2M was an independent predictor cardiovascular events | [40] |
| 2017 | Prospective cohort | 2496 participants from the Health Aging and Body Composition study | serum klotho | Higher klotho levels were associated with lower odds of kidney function decline, but not with incident CKD | [41] |
| 2017 | Cross-sectional | 50 individuals with type 2 diabetes and 25 healthy controls | serum BTP | BTP level was significantly higher in T2Dwith the microalbuminuria group than T2DM with normoalbuminuria and control groups | [18] |
| 2017 | Cross-sectional | 566 individuals aged 70+ from the Berlin Initiative Study | serum BTP | Combination of creatinine, cystatin C and BTP showed the best prediction of GFR; single usage of BTP showed the worst prediction within models with only one biomarker | [42] |
| 2017 | Prospective cohort | 317 participants from MDRD and 373 from AASK | serum BTP, B2M | Declines in eGFR based on the average of four filtration markers (creatinine, cystatin C, BTP, and B2M) were consistently associated with progression to ESRD; only the decline in eGFR-BTP was significantly more strongly associated with ESRD risk | [23] |
| 2017 | Meta-analysis | 23,318 individuals from six different studies | serum BTP, B2M | eGFR-BTP, eGFR-B2M, and their average showed stronger risk associations with ESRD and all-cause mortality when compared with eGFRcr | [27] |
| 2017 | Cross-sectional | Elderly participants from the AGES-Kidney study (683) and the MESA-Kidney (273) | serum BTP, B2M | eGFR-cys, eGFR-B2M and eGFR-BTP had significantly less strong residual associations with age and sex than eGFRcr | [11] |
| 2018 | Cross-sectional | 125 maintenance hemodialysis patients | serum klotho | Klotho levels were associated with the degree of bone mineral density; osteoporosis groups presented lower levels than the normal bone mass group | [37] |
| 2018 | Prospective cohort | 112 adults with stages 1–5 CKD | serum klotho | Klotho levels were positively associated with baseline eGFR; reduction in klotho levels was associated with renal function decline | [31] |
| 2018 | Cross-sectional | 150 patients with CKD at stages 1–4 and 50 healthy controls | serum BTP | Increased BTP concentrations in CKD patients are highly significantly correlated with the concentrations of Cr and Cys; BTP had a higher value of correlation with mGFR | [17] |
| 2018 | Systematic review and meta-analysis | 9 publications, comprising 1457 CKD patients | serum klotho | There was a positive correlation between serum klotho levels and eGFR; no significant correlations were found between serum klotho levels and calcium and phosphorus circulating levels | [32] |
| 2018 | Cross-sectional | 566 individuals aged 70+ from the Berlin Initiative Study | serum BTP | The addition of BTP to serum creatinine-based eGFR equations does not result in the same improvement as the addition of Cys | [25] |
| 2018 | Cross-sectional | 50 healthy term neonates | serum BTP | BTP concentrations were positively associated with the concentrations of serum Cr level; inverse serum BTP is associated with estimated GFR level among neonates | [43] |
| 2019 | Prospective cohort | 86 adults with stable CKD | serum BTP, B2M | The addition of BTP/B2M eGFR to Cr/cysC eGFR equations did not improve GFR estimation | [26] |
| 2019 | Systematic Review and Meta-analysis | 8 cohort studies with 3586 participants | serum klotho | Klotho levels were positively correlated with the eGFR; lower klotho levels were significantly associated with an increased risk of poor kidney outcomes | [44] |
| 2019 | Prospective cohort | 107 diabetic patients with CKD at stages 2 and 3 | serum klotho | Lower levels of klotho were associated with cardiac pathological changes and higher CVD risk | [34] |
| 2019 | Prospective cohort | 79 CKD patients on hemodialysis | serum klotho | Lower klotho levels were associated with the risk of CVD, independently from factors associated with mineral bone disease | [35] |
| 2019 | Cross-sectional | 286 CKD patients at stages 2–5 | serum klotho | The serum levels of inflammatory markers were negatively associated with klotho levels | [36] |
| 2019 | Cross-sectional | 152 patients with CKD at stages 3–5 and 30 healthy controls | serum klotho | eGFR reduction was associated with decreased klotho levels; serum phosphate levels were negatively associated with klotho levels | [38] |
| 2020 | Cross-sectional | 1066 participants with Cr and Cys and 666 with all 4 markers | serum BTP, B2M | eGFR-B2M and eGFR-BTP were not more accurate than eGFR-cr and eGFR-cys; accuracy was significantly better for the eGFR equation considering the four markers when compared to eGFRcr-cys equation | [15] |
| 2020 | Prospective cohort | 830 Chinese CKD patients | serum B2M | The B2M equation had smaller bias in the subgroup of GFR 60–89 mL/min/1.73 m2, but a larger bias and worse precision and accuracy in the subgroup of GFR > 90 mL/min/1.73 m2 when compared to the CKD-EPI equation | [45] |
| 2020 | Cross-sectional | 1793 patients from the KNOW-CKD study | serum klotho | Decreased klotho levels correlated negatively with phosphate levels and with the degree of proteinuria | [46] |
Abbreviations: AASK, African American Study of Kidney Disease and Hypertension; AGES, Age, Gene/Environment Susceptibility; ARIC, Atherosclerosis Risk in Communities; B2M, beta-2 microglobulin; BTP, beta trace protein; CKD, chronic kidney disease; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; Cr, creatinine; CRIC, Chronic Renal Insufficiency Cohort; CVD, Cardiovascular disease; Cys, cystatin C; eGFR, estimated glomerular filtration rate; ESRD, End-stage renal disease MDRD, Modification of Diet in Renal Disease; MESA, Multi-Ethnic Study of Atherosclerosis; mGFR, measured glomerular filtration rate; T2D, type 2 diabetes.