Assessment of kidney function is clinical routine and part of every laboratory screening irrespective of medical discipline.
Kidney function in chronic kidney disease (CKD) correlates tightly with morbidity and mortality and has a great impact on quality of life (1,2). In addition, patients with CKD are predisposed to severe threats, especially cardiovascular disorders like atherosclerosis and myocardial infarction (MI) (3).
For decades, the assessment of kidney function has mainly been based on determination of serum creatinine and creatinine-based equations to assess GFR. However, it is increasingly recognized that this marker is neither perfect nor accurate (4). This highlights the clinical necessity for new biomarkers and equations based on other cost-effective biomarkers, especially for a longitudinal monitoring of kidney function in patients with CKD.
With respect to the great variety of pathological entities leading to CKD identification of a single biomarker, which provides a specific and reliable non-invasive measurement with minimal confounders might appear utopian.
This review therefore gives an updated overview about new and conventional filtration markers and introduces new biomarkers with special attention to cardiovascular disorders in patients with CKD.
Assessment of kidney function based on new and conventional filtration markers
Over the past years, several endogenous markers of kidney function have been introduced. Of those, the most intensively investigated biomarkers are beta-trace protein (BTP), cystatin C and beta-2 microglobulin (B2MG) (5-8).
They are low-molecular-weight proteins (BTP, 23–29 kDa; cystatin C, 13.3 kDa; B2MG, 11.8 kDa) which accumulate in serum if renal function declines. Compared to creatinine, they have been shown to be influenced less by age, sex, race and muscle mass (9).
BTP has a minimal non-renal elimination (10). However, this study was published in 1973 and included only four patients. In contrast, cystatin C shows a considerable non-renal clearance of 22.3 mL/min/1.73 m2 and thus greatly overestimates renal clearance in advanced renal failure (11,12). B2MG is filtered by the kidney, but is also increased in acute and chronic inflammation, malnutrition and malignancy (13).
Albeit these biomarkers appear to be at least partially superior to creatinine, all of them have serious confounders or are poorly investigated, which limit their ability to predict kidney function in clinical routine. In summary, determination of a single biomarker certainly does not fit every pathology. Since invasive measurement of GFR is not feasible, it has to be estimated based on endogenous biomarkers. Several investigations addressed this issue recently.
Routinely estimated GFR (eGFR) is still based solely on serum creatinine, although it has been reported that the addition of cystatin C improves the accuracy of GFR estimation compared to equations based on single biomarkers (14,15). Furthermore, equations based on cystatin C combined with creatinine seem to fortify the association between a declining eGFR and cardiovascular diseases (16).
To close this gap, a recent study by Inker et al. developed GFR equations based on serum BTP and B2MG in a cohort derived from three study populations with CKD (9). Even though these equations might not be superior for determination of kidney function at a time, predictive assessment based on filtration markers at multiple time points may improve the prediction of clinical outcomes over a single measurement (19). An observational analysis of two trials tested the predictive value of the change in eGFR either creatinine-based or using BTP, B2MG and cystatin C along with invasive measurement of GFR for end-stage renal disease (ESRD) and mortality in a 12- and 24-month follow-up. A decline in eGFR (BTP) was associated more strongly with the risk for ESRD than invasively measured GFR. This leads to the assumption, that BTP potentially shows a predictive value for ESRD and might be a valuable tool for repeated assessment of kidney function.
Two recently published equations based on B2MG have been suggested for assessment of residual kidney function in hemodialysis patients (11,20). The first claims an equation combining serum B2MG and BTP for estimation of residual kidney function in patients undergoing hemodialysis, the latter provides an equation based solely on B2MG.
Biomarkers in CKD related diseases
Soluble fms-like tyrosine kinase (sFlt-1)
Primarily, the sFlt-1 was found to be a biomarker for preeclampsia in pregnant women (22,23). sFlt-1 is a soluble isoform of the Flt-1 receptor which plays an important role in the development of atherosclerotic disease. After binding with placental growth factor (PlGF) on the epithelial cell Flt-1 promotes atherosclerotic processes by mediating intramural angiogenesis and release of proinflammatory cytokines (24,25). sFlt-1, a product of splicing Flt-1 mRNA binds to PlGF inhibiting the Flt-1/PlGF-pathway and therefore inducing an antiangiogenic state (26). Elevated levels of sFlt-1 in CKD patients were associated with endothelial dysfunction and subsequently with cardiovascular mortality (27-29). This even seems to be apparent in patients undergoing haemodialysis (HD) (30). Matsui et al. showed that plasma sFlt-1 levels are higher in patients with CKD. Surprisingly, this changed after intravenous heparin injection. While sFlt-1 serum levels rose in all 343 subjects, peak concentrations were significantly lower in the 291 CKD patients (eGFR below 60 mL/min per 1.73 m2 and/or continuous proteinuria over 3 months) compared to patients in the control group. Furthermore, higher postheparin PlGF/sFlt-1 ratio was associated with significantly higher incidence of cardiovascular events during a roughly 6 months median follow-up period. However, this was not the case for PlGF/sFlt-1 ratio before heparin injection (31). As mentioned above, previous studies have shown high sFlt-1 plasma levels being associated with increased mortality in renal failure suggesting an increased production in endothelial cells (32,33). In an experimental mouse model sFlt-1 mRNA expression was reduced in nephrectomized mice compared to wild-type mice. sFlt-1 was stored on endothelial cells and was released following heparin treatment. In vitro experiments with cultured human endothelial cells support these findings and reveal that sFlt-1 is reduced in presence of endothelial damage markers. Therefore, sFlt-1 production seems to decline with a reduction in eGFR, while sFlt-1 plasma levels rise (31). The release of sFlt-1 by heparin replacing it from its binding site from heparan sulfate proteoglycans was previously shown (34). However, Matsui et al. showed that the postheparin sFlt-1 levels reflect its overall production and thus could be a biomarker to estimate cardiovascular mortality (31,35).
High sensitive troponin (hsTn)
As descried above patients with renal impairment are in greater risk of dying from MI. Even in early-stage CKD risk of long-term cardiovascular death after acute MI is higher compared to patients with preserved renal function (36). In recent years, hsTn has shown to have diagnostic and prognostic utility in acute MI (37,38). However, patients with CKD were often excluded in those studies. Elevated levels of cardiac troponin in those patients can occur not only in MI but also in other cardiac diseases as well as noncardiac diseases (39). Ballocca et al. analysed data from seven different centres over a 2-year period. Overall 647 patients with an eGFR below 60 mL/min/m2 were admitted into the emergency room with suspected acute MI. hsTnI or hsTnT levels were assessed before coronary angiography as well as 3 and 6 hours after admission. Seventy-eight percent of the patients were treated with percutaneous transluminal angioplasty. Both hsTnI and hsTnT peak levels were predictive for short-term all cause death with hsTnI being more accurate than hsTnT in detecting coronary disease (40). Those findings are in contrast to previous studies that showed hsTnT as a poor marker for detecting acute MI in patients with renal failure (41).
Profiling of inflammatory biomarkers
Increased mortality in patients with CKD is attributed to inflammation. This is reflected by investigations suggesting cytokines and chemokines as new biomarkers. In the Chronic Renal Insufficiency Cohort (CRIC) study in 2012, kidney function was inversely associated with serum levels of proinflammatory biomarkers (IL-1β, IL-1 receptor antagonist, IL-6, TNF-α, CRP, and fibrinogen) and positively with albuminuria (42). This association is even highlighted by a recently published study in a cohort of diabetics with kidney disease (43). Here, TNF-receptor 1 and TNF-receptor 2 as well as kidney injury molecule-1 (KIM-1) were independently associated with higher risk of decline in eGFR. Importantly, these results were validated in a cohort of incident diabetic kidney disease and a cohort of patients with progressive diabetic kidney disease implying that these biomarkers might serve as good predictors for the progression of CKD, at least in patients suffering from diabetes.
With regard to the association of CKD and cardiovascular disorders, evidence suggests an influence of uremic toxins on cardiovascular morbidity and mortality by activation of leukocytes and enhancement of monocyte-endothelial interactions, which has been reviewed elsewhere (44).
Addressing this issue, a recently published study on 14 individuals of a CKD cohort investigated arterial wall inflammation in aorta and carotid arteries by PET/CT imaging. The CKD cohort displayed an increase in arterial wall inflammation, chemokine receptor expression and transepithelial migration capacity compared to the control cohort (45). Since severe confounders like body mass index (BMI), blood pressure and plasma cholesterols were comparable between the CKD and control cohort, the data is convincing. However, no definite conclusions of the contribution of CKD on arterial wall inflammation can be drawn so far.
Soluble urokinase plasminogen activator receptor (suPAR)
Recently published data shed light on the association of gene variants of apolipoprotein L1 (APOL1), suPAR (a member of a signaling protein family and a marker for immune activation) (46-48) and αvβ3 integrin (49).
Gene variants in the APOL1 gene of individuals of African ancestry (50-54) have been described to be associated with distinct forms of CKD. Irrespective of this, measurement of plasma levels of suPAR (55) identified a tight association between elevated level of suPAR and incident CKD as well as an accelerated decline of eGFR. Podocytes express αvβ3 integrin, which has been suggested as a suPAR binding molecule regulating the glomerular filtration barrier (56-60). This study investigated a putative pathophysiological link between podocyte dysfunction, suPAR levels and APOL1 gene variants.
They demonstrated higher levels of suPAR modifying the association between APOL1 genotype and eGFR decline in two cohorts of African American individuals. Further, individuals with APOL1 risk genotype revealed an even steeper decline in eGFR. This effect was suggested to be mediated by protein-protein binding of APOL1 and suPAR as well as between APOL1 and αvβ3 integrin on podocytes. This tripartite complex leads to activation of the αvβ3 integrin pathway on podocytes resulting in dysregulation of the cytoskeleton and cell detachment. Importantly, only risk variants of APOL1 synergize with suPAR allowing complex formation with αvβ3 integrin on podocytes. These results are underlined by data generated in mice models where expression of APOL1 risk alleles is causal for altered podocyte function and glomerular disease in vivo. Expression of the risk-variant APOL1 alleles led to inflammatory-mediated podocyte death and glomerular scarring (61).
Conclusions and perspectives
We have presented an update on biomarkers for the assessment of kidney function with focus on cardiovascular diseases. Due to the great variety, only a small excerpt of available biomarkers could be reviewed here (Table 1). We pointed out, that until now no biomarker appears to be particularly suitable in clinical routine. The biggest challenge might be to identify biomarkers and equations, which are cost-effective, reliable and beneficial for the assessment of kidney function. Insights in pathophysiological mechanisms will allow more accurate choices of biomarkers for specific populations.
Conflicts of Interest: The authors have no conflicts of interest to declare.
- GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2015;385:117-71. [Crossref] [PubMed]
- Rhee CM, Kovesdy CP. Epidemiology: Spotlight on CKD deaths-increasing mortality worldwide. Nat Rev Nephrol 2015;11:199-200. [Crossref] [PubMed]
- Shastri S, Sarnak MJ. Cardiovascular disease and CKD: core curriculum 2010. Am J Kidney Dis 2010;56:399-417. [Crossref] [PubMed]
- Stevens LA, Coresh J, Greene T, et al. Assessing kidney function--measured and estimated glomerular filtration rate. N Engl J Med 2006;354:2473-83. [Crossref] [PubMed]
- White CA, Akbari A. The estimation, measurement, and relevance of the glomerular filtration rate in stage 5 chronic kidney disease. Semin Dial 2011;24:540-9. [Crossref] [PubMed]
- Filler G, Priem F, Lepage N, et al. Beta-trace protein, cystatin C, beta(2)-microglobulin, and creatinine compared for detecting impaired glomerular filtration rates in children. Clin Chem 2002;48:729-36. [PubMed]
- Juraschek SP, Coresh J, Inker LA, et al. Comparison of serum concentrations of beta-trace protein, beta2-microglobulin, cystatin C, and creatinine in the US population. Clin J Am Soc Nephrol 2013;8:584-92. [Crossref] [PubMed]
- Bhavsar NA, Appel LJ, Kusek JW, et al. Comparison of measured GFR, serum creatinine, cystatin C, and beta-trace protein to predict ESRD in African Americans with hypertensive CKD. Am J Kidney Dis 2011;58:886-93. [Crossref] [PubMed]
- Inker LA, Tighiouart H, Coresh J, et al. GFR Estimation Using beta-Trace Protein and beta2-Microglobulin in CKD. Am J Kidney Dis 2016;67:40-8. [Crossref] [PubMed]
- Olsson JE, Link H, Nosslin B. Metabolic studies on 125I-labelled beta-trace protein, with special reference to synthesis within the central nervous system. J Neurochem 1973;21:1153-9. [Crossref] [PubMed]
- Vilar E, Boltiador C, Wong J, et al. Plasma Levels of Middle Molecules to Estimate Residual Kidney Function in Haemodialysis without Urine Collection. PLoS One 2015;10:e0143813. [Crossref] [PubMed]
- Vilar E, Boltiador C, Viljoen A, et al. Removal and rebound kinetics of cystatin C in high-flux hemodialysis and hemodiafiltration. Clin J Am Soc Nephrol 2014;9:1240-7. [Crossref] [PubMed]
- Poge U, Gerhardt T, Stoffel-Wagner B, et al. Beta-trace protein-based equations for calculation of GFR in renal transplant recipients. Am J Transplant 2008;8:608-15. [Crossref] [PubMed]
- Inker LA, Schmid CH, Tighiouart H, et al. Estimating glomerular filtration rate from serum creatinine and cystatin C. N Engl J Med 2012;367:20-9. [Crossref] [PubMed]
- Anderson AH, Yang W, Hsu CY, et al. Estimating GFR among participants in the Chronic Renal Insufficiency Cohort (CRIC) Study. Am J Kidney Dis 2012;60:250-61. [Crossref] [PubMed]
- Shlipak MG, Matsushita K, Arnlov J, et al. Cystatin C versus creatinine in determining risk based on kidney function. N Engl J Med 2013;369:932-43. [Crossref] [PubMed]
- White CA, Akbari A, Doucette S, et al. Estimating GFR using serum beta trace protein: accuracy and validation in kidney transplant and pediatric populations. Kidney Int 2009;76:784-91. [Crossref] [PubMed]
- White CA, Akbari A, Doucette S, et al. Effect of clinical variables and immunosuppression on serum cystatin C and beta-trace protein in kidney transplant recipients. Am J Kidney Dis 2009;54:922-30. [Crossref] [PubMed]
- Rebholz CM, Inker LA, Chen Y, et al. Risk of ESRD and Mortality Associated With Change in Filtration Markers. Am J Kidney Dis 2017;70:551-60. [Crossref] [PubMed]
- Wong J, Sridharan S, Berdeprado J, et al. Predicting residual kidney function in hemodialysis patients using serum beta-trace protein and beta2-microglobulin. Kidney Int 2016;89:1090-8. [Crossref] [PubMed]
- Go AS, Chertow GM, Fan D, et al. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004;351:1296-305. [Crossref] [PubMed]
- Levine RJ, Maynard SE, Qian C, et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 2004;350:672-83. [Crossref] [PubMed]
- Anderson UD, Olsson MG, Kristensen KH, et al. Review: Biochemical markers to predict preeclampsia. Placenta 2012;33 Suppl:S42-7. [Crossref] [PubMed]
- Khurana R, Moons L, Shafi S, et al. Placental growth factor promotes atherosclerotic intimal thickening and macrophage accumulation. Circulation 2005;111:2828-36. [Crossref] [PubMed]
- Lee HK, Chauhan SK, Kay E, et al. Flt-1 regulates vascular endothelial cell migration via a protein tyrosine kinase-7-dependent pathway. Blood 2011;117:5762-71. [Crossref] [PubMed]
- Palmer KR, Kaitu'u-Lino TJ, Hastie R, et al. Placental-Specific sFLT-1 e15a Protein Is Increased in Preeclampsia, Antagonizes Vascular Endothelial Growth Factor Signaling, and Has Antiangiogenic Activity. Hypertension 2015;66:1251-9. [PubMed]
- Maynard SE, Min JY, Merchan J, et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest 2003;111:649-58. [Crossref] [PubMed]
- Di Marco GS, Reuter S, Hillebrand U, et al. The soluble VEGF receptor sFlt1 contributes to endothelial dysfunction in CKD. J Am Soc Nephrol 2009;20:2235-45. [Crossref] [PubMed]
- Stam F, van Guldener C, Becker A, et al. Endothelial dysfunction contributes to renal function-associated cardiovascular mortality in a population with mild renal insufficiency: the Hoorn study. J Am Soc Nephrol 2006;17:537-45. [Crossref] [PubMed]
- Yuan J, Guo Q, Qureshi AR, et al. Circulating vascular endothelial growth factor (VEGF) and its soluble receptor 1 (sVEGFR-1) are associated with inflammation and mortality in incident dialysis patients. Nephrol Dial Transplant 2013;28:2356-63. [Crossref] [PubMed]
- Matsui M, Takeda Y, Uemura S, et al. Suppressed soluble Fms-like tyrosine kinase-1 production aggravates atherosclerosis in chronic kidney disease. Kidney Int 2014;85:393-403. [Crossref] [PubMed]
- Guo Q, Carrero JJ, Yu X, et al. Associations of VEGF and its receptors sVEGFR-1 and -2 with cardiovascular disease and survival in prevalent haemodialysis patients. Nephrol Dial Transplant 2009;24:3468-73. [Crossref] [PubMed]
- Gruson D, Hermans MP, Ferracin B, et al. Sflt-1 in heart failure: relation with disease severity and biomarkers. Scand J Clin Lab Invest 2016;76:411-6. [Crossref] [PubMed]
- Searle J, Mockel M, Gwosc S, et al. Heparin strongly induces soluble fms-like tyrosine kinase 1 release in vivo and in vitro--brief report. Arterioscler Thromb Vasc Biol 2011;31:2972-4. [Crossref] [PubMed]
- Onoue K, Uemura S, Takeda Y, et al. Reduction of circulating soluble fms-like tyrosine kinase-1 plays a significant role in renal dysfunction-associated aggravation of atherosclerosis. Circulation 2009;120:2470-7. [Crossref] [PubMed]
- Nagashima M, Hagiwara N, Koyanagi R, et al. Chronic kidney disease and long-term outcomes of myocardial infarction. Int J Cardiol 2013;167:2490-5. [Crossref] [PubMed]
- Li WJ, Chen XM, Nie XY, et al. Early diagnostic and prognostic utility of high-sensitive troponin assays in acute myocardial infarction: a meta-analysis. Intern Med J 2015;45:748-56. [Crossref] [PubMed]
- Reichlin T, Hochholzer W, Bassetti S, et al. Early diagnosis of myocardial infarction with sensitive cardiac troponin assays. N Engl J Med 2009;361:858-67. [Crossref] [PubMed]
- Flores-Solis LM, Hernandez-Dominguez JL. Cardiac troponin I in patients with chronic kidney disease stage 3 to 5 in conditions other than acute coronary syndrome. Clin Lab 2014;60:281-90. [PubMed]
- Ballocca F, D'Ascenzo F, Moretti C, et al. High sensitive TROponin levels In Patients with Chest pain and kidney disease: A multicenter registry - The TROPIC study. Cardiol J 2017;24:139-50. [Crossref] [PubMed]
- Pfortmueller CA, Funk GC, Marti G, et al. Diagnostic performance of high-sensitive troponin T in patients with renal insufficiency. Am J Cardiol 2013;112:1968-72. [Crossref] [PubMed]
- Gupta J, Mitra N, Kanetsky PA, et al. Association between albuminuria, kidney function, and inflammatory biomarker profile in CKD in CRIC. Clin J Am Soc Nephrol 2012;7:1938-46. [Crossref] [PubMed]
- Coca SG, Nadkarni GN, Huang Y, et al. Plasma Biomarkers and Kidney Function Decline in Early and Established Diabetic Kidney Disease. J Am Soc Nephrol 2017;28:2786-93. [Crossref] [PubMed]
- Moradi H, Sica DA, Kalantar-Zadeh K. Cardiovascular burden associated with uremic toxins in patients with chronic kidney disease. Am J Nephrol 2013;38:136-48. [Crossref] [PubMed]
- Bernelot Moens SJ, Verweij SL, van der Valk FM, et al. Arterial and Cellular Inflammation in Patients with CKD. J Am Soc Nephrol 2017;28:1278-85. [Crossref] [PubMed]
- Thunø M, Macho B, Eugen-Olsen J. suPAR: the molecular crystal ball. Dis Markers 2009;27:157-72. [Crossref] [PubMed]
- Sidenius N, Ullum H, Pedersen BK, et al. Serum level of soluble urokinase-type plasminogen activator receptor is a strong and independent predictor of survival in human immunodeficiency virus infection. Blood 2000;96:4091-5. [PubMed]
- Ostrowski SR, Høyer-Hansen G, Gerstoft J, et al. High Plasma Levels of Intact and Cleaved Soluble Urokinase Receptor Reflect Immune Activation and Are Independent Predictors of Mortality in HIV-1–Infected Patients. J Acquir Immune Defic Syndr 2005;39:23-31. [Crossref] [PubMed]
- Hayek SS, Koh KH, Grams ME, et al. A tripartite complex of suPAR, APOL1 risk variants and alphavbeta3 integrin on podocytes mediates chronic kidney disease. Nat Med 2017;23:945-53. [PubMed]
- Chen TK, Estrella MM, Parekh RS. The evolving science of apolipoprotein-L1 and kidney disease. Curr Opin Nephrol Hypertens 2016;25:217-25. [Crossref] [PubMed]
- Tzur Shay SR, Shemer Revital, Yudkovsky Guennady, et al. Missense mutations in the APOL1 gene are highly associated with end stage kidney disease risk previously attributed to the MYH9 gene. Hum Genet 2010;128:345-50. [Crossref] [PubMed]
- Genovese G, Friedman DJ, Ross MD, et al. Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science 2010;329:841-5. [Crossref] [PubMed]
- Kao WH, Klag MJ, Meoni LA, et al. MYH9 is associated with nondiabetic end-stage renal disease in African Americans. Nat Genet 2008;40:1185-92. [Crossref] [PubMed]
- Parsa A, Kao WH, Xie D, et al. APOL1 risk variants, race, and progression of chronic kidney disease. N Engl J Med 2013;369:2183-96. [Crossref] [PubMed]
- Hayek SS, Sever S, Ko YA, et al. Soluble Urokinase Receptor and Chronic Kidney Disease. N Engl J Med 2015;373:1916-25. [Crossref] [PubMed]
- Alfano M, Cinque P, Giusti G, et al. Full-length soluble urokinase plasminogen activator receptor down-modulates nephrin expression in podocytes. Sci Rep 2015;5:13647. [Crossref] [PubMed]
- Borza CM, Borza DB, Pedchenko V, et al. Human podocytes adhere to the KRGDS motif of the alpha3 alpha4 alpha5 collagen IV network. J Am Soc Nephrol 2008;19:677-84. [Crossref] [PubMed]
- Reiser J, Sever S. Podocyte biology and pathogenesis of kidney disease. Annu Rev Med 2013;64:357-66. [Crossref] [PubMed]
- Reiser J, Wei C, Tumlin J. Soluble urokinase receptor and focal segmental glomerulosclerosis. Curr Opin Nephrol Hypertens 2012;21:428-32. [Crossref] [PubMed]
- Wei C, Moller CC, Altintas MM, et al. Modification of kidney barrier function by the urokinase receptor. Nat Med 2008;14:55-63. [Crossref] [PubMed]
- Beckerman P, Bi-Karchin J, Park AS, et al. Transgenic expression of human APOL1 risk variants in podocytes induces kidney disease in mice. Nat Med 2017;23:429-38. [Crossref] [PubMed]
Cite this article as: Schwab S, Marwitz T, Woitas RP. The role of prognostic assessment with biomarkers in chronic kidney disease: a narrative review. J Lab Precis Med 2018;3:12.