Potential |
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Biomarkers of tubular damage |
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Plasma KIM-1, TNFR-1, and TNFR-2 |
Coca et al. [77] |
Nested case-control study (n=380) |
T2DM |
Doubling in KIM-1, TNFR-1, and TNFR-2 levels were associated with higher risk of eGFR decline |
Treatment arm, baseline eGFR, albuminuria, age, race, systolic and diastolic blood pressure, medications |
Prospective cohort study (n=1,156) |
T1DM and T2DM |
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Plasma KIM-1, TNFR-1, TNFR-2, and MCP-1 |
Schrauben et al. [78] |
Case-cohort study (n=894) |
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Higher plasma levels of KIM-1, TNFR-1, TNFR-2, and MCP-1 were associated with risk of progression of DKD |
Age, sex, race/ethnicity, education, clinical center, systolic and diastolic blood pressure, BMI, hsCRP, HbA1c, antihypertensive medication use, smoking status, baseline eGFR, and UPCR |
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Urinary KIM-1 and NGAL |
de Carvalho et al. [79] |
Cross-sectional study (n=117) |
T2DM |
Urinary KIM-1 and NGAL were increased in T2DM patients with normal or mildly increased albuminuria |
HbA1c, LDL cholesterol, fasting glucose, and medication |
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Urinary NGAL |
Yuruk Yildirim et al. [80] |
Cross-sectional study (n=111) |
T1DM |
Urinary NGAL level increase in the early phase of T1DM before microalbuminuria development |
No adjustments |
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Serum NGAL |
Lacquaniti et al. [81] |
Cross-sectional study (n=85) |
T1DM |
NGAL increases in patients with T1DM before onset of microalbuminuria |
No adjustments |
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Urinary L-FABP |
Nielsen et al. [82] |
Prospective cohort study (n=165) |
T1DM |
High levels of urinary L-FABP predict the initiation and progression to DKD and all- cause mortality |
Age, sex, HbA1c, systolic and diastolic blood pressure, albuminuria, serum creatinine, smoking |
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Urinary L-FABP |
Panduru et al. [84] |
Prospective cohort study (n=1,549) |
T1DM |
High urinary L-FABP levels were found to be a strong and independent predictor of DKD progression |
Risk factors of DKD and albuminuria |
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Urinary cystatin C |
Kim et al. [85] |
Prospective cohort study (n=237) |
T2DM |
Urinary cystatin C and albuminuria may be sensitive and specific markers for predicting kidney impairment |
Age, HbA1c, systolic blood pressure, uric acid, albuminuria, baseline eGFR, use of RAS inhibitors and lipid-lowering agents, serum cystatin C |
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Biomarkers of inflammation |
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Plasma TNF-α, TNFR1, TNFR2 |
Niewczas et al. [89] |
Prospective cohort study (n=410) |
T2DM |
Elevated circulating TNFR levels are strong predictors of progression to ESKD in subjects with and without proteinuria |
Age, HbA1c, albuminuria, eGFR |
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Serum TNFR |
Skupien et al. [90] |
Prospective cohort study (n=349) |
T1DM |
Circulating TNFR2 is a major determinant of kidney function decline |
No adjustments |
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Serum TNFR1, TNFR2, E-selectin |
Lopes-Virella et al. [91] |
Prospective cohort study (n=1,237) |
T1DM |
High levels of E-selectin and soluble TNFR1 and TNFR2 levels were important predictors of incident albuminuria |
Treatment, albuminuria, use of RAS inhibitors, baseline retinopathy, sex, age, HbA1c, diabetes duration |
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Biomarkers of oxidative stress |
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Urinary 8-OHdG |
Xu et al. [93] |
Cross-sectional study (n=69) |
T2DM |
Individuals with T2DM have higher levels of 8-OHdG compared to healthy individuals |
No adjustments |
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Plasma 8-OHdG |
Sanchez et al. [94] |
Prospective cohort study (n=704) |
T1DM |
Higher levels of 8-OHdG were associated with increased risk of kidney disease |
Age, sex, cohort, duration of diabetes, HbA1c, insulin therapy, systolic blood pressure, use of antihypertensive drugs, RAS inhibitors, diabetic retinopathy stage, lipid-lowering drugs, eGFR, albuminuria |
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Urinary 8-OHdG |
Serdar et al. [95] |
Cross-sectional study (n=92) |
T2DM |
Although urinary 8-OHdG levels increase in diabetic patients, their levels do not improve prediction of progressive DKD over and above measuring albuminuria |
No adjustments |
Omics-based novel biomarkers |
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Proteomics |
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Urinary haptoglobin |
Bhensdadia et al. [97] |
Prospective cohort study (n=204) |
T2DM |
The haptoglobin to creatinine ratio may be useful to predict risk of DKD before the development of albuminuria or kidney function decline |
Treatment arm, use of ACEi |
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Urinary CKD-273 |
Zurbig et al. [99] |
Prospective cohort study (n=35) |
T1DM and T2DM |
CKD-273 predicted progression to macroalbuminuria 5 years prior to actual onset |
Age, sex, DM type, albuminuria, eGFR, systolic and diastolic blood pressure, HbA1c, glucose |
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Urinary CKD-273 |
Roscioni et al. [100] |
Prospective cohort study (n=88) |
T2DM |
CKD-273 predicted development of albuminuria independent of other kidney biomarkers used to predict DKD development or progression |
Albuminuria, eGFR, use of RAS inhibitors |
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Urinary CKD-273 |
Zurbig et al. [101] |
Prospective cohort study (n=1,014) |
T1DM and T2DM |
In patients with T1DM or T2DM, baseline eGFR ≥70 mL/min/1.73 m2, and normoalbuminuria, CKD-273 was able to identify progression to eGFR <60 mL/min/1.73 m2 in the absence of albuminuria |
Age, baseline eGFR, systolic and diastolic blood pressure |
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Urinary CKD-273 |
Tofte et al. [102] |
Prospective cohort study (n=1,775) |
T2DM |
High-risk patients defined by CKD-273 were more likely to develop microalbuminuria |
Age, sex, HbA1c, systolic blood pressure, retinopathy, albuminuria, eGFR |
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Urinary CKD-273 |
Lindhardt et al. [103] |
Prospective cohort study (n=737) |
T2DM |
CKD-273 predicted development of albuminuria |
Treatment group, age, sex, systolic blood pressure, albuminuria, eGFR, HbA1c, diabetes duration |
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Metabolomics |
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35 Serum non-esterified and 32 serum esterified fatty acids |
Han et al. [106] |
Cross-sectional study (n=150) |
T2DM |
Non-esterified and esterified fatty acid discriminated albuminuria stages |
No adjustments |
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19 Serum metabolites |
Hirayama et al. [107] |
Cross-sectional study (n=78) |
T2DM |
Combination of 19 serum metabolites enabled accurate discrimination of DKD |
No adjustments |
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Serum leucine, dihydrosphingosine, phytosphingosine |
Zhang et al. [108] |
Cross-sectional study (n=66) |
T2DM |
Serum metabolite levels of leucine, dihydrosphingosine, and phytosphingosine were significantly different in patients with T2DM and healthy controls |
No adjustments |
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Urine hexose, glutamine, tysorine, plasma butenoylcarnitine, histidine |
Pena et al. [109] |
Prospective cohort study (n=90) |
T2DM |
Urine hexose, glutamine, tyrosine, plasma butenoylcarnitine and histine predicted development of albuminuria |
Albuminuria, eGFR, RAS inhibitors |
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207 Serum biomarkers that included dimethylarginine, C16-acylcarnitine |
Looker et al. [110] |
Nested case-control study (n=307) |
T2DM |
A panel of 14 biomarkers that included the symmetric to asymmetric dimethylarginine ratio, and C16-acylcarnitine increased the predictive ability of rapid progression |
Age, sex, baseline eGFR, albuminuria, HbA1c, use of RAS inhibitors |
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Urinary 3-hydroxy-isobutyrate, 3-methyl-crotonyglycine, aconitic acid, citric acid |
Kwan et al. [111] |
Prospective cohort study (n=1,001) |
T1DM and T2DM |
3-Hydroxyisobutyrate and 3-methylcrotonygly- cine had a significant negative association with eGFR slope, while aconitic and citric acid showed a positive association. |
Age, race, sex, smoking, body mass index, HbA1c, mean arterial pressure, albuminuria, baseline eGFR |
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Urinary leucine, valine, isoleucine, pseudouridine, threonine, citrate, 2-hydroxyiso- butyrate, pyroglutamate, tyrosine, alanine |
Mutter et al. [112] |
Prospective cohort study (n=2,670) |
T1DM |
7 Urinary metabolites that included leucine, valine, isoleucine, pseudouridine, threonine, and citrate were associated with DKD progression. 6 amino acids and pyroglutamate were associated with DKD progression in those with macroalbuminuria |
Baseline albuminuria, baseline glycemic |
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Transcriptomics |
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Let-7c-5p, miR-29a-3p, let-7b- 5p, miR-21-5p, miR-29c-3p |
Pezzolesi et al. [113] |
Prospective cohort study (n=116) |
T1DM |
Baseline miRNA levels of let-7c-5p and miR-29a- 3p were independently associated with more than a 50% reduction in the risk of rapid progression to ESKD, while levels of let-7b-5p and miR-21-5p were associated with a higher risk of ESKD |
Age, sex, HbA1c, duration of diabetes |
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18 miRNAs |
Argyropoulos et al. [114] |
Prospective cohort study (n=30) |
T1DM |
18 miRNAs were associated with the development of albuminuria, while 15 miRNAs exhibited gender-related differences in expression |
Sex |
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miR-130a, miR-145, miR-155, miR-424 |
Barutta et al. [115] |
Cross-sectional study (n=24) |
T1DM |
22 of 377 urinary EV-miRNAs were differentially expressed in patients with normoalbuminuria compared to albuminuric patients |
No adjustments |