Table 1.
Main studies on biomarkers and DKD published between 2012 and 2017
| Author, ref. | Sample size and population | Study design | DKD stage | Biomarkers | Main results | Adjustments |
|---|---|---|---|---|---|---|
| Single biomarkers or several biomarkers not as a panel | ||||||
| Burns et al [102] | N = 259 (n = 194 T1D, n = 65 controls) | Cross-sectional | Normoalbuminuria; varying levels of GFR | Urinary angiotensinogen and ACE2 levels, activity of ACE and ACE2 | Urinary angiotensinogen and ACE activity associated with ACR | No adjustments |
| Velho et al [44] |
N = 986 T1D |
Prospective | Varying levels of albumin excretion and GFR | Plasma copeptin | Upper tertiles of copeptin associated with a higher incidence of ESRD | Baseline sex, age, and duration of diabetes |
| Carlsson et al [103] |
N = 607 T2D |
Prospective | Varying levels of albumin excretion | Plasma endostatin | Endostatin levels associated with increased risk of GFR decline and mortality | Baseline age, sex, eGFR and ACR |
| Dieter et al [104] |
N = 135 T2D |
Prospective | Proteinuria | Serum amyloid A | Higher serum amyloid A levels predicted higher risk of death and ESRD | UACR, eGFR, age, sex and ethnicity |
| Wang et al [105] | N = 100 (n = 80 with T2D, n = 20 healthy controls) | Cross-sectional | Varying levels of eGFR and ACR | Serum and urinary ZAG | Serum and urinary ZAG associated with eGFR and UACR, respectively | No adjustments |
| Pikkemaat et al [47] | N = 161 T2D | Prospective | eGFR >60 ml min−1 1.73 m−2 | Copeptin | Copeptin predicted development of CKD stage 3, borderline significant on adjustment for baseline eGFR | Age, sex, diabetes duration, antihypertensive treatment, HbA1c, BMI, SBP |
| Garg et al [50] |
N = 91 T2D (including n = 30 with prediabetes) |
Cross-sectional | Varying levels of albumin excretion | Urinary NGAL and cystatin C | NGAL and cystatin C were significantly higher in participants with vs those without microalbuminuria | No adjustments |
| Viswanathan et al [52] | N = 78 (n = 65 T2D, n = 13 controls) | Cross-sectional | Varying degrees of albuminuria | Urinary L-FABP | L-FABP inversely associated with eGFR and positively associated with protein to creatinine ratio | No adjustments |
| Panduru et al [62] |
N = 1573 T1D |
Prospective + Mendelian randomisation |
Varying degrees of albuminuria | Urinary KIM-1 | KIM-1 did not predict progression to ESRD independently of AER Mendelian randomisation supported a causal link between KIM-1 and eGFR |
HbA1c, triacylglycerols, AER |
| Pavkov et al [31] |
N = 193 T2D |
Prospective | Varying levels of albumin excretion, eGFR: ≥60 ml/min in 89% participants |
Serum TNFR1 and TNFR2 | Elevated concentrations of TNFR1 or TNFR2 associated with increased risk of ESRD | Age, sex, HbA1c, MAP, ACR and GFR |
| Fufaa et al [106] |
N = 260 T2D |
Prospective | Varying levels of albumin excretion and eGFR | Urinary KIM-1, L-FABP, NAG and NGAL | NGAL and L-FABP independently associated with ESRD and mortality | Baseline age, sex, diabetes duration, hypertension, HbA1c, GFR, ACR |
| Bouvet et al [107] |
N = 36 T2D |
Cross-sectional | Normoalbuminuria and macroalbuminuria | Urinary NAG | Higher NAG levels associated with microalbuminuria | No adjustments |
| Har et al [40] |
N = 142 T1D |
Cross-sectional | Varying levels of eGFR Normoalbuminuria |
Urinary cytokines/chemokines | Increased urinary cytokine/chemokine excretion according to filtration status with highest levels in hyperfiltering individuals, although not significant after adjustments | Glycaemia |
| Petrica et al [108] | N = 91 (n = 70 T2D, n = 21 controls) | Cross-sectional | Normoalbuminuria and microalbuminuria | Urinary α1-microglobulin and KIM-1 (proximal tubule markers), nephrin and VEGF (podocyte markers), AGE, UACR and serum cystatin C | Significant association between biomarkers of proximal tubule dysfunction and podocyte biomarkers (independently of albuminuria and renal function) | UACR, cystatin C, CRP |
| Wu et al [109] |
N = 462 T2D |
Cross-sectional | Varying levels of albumin excretion | Serum Klotho, NGAL, 8-iso-PGF2α, MCP-1, TNF-α, TGF-β1 | Klotho and NGAL associated with ACR | No adjustments |
| Sabbisetti et al [58] |
N = 124 T1D |
Prospective | Proteinuria CKD 1-5 |
Serum KIM-1 | KIM-1 associated with eGFR slopes and progression to ESRD | Baseline ACR, eGFR, and HbA1c |
| Velho et al [45] |
N = 3101 T2D |
Prospective | Albuminuria | Plasma copeptin | Copeptin independently associated with renal events (doubling of creatinine or ESRD) | Baseline sex, age, diabetes duration, hypertension, diuretics use, HbA1c, eGFR, triacylglycerols, HDL-cholesterol, AER |
| do Nascimento et al [110] |
N = 101 (n = 19 prediabetes, n = 67 diabetes [T1D, T2D] and n = 15 controls) |
Cross-sectional | Varying levels of albumin excretion | Urinary mRNA levels of podocyte-associated proteins (nephrin, podocin, podocalyxin, synaptopodin, TRPC6, α-actinin-4 and TGF-β1) | Urinary nephrin discriminated between the different stages of DKD and predicted increases in albuminuria | No adjustments |
| Boertien et al [46] |
N = 1328 T2D |
Prospective | Varying degrees of albuminuria and eGFR | Copeptin | Copeptin associated with change in eGFR independently of baseline eGFR. This association not present in those on RASi | Age, sex, diabetes duration, antihypertensive use, HbA1c, cholesterol, BP,BMI, smoking |
| Lopes-Virella et al [33] |
N = 1237 T1D |
Prospective | Normoalbuminuria | Serum E-selectin, IL-6, PAI-1, sTNFR1, TNFR2 | TNFR1 and TNFR2 and E-selectin best predictors of progression to macroalbuminuria | Treatment allocation, baseline AER, ACEi/ARB use, retinopathy cohort, sex, age, HbA1c, diabetes duration |
| Panduru et al [111] | N = 2454 (n = 2246 T1D, n = 208 controls) | Prospective | Varying degrees of albuminuria | Urinary L-FABP | L-FABP was an independent predictor of progression at all stages of DKD, but L-FABP did not significantly improve risk prediction above AER | Baseline WHR, HbA1c, triacylglycerols, ACR |
| Araki et al [53] |
N = 618 T2D |
Prospective | Varying levels of albumin excretion, serum creatinine ≤ 8.8×10−2 mmol/l | Urinary L-FABP | L-FABP associated with decline in eGFR | Age, sex, BMI, HbA1c, cholesterol, triacylglycerols, HDL-cholesterol, hypertension, RASi use, BP |
| Lee et al [112] |
N = 380 T2D |
Prospective | Varying levels of albumin excretion | Plasma TNFR1 and FGF-23 | FGF-23 was associated with increased risk of ESRD, only in unadjusted model | Sex, baseline diabetes duration, HbA1c, eGFR, AER |
| Cherney et al [41] |
N = 150 T1D |
Cross-sectional | Normoalbuminuria | 42 urinary cytokines/chemokines | IL-6, IL-8, PDGF-AA and RANTES levels differed across ACR tertiles | No adjustments |
| Conway et al [60] |
N = 978 T2D |
Prospective | Varying degrees of albuminuria and eGFR | Urinary KIM-1 and GPNMB | KIM-1 and GPNMB associated with faster eGFR decline, only in unadjusted models Higher KIM-1 associated with mortality risk, only in unadjusted models |
Baseline eGFR, ACR, sex, diabetes duration, HbA1c, BP |
| Nielsen et al [48] |
N = 177 T2D |
Prospective | Proteinuria | Urinary NGAL and KIM1 and plasma FGF23 | Higher levels of the biomarkers associated with a faster decline in eGFR, although this was not independent of known promoters | Age, sex, HbA1c, SBP and urinary albumin |
| Jim et al [113] | N = 76 (n = 66 T2D, n = 10 controls) | Cross-sectional | Normoalbuminuria and microalbuminuria | Urinary nephrin levels | Nephrinuria occurred before the onset of microalbuminuria | No adjustments |
| Gohda et al [30] |
N = 628 T1D |
Prospective | Normal renal function; normoalbuminuria and microalbuminuria | TNFR1 and TNFR2 | TNFR1 and TNFR2 strongly associated with risk for early renal decline | HbA1c, AER, and eGFR |
| Niewczas et al [29] |
N = 410 T2D |
Prospective | CKD 1-3 | Plasma TNF-α, TNFR1, and TNFR2, ICAM-1, VCAM-1, PAI-1, IL-6 and CRP | TNFR1 and TNFR2 were strongly associated with risk of ESRD | Age, HbA1c, AER, and eGFR |
| Fu et al [49] | N = 112 (n = 88 with T2D, n = 24 controls) | Cross-sectional | Varying degrees of albuminuria | Urinary KIM-1, NAG, NGAL | Higher levels of the three markers in T2D than controls. Positive association of NGAL and NAG with ACR; negative association of NGAL and eGFR |
No adjustments |
| Nielsen et al [59] |
N = 63 T1D |
Prospective | Varying levels of albumin excretion and GFR | Urinary NGAL, KIM-1 and L-FABP | Elevated NGAL and KIM-1 were associated with faster decline in GFR, but not after adjustments for known progression promoters | Age, sex, diabetes duration, BP, HbA1c, AER |
| Kamijo-Ikemori et al [51] | N = 552 (n = 140 T2D and n = 412 controls) | Cross-sectional and prospective | Varying degrees of albuminuria and GFR | Urinary L-FABP | L-FABP associated with progression of nephropathy | Age, sex, HbA1c, albuminuria status at baseline, BP |
| Vaidya et al [61] | N = 697 (n = 659 T1D, n = 38 controls) | Cross-sectional and prospective | Varying levels of albumin excretion | Urinary IL-6, CXCL10/IP-10, NAG and KIM-1 | KIM-1 and NAG both individually and collectively were significantly associated with regression of microalbuminuria | Age, sex, AER, HbA1c, SBP, renoprotective treatment and cholesterol |
| Panel of biomarkers /proteomics signatures | ||||||
| Coca et al [114] | N = 1536 (n = 1346 T2D, n = 190 controls) | Nested case–control study and prospective | CKD at various stages | TNFR1, TNFR2 and KIM-1 | Higher levels of the three biomarkers associated with higher risk of eGFR decline in persons with early or advanced DKD | Clinical variables |
| Bjornstad et al [69] |
N = 527 T1D |
Prospective | Varying levels of albumin excretion and eGFR | Plasma biomarkers | B2M, cystatin C, NGAL and osteopontin predicted impaired eGFR | Age, sex, HbA1c, SBP, LDL-cholesterol, baseline log ACR and eGFR |
| Peters et al [70] |
N = 354 T2D |
Prospective | Varying levels of albumin excretion and eGFR | Plasma ApoA4, ApoC-III, CD5L, C1QB, complement factor H-related protein 2, IGFBP3 | ApoA4, CD5L, C1QB and IBP3 improved the prediction of rapid decline in renal function independently of recognised clinical risk factors | Age, diabetes duration, diuretic use, HDL-cholesterol |
| Mayer et al [66] |
N = 1765 T2D |
Prospective | CKD at various stages | YKL-40, GH-1, HGF, matrix metalloproteinases: MMP2, MMP7, MMP8, MMP13, tyrosine kinase and TNFR1 | Biomarkers explained variability of annual eGFR loss by 15% and 34% (adj R2) in patients with eGFR ≥60 and <60 ml min−1 1.73 m−2 respectively. A combination of molecular and clinical predictors increased the adjusted R2 to 35% and 64% in these two groups, respectively. |
Sex, age, smoking, baseline eGFR, ACR, BMI, total cholesterol, BP and HbA1c |
| Saulnier et al [115] |
N = 1135 T2D |
Prospective | Varying levels of albumin excretion and eGFR | Serum TNFR1, MR-proADM and NT-proBNP | TNFR1, MR-proADM and NT-proBNP improved risk prediction for renal function decline | Age, sex, diabetes duration, HbA1c, BP, baseline eGFR and ACR |
| Looker et al [25] |
N = 307 (n = 154 T2D, n = 153 controls) |
Nested case–control | CKD 3 | 207 serum biomarkers | Panel of 14 biomarkers improved clinical prediction (from 0.706 to 0.868) | Age, sex, eGFR, albuminuria, HbA1c, ACEi and ARB use, BP, weighted average of past eGFRs, diabetes duration, BMI, prior CVD, insulin use, antihypertensive drugs |
| Pena et al [116] |
N = 82 T2D |
Prospective | Normoalbuminuria and macroalbuminuria | Plasma peptides | 18 peptides (related to PI3K-Akt, VEGF, mTOR, MAPK, and p38 MAPK, Wnt signalling) improved risk prediction for transition from micro to macroalbuminuria (C statistic from 0.73 to 0.80) | Baseline albuminuria status, eGFR, RASi use |
| Pena et al [64] |
N = 82 T2D |
Prospective | Varying levels of albumin excretion and eGFR | 28 biomarkers | MMPs, tyrosine kinase, podocin, CTGF, TNFR1, sclerostin, CCL2, YKL-40, and NT-proCNP improved prediction of eGFR decline when combined with established risk markers | Baseline smoking, sex, SBP, eGFR, use of oral diabetic medication |
| Foster et al [117] |
N = 250 T2D |
Prospective | Unselected but 54% albuminuric | β-Trace protein and B2M | β-Trace protein associated with ESRD | GFR, albuminuria, age, sex, diabetes duration, hypertension, cholesterol |
| Agarwal et al [67] | N = 87 (n = 67 T2D, n = 20 controls) | Prospective | CKD 2-4 Varying levels of albumin excretion |
17 urinary and 7 plasma biomarkers | Urinary C-terminal FGF-2: strongest association with ESRD Plasma VEGF associated with the composite outcome of death and ESRD |
Baseline albuminuria and eGFR |
| Siwy et al [75] |
N = 165 T2D |
Prospective | Wide ranges of eGFR and urinary albumin | Urinary CDK273 | Validation of this urinary proteome-based classifier in a multicentre prospective setting | Albuminuria |
| Verhave et al [68] |
N = 83 T1D and T2D |
Prospective | Overt diabetic nephropathy | Urinary IL-1β, IL-6, IL-8, MCP-1, TNF-α, TGF-β1, and PAI-1 | MCP-1 and TGF-β1 were independent and additive to proteinuria in predicting the rate of renal function decline | Albuminuria |
| Bhensdadia et al [84] |
N = 204 T2D |
Prospective | eGFR stage 1-2 and normo-/macroalbuminuria | Urine peptides | Haptoglobin to creatinine ratio: best predictor of early renal function decline | Albuminuria, ACEi use |
| Merchant et al [82] |
N = 33 T1D |
Prospective | Microalbuminuria | Small (<3 kDa) plasma peptides | Plasma kininogen and kininogen fragments associated with renal function decline | No adjustments but stratum matched for eGFR and albuminuria |
| Roscioni et al [78] |
N = 88 T2D |
Prospective | Normoalbuminuria and microalbuminuria | CKD273 (urine) | Able to detect progression from normo- to micro- and micro- to macroalbuminuria | Baseline albuminuria status, eGFR, RASi use |
| Zürbig et al [76] |
N = 35 T1D and T2D |
Prospective | Normoalbuminuria; normal eGFR | Urinary CKD273 | Early detection of progression to macroalbuminuria: AUC 0.93 vs 0.67 for urinary albumin | Albuminuria |
| Titan et al [118] |
N = 56 T2D |
Prospective | Macroalbuminuria | Urinary RBP and serum and urinary cytokines (TGF-β, MCP-1 and VEGF) | Urinary RBP and MCP-1: independently related to the risk of CKD progression | Creatinine clearance, proteinuria, BP |
| Schlatzer et al [83] |
N = 465 T1D |
Nested case–control | CKD 1 Normoalbuminuria |
Panel of 252 urine peptides | A panel including Tamm–Horsfall protein, progranulin, clusterin, and α-1 acid glycoprotein improved the AUC from 0.841 (clinical variables) to 0.889 | Age, diabetes duration, HbA1c, BMI, WHR, smoking, total and HDL-cholesterol, SBP, ACR, uric acid, cystatin C, BP/lipid treatment |
| Metabolomics | ||||||
| Niewczas et al [119] |
N = 158 T1D |
Prospective | Proteinuria and CKD 3 | Global serum metabolomic profiling | 7 modified metabolites were associated with renal function decline and time to ESRD | Baseline HbA1c, ACR, eGFR, BP, BMI, smoking, uric acid levels, RASi use, other antihypertensive treatment, and statins |
| Klein et al [120] |
N = 497 T1D |
Prospective | Normoalbuminuria | Multiple plasma ceramide species and individual sphingoid bases and their phosphates | Increased plasma levels of very long chain ceramide species associated with reduced macroalbuminuria risk | Treatment group, baseline retinopathy, sex, HbA1c, age, AER, lipid levels, diabetes duration, ACEi/ARB use |
| Pena et al [121] |
N = 90 T2D |
Case–control and prospective | Normoalbuminuria and macroalbuminuria | Plasma and urinary metabolomics | Urine hexose, glutamine and tyrosine and plasma histidine and butenoylcarnitine associated with progression from micro- to macroalbuminuria | Albuminuria, eGFR, RASi use |
| Niewczas et al [122] |
N = 80 T2D |
Prospective nested case–control study |
CKD 1-3 | 78 plasma metabolites (uremic solutes) and essential amino acids | Abnormal levels of uremic solutes and essential amino acids associated with progression to ESRD | Albuminuria, eGFR, HbA1c |
| Sharma et al [123] |
N = 181 (n = 114 T2D, n = 44 T1D, n = 23 control) | Cross-sectional | Different CKD stages | 13 urine metabolites of mitochondrial metabolism | Differences in urine metabolome between healthy controls and diabetes mellitus and CKD cohorts | Age, race, sex, MAP,BMI, HbA1c, diabetes duration |
| Hirayama et al [124] |
N = 78 T2D |
Cross-sectional | Varying levels of albumin excretion | 19 serum metabolites | Able to discriminate presence or absence of diabetic nephropathy | No adjustments |
| Van der Kloet et al [125] |
N = 52 T1D |
Prospective | Normoalbuminuria | Metabolite profiles of 24 h urines | Acylcarnitines, acylglycines and metabolites related to tryptophan metabolism were discriminating metabolites for progression to micro or macroalbuminuria | No adjustments |
| Ng et al [126] |
N = 90 T2D |
Cross-sectional | Varying levels of eGFR | Octanol, oxalic acid, phosphoric acid, benzamide, creatinine, 3,5-dimethoxymandelic amide and N-acetylglutamine | Able to discriminate low vs normal eGFR | Age at diagnosis, age at examination, baseline serum creatinine |
| Han et al [127] | N = 150 (n = 120 T2D, n = 30 controls) | Cross-sectional | Varying levels of albumin excretion | 35 plasma non-esterified and 32 esterified fatty acids | Able to discriminate albuminuria status | No adjustments |
8-iso-PGF2α, 8-iso-prostaglandin F2α; ACEi, ACE inhibitors; ACR, albumin-creatinine ratio; Apo, apolipoprotein; ARB, angiotensin receptor blockers; B2M; β2-microglobulin; C1QB, complement C1q subcomponent subunit B; CD5L, CD5 antigen-like; CCL2, chemokine ligand 2; CKD, chronic kidney disease; CRP, C-reactive protein; CTGF, connective tissue growth factor; CVD, cardiovascular disease; CXCL10, CXC chemokine ligand-10; DKD, diabetic kidney disease; ESRD, end-stage renal disease; FGF, fibroblast growth factor; GPNMB, glycoprotein non-metastatic melanoma protein B; GH, growth hormone; HGF, hepatocyte growth factor; IGFBP3, insulin-like growth factor binding protein 3; ICAM-1, intercellular adhesion molecule-1; IP-10, inducible protein 10; L-FABP, liver-type fatty acid-binding protein; MAP, mean arterial blood pressure; MAPK, mitogen-activated protein kinases; MCP-1, monocyte chemoattractant protein-1; MMP, matrix metalloproteinase; MR-proADM, mid-regional pro-adrenomedullin; mTOR, mechanistic target of rapamycin; NAG, N-acetylglucosamine; NGAL, neutrophil gelatinase-associated lipocalin; NT-proBNP, N-terminal pro-B-type natriuretic peptide; NT-proCNP, N-terminal pro-C-type natriuretic peptide; P13K-Akt, phosphatidylinositol-3-kinase and protein kinase B; PAI-1, plasminogen activator inhibitor-1; PDGF-AA, platelet-derived growth factor-AA; RANTES, regulated on activation, normal T cell expressed and secreted; RASi, renin–angiotensin system inhibitor; RBP, retinol binding protein; SBP, systolic BP; sTNFR1, soluble TNF receptor-1; T1D, type 1 diabetes; T2D, type 2 diabetes; TNFR, TNF receptor; TRPC6, transient receptor potential cation channel subfamily member 6; UACR, urine albumin-to-creatinine ratio; VCAM-1, vascular cell adhesion molecule 1; VEGF, vascular endothelial growth factor; YKL-40, chitinase-3-like protein 1; ZAG, zinc α2-glycoprotein