Early detection of diabetic kidney disease: Present limitations and future perspectives

Table 1 Advantages of novel biomarkers in the early diagnosis of diabetic kidney disease

Biomarker	Validation study design	Sample size	Type of diabetes	Specimen	Advantages	Ref.
CysC	CO	52[38]	2	Serum	Not affected by lean body mass	[35-39]
		30[39]			Estimates more accurate than creatinine-based ones when GFR > 60 mL/min per 1.73 m2
NGAL	CC	112	2	Urine	Indicator of glomerular hyperfiltration	[44]
KIM1	CC	112	2	Urine	Indicator of glomerular hyperfiltration	[44]
NAG	CC	434	1	Urine	Baseline level predicts development of DKD	[51]
	CC	946	2			[52]
8-oxodG	PC	396	2	Urine	Baseline level predicts development of DKD	[59]
Pentosidine	CC	434	1	Urine	Baseline level predicts progression of albuminuria	[51]
TNFR1/2	RC	628	1	Serum	Baseline level predicts development of advanced CKD	[65]
	RC	410	2			[66]

CysC: Cystatin C; NGAL: Neutrophil gelatinase-associated lipocalin; KIM1: Kidney injury molecule 1; NAG: N-acetyl-β-(D)-glucosaminidase; 8-oxodG: 8-oxo-7,8-dihydro-2’-deoxyguanosine; TNFR: Tumor necrosis factor receptor; CO: Case-only; CC: Case-control; PC: Prospective cohort; RC: Retrospective cohort; GFR: Glomerular filtration rate; DKD: Diabetic kidney disease; CKD: Chronic kidney disease.

Table 2 In vitro and in vivo renal cell models demonstrating the potential involvement of miRNAs in development of diabetic kidney disease

miRNA	Species	Specimen	miRNA expression	Mechanism of action	Ref.
miR-192	Mice/Rat	M, Te, KT	Inconsistent results	Interaction with TGFβ-associated and other pro-fibrotic genes	[94-96]
	Human	Te, KT	Reduced		[97]
miR-216a	Mice	M, KT	Elevated		[98]
miR-377	Mice	M, KT	Elevated		[99]
	Human	M
miR-29c	Mice	P, KT	Elevated		[100]
miR-200b/c	Mice	M, KT	Elevated		[101]
miR-21	Mice	KT	Elevated		[102]
	Human	Te
miR-1207-5p	Human	P, M, Te	Elevated		[103]
miR-200a	Rat	Te	Reduced		[104]
	Mice	KT
miR-23b	Mice	KT	Reduced		[105]
	Human	Te, HEK-293A
miR-93	Mice	P, En, KT	Reduced	Regulation of VEGF expression	[106]
miR-25	Rat	M, KT	Reduced	Regulation of NOX4 expression	[107]
miR-451	Mice	M, KT	Reduced	Targeting YwhaZ and p38 MAPK signaling pathways	[108]

M: Mesangial cells; Te: Tubular epithelial cells; KT: Kidney tissue; P: Podocytes; En: Endothelial cells; TGFβ: Transforming growth factor β; VEGF: Vascular endothelial growth factor; NOX4: Nicotinamide adenine dinucleotide phosphate hydrogen oxidase 4; YwhaZ: Tyrosine3-monooxygenase/tryptophan 5-monooxygenase activation protein, zeta; MAPK: Mitogen-activated protein kinase; HEK-293A: Human Embryonic Kidney-293A cells.

Table 3 Urinary and serum miRNA profiles in patients with diabetic kidney disease

Type of diabetes	Specimen	miRNA expression		Ref.
1	Urine	Decreased	Increased	[109]
		miR-323b-5p, miR-221-3p, miR-524-5p, miR-188-3p	miR-214-3p, miR-92b-5p, hsa-miR-765, hsa-miR-429, miR-373-5p, miR-1913, miR-638
1	Urine	Decreased	Increased	[110]
		miR-155, miR-424	miR-130a, miR-145
2	Urine	miR-29 expression positively correlated to the severity of albuminuria		[111]
2	Blood	Reduced expression of miR-let-7a		[112]

Table 4 Applications of metabolomics in the diagnosis of diabetic kidney disease

Specimen	Panel	Application	Ref.
Plasma	Fatty acids C10:0, C12:0, C14:0, C16:1n-9, C16:0, C18:2, C18:1n-9, C18:1n-11, C18:0, C20:4, C20:5, C20:3, C20:2, C20:0, C22:6	Diverse profiles in different stages of DKD	[122]
Plasma	Phospholipids C18:2-LPC, C16:0/18:1-PE, pC18:0/20:4-PE, C18:0/22:6-PI, C18:0/18:0-PS, dC18:0/20:2-SM	Diagnosis of DKD	[123]
Serum	γ-butyrobetaine, SDMA, azelaic acid, MID 114, MID 127	Diagnosis of DKD	[124]
Urine	3-hydroxy isovalerate, aconitic acid, citric acid, 2-ethyl 3-OH propionate, glycolic acid, homovanillic acid, 3-hydroxy isobutyrate, 2-methyl acetoacetate, 3-methyl adipic acid, 3-methyl crotonyl glycine, 3-hydroxy propionate, tiglylglycine, uracil	Reduced expression in DKD patients	[125]
Plasma and urine	Plasma: Histidine, butenoylcarnitine Urine: Hexose, glutamine, tyrosine	Addition to the original predictive model improved risk estimation for albuminuria progression	[126]
Plasma	P-cresol sulfate, phenylacetylglutamine, myoinositol, pseudouridine, urate	Predicting progression toward ESRD	[127]

LPC: Lysophosphatidylcholine; PE: Phosphatidylethanolamine; PI: Phosphatidylinositol; PS: Phosphatidylserine; SM: Sphingomyelin; SDMA: Symmetric dimethylarginine; MID: Metabolite ID; DKD: Diabetic kidney disease; ESRD: End-stage renal disease.