Table 3.
Circulating metabolites associated with diabetic kidney disease in human studies.
| Reference; Year | Study Design | Number, Follow-Up | Technique | Biological Matrix | Outcome, Number | Adjustments | Major Findings | Replication |
|---|---|---|---|---|---|---|---|---|
| [81]; 2009 | China; case–control | 119 (31 control: no DM and DN, 23 T2D without DN, 65 T2D and DN) | Targeted; LC-MS | Plasma | NA | NA | Higher levels of inosine, adenosine, uric acid, and xanthine in DN group compared with control or T2D without DN group | No |
| [82]; 2012 | Japan; case–control | 78 T2D (20 normoalbuminuria, 32 microalbuminuria, 26 macroalbuminuria) | Untargeted; MS | Serum | NA | No | Higher levels of creatinine, aspartic acid, γ-butyrobetaine, citrulline, SDMA and kynurenine and lower levels of azelaic acid and galactaric acid in macroalbuminuria group compared with normoalbuminuria group | No |
| [83]; 2012 | FinnDiane; Finland; nested case–control | 52 T1D (26 progressing to micro/macroalbuminuria, 26 nonprogressor); 5.5 years | Untargeted; LC-MS and GC-MS | Urine | Progression from normoalbuminuria to micro- or macro-albuminuria; 26 | No | Higher level of substituted carnitine and S-(3-oxododecanoyl) cysteamine and lower level of hippuric acid in progressors | No |
| [84]; 2012 | FinnDiane; Finland; cross-sectional | 326 T1D (182 normal AER, 58 microalbuminuria, 86 macroalbuminuria) | Targeted; NMR | Serum | 24 h AER | Diabetes duration, gender, waist, SBP, HbA1C, triglycerides, HDL cholesterol, and serum creatinine | (+): sphingomyelin | No |
| [85]; 2013 | America; case–control | 47: 23 healthy control, 24 T2D with CKD (screening group) | Targeted; GC-MS | Urine and plasma | NA | Age, race, and sex | Lower levels of urine 3-hydroxy isovalerate, aconitic acid, citric acid, 2-ethyl 3-OH propionate, glycolic acid, homovanillic acid, 3-hydroxyisobutyrate, 2-methylacetoacetate, 3-methyladipic acid, 3-methylcrotonylglycine, 3-hydroxypropionate, tiglylglycine, and uracil in DM with CKD group compared with control group | Yes; 61 diabetes (12 T1D and 49 T2D) with CKD as validation group |
| [86]; 2014 | PREVEND; Netherlands; The Steno Diabetes Center; Denmark; nested case–control | 90 T2D (24 from normoalbuminuria to microalbuminuria, 24 normoalbuminuria control; 21 from microalbuminuria to macroalbuminuria, 21 microalbuminuria control); 2.9 years | Targeted; LC-MS | Urine and Plasma | Transition from normo- to micro-albuminuria or from micro- to macro-albuminuria; 24 from normo- to micro-albuminuria, 21 from micro- to macro-albuminuria | Baseline UAE and eGFR | Higher plasma levels of butenoylcarnitine and lower levels of plasma histidine, urine hexose, urine glutamine, and urine tyrosine in patients progressing from microalbuminuria to macroalbuminuria compared with controls | No |
| [87]; 2014 | DCCT; America; prospective | 497 T1D; 14–20 years | Targeted; LC-MS | Plasma | Incident macroalbuminuria; 65 | DCCT Treatment Group, baseline retinopathy status, use of ACE/ARB drugs during study period, gender, and baseline measures of duration of T1DM, age, HbA1C %, BMI, triglyceride levels, and AER | (−): very long chain ceramide species (C20, C22:1, C24, C26, and C26:1) | No |
| [88]; 2014 | The Joslin Study of the Genetics of Type 2 Diabetes and Kidney Complications; America; nested case–control | 80 T2D (40 incident ESRD, 40 without ESRD); 8–12 years | Targeted and untargeted; LC-MS and GC-MS | Plasma | Incident ESRD: renal death, renal replacement therapy | HbA1C, AER, and eGFR | (+): p-cresol sulfate, gulono-1,4-lactone, threitol, erythronate, pseudouridine, N2,N2-dimethylguanosine, N4-acetylcytidine, C-glycosyltryptophan, glutaroyl carnitine, methylglutarylcarnitine, 3-dehygrocarnitine, urea, myo-inositol, urate, phenylacetylglutamine; (−): 2-hydroxyisocaproate, 2-oxoisoleucine, 2-hydroxyisovalerate, 2-hydroxybutyrate |
No |
| [89]; 2015 | GO-DARTS; Scotland; nested case–control | 307 T2D with baseline eGFR 30–60 mL/min/1.73 m2; 3.5 years | Targeted; LC-MS | Serum | Rapid eGFR progression: >40% compared with baseline; 154 | Age, sex, eGFR, albuminuria status, HbA1C, use of ACE inhibitors, and use of ARBs | (+): C16-acylcarnitine, creatinine, methylmalonic acid, n-acetylaspartate, sialic acid, SDMA, SDMA/ADMA, uracil; (-): lysine, tryptophan |
No |
| [90]; 2016 | Singapore; case–control | 129 T2D without DKD (control), 126 T2D with ACR 30–299 mg/g and eGFR 60 mL/min/1.73 m2 (early DKD), 154 T2D with ACR ≥300 mg/g or eGFR <60 mL/min/1.73 m2 (overt DKD) | Targeted; LC-MS and GC-MS | Plasma | NA | Age, sex, and ethnicity | Higher levels of C2, C3, C4, C4-OH, C5, C4-DC, C5:1, C5-DC, C5-OH/C3-DC, C6, C8-OH/C6-DC, C14:1-OH, C14-OH/C12-DC, C18-OH/C16-DC acylcarnitines, Cer 18:1/16:0, GlcCer 18:1/18:0, SM 18:1/16:1, and sphingosine and lower levels of serine, (32:2, 34:3, 36:6, 38:3, 40:5) in overt DKD compared with control group | Yes, 149 T2D without DKD, 149 T2D with overt DKD |
| [91]; 2016 | Italy; prospective | 286 T2D; 3 years | Untargeted; LC-MS and GC-MS | Urine and serum | Association with baseline eGFR and ACR; incident >10 mL/min/1.73 m2 eGFR decline; incident >14 mg/g ACR increase; number not given | Gender, age, glucose, and baseline eGFR | (+): C-glycosyl tryptophan, pseudouridine, N-acetylthreonine | No |
| [92]; 2017 | China; case–control | 20 healthy controls (control); 25 T2D with UACR <30 mg/g (T2D); 24 T2D with UACR ≥30 mg/g (DKD) | Untargeted; GC-MS | Urine | NA | No | Higher levels of uric acid, stearic acid, palmitic acid, and hippuric acid and lower levels of uracil, glycine, aconitic acid, isocitric acid, 4-hydroxybutyrate, glycolic acid, and 2-deoxyerythritol in DKD compared with control or compared with T2D group | No |
| [93]; 2017 | The Joslin Proteinuria Cohort Study; America; prospective | 158 T1D with proteinuria and stage three CKD; 11 years | Targeted; LC-MS and GC-MS | Serum | Incident ESRD: renal death or renal replacement therapy; 99 | Blood pressure, BMI, smoking status, HbA1C, ACR, eGFR, uric acid levels, treatment with renin-angiotensin system inhibitors, other antihypertensive treatment, and statins | (+): n-acetylserine, n-acetylthreonine, n6-acetyllysine, n6-carbamoylthreonyladenosine, c-glycosyltryptophan, pseudouridine, o-sulfotyrosine | No |
| [94]; 2018 | FinnDiane; Finland; nested case–control | 200 T1D (102 progressing to microalbuminuria, 98 nonprogressors); 3.2 and 7.1 years, respectively | Untargeted; LC-MS and GC-MS | Serum | Progression to microalbuminuria; 102 | Age of diabetes onset, HbA1C, and AER | (+): erythritol, 3-phenylpropionate, N-trimethyl-5-aminovalerate | No |
| [95]; 2018 | ADVANCE; Australia; case–cohort | 3587 T2D; 5 years | Targeted; NMR | Plasma | Major microvascular events: a composite of new or worsening nephropathy or retinopathy; 342 | Age, sex, region and randomized treatment, a prior macrovascular complication, duration of diabetes, current smoking, systolic blood pressure, BMI, ACR, eGFR, HbA1C, plasma glucose, total cholesterol, HDL-cholesterol, triacylglycerols, aspirin or other antiplatelet agent, statin or other lipid-lowering agent, β-blocker, ACE inhibitor or angiotensin receptor blocker, metformin use, history of heart failure, participation in moderate and/or vigorous exercise for >15 min at least once weekly, and high-sensitivity CRP | (−): alanine, tyrosine | No |
| [96]; 2018 | Macroalbuminuric DKD; Brazil; prospective | 56 with T2D; 2.5 years | Untargeted, GC-MS | Plasma | All-cause death, doubling of baseline serum creatinine and/or dialysis initiation; 17 | eGFR | (−): 1,5-anhydroglucitol, norvaline, l-aspartic acid | No |
| [97]; 2018 | GenodiabMar; not given; TwinsUK; Britain; KORA; Germany; prospective | 655 T2D from GenodiabMar; 111 T2D from TwinsUK; 160 T2D from KORA; cross-sectional | Targeted; NMR | Serum | Association with baseline eGFR; 926 | Age, gender, and BMI | (+): apolipoprotein A1, total cholesterol in HDL2, total cholesterol in very large HDL, total cholesterol in HDL, free cholesterol in medium HDL, cholesterol esters in very large HDL, concentration of very large HDL particles, concentration of medium HDL particles, total lipids in medium HDL, phospholipids in medium HDL, esterified cholesterol, total cholesterol, total cholesterol in large LDL, total cholesterol in large LDL, total cholesterol in medium LDL, total cholesterol in small LDL, total cholesterol in LDL, total cholesterol in IDL, free cholesterol in large LDL, free cholesterol in medium LDL, free cholesterol in small LDL, free cholesterol in IDL, cholesterol esters in large LDL, cholesterol esters in medium LDL, cholesterol esters in small LDL, cholesterol esters in IDL, concentration of large LDL particles, concentration of IDL particles, total lipids in large LDL, total lipids in medium LDL, total lipids in small LDL, total lipids in IDL, phospholipids in large LDL, phospholipids in medium LDL, phospholipids in small LDL, phospholipids in IDL; (−): glycine, phenylalanine, citrate, glycerol |
No |
| [98]; 2019 | The Renoprotection in Early Diabetic Nephropathy in Pima Indians trial; America; prospective | 92 T2D with baseline eGFR ≥90 mL/min/1.73 m2; 9.6 years | Untargeted; LC-MS | Serum | ≥40% reduction in eGFR compared with baseline; 32 | GFR and ACR | (+): unsaturated PEs; (−): unsaturated FFAs |
No |
| [99]; 2019 | Denmark; prospective cohort study | 637 T1D; 5.5 years | Targeted; GC-MS | Serum | Combined renal endpoint: ≥30% decrease in eGFR, ESRD, or all-cause mortality; 123 | Age, sex, HbA1C, SBP, smoking, BMI, statin treatment, triglycerides, total cholesterol, eGFR, and logAER | (+): ribonic acid; (−): isoleucine, leucine, valine |
No |
| [100]; 2019 | China; nested case–control | 52 T2D with macroalbuminuria and eGFR >90 mL/min/1.73 m2 (25 progressors and 27 nonprogressors); 5–6 years | Targeted and untargeted; LC-MS | Urine | Early progressive renal function decline: at least a 33.3% decline of eGFR and eGFR <60 mL/min/1.73 m2; 25 | No | (−): 5-hydroxyhexanoic acid | No |
| [101]; 2019 | GoDARTS; Scotland; nested case–control; SDR; Sweden; prospective; CARDS; Britain; clinical trial | 430 T2D from GoDARTS, 227 T2D from SDR, 183 from CARDS; 7 years | MS | Serum | >20% eGFR reduction compared with baseline; 403 | Age, sex, baseline eGFR, albuminuria, HbA1C, and calendar time | (+): ADMA, SDMA | No |
| [102]; 2019 | SDRNT1BIO; Scotland; prospective | 859 T1D with baseline eGFR 30–75 mL/min/1.73 m2; 5.2 years | Targeted; LC-MS | Serum | Rapid eGFR decline during follow-up: > 3 mL/min/1.72 m2/year; 194 | Age, sex, duration of diabetes, study day eGFR, and length of follow-up | (+): free sialic acid; (−): tryptophan/kynurenine, threonine, methionine, tryptophan |
No |
| [103]; 2020 | Denmark; case–control | 211 (50 heathy control, 161 T1D: 50 normoalbuminuria, 50 micoralbuminuria, 61 macroalbuminuria); cross-sectional | Targeted; MS | Plasma | NA | Use of medication, HbA1C, and diabetes duration | Higher levels of indoxyl sulphate, L-citrulline in T1D and macroalbuminuria group compared with normo-or microalbuminuria group; higher levels of homocitrulline, L-kynurenine and lower level of tryptophan in macroalbuminuria group compared with normoalbuminuria group | No |
| [104]; 2020 | KORA; Germany; population-based cohort | 385 prediabetes or T2D; 6.5 years | Targeted; LC-MS | Serum | Incident CKD: eGFR <60 mL/mL/min/1.73 m2 and/or UACR ≥ 30 mg/g; 85 | Age, sex, BMI, SBP, smoking status, triglyceride, total cholesterol, HDL cholesterol, fasting glucose, use of lipid-lowering, antihypertensive and antidiabetic medications, baseline eGFR, and ACR | (+): PC aa (C38:0, C42:0, C40:6), SM (OH) (C14:1, C16:1), SM (C16:0, C16:1, C18:0, C18:1, C20:2, C24:1, C26:1); (−): PC aa C32:2 |
No |
| [105]; 2020 | CRIC; America; prospective cohort study | 1001 diabetes with baseline eGFR 20–70 mL/min/1.73 m2; 8 years | Untargeted; MS | Urine | ESRD (incident kidney failure with replacement therapy); 359 | Age, race, sex, smoked more than 100 cigarettes, BMI, HbA1C, mean arterial pressure, AER, and baseline eGFR | (+): 3-hydroxypropionate, 3-hydroxyisobutyrate, glycolic acid | No |
| [106]; 2020 | 5 Dutch cohort studies: DCS West-Friesland, the Maastricht study, the Rotterdam study, the Netherlands Epidemiology of Obesity study, the Cohort of Diabetes and Atherosclerosis Maastricht study | 3089 T2D; 4–7 years | Targeted; NMR | Plasma | Cross-sectional association with baseline eGFR and ACR | Age, sex, use of statins, other lipid-modifying agents, oral glucose-lowering medications, insulins, RAS-blocking agents and other antihypertensives, SBP, BMI, smoking, diabetes duration, HbA1C, and baseline ACR/UAE | 1) For baseline eGFR: (+): tyrosine, lactate, glucose, HDL particle, HDL cholesterol, apo A1, (−): phenylalanine, isoleucine, glutamine, histidine, leucine, glycoprotein acetyls, citrate, acetoacetate, VLDL particle, non-HDL cholesterol, triglycerides, lipid components in IDL and LDL 2) for baseline ACR: (+): glucose, glycoprotein acetyls, phosphatidylcholine and other cholines, free cholesterol in large VLDL; (−): very large HDL particle, glutamine |
No |
| [107]; 2020 | FinnDiane; Finland; nationwide prospective cohort | 1087 T1D; 10.7 years | Targeted; NMR | Serum | Fastest eGFR decline: highest quartile of eGFR decline over follow up (−4.4 mL/min/1.73 m2) and progression from macroalbuminuria to ESRD | Age at diabetes onset, sex, diabetes duration, smoking, SBP, HbA1C, BMI, HDL cholesterol, and triacylglycerols | (+): sphingomyelin | No |
FinnDiane, Finnish Diabetic Nephropathy Study Group; PREVEND, Prevention of Renal and Vascular End-stage Disease; DCCT, Diabetes Control and Complications Trial; GO-DARTS, Genetics of Diabetes Audit and Research Tayside Study; ADVANCE, Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation; SDR, Scania Diabetes Registry; CARDS, Collaborative Atorvastatin in Diabetes Study; SDRNT1BIO, Scottish Diabetes Research Network Type 1 Bioresource; CRIC, The Chronic Renal Insufficiency Cohort; DCS, Hoorn Diabetes Care System; ACE, angiotensin converting enzyme; ADMA, asymmetric dimethylarginine; AER, albumin excretion rate; Apo A1, apolipoprotein A1; ARB, angiotensin receptor blocker; Cer, ceramide; CRP, C-reactive protein; DN, diabetic nephropathy; FFAs, free fatty acids; GlcCer, glucosylceramide; PC; phosphatidylcholine; Pes, phosphatidylethanolamines; SDMA, symmetric dimethylarginine; SM, sphingomyelin; UAE, urinary albumin excretion.