1
Table 1: Studies selected for review according to search criteria (those marked * discussed in more detail in the main text)
Renal condition
Acute Kidney Injury
(AKI)
Samples†
Urine, rat (sepsis model, n=3)
Urine, rat (ischaemia reperfusion model, n=3)
Urine, rat (cisplatin induced AKI, ischaemia reperfusion,
volume depletion; n=12 per group, pooled)
Urine, rat (4-aminophenol model, n=5 for 3 dosage levels)
Urine (CPB, n=22)
Urine (Intensive care patients post CABG, n = 20)
Urine (Contrast nephropathy, n=10)
Rat proximal tubular cell lysates exposed DCVC
Lysed rat IMCD cell isolates from lithium treated rats
Rat renal cortex +/- gentamicin exposure (n=5 for 3 dosage
groups)
Kidney sections from gentamicin treated rats (n=3)
Mouse model of aristolochic acid nephropathy (n=12 total)
Lead toxicity in rats, medulla + cortex rat kidney homogenates
(n=5)
Urine, rats undergoing total body irradiation
Urine (Paediatric patients undergoing cardiac bypass, n=32)
Urine (n=22)
Biomarkers detected/identified and other findings (proteomic technique employed‡)
Mephrin-1α-decrease , reduction in serine-protease inhibitors and uromodulin (2D-DIGE)
Sex-specific meprin-α increase in males (2D-DIGE)
Increased exosomal Fetuin-A which preceeded changes in creatinine in AKI from cisplatin and ischaemia
reperfusion injury, but not in volume depletion (2D-DIGE)
Increased fumarylacetoacetate (before creatinine) /T-kininogen/inter-alpha-inhibitor H4P heavy chain (2D-DIGE)
Hepcidin-25 less commonly observed in AKI-patients than controls (SELDI-TOF-MS)
Increased α-1-microglobulin and β-2-microglobulin in AKI (SELDI-TOF-MS and 2D-DIGE)
Variant of human β-defensin-1 elevated in patients less likely to develop nephropathy (SELDI-TOF-MS).
Increased phosphorylation of actin-related protein-2 (2D-PAGE)
Several signalling pathways altered including PkB/Akt, p38 and JNK. ↓aquaporin expression with Li+ (2D-DIGE)
20 proteins altered (e.g. carbohydrate metabolism, fatty acid oxidation, oxidiative phosphorylation) (2D-PAGE)
Transthyretin-fragment differentiated normal kidneys from gentamicin nephrotoxicity (MALDI-Imaging)
Mouse urinary protein↓; serum amyloid, transthyretin, and others all ↑ (1D-PAGE and LC-MS/MS)
76 cortical proteins altered, though only 13 medullary proteins altered; e.g. aldose reductase↑ (medulla), α 2
microglobulin ↓(medulla and cortex), transferrin ↓(medulla and cortex) - (2D-PAGE)
264 proteins altered after irradiation, significant changes in 24h (2D-PAGE and LC-MS/MS)
In those given it, urinary aprontinin levels ↑ 2h after CPB in those who went on to develop AKI (SELDI-TOF-MS)
Diabetic
11 differentially expressed proteins identified distinguishing DN samples and normal (including transthyretin
Nephropathy (DN)
precursor, IgG-chains and retinol-binding protein) (2D-PAGE)
Urine (n=89)
65 peptides detected which differentiate diabetics from normal; fragments of collagen I accounted for a number of
the peaks seen (CE-MS)
Urine (n = 112)
2000 peptides detected which differentiate diabetics from normal (CE-MS)
Urine (n=58)
11 of 113 polypeptides that appeared to represent renal damage identified. 15 of 113 changed in the
macroalbuminuric subgroup with candesartan treatment (CE-MS)
Urine (n=80, total)
Changes in collagen α-1 and α-5 fragments seen in DN (MALDI-TOF-MS)
Urine (n = 21)
Peptide fragments of urinary collagen decreased in progressors, over 10-12 years (MALDI-TOF-MS)
Urine (n=32, total)
Soluble E-cadherin upregulated with increasing proteinuria (2D-DIGE)
Urine (n = 3)
Alpha-1-antitrypsin increase, localised to areas of renal fibrosis by subsequent immunostaining (2D-DIGE)
OVE26 mouse model - whole kidney extract (n=5)
92 proteins identified as altering in diabetes including ↑ renal elastase inhibitor and ↓ elastase IIIB (2D-PAGE)
Urine, rat (streptozotozin model)
19 altered proteins, inc. ↑pro-α-collagen, confirmed with selected reaction monitoring (Label-free LC-MS/MS)
Lysates of skin fibroblasts from diabetics (n=15, total)
Altered cytoskeletal proteins (including α-actinin-4 and moesin) in DN-patient fibroblasts (2D-PAGE)
Glomerular
Plasma (n=34)
Oxidised forms of albumin detected in patients with FSGS compared to other diseases and normals (LC-MS/MS)
diseases
Urine (n=17)
Fragments of albumin and α1-antitrypsin present representing 72 altered protein spots (2D-PAGE)
1)Nephrosis
Urine (paediatric, SSNS n=14, SRNS n=11)
Unidentified 4144kDa peak discriminated SSNS vs SRNS, though PCRs varied significantly (SELDI-TOF-MS)
Glomeruli from 5/6 nephrectomised rats (n=3)
↑thymosin-β4 in sclerotic glomeruli, possibly related to inhibition of ECM degradation (MALDI-TOF-MS)
Glomeruli from 5/6 nephrectomised rats (n=6)
33 proteins altered inc. dimethylarginine dimethylaminohydrolase-1, possible link to ↑vascular tone (2D-DIGE)
Cultured murine podocytes
106 proteins differ in podocytes upon exposure to dexamethasone including cytoskeletal proteins, ciliary
neurotrophic factor, αB-crystallin, and 3 proteins with cellular protective roles (2D-PAGE)
†Samples are human unless specified; n numbers refer to number with condition unless otherwise stated; where >2 groups were used in a study, a total n number is usually given
‡Abrreviations used for proteomic techniques defined both in text and Boxes. Other abbreviations: CABG, coronary artery bypass graft; CPB, cardiopulmonary bypass; DCVC, dichlorovinyl cysteine; ECM,
extra-cellular matrix; FSGS, focal segmental glomerulosclerosis; IMCD, inner medullary collecting duct; PCR, protein creatinine ratio; SSNS, steroid sensitive nephrotic syndrome; SRNS, steroid resistant
nephrotic syndrome
Ref.
1
2
3*
4*
5*
6
7*
8
9*
10*
11
12
13
14
15
16*
17*
18*
19*
20*
21*
22*
23*
24*
25*
26
27*
28*
29*
30*
31*
32
2
Table 1: Studies selected for review according to search criteria continued (those marked * discussed in more detail in the main text)
Renal condition
Glomerular
diseases
2)IgA Nephropathy
3)Lupus Nephritis
(LN)
3)Membranous
Nephropathy (MN)
4)AAV
Kidney Stone
Disease
Haemodialysis and
haemofiltration
Samples†
Urine (n=45)
Urine (n=17)
Urine (n=18)
Urine (n = 19; 25 longitudinal samples during 25 flare cycles)
Urine (n=55)
Urine, rat model of MN (n=10)
Urine, rat model of MN (n=6)
Urine (n=37)
MDCK cells exposed to calcium oxalate monohydrate (n=5)
MDCK cells exposed to calcium oxalate dihydrate extract (n=5)
Stone Matrix Proteins, 3 stones from 3 different individuals
Haemodialysis patients (n=4)
Haemodialysis patients divided by low vs high flux filter types
(n = 26), peritoneal dialysis patients (n=10)
Slow Continuous Ultrafiltrate (1 patient with AKI)
Biomarkers detected/identified and other findings (proteomic technique employed‡)
Peptide patterns distinguished IgA nephropathy from controls and other nephropathies (CE-MS)
Ratio of α1-microglobulin:(albumin/transferrin) distinguished IgA nephropathy from controls and DN (2D-PAGE)
↑kininogen and others, and ↓transthyretin in ACE-inhibitor responders cf. non-responders (2D-PAGE)
Increased hepcidin-20 four months pre-flare; decreased hepcidin-25 during renal flare (SELDI-TOF-MS)
Peaks m/z 3340 and 3980Da distinguished active vs inactive LN (SELDI-TOF-MS)
Prehaptoglobin and haptoglobin increased in urine from compared to controls (2D-DIGE)
37 differentially expressed proteins involved in glomerular trafficking/permeability (2D-PAGE)
113 polypeptides distinguish AAV from controls (58 sequenced, mostly haemoglobin fragments) (CE-MS)
53 proteins altered and interaction with calcium oxalate monohydrate promoted cell death (2D-PAGE)
11 proteins altered, including annexin 2, which is known to bind calcium oxalate (2D-PAGE)
158 proteins seen inc. calcium binding and inflammatory proteins; 28 seen in all 3 stones (1D-PAGE, LC-MS/MS)
30 peaks detected as differing-peptides responsible not identified (SELDI-TOF-MS)
Distinct protein profiles between groups-high flux dialysates contained β2-micoglobulin, α-defensins, and
inflammatory proteins. Low flux filters released virtually no mid- to high-MW proteins (SELDI-TOF-MS)
Potentially beneficial losses, e.g. zinc α2-glycoprotein; potentially detrimental losses, e.g. albumin (gel-LCMSMS)
292 proteins seen inc. N-Ac proteins and proteins < 40kDa, some not known in serum (1D-PAGE, LC-MSMS)
58 proteins altered on exposure to PD fluid; possible adaptive response on repeated exposure (2D-PAGE)
C4A, Ig κ light chain VLJ region, albumin, α1-antitrypsin, apo-AI altered in varying membrane types (2D-PAGE)
Cleaved β2-microglobulin increase seen in AR not other groups, including acute tubular necrosis (SELDI-TOF-MS)
Cleaved β2-microglobulin peak, NGAL, α1-m, RBP all altered but none statistically significant (SELDI-TOF-MS)
Peaks representing α-1-antichymotrypsin and β-defensin-1 discriminated AR (SELDI-TOF-MS)
Urinary polypeptide pattern identified 16 of 19 ARs, and 6 of 9 in validation set (CE-MS)
Increases in several proteins seen in chronic allograft nepropathy e.g. α1-m, β2-m, endorepellin (SELDI-TOF-MS)
Peak cluster m/z 1539.8-1657.4Da differentiated IF/TA from CAAR (MALDI-TOF-MS)
Uromodulin and kininogen derived peaks m/z 645.9 and 642.61Da differentiated CAD groups (Label-free MS)
6 peaks identified which distinguished BK nephropathy from normal urine and acute rejection (SELDI-TOF-MS)
197 proteins differed between normal and PKD. 38sequenced - mainly collagen fragments (CE-MS)
Alteration of proteins involved e.g. in cell-proliferation, cell-matrix contact, fluid secretion (iTRAQ, LC-MS/MS)
Increased expression of numerous proteins linked to polycystin / fibrocystin signalling pathway (2D-PAGE)
552 differential proteins including polycystin-1 and -2, cystin and ADP-ribosylation factor like-6 (2D-PAGE)
Peptides unique to Dent’s seen e.g. leukotactin-I, IGF-I / II and growth factors (1D + 2D-PAGE , LC-MS/MS)
30 proteins enabled discrimination of Dent’s / Lowe’s vs. controls (1D and 2D-PAGE, LC-MS/MS)
Increased phosphorylation of AQP2, AQP4 and urea-transport isoforms-A1 and A3 (LC-MS/MS)
Phosphorylated AQP2 enriched in DRM. Vasopressin treatment caused ↓Rab7, annexin-2 in DRM (LC-MS/MS)
↑phosphorlyation of myosin-light chain IIA/B via MLCK. MLCK-inhibitors ↓IMCD water permeability (2D-PAGE)
Pathway analysis revealed 33 proteins involved in vasopressin-escape (2D-DIGE)
Ref.
33*
34
35
36*
37*
38
39
40*
41
42
43
44*
45*
46
CVVH effulent (1 patient with AKI following CPB)
47*
Mesothelial cell lysate (n=16 for control and treated cells)
48
Peritoneal dialysate fluid (n=20, total)
49*
Urine (n=83, total)
50*
Urine, trying to detect subclinical tubultits (n=100, total)
51*
Urine (n=65, total)
52*
Urine (n=58, total)
53*
2)Chronic Allograft
Urine (n=75, total)
54*
Dysfunction (CAD)
Urine (n=50, total)
55*
Urine (n=32; separate validation set also included)
56*
3) BK nephropathy
Urine (n=21)
57
Polycystic Kidney
Urine (n = 17, separate validation set also included)
58*
Disease (PKD)
Membrane fractions from PDK1-/- mouse models
59*
Kidney homogenate from jck-mutant mice (n=3)
60*
Urinary exosome fraction from PKHD1-/- mice
61*
Fanconi Syndrome
Urine (n=4)
62*
(FS)
Urine (n=28)
63*
Fluid and
Rat IMCD cells exposed to vasopressin
64*
electrolyte
Profiling of rat CDC detergent-resistant membrane (DRM)
65*
disorders
Rat IMCD cells exposed to vasopressin +/- inhibitor
66*
Vasopressin treated rat IMCD cells (n=4) +/- vasopressin
67*
escape
Rabbit LoH cells, low vs. high resistance to osmotic stress
40 proteins differentially expressed inc. sorbitol pathway enzymes, cytoskeletal proteins and HSPs (2D-PAGE)
68*
IMCD cells adapted to hypertonicity vs controls
Increased expression of S100A4 in both acute and chronic hypertonicity (2D-DIGE)
69*
†Samples are human unless specified; n numbers refer to number with condition unless otherwise stated; where >2 groups were used in a study, a total n number is usually given
‡Abrreviations used for proteomic techniques are defined in text and Boxes. Other abbreviations: AAV, ANCA associated vasculitis; ACE, angiotensin converting enzyme; AQP, aquaporin; CAAR, chronic active
antibody-mediated rejection; CVVH, continuous veno-venous haemofiltration; HSP, heat-shock protein; IF/TA, interstitial fibrosis/tubular atrophy; IMCD, inner medullary collecting duct; LoH, loop of Henle; N-Ac,
N-acetylated; NGAL, neutrophil gelatinase associated lipocalin; MDCK, Madin-Darby canine kidney; MLCK, myosin light-chain kinase; RBP, retinol binding protein; α1-m, alpha 1 microglobulin; β2-m, beta 2
microglobulin
Peritoneal Dialysis
(PD)
Transplantation
1)Acute Rejection
(AR)
3
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