TABLE 2.
Methodological details reported in the publications included by the systematic search
| Article | Species | Breed |
Age Weight |
Ischemia: transplantation, surgery, or clamping | Cold ischemia time (h) | Warm ischemia time (min) | Sample type | Sampling time points | Control(s) | Relevant measurement techniques |
|---|---|---|---|---|---|---|---|---|---|---|
| Rat | ||||||||||
| Andrianova et al. 2020 7 | Rat |
Outbred Wistar rats Male |
3–4 months 300–400 g |
Clamping Right nephrectomy, clamping of left renal vascular bundle for 40 min. |
— | 40 |
Blood (carotid artery) |
Blood: 48 h post‐IR |
Blood: intact control |
Blood metabolomics: FIA‐MS/MS Serum levels urea & creatinine: AU480 Chemistry System |
| Choi et al. 2019 8 | Rat |
Sprague‐Dawley rats Male |
3–4 months 410–450 g |
Surgery 20 min of cardiac arrest through asphyxia, then resuscitation by cardiopulmonary bypass. |
— | 20 |
Tissue |
Tissue: post‐I and 30 min post‐IR After 30 min of cardiopulmonary bypass resuscitation, rats were euthanized to recover brain, heart, kidney, and liver tissue samples. |
Tissue: intact control, no cardiac arrest, euthanized 7 min before recovering tissues. | Tissue metabolomics: LC‐MS/MS |
| Duran et al. 1990 9 | Rat |
Sprague‐Dawley rats Female |
??? 240–312 g |
Clamping Unilateral clamping of left renal artery for 1 h. |
— | 60 |
Blood (cardiac puncture) Tissue (cortex) |
Blood, tissue: 3 and 24 h post‐IR |
Blood, tissue: “control” rats Blood (for BUN): prior to IR, from tail |
Blood/tissue metabolomics: dansylation of amino acids and subsequent chromatography BUN: autoanalyzer technique |
| Gaudio et al. 1991 10 | Rat | Sprague‐Dawley rats |
??? 250 g |
Clamping Clamping of aorta proximal to both renal arteries for 45 min. |
— | 45 | Tissue | Tissue: 15 min or 2 h post‐IR, measurements of proximal tubule suspensions. | Tissue: sham‐operated rats |
ATP content: HPLC |
| Huang et al. 2018 11 | Rat | Fisher F344 rats |
??? 250–300 g |
Clamping Unilateral clamping of left renal artery for 45 min. |
— | 45 |
Blood (???) Tissue (cortex) |
Blood, tissue: 4 h and 24 h post‐IR | Blood and tissue: contralateral kidney and kidneys from healthy control rats |
Tissue metabolomics: 1H‐NMR & GCxGC‐MS |
| Lan et al. 2016 12 | Rat |
Sprague‐Dawley rats Male |
??? |
Clamping Right nephrectomy, clamping of left renal vascular pedicle for 45 min. |
— | 45 |
Blood (???) Tissue (cortex and outer stripe of outer medulla) |
Blood: daily post‐IR Tissue: 3, 7, and 14 days post‐IR |
Blood: prior to surgery Tissue: sham‐operated rats |
Tissue lactate and pyruvate levels: fluorimetry SCr:??? |
| Legouis et al. 2020 3 | Rat |
Sprague–Dawley rats Male |
8–10 weeks ??? |
Clamping Right nephrectomy, clamping of left renal artery for 25 min. |
— | 25 | Blood (left femoral artery, left femoral vein, and renal vein) | Blood: 60 and 120 min post‐IR | Blood: sham‐operated rats | Gluconeogenesis (plasma D2‐glucose enrichment after administration of D2‐glucose) measurement in blood: GC‐MS |
| Lindhardt et al. 2020 13 | Rat |
Wistar rats Male |
??? 205–290 g |
Clamping Unilateral clamping of left renal artery for 40 min. |
— | 40 |
Blood (tail vein) Tissue imaging in vivo Urine (metabolic cage) |
Blood, tissue (imaging in vivo): 24 h post‐IR Urine: 24 h post‐IR |
Blood: no control Tissue imaging in vivo: contralateral kidney Urine: no control |
Tissue metabolomics: In vivo 1H and hyperpolarized 13C MRI Urinary creatinine, BUN and SCr: COBAS 6000 device (Roche) |
| Liu et al. 2012 14 | Rat |
Sprague‐Dawley rats Male |
Adult 175–225 g |
Clamping Clamping of renal arteries for 45 min. |
— | 45 |
Blood (posterior orbital venous plexus) Tissue (cortex) |
Blood: 2, 4, 6, 12, 24, 48, 72, and 96 h post‐IR Tissue: 24 h and 96 h post‐IR |
Blood and tissue: sham‐operated rats |
Blood metabolomics: HPLC/MS |
| Nielsen et al. 2017a 15 | Rat |
Wistar rats Male |
??? 200–250 g |
Clamping Unilateral clamping of left renal artery for 40 min. |
— | 40 |
Blood (arterial) Tissue Urine (metabolic cage) |
Blood, tissue imaging in vivo, and samples: 24 h post‐IR Urine: 24 h post‐IR |
Blood: prior to surgery Tissue (imaging in vivo and samples): contralateral kidney Urine: 24 h prior to surgery |
Tissue metabolomics: In vivo 1H and hyperpolarized 13C MRI |
| Nielsen et al. 2017b 16 | Rat |
Wistar rats Male |
??? 250–290 g |
Clamping Unilateral clamping of left renal artery for 30 or 60 min. |
— | 30 or 60 |
Blood (??? before surgery and aorta post‐IR) Tissue imaging in vivo Tissue samples (cortex) |
Blood, tissue imaging in vivo, and samples: 24 h post‐IR |
Blood: prior to surgery (24 h) and sham‐operated rats Tissue: contralateral kidneys and sham‐operated rats |
Tissue metabolomics: In vivo 1H and hyperpolarized 13C MRI Tissue lactate levels: enzymatic assay BUN and SCr: COBAS 6000 device (Roche) Renal KIM−1 and NGAL expression: qPCR |
| Nielsen et al. 2020 17 | Rat |
Wistar rats Male |
??? 200–245 g |
Clamping (2 distinct procedures) Procedure 1: Unilateral clamping of left renal artery for 30 min. Procedure 2: Unilateral clamping of left renal artery for 20 or 40 min. |
— | 20, 30 or 40 |
Blood (tail vein) Tissue imaging in vivo Tissue samples (cortex and inner medulla) |
Blood: directly before tissue imaging in vivo Tissue imaging in vivo: Procedure 1 – 2 and 60 min post‐IR Procedure 2 – 1 and 7 days post‐IR Tissue samples: 60 min post‐IR and 7 days post‐IR |
Blood: no control Tissue (imaging in vivo and samples): contralateral kidney |
Tissue metabolomics: In vivo 1H and hyperpolarized 13C MRI SCr: COBAS 6000 device (Roche) |
| Peto et al. 2018 18 | Rat |
Crl:WI rats Male |
??? 342.2 ± 29.5 g |
Clamping Ligation of right renal artery and clamping of left renal vessels for 60 min. After WI, excision of right kidney and clamp removal from the left renal vessels. |
— | 60 |
Blood (left femoral artery) Tissue |
Tissue: 120 min post‐IR Blood: pre‐I, post‐I, 60 min post‐IR, and 120 min post‐IR |
Blood and tissue: prior to surgery and sham‐operated rats | Blood acid‐base parameters, glucose and electrolytes: EPOC portable blood analysis device |
| Serkova et al. 2005 19 | Rat | Lewis rats Male |
??? 200–250 g |
Transplantation After removal from living donors, kidneys were kept cold for 24 or 42 h. Implantation after removal of both kidneys from recipient. |
24 or 42 | ??? |
Blood (???) Tissue |
Blood: pre‐IR and 24 h post‐IR Tissue: pre‐IR, post‐I, and 24 h post‐IR |
Blood and tissue: recipient's kidney and blood prior to nephrectomy and transplantation | Blood/tissue metabolomics: 1H‐NMR |
| Shen et al. 2017 20 | Rat |
Sprague‐Dawley rats Female |
Adult 200–220 g |
Clamping Clamping of renal pedicles for 30 min. |
— | 30 | Tissue | Tissue: post‐IR (reperfusion time unknown) | Tissue: sham‐operated rats | Tissue metabolomics: GC/MS |
| Tani et al. 2019 21 | Rat |
Sprague‐Dawley rats Male |
6 weeks ??? |
Clamping Unilateral clamping of left renal pedicle for 30 min. |
— | 30 |
Tissue |
Tissue: 60 min after drug administration, post‐I, and 30 min post‐IR |
Tissue: “vehicle treatment group,” no surgery, 60 min after receiving 0.5 mL 0.5% methylcellulose. |
Tissue purine nucleotide concentration: HPLC Tissue metabolomics: CE‐ToFMS |
| Trifillis et al. 1984 22 | Rat |
Sprague‐Dawley rats Male |
??? 220–250 g |
Clamping Clamping of aorta above left renal artery, below the right renal artery, and superior mesenteric artery, as well as clamping right renal artery and vein for 15, 10, 60, 90, or 120 min. |
— | 5, 15, 30, 60, 90, or 120 |
Blood (aorta) Tissue |
Blood:??? Tissue: post‐I, and 0.25, 1, 6, 24, or 48 h post‐IR |
Blood:??? Tissue: control rats (no sham surgery) |
Tissue ATP/ADP/AMP/lactate measurements: specific enzymatic methods coupled with NADH or NADPH Tissue Pi measurements: modification of Fiske and SubbaRow method SCr: Beckman creatinine analyzer II BUN: Beckman urea nitrogen analyzer. |
| Varga et al. 2019 23 | Rat |
Crl:WI rats Male |
??? 301.6 ± 38.6 g |
Clamping Unilateral clamping of left renal vessels for 45 min. |
— | 45 | Blood (right femoral artery) |
Blood: pre‐I, and 30, 60, and 120 min post‐IR |
Blood: prior to surgery and sham‐operated rats | Blood acid‐base parameters, metabolites and electrolytes: EPOC portable blood analysis device |
| Mouse | ||||||||||
| Beier et al. 2020 24 | Mouse |
C57BL/6 mice Female |
??? |
Clamping Unilateral clamping of renal pedicle for 28 min. |
28 | Tissue | Tissue: 24 h post‐IR | Tissue: contralateral kidney | Tissue metabolomics: UPLC‐MS | |
| Chihanga et al. 2018 25 | Mouse | Swiss‐Webster mice |
??? 25–30g |
Clamping Clamping of renal pedicles for 30 min. |
— | 30 |
Blood (inferior vena cava for SCr, cardiac puncture for NMR) Tissue Urine (metabolic cage) |
Blood: 24 h post‐IR Tissue: 24 h post‐IR Urine: 3 days pre‐IR and 24 h post‐IR |
Blood: control mice (pre‐IR) Tissue: control mice (pre‐IR) Urine: 3 days pre‐IR |
Blood/urine metabolomics: 1H‐NMR Urinary creatinine, SCr and urinary NGAL: spectroscopy |
| Cho et al. 2017 26 | Mouse | C57BL/6 mice Male |
9 weeks ??? |
Clamping Unilateral clamping of left renal pedicle for 45 min. |
— | 45 |
Blood (???) Tissue Urine (metabolic cage) |
Blood: 24 h post‐IR Tissue: 24 h post‐IR Urine: 24 h post‐IR |
Blood, tissue, and urine: sham‐operated mice |
Blood/tissue/urine metabolomics: HPLC‐Q‐ToF MS |
| a Chouchani et al. 2014 27 |
Mouse |
C57BL/6J mice Male |
8–10 weeks ??? |
Clamping Unilateral clamping of one renal pedicle for 45 min. |
— | 45 | Tissue | Tissue: post‐I and 5 min post‐IR | Tissue:??? (normoxic controls) | Tissue metabolomics: LC‐MS |
| Fujii et al. 2019 28 | Mouse |
C57BL/6 Male |
8 weeks ??? |
Clamping Unilateral clamping of left renal artery for 1, 10, and 40 min. |
— | 1, 10, and 40 |
Blood (???) Tissue Urine (???) |
Tissue: after 1, 10, and 40 min WI, and 24 h post‐IR Blood and urine: 24 h post‐IR |
Blood and urine:??? Tissue: sham‐operated mice |
Tissue metabolomics: Matrix‐assisted laser desorption/ionization–imaging mass spectrometry (MALDI‐IMS) + data calibration by CE‐MS Serum/urine samples: “standard method” |
| Jouret et al. 2016 29 | Mouse |
C57BL/6J mice Male |
10 weeks ~20 g |
Clamping Clamping of renal pedicles for 30 min. |
— | 30 |
Blood (vena cava) Tissue Urine (metabolic cage) |
Blood, tissue, and urine: 6 h, 24 h, and 48 h post‐IR |
Blood, tissue and urine: sham‐operated mice |
Blood/tissue/urine metabolomics: 1H‐NMR Serum levels urea & creatinine: COBAS 6000 device (Roche) |
| Legouis et al. 2020 3 | Mouse |
C57Bl/6 J mice Male |
10–12 weeks 25–28 g |
Clamping Clamping of renal pedicles for 25 min. |
— | 25 |
Blood (???) Urine (???) |
Blood and urine: 24 and 48 h post‐IR Blood (for lactate clearance test): 15, 30, 60, 90, and 120 min postinjection of sodium lactate (injection at 6 h post‐IR) |
Blood and urine: sham‐operated mice |
Blood lactate and glucose: Aviva Accu‐Check glucometer and Novabio StatStrip Xpress lactate meter SCr: capillary electrophoresis BUN: quantitative colorimetric determination using Stanbio Excel analyzer |
| Poyan Mehr et al. 2018 30 | Mouse |
C57BL/6J mice Male |
8–12 weeks ??? |
Clamping Clamping of renal pedicles for 20 min. |
— | 25 |
Blood (???) Tissue Urine (???) |
Blood, urine, and tissue: 24 h post‐IR | Blood, tissue, and urine: sham‐operated mice |
Tissue/urine metabolomics: LC‐MS SCr: LC‐MS |
| Rao et al. 2016 31 | Mouse |
C57BL/6 mice Male |
10–12 weeks ??? |
Clamping Right nephrectomy, clamping of left renal pedicle for 30 min. |
— | 30 | Tissue | Tissue: 6 and 24 h post‐IR | Tissue: sham‐operated mice |
Tissue lipid concentrations: SWATH‐MS Tissue hydroxyoctadeca dienoic acid/ hydroxyeicosatetra enoic acid measurement: LC‐MS/MS |
| Wei et al. 2014 32 | Mouse |
C57BL/6 mice Male |
9 weeks ??? |
Clamping Clamping of renal pedicles for 25 min. |
— | 25 |
Blood (???) Tissue (cortex and medulla) |
Blood and tissue: 2 h, 48 h, or 1 week post‐IR | Blood and tissue: sham‐operated mice | Blood/tissue metabolomics: GC/MS and LC/MS |
| Zager et al. 2014 33 | Mouse |
CD−1 mice Male |
??? 30–45 g |
Clamping Unilateral clamping of left renal pedicle for 15, 30, or 60 min. |
— | 15, 30, or 60 |
Blood (vena cava) Tissue (cortex) |
Blood and tissue: after 15, 30, or 60 min WI, and 2 or 18 h post‐IR |
Blood: sham‐operated mice Tissue: contralateral kidney and sham‐operated mice |
Tissue/blood lactate, pyruvate, glucose and glycogen levels: enzymatic assays |
| Pig | ||||||||||
| Clendenen et al. 2019 34 | Pig |
Farm pigs Male |
??? 50–55 kg |
Clamping Clamping of renal pedicles for 30 min. |
— | 30 | Blood (renal vein) | Blood: pre‐IR, after 15 and 30 min WI, and 5 min post‐IR | Blood: pre‐IR | Blood metabolomics: UHPLC‐MS |
| Fonouni et al. 2011 35 | Pig | Landrace pigs |
??? 26–33 kg |
Transplantation Living donor left kidney explantation (30 min), implantation in recipient after 6 h CI. 120 min reperfusion. |
6 | 60 (anastomosis) |
Blood (???) Extracellular fluid (microdialysis = MD) |
Blood: during procurement, post‐I, and 120 min post‐IR MD: 10‐min intervals during kidney procurement, CI (2 samples in the first and 2 samples at the end of CI), and at 20‐min intervals during kidney implantation (WI) and postreperfusion (120 min). |
Blood and extracellular fluid: during explantation procedure |
MD: CMA 600 Microdialysis Analyzer Blood analysis: hospital laboratory |
| Hauet et al. 2000 36 | Pig |
Large White pigs Male |
??? 41–52 kg |
Transplantation Left nephrectomy, kidneys were flushed with EC solution or UW solution. After 48 h CI, heterotopic autotransplantation was performed and contralateral nephrectomy was carried out. |
48 | ??? |
Blood (right jugular vein) Urine (metabolic cage) |
Blood and urine: 2 days before kidney preservation (D−2) and at 1, 3, 5, 7, 11, and 14 days (D1–D14) post‐IR. Also examined these kidneys 30–40 min after implantation and on the sacrifice day. |
Blood and urine: control group uninephrectomized, no flushing or cold preservation | Blood/urine metabolomics: 1H‐NMR |
| Malagrino et al. 2019 37 | Pig |
Pigs Female |
Juvenile 15–20 kg |
Clamping Unilateral clamping of the right renal artery for 120 min. |
— | 120 |
Blood (inferior vena cava above the renal veins) Tissue Urine (directly from bladder) |
Tissue: 24 h post‐IR Blood and urine: pre‐IR (before occlusion), after 1 h WI, 0.5 h post‐IR, 4 or 6 h post‐IR, and 11 h post‐IR |
Tissue: contralateral kidney Blood and urine: pre‐IR samples |
Blood/urine metabolomics: 1H‐NMR |
| Dog | ||||||||||
| Maessen et al. 1989 38 | Dog | Mongrel dogs |
Adult 18–25 kg |
Transplantation Clamping of left renal vessel pedicle for 0 or 30 min. Then, kidney explantation and storage on ice. Autologous reimplantation and contralateral nephrectomy. |
24 or 48 | 0 or 30 +??? | Tissue (cortex) | Tissue: after WI, after CI, and 1 h post‐IR | Tissue: non‐ischemic control | Tissue energy metabolite levels: HPLC |
| Montañés et al. 1991 39 | Dog | Mongrel dogs |
??? 17–34 kg |
Clamping Right nephrectomy, clamping of left renal artery for 60 min. |
— | 60 |
Blood (femoral artery, left ovarian, or spermatic vein) Tissue (cortex) Urine (left ureter and metabolic cage) |
Blood, tissue, and urine: 2 days post‐IR |
Blood, tissue and urine: sham‐operated dogs |
Blood/tissue metabolomics: enzymatic assays SCr: enzymatic assay Blood/urine pH and gasses: blood gas analyzer model 168 (Corning Medical) |
For the sake of clarity, the induction of ischemia was classified as “clamping,” including several approaches to occlude blood flow, or “transplantation,” in which the kidney was removed and transplanted.
Abbreviations: AV, arteriovenous; BUN, blood urea nitrogen; CE‐MS, capillary electrophoresis–mass spectrometry; CE‐ToFMS, capillary electrophoresis–time of flight mass spectrometry; CI, cold ischemia; DGF, delayed graft function; fDGF, functional DGF; FIA‐MS/MS, flow injection analysis tandem mass spectrometry; GC, gas chromatography; GCxGC‐MS, two‐dimensional gas chromatography–mass spectrometry; HPLC‐Q‐ToF MS, high‐performance liquid chromatography–quadrupole–time of flight mass spectrometry; IR, ischemia reperfusion; KIM‐1, kidney injury molecule‐1; LC, liquid chromatography; MALDI‐MS, matrix‐assisted laser desorption/ionization mass spectrometry; MD, microdialysis; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; NGAL, neutrophil gelatinase‐associated lipocalin; NMR, nuclear magnetic resonance; Post‐I, postischemia; Pre‐I, preischemia; qPCR, quantitative polymerase chain reaction; SCr, serum creatinine; SWATH‐MS, sequential window acquisition of theoretical spectra–mass spectrometry; UHPLC, ultrahigh‐performance liquid chromatography; UPLC‐MS/MS, ultra‐performance liquid chromatography tandem mass spectrometry; WI, warm ischemia; ???, data unknown.
Additionally included study.