Table 1 Summary of the experimental and clinical studies regarding the effects of potential nephroprotective agents against colistin-induced nephrotoxicity

Aged black garlic extract

Rats

1% of ABGE (100 µL per individual) injection intragastrically 30 min before colistin injection for 6 days

10 mg/kg of I.P. colistin for 6 consecutive days

Injection was intragastrically done 30 min

prior to colistin injection for 6 days

SCr, BUN, IL-1β

TNFα, SOD, CAT, GSH, renal apoptosis (by TUNEL assay), ED1-positive cells infiltration, 8-OHdG, MDA, NF-κB, INOS, COX-2,

TGF-β1, renal histology

Prevented colistin-induced elevation of BUN and SCr, reduced TUNEL- and CD68, suppressed oxidative stress and inflammatory biomarkers including 8-OHdG, MDA, NF-κB, iNOS, COX-2, TGF-β1, IL-1β, and TNF-α., restored antioxidant levels such as renal SOD, CAT, and GSH, and alleviated tubular damage including vacuolation and necrosis

[20]

Albumin fragments

Rats

50 mg/kg I.P. before the injection of colistin

1.0 mg/kg of I.V. colistin sulfate

Urine NAG,

urinary colistin excretion

Decreased urinary NAG excretion and increased the urinary excretion of colistin

[26]

Alpha-lipoic acid

Rats

100 mg/kg I.P. 30 min before the administration of CMS for 10 days

450.000 IU/kg/day of I.P. CMS for 10 days

Renal MDA, SOD,

TNF-α, urine KIM-1, urine microalb/Cr, Scr, MRNA expression of KIM-1, Nox4, and p22phox in the

kidney, kidney active caspase-3 protein expression

Attenuated renal injury,

decreased urine KIM-1, mRNA expression of KIM-1, Nox4d and p22phox in the kidney, and kidney active caspase-3 protein expression

[35]

Astaxanthin

Rats

20 mg/kg/day given by oral gavages for seven days

300,000 or 450,000 IU/kg/day of I.M. CMS in twice daily doses for seven days

Plasma/urine Cr,

Urine GGT, MDA, SOD, CAT, GPx, GSH, and

renal histology

Attenuated PCr and urine GGT levels, partially diminished the degree of renal tissue damage induced by colistin

[43]

Baicalein

Mice

25, 50, and 100 mg/kg/day

orally for seven days

18 mg/kg/day of I.P. colistin (sulphate) for 7 days

Serum BUN, SCr,

MDA, NO, GSH, SOD, CAT, iNOS, Caspase-3, Caspase-9, TNF-a, IL-1β, MRNA expression of Nrf2, HO-1, and NF-kB,

histopathological changes

Attenuated colistin-induced tissue damage,

decreased BUN, SCr, IL-1b, and TNF-a levels,

attenuated all the colistin-induced biomarkers of oxidative stress including MDA, iNOS, NO, SOD, and CAT, upregulated the expression of Nrf2 and HO-1 mRNAs, and downregulated the expression of NF-κB mRNA

[49]

Chrysin

Rats

50 mg/kg/day orally for 7 days

73 mg/kg I.M. colistin:

1.0 and 2.0 mg/kg on day 1; 2.50 mg/kg twice daily on day 2;

3.5 and 5.5 mg/kg on day 3; 8.0 mg/kg twice daily on days 4, 5, and 6;

and 8.0 mg/kg on day 7

Serum urea, SCr,

MDA, GSH, SOD, CAT, GPx, TNF-α, IL-6, IL-1β, Cystatin C, and calbindin D28K immunopositivities,

injuries to the proximal and distal tubules

Decreased MDA, TNF-α, IL-6, and IL-1β, increased GSH, SOD, CAT, GPx, cystatin C, and calbindin D28K immunopositivities,

alleviated renal injury

[56]

Cilastatin

Mice

100 mg/kg /day for 4 days

30 mg/kg/day of S.Q. colistin for 4 days

Urinary NAG,

KIM-1 expression

in kidney tissue,

tubular injury (morphologic changes)

Decreased urinary NAG and KIM-1 expression in proximal tubule epithelial cells and suppressed colistin-induced tubulointerstitial injury

[23]

Colchicine

Rats

3.5 mg/kg I.P. before the injection of colistin

1.0 mg/kg of I.V. colistin sulfate

Urine NAG

Decreased urinary NAG excretion

[26]

Curcumin

Rats

200 mg /kg/day orally for 6 days

300,000 IU/kg/day of I.P. CMS IP for 6 days

Serum urea, SCr, Serum UA, GSH,

MDA, CAT, NO, TNF-α, IL-6, Bcl-2,

Caspase-3, histopathological changes

Partially restored altered biochemical markers including increased SCr, serum urea, and UA, MDA, NO, TNF-α, IL-6, and caspase-3 expression levels and decreased CAT, GSH, and Bcl-2 expressions and alleviated histopathological changes

[65]

Cytochrome c

Rats

100 mg/kg I.P. before the injection of colistin

1.0 mg/kg of I.V. colistin sulfate

Urine NAG,

urinary colistin excretion, inhibitory effect on the binding of colistin to megalin

Decreased urinary NAG excretion, increased the urinary excretion of colistin, inhibited the binding of colistin to megalin competitively

[26]

Dexmedetomidine

Rats

10 and 20 mcg/kg I.P. twice a day 20 min before the injection of colistin for seven days

10 mg/kg of I.P. CMS

BUN, SCr,

KIM-1, TAS,

TOS, caspase-3

Decreased BUN, Cr, and TOS

[71]

Gelofusin

Mice

Cumulative I.P. doses of 450, 900, 1,800, and 3,600 mg/kg:

75, 150, 300, and 600 mg/kg every 2 h (6 doses)

S.Q. colistin sulfate at a cumulative dose of 84 mg/kg:

14 mg/kg every 2 h (6 doses)

Renal histology

Ameliorated colistin-induced nephrotoxicity in a dose-dependent manner

[75]

Grape seed proanthocyanidin extract

Rats

100 mg/kg/day orally

300,000 IU/kg/day of I.P. CMS for 7 days

BUN, SCr, TOS, TAS, MDA,

OSI, Caspase 1,

Caspase 3, Calpain 1, iNOS, eNOS, renal apoptosis (TUNEL assay), histopathological changes

Decreased BUN, SCr, renal histopathological scores, TUNEL, caspase 1 and 3, calpain 1, iNOS, and eNOS staining

[79]

Hesperidin

Rats

300 mg/kg/day

orally for 7 days

73 mg/kg I.M. colistin:

1.0 and 2.0 mg/kg on day 1; 2.50 mg/kg twice daily on day 2;

3.5 and 5.5 mg/kg on day 3; 8.0 mg/kg twice daily on days 4, 5, and 6;

and 8.0 mg/kg on day 7

MDA, GSH, SOD,

CAT, GPx, serum urea, SCr, TNF-α, IL-6, IL-1β, Cystatin C,

and calbindin D28K immunopositivities and injuries to the proximal and distal tubules

Decreased MDA, TNF-α, IL-6, and IL-1β, increased GSH, SOD, CAT, GPx, cystatin C, and calbindin D28K immunopositivities, and

alleviated renal injury

[56]

Luteolin

Rats

10 mg/kg I.P 4 h

before colistin administration

for 7 days

480,000 IU/kg/day of IP colistin for 7 days

Renal histology

Decreased the number of apoptotic cells and renal histological damage score

[94]

Lycopene

Mice

5 and 20 mg /kg/day orally 2 h before colistin administration for 7 days

15 mg/kg/day of I.V. colistin sulfate in two doses via a 3-min infusion for 7 days

BUN, SCr, MDA,

NO, iNOS, GSH,

SOD, CAT, MDA,

caspase-3, caspase-9, HO-1, MRNA expression of OH-1, Nrf2, and NF-κB in the kidney, and

histopathological changes

Increased levels of GSH, SOD, and Cat, decreased concentrations of BUN and SCr, caspase-dependent tubular apoptosis/necrosis, MDA, NO, iNOS, and HO-1 activity, downregulated the mRNA expression of NF-κB, and upregulated the mRNA expression of Nrf2 and HO-1 mRNA

[97]

Melatonin

Rats

5 mg/kg I.V. twice a day 20 min prior to each colistin dose for 7 days

36.5 mg/kg of I.V. colistin sulfate:

0.5 and 1.0 mg/kg on day 1; 1.25 mg/kg twice daily on day 2;

1.75 and 2.75 mg/kg on day 3; 4.0 mg/kg twice daily on days 4, 5, and 6; and 4.0 mg/kg on day 7

Urine NAG, PCr, SOD, renal histology

Mitigated the consequences of colistin-induced renal injury including increased urine NAG and PCr as well as renal histological abnormalities

[103]

N-Acetyl cysteine

Rats

150 mg/kg/day I.P. for 6 days

300,000 IU/kg/day of I.P. colistin (CMS)

BUN, PCr, UCr,

ClCr, urine protein,

plasma TNF-α, SOD, MDA, e-NOS, i-NOS, NT-3

Reduced renal tissue

SOD level and reversed immunocytochemical

staining of

i-NOS and NT-3

N-Acetyl cysteine

Rats

300

mg/kg/day I.P in two divided doses for 10 days

300,000 IU/kg/day of I.P. CMS for 10 days

SCr, urine NAG, TOS, TAS, OSI, eNOS, SOD2, MMP, renal apoptosis (by TUNEL assay),

renal histology examination

Reversed colistin-induced negative effects, as determined by increased SCr, urine NAG, apoptosis index, and renal histological damage score as well as by decreased renal expression levels of eNOS, SOD2, and MMP

[110]

Silymarin

Rats

50 mg/kg I.V

silymarin

twice a day 2 h before polymyxin E injection for 7 days

A cumulative dose of 36.5 mg/kg I.V. polymyxin E given twice a day, 8 h apart, for 7 days

Histological, ultrastructural, and morphometric

changes

Alleviated the degenerative changes on the rat kidney induced by polymyxin E

[111]

Silymarin

Rats

50 mg/kg I.V

silymarin twice a day 2 h before polymyxin E injection for 7 days

A cumulative dose of 36.5 mg/kg I.V. polymyxin E given twice a day, 8 h apart, for 7 days

SCr, serum urea, serum UA, serum Na, serum K,

ameliorated the biochemical changes induced by polymyxin E in rats including elevated urinary NAG and serum levels of urea, creatinine, uric acid, sodium, and potassium. However, the differences between polymyxin and polymyxin + silybin groups were statistically significant only for NAG

[117]

Silymarin

Rats

100 mg/kg/day in two divided doses given by oral gavages for 7 days

750.000 IU/kg/day of I.P. colistin in two divided doses for seven days

SCr, Cystatin C,

GPx, SOD,

MDA, Renal apoptosis (by TUNEL assay),

histopathological changes

Increased GPx and SOD and made some improvements in tubular necrosis

[118]

Taurine

Mice

500 and 1000 mg/kg, IP)

15 mg/kg/day of I.V. colistin for 7 days

PCr, BUN,

renal and mitochondrial GSH, renal and mitochondrial GSSG, renal and mitochondrial LPO,

renal FRAP, mitochondrial dehydrogenases activity, mitochondrial depolarization,

mitochondrial ATP,

mitochondrial swelling and permeabilization,

histopathological changes

Decreased colistin-induced elevation in plasma Cr and BUN, reversed colistin-induced negative effects such as increased renal ROS, LPO, and GSSG, mitochondrial LPO, permeabilization, and GSSG content, and decreased renal TAC, GSH stores, mitochondrial dehydrogenase activity, membrane potential, GSH, and ATP

[119]

Vitamin C

Rats, rat proximal tubular cells (NRK-52E)

50 or 200 mg/kg I.V. twice daily 20 min before each colistin dose for 7 day

36.5 mg/kg of I.V. colistin sulfate:

0.5 and 1.0 mg/kg on day 1; 1.25 mg/kg twice daily on day 2;

1.75 and 2.75 mg/kg on day 3; 4.0 mg/kg twice daily on days 4, 5, and 6; and 4.0 mg/kg on day 7

PCr, urine NAG,

SOD, renal apoptosis (by TUNEL assay),

renal histology

Decreased SCr, urine NAG, and histological abnormalities and had a dose-dependent inhibitory effect on colistin-induced apoptosis

[123]

Vitamin C

Humans

2 g I.V. every 12 h 20 min before CMS administration

CMS at a loading dose of 300 mg of CBA followed by renally adjusted maintenance doses every 12 h

SCr, CrCl, AKI, urine NGAL,

urine NAG, clinical outcome,

microbiological outcome, mortality,

plasma colistin concentrations

No significant differences

[128]

Vitamin E

Rats

100 mg/kg/day given by oral gavage for 7 days

300,000 and 450,000 IU/kg/day of I.M. CMS in twice daily doses for 7 days

PCr, UCr, urine GGT, MDA, SOD,

CAT, GPx, GSH, renal histology

Attenuated PCr and urine GGT levels and partially diminished the degree of colistin-induced renal damage

[129]

Vitamin E

Rats

100 mg/kg/day for 2 weeks after colistin discontinuation

300,000 and 450,000 IU/kg/day of I.M. CMS in twice daily doses for 7 days

PCr, UCr, urine NAG, MDA,

SOD, GSH,

renal histology

Attenuated increased NAG and MDA levels,

attenuated decreased SOD and GSH activities, and

improved tubular regeneration

[43]

Vitamin E + Vitamin C

Rats

100 mg/kg/day given by oral gavages for 7 days

450,000 IU/kg/day of CMS for 7 days

Urine NAG, urine GGT, PCr, plasma level of vitamins E and C, MDA, SOD, CAT, GPx, renal histology

Restored all biochemical parameters (increased NAG GGT and MDA and decreased the plasma levels of vitamin E and C, SOD, CAT, and GPx, and improved histopathological damage

[133]

Vitamin E

Humans

400 mg vitamin E in form of alpha

tocopherol daily

–

–

–

[134]