Mannitol nephrotoxicity

Gadllah ME, Lynn M,WorkJ. Case Report Mannitol nephrotoxicity syndrome role of hemodialysis and postulate of mechanisms. Am J Med Sci 1995 309(4) 219-222. 

The platinum complexes appear to synergize with certain other anticancer drugs. Aggressive hydration with intravenous saline infusion alone or with saline and mannitol or other diuretics appears to significantly reduce the incidence of nephrotoxicity. 

Plouvier B, Baclet JL, de Coninck P. Une association nephrotoxique mannitol et furosemide. [A nephrotoxic combination mannitol and furosemide.] Nouv Presse Med 1981 10(21) 1744-5. 

A report from Italy has suggested that intravenous saline 0.4% before and after administration of the contrast medium, an infusion of dopamine 3 micrograms/kg/ minute for 24 hours after the contrast medium, intravenous furosemide 80 mg 30 minutes before the contrast medium, or intravenous mannitol (20%) 250 ml 1 horn-before and 1 hour after the contrast medium each prevented the reduction in renal function caused by the nonionic agents iobitridol, ioversol, or iodixanol (193). However, the protocol of the study was not described, and previous studies have shown that dopamine, furosemide, and mannitol do not offer good protection against contrast media-induced nephrotoxicity. On the other hand, volume expansion with intravenous saline has been found to offer some protection (190). 

Heptaplatin (cis-malonate[(4i ,5i )-4,5-bis(aminomethyl)-2-isopropyl-l,3-dioxolane]platinum(II), SKT2053R, Sunpla) has high antitumor activity against various cancer cell lines, including cisplatin-resistant tumor cells. PreUminary results suggested that it is less nephrotoxic than cisplatin. However, a comparative trial showed that intravenous heptaplatin 400 mg/m was more nephrotoxic than intravenous cisplatin 60 mg/m in terms of uremia and proteinuria, which occurred despite the use of hyperosmolar mannitol and appropriate concomitant hydration (fluid intake at least 3500 ml/day) (34,35). 

Rosch JM, Pazin GJ, Fireman P. Reduction of amphotericin B nephrotoxicity with mannitol. JAMA 1976 235 1995-6. 

As mannitol and furosenude reduce the concentration of platinum in the urine, it has been suggested that these agents may attenuate cisplatin nephrotoxicity [40, 41]. However, neither platinum content in the plasma or kidney nor the degree of cellular necrosis it produces is modified by these diuretics [41]. Platinum is not reabsorbed to an important degree after its intra tubular microinjection and, therefore, platinum content in the cell should not be dependent on its luminal concentration [13]. 

While several experimental reports have suggested that diuretics [mannitol and furosemide] decrease cisplatin nephrotoxicity [36, 41] others have shown that they may aggravate it [43]. Further, in humans, there is no convincing evidence than diuretics may attenuate cisplatin nephrotoxicity as shown in a randomized study by Alsarraf et al. [44] hydration + cisplatin was compared to hydration + mannitol + cisplatin. 

Protection of kidney function by mannitol was observed after the first cycle, but no convincing effect was observed during the subsequent cycles. So far there is thus no reason to advocate for the use of diuretics in prevention of cisplatin induced nephrotoxicity. Hydration well in advance [at least 12 hours] of cisplatin administration will induce a diuresis of at least 100 ml/hr and will not make compensation of electrolytes losses mandatory as it is the case with diuretics. 

Pera MF Jr, Zook BC, Harder HC. Effects of mannitol or furosemide diuresis on the nephrotoxicity and physiological disposition of cis-dichlorodiammine platinum [II] In rats. Cancer Res 1979 29 1269-78. 

Nephrotoxicity is best minimized by limiting the cumulative dose and avoiding concomitant administration of other nephrotoxins, particularly cyclosporine. Additionally, providing hydration with a high sodium diet and 1 L intravenous 0.9% sodium chloride daily appears to reduce toxicity. Mannitol infusion to induce an osmotic diuresis has not been protective. Lastly, several liposomal amphotericin B formulations are now available and have been reported to reduce nephrotoxicity by enhancing drug delivery to sites of infection and thereby reducing exposure of mammalian cell membranes. ... 

Bullock WE, Luke RG, Nuttal CE, Bhathena D. Can mannitol reduce amphotericin B nephrotoxicity Double blind study and description of a new vascular lesion in kidneys. Antimicrob Agents Chemother 1976 10 555-563. 

Olivero TJ, Lozano-Mendez L, Ghafary EM, Eknoyan G, Suki WN. Mitigation of amphotericin B nephrotoxicity with mannitol. Br MedJ 1975 1 550-551. 

Said R, Martin P, Anicama H, Quintanilla A, Levin ML. Effect of mannitol on acute amphotericin B nephrotoxicity. Res Exp Med 1980 177 85-90. 

Conclusions regarding the renoprotective action of mannitol and furosemide to decrease experimentally induced cisplatin nephrotoxicity are conflicting [36,41, 43]. However, in humans, a randomized study hy Alsarraf et al. [44] comparing hydration + cisplatin to hydration + mannitol + cisplatin concluded that mannitol did not attenuate cisplatin nephrotoxidly. 

Cisplatin Alkylating agent—crosslinks DNA strands Testicular, ovarian, bladder, lung CA Nephrotoxicity (hydrate and use mannitol), neurotoxicity (deafness)... 

Toxicity Cisplatin causes gastrointestinal distress and mild hematotoxicity and is neurotoxic (peripheral neuritis and acoustic nerve damage) and nephrotoxic. Renal damage may be reduced by the use of mannitol with forced hydration. Carboplatin is less nephrotoxic than cisplatin and is less likely to cause tinnitus and hearing loss, but it has greater myelo-suppressant actions. 

The characteristic nephrotoxicity of cisplatin may be reduced by slow intravenous infusion, the maintenance of good hydration, and the administration of mannitol (to maximize urine flow). Bear in mind that cisplatin also has dose-dependent neurotoxic effects. The answer is (B). 

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