Cisplatin-Induced Kidney Injury: Delivering the Goods

Cisplatin is highly effective in the treatment of many solid tumors, but detrimental effects on the kidney frequently curtail its use. Even with targeted management to minimize nephrotoxicity, an incidence of 30% of AKI has been reported in adults receiving a single dose.¹ Existing approaches to minimize nephrotoxicity primarily focus on hydration, with diuretics such as mannitol given to selected patients. K⁺ and Mg²⁺ are also supplemented to reduce hypokalemia and hypomagnesemia, although Mg²⁺ supplementation may also exert direct protective effects.² If AKI develops, lower doses of cisplatin or less nephrotoxic analogs such as carboplatin can be used at the risk of reduced efficacy. Although most patients recover from cisplatin-induced AKI, in some patients there is progression to CKD.

The sensitivity of the kidney to cisplatin derives primarily from basolateral uptake along the proximal tubule through the organic cation transporter 2, leading to intracellular cisplatin concentrations up to five times higher than plasma levels. Cisplatin is converted to toxic metabolites that affect many pathways, including oxidative stress, reactive nitrogen species, and induction of proapoptotic and inflammatory pathways.³ Cisplatin-mediated vasoconstriction may exacerbate direct effects on proximal tubule cells by inducing acute ischemia. Tubular injury can often occur without AKI, manifesting as electrolyte disturbances, ranging in severity from isolated proximal abnormalities to Fanconi syndrome. Proposed approaches to more directly and effectively reduce cisplatin-induced nephrotoxicity largely target the above pathways.³ However, some of these approaches counteract the anticancer effects of cisplatin, and no effective alternatives have been developed to date.

In this issue of JASN,⁴ Guo and colleagues report a beneficial effect of delivering a peptide-agonist derivative of the flavoprotein renalase in cisplatin-induced CKD. Renalase is secreted into the circulation from the kidney, but is also expressed in heart, skeletal muscle, intestine, and the reproductive system. A potential role in CKD was proposed early in its discovery, because its expression was dramatically lower in plasma from patients with stage 5 CKD.⁵ This group previously showed disruption of renalase in mice exacerbated AKI induced by ischemia⁶ or by cisplatin.⁷ Although full-length renalase has amine oxidase activity with the ability to directly metabolize catecholamines in vitro, administration of a 20 amino acid renalase peptide lacking this activity mitigated cisplatin-induced AKI in wild-type mice by activating cell survival pathways.⁷ This study moves renalase agonists a step closer to becoming a new tool that will allow more effective chemotherapy by reducing renal injury.

The authors first demonstrated a rationale for using renalase agonists in cisplatin-induced CKD in humans. A single dose of cisplatin led to sustained subclinical kidney injury in patients with head and neck squamous cell carcinoma. Although GFR was unchanged in most patients, plasma levels of kidney injury marker 1 were elevated at 2 weeks, and this was associated with reduced plasma renalase in some patients. Experiments in healthy wild-type mice supported this finding of chronic cisplatin-induced suppression of renalase. The 14 days after a dose of cisplatin, renalase mRNA and protein levels were reduced in kidney, and they were further reduced 2 weeks after a second dose. The authors next examined the chronic effects of two doses of cisplatin given 2 weeks apart. Each cisplatin dose led to a loss of body weight and increased plasma creatinine in wild-type mice, but this was exacerbated in renalase knockout mice. Wild-type mice survived this treatment, but renalase knockouts displayed almost 50% mortality. Transcriptome and cell population analysis using single-cell RNA sequencing indicated that cisplatin induced dramatically higher proximal tubule cell stress and injury, and a greater inflammatory response in renalase knockout mice. These data suggest that renalase exerts a protective and anti-inflammatory response during cisplatin exposure.

Building on their previous work, the authors developed a new 36 amino acid renalase agonist (RP81) derived from the region where renalase binds its putative receptor, PMCA4b.⁸ To enhance delivery, RP81 was encapsulated in a biodegradable polymer, poly(lactic-coglycolic acid)-polyethylene glycol (PLGA), which specifically targets proximal tubule.⁹ The resulting mesoscale nanoparticles (RP81-MNP), with a diameter of around 400 nm, were confirmed to deliver RP81 to the proximal tubule by immunostaining. The ability of RP81-MNP to protect against cisplatin-induced injury was determined in wild-type and renalase knockout mice. RP81-MNP was infused intravenously starting at day 0 then weekly, with cisplatin administered at days 0 and 14. Analysis of samples collected on day 28 showed that kidney weights were higher and plasma creatinine lower in both wild-type and renalase knockout mice, compared with controls receiving the nanoparticles alone. However, it was not reported whether RP81-MNP increased survival. The authors then focused on possible protective mechanisms in renalase knockout mice. Single-cell RNA sequencing showed that RP81-MNP ameliorated cisplatin-induced injury and stress to proximal tubule cells, and decreased the numbers of infiltrating T cells, macrophages, and myofibroblasts. Although many cell-injury pathways were downregulated, RP81-MNP appeared to stimulate mitochondrial biogenesis and improve mitochondrial function. RP81-MNP also decreased inflammatory marker expression in macrophages. Finally, RP81-MNP administration largely prevented cisplatin-induced increases in plasma cytokines, renal injury markers (kidney injury marker 1 and NGAL), and histologic changes reflecting nephrotoxicity.

The next challenge lies in bringing RP81-MNP to the clinic. A significant barrier remains because efficacy was not tested in the setting of cancer. Although activation of renalase pathways is desired along the proximal tubule, renalase inhibition may have antitumor effects.¹⁰ Theoretically, the usage of PLGA to specifically target proximal tubule avoids unwanted disruption of cisplatin’s antitumor effects. PLGA has been approved by the US Food and Drug Administration for use in drug delivery systems, potentially easing the way to human trials. However, it remains to be seen whether RP81-MNP will behave differently in humans than in mice, that is, in targeting the proximal tubule and/or altering proximal function in unexpected ways. It may also not work for all patients, given the wide range of cisplatin dosage regimens and tumor types. Ultimately, the potential to translate these findings to a novel effective and safe therapy for the prevention of cisplatin-induced CKD depends on well-designed future clinical and preclinical studies to address these questions.

Disclosures

All authors have nothing to disclose.

Funding

None.