Evaluation of the nephroprotective role of cystone in patients receiving cisplatin-based chemotherapy

INTRODUCTION

Renal dysfunction frequently arises in oncology patients, stemming either from direct tumour effects or the adverse impact of treatment modalities. Cisplatin, a cornerstone in cancer chemotherapy, is limited by its nephrotoxic potential, with acute kidney injury (AKI) developing in approximately 20–30% of recipients.^[1] Cisplatin-induced AKI (CIAKI) carries significant short- and long-term clinical consequences that extend beyond the immediate episode of renal dysfunction. Even after apparent recovery, many patients experience incomplete restoration of baseline renal function, predisposing them to chronic kidney disease.^[2] Repeated cisplatin exposure further compounds this risk, with cumulative tubular injury contributing to progressive decline in glomerular filtration rate (GFR). CIAKI is also frequently accompanied by electrolyte derangements, most notably hypomagnesaemia, hypokalaemia and hypocalcaemia, which can exacerbate morbidity and complicate oncologic care.^[3] Furthermore, the occurrence of CIAKI often necessitates chemotherapy dose reductions, treatment delays or substitution with less effective regimens, potentially compromising cancer control outcomes.^[4] Severe CIAKI has been independently associated with increased hospitalisation rates and a higher risk of all-cause mortality in oncology populations.^[5] These sequelae underscore the critical importance of implementing effective preventive strategies and vigilant renal monitoring throughout cisplatin-based treatment courses.

To mitigate nephrotoxicity, the European Society of Medical Oncology and ASCO recommend hydration strategies and dosing adjustments based on renal function. Despite these measures, CIAKI remains a substantial clinical challenge, often compromising therapeutic continuity.^[1,6,7] Among cytotoxic agents, cisplatin is particularly notorious for its renal toxicity, which involves a combination of renal tubular uptake, oxidative damage, inflammatory signalling and apoptosis.^[4,8]

Among the pathways implicated in CIN is the overproduction of reactive oxygen species (ROS), along with renal vasoconstriction and nitric oxide imbalance. Given these mechanisms, antioxidant therapy has been proposed as a supportive measure.^[9,10] Cystone contains multiple botanicals with reported antioxidant and anti-inflammatory actions, and its protective effect against nephrotoxic agents was first described in 1999.^[11,12] Multiple clinical trials have confirmed the safety and tolerability of Cystone in both short and long-term use. In a randomised trial, only mild and self-limiting adverse effects such as dyspepsia were reported.^[13] A double-blind, placebo-controlled study by Kumaran and Patki (2011) similarly found no serious adverse events.^[14] Another prospective trial confirmed its safety in patients with ureteric calculi.^[15] However, the clinical literature evaluating Cystone’s efficacy in this context is sparse and dated. This knowledge gap warrants updated investigations, particularly in the setting of modern chemotherapy protocols.

Despite the clinical importance of cisplatin-induced nephrotoxicity (CIN), the existing literature on the use of Cystone or similar polyherbal formulations remains limited and relatively outdated. This scarcity of recent evidence underscores a notable gap in current knowledge. Nevertheless, due to the complexity and clinical relevance of this topic, it remains essential to revisit and critically evaluate earlier studies, while also promoting new, high-quality research efforts to enhance clinical understanding and therapeutic guidance.

MATERIALS AND METHODS

This phase II interventional, randomised, controlled, prospective, open-label study was conducted at Ain Shams University Hospitals, involving patients receiving cisplatin-based chemotherapy.

RESULTS

A total of 99 patients were randomly allocated to either study arm (n = 49) or control arm (n = 50). Our patients’ characteristics are described in Table 2. There was balanced distribution among the two arms regarding gender, age (mean), weight (mean) and body surface area (mean). The presence of diabetic versus non-diabetic patients, as well as hypertensive versus non-hypertensive patients, was also balanced between the two groups. The study population was heterogeneous in diagnosis and consequently in the used cisplatin-containing protocol. However, their difference in distribution between the two arms was statistically insignificant. We used 70 mg/m² as a cut-off level, above which the cisplatin standard dose per cycle is high, and below 70 mg/m² is considered low-dose cisplatin. There was predominance of high-dose cisplatin protocols among the study population, with 75 patients (75.5%), and their distribution was well balanced between the two groups. The mean cumulative dose in the Cystone arm was 352 mg, and in the control arm was 407 mg (P = 0.188).

Of 99 patients, 29 patients (29.2%) have developed AKI of any grade, and their distribution is shown in Table 3. According to CTCAE v5, only AKI grades 1 and 2 were reported in our study population. No AKI grade 3, 4 or 5 was reported. There was a numerical difference between the two groups regarding the incidence of grade 1 and 2 AKI. In Cystone group, 11 patients developed Grade 1 compared to 14 in the control group. Two patients in the Cystone group and three in the control group had Grade 2 AKI, but this difference was not statistically significant (P = 0.45).

At the end of treatment, abnormal s.Cr level was found in 5 patients in Cystone arm compared to 11 patients in the control arm. In addition, an abnormal CrCl level was found in 1 patient in Cystone arm and 3 patients in the control arm. However, there was nonstatistically significant difference between the two groups (P = 0.11 and P = 0.3, respectively).

Need to dose modification due to nephrotoxicity occurred in 5 patients in Cystone arm versus 12 in control arm, but with no statistical significance (P = 0.8).

As shown in Table 4, there was a difference between the mean value of initial s.Cr (0.8) and the mean value at the end of treatment (0.9) in Cystone arm. In the control arm, the mean value of initial s.Cr was 0.8 (P = 0.139), and at the end of treatment, it significantly increased to a mean value of 1 (P = 0.0001). Similarly, there was a statistically significant drop in CrCl from an initial mean value of 111 to a mean value of 97 at the end of treatment in the control arm (P = 0.003).

As presented in Table 5, we examined the relationship between AKI incidence, any grade and various patient and treatment factors, including the use of other nephrotoxic agents. Among these variables, only diabetes was discovered to have a significant correlation with AKI (P = 0.03).

DISCUSSION

CIN remains a common and impactful adverse event, with estimates indicating that up to one-third of patients may experience some degree of kidney injury during treatment.^[1,4,18] Our findings align with this, showing a CIAKI incidence of 29.2%, reinforcing the relevance of our cohort to general clinical practice.

Our selected dosing regimen–two tablets administered every 8 h–was informed by these earlier trials.^[16,19] It was instructed that Cystone would be continued until 21 days after the last chemotherapy cycle, considering that CIN most often occurs within the first 10 days following administration.^[5,18]

A previous clinical trial investigated Cystone, and it used both s.Cr-based and 24-h urine creatinine-based GFR, while another study measured cystatin C levels in addition to s.Cr and CG equation for CrCl to assess CIAKI.^[16,20] GFR remains the most widely accepted parameter for assessing renal function.^[21] GFR and CrCl were evaluated using the CG equation, a widely accepted and practical method in oncology care.^[7,22,23]

By excluding individuals with baseline renal impairment, uncontrolled diabetes or uncontrolled hypertension, we aimed to minimise confounding variables. This allowed for a more focused assessment of Cystone’s potential role in preserving renal function across various cisplatin dosing strategies.^[9]

Unlike some prior trials^[16,20] that only evaluated standard-dose cisplatin (75 mg/m²), we included a broader spectrum of dosing protocols. Patients were subsequently stratified by dose intensity, using 70 mg/m² as a cut-off, which may have influenced statistical outcomes. A more targeted stratified randomisation approach may yield clearer results in future investigations.

Comparative studies, including one by El-Ghiaty et al., reported significant renal protection with Cystone among 48 Egyptian patients, like our population. In their study, Cystone group was significantly less affected by CIN, 64% compared to 23% in the control arm (P = 0.01).^[16] In a pilot study involving 43 cancer patients receiving cisplatin at a dose of 75 mg/m², no significant changes were observed in either s.Cr-based GFR (P = 0.453) or 24-h urine creatinine-based GFR (P = 0.397) throughout the study. Conversely, the control group exhibited significant alterations in both s.Cr-based GFR (P = 0.013) and 24-h urine creatinine-based GFR (P = 0.016), with the s.Cr-based GFR increased by 2.3 units in the intervention group compared to a rise of 10.5 units in the control group (P = 0.005).^[20]

However, our study did not demonstrate a statistically significant reduction in CIAKI incidence (P = 0.4). Despite this, our findings paralleled previous work in that the control group showed a significantly greater decline in renal function markers. As shown in Table 4, the control group demonstrated a statistically significant increase in s.Cr of 3 units between baseline and end-of-treatment values (P = 0.0001; [Table 4]). Moreover, the reduction in mean CrCl from 111 to 97 was also significant (P = 0.003), indicating a notable decline in renal function over the course of treatment.

Furthermore, we addressed the theoretical concern that Cystone, by modulating oxidative stress, might compromise cisplatin’s antitumour efficacy. Our review of available literature found no definitive evidence supporting or refuting this possibility, underscoring the need for long-term outcome studies.^{[10,16,20,24]}

A noteworthy observation was the higher CIAKI incidence among diabetic patients, reinforcing the known vulnerability of this subgroup. While we ensured balanced distribution between study arms, the significant difference (13.8% vs. 2.9%, P = 0.03) emphasises the need for tailored preventive strategies in diabetic oncology patients.

CONCLUSION

In this open-label, randomised trial, Cystone demonstrated a potential trend toward nephroprotection in patients receiving cisplatin-based chemotherapy, although the primary endpoint of AKI incidence did not reach statistical significance. While the heterogeneity of tumour types and treatment protocols limits strict generalisability, the pragmatic design reflects real-world clinical practice in which cisplatin is used across diverse cancer settings. The observed findings suggest a potential nephroprotective effect of Cystone; however, these results are exploratory and should be interpreted as hypothesis-generating. Confirmation through larger, homogeneous, placebo-controlled trials is warranted before these findings can be translated into routine clinical practice.