RCC comprises the largest proportion of kidney tumours and is histologically categorised into clear cell (70%), papillary (10–15%), chromophobe (5–10%), and collecting duct carcinoma (<1%). At the time of diagnosis, approximately 30% of RCC patients exhibit metastatic disease, while nearly 50% of those who receive curative surgery encounter relapse accompanied by distant metastases. Over the past few years, the prognosis of RCC patients has witnessed substantial enhancement owing to the advent of molecular targeted therapies. These treatment modalities encompass various therapies including small-molecule TKIs such as sorafenib, sunitinib, pazopanib, and axitinib; mTOR inhibitors such as temsirolimus and everolimus; and an antiangiogenic antibody named bevacizumab that is typically administered alongside interferon alpha. Among them, pazopanib stands out as a multi-TKI that can be taken orally and targets kinase receptors crucial for tumour cell angiogenesis and proliferation (such as VEGF receptors, PDGF receptors, and the c-Kit receptor). Consequently, this leads to the inhibition of angiogenesis, impeding cell growth and survival and ultimately preventing tumour progression and propagation. Pazopanib received approval from the United States Food and Drug Administration (US FDA) in October 2009 for treating advanced or metastatic RCC based on encouraging results from a phase III randomised clinical trial [9]. The study demonstrated a significant improvement in PFS when compared to the placebo across the entire study population (median PFS 9.2 vs. 4.2 months; hazard ratio (HR), 0.46; 95% CI, 0.34 to 0.62; p < 0.0001), as well as within both the treatment-naive subgroup (median PFS 11.1 vs. 2.8 months; HR, 0.40; 95% CI, 0.27 to 0.60; p < 0.0001) and the subgroup of patients previously treated with cytokines (median PFS 7.4 vs. 4.2 months; HR, 0.54; 95% CI, 0.35 to 0.84; p < 0.001). However, it is important to note that the inhibition of multiple targets by pazopanib can lead to various adverse events, among which hematologic and hepatic toxicities such as elevated aspartate and alanine aminotransferase levels (as well as bilirubin elevation) are particularly significant and necessitate careful monitoring [10]. However, there is still no definitive evidence to support a relationship between the severity of adverse events and efficacy. Because pazopanib blocks the VEGF receptor, it is associated with hypertension and other cardiovascular complications [11]. Apart from hypertension and hematologic and hepatic toxicities, pazopanib may induce hair depigmentation, diarrhea, nausea, anorexia, and vomiting.

PRES is a condition that manifests as various neurological symptoms that include seizures and hypertensive emergencies. However, diagnosing PRES based on clinical presentation alone can be challenging because these findings lack specificity. On the other hand, MRI findings often provide a characteristic pattern and are a critical component in diagnosing PRES. Lesions typically appear in the posterior white matter and may involve the overlying cortex. They show up as hyperintense on T2-weighted images and usually hypointense or isointense on diffusion-weighted images with an increase in the apparent diffusion coefficient, indicating vasogenic oedema [5]. The availability and advancement of brain imaging techniques, especially MRI, have contributed to the increasing recognition of PRES as a clinical syndrome.

The pathophysiology of the development of PRES is still poorly understood. Three hypotheses have been proposed to explain the pathogenesis of PRES. The first hypothesis suggests that cerebral vasoconstriction causes subsequent infarcts in the brain. The second hypothesis proposes that there is a failure of cerebral autoregulation, which leads to vasogenic edema. The third hypothesis involves endothelial damage with blood–brain barrier disruption, resulting in fluid and protein transudation in the brain [12]. Endothelial dysfunction, which is characterised by an impaired vasodilation phenotype and a proinflammatory state of the endothelium, is an on-target effect of VEGF receptor inhibitors. The vasoconstrictive response to these drugs is related to a reduction in the levels of the vasodilator nitric oxide and an increase in vasoactive peptides such as endothelin and arginine vasopressin (AVP). Recent studies suggested that AVP overstimulation plays a significant role in the development of PRES and its associated symptoms, particularly due to its pathophysiologic role in brain edema formation and its involvement in most PRES etiologies [13]. The preferential involvement of posterior brain regions is likely due to regional heterogeneity of the arterial sympathetic innervation. This innervation is highest in the anterior circulation and decreases with an anterior-to-posterior gradient. Therefore, the occipital lobes and other posterior brain regions are at a relatively higher risk for hydrostatic edema [14]. From the diagnostic perspective, if a patient presents with neurologic symptoms and signs and the medical history suggests hypertension, immunosuppressive agents, TKI inhibitors, and/or kidney disease, a brain MRI is strongly recommended. Treatment of PRES is mainly symptomatic, including an effective management of blood pressure, control of seizures, and management of underlying disease or elimination of causative factors [15]. In most cases, PRES is completely reversible, but in severe forms, it might cause substantial morbidity and even mortality, often due to acute hemorrhage or extensive edema in the posterior fossa that leads to obstructive hydrocephalus or compression of the brainstem [16].

VEGF inhibition led to structural remodelling of the resistance vasculature as evidenced by microvascular rarefaction and a significant increase in peripheral vascular resistance with a subsequent increase in blood pressure [17]. Given that VEGF receptor inhibition has been theorised to play a prominent role in the development of hypertension, it may subsequently mediate PRES. Indeed, significant elevation in blood pressure above the limit of cerebral autoregulation can cause the leaking of blood products into the white matter parenchyma. To prevent this, the National Cancer Institute recommends lowering blood pressure to below 140/90 mmHg during VEGF receptor inhibitor treatment (or below 130/80 mmHg for patients with chronic kidney disease or diabetes) [18].

Apart from the supportive measures for the treatment of PRES, if a targeted biological agent or immunosuppressant drug is identified as the underlying trigger for development of this syndrome, then consideration should be given to either discontinuation or dose modification of the offending agent early in the course of disease [19]. Blood pressure management includes gradual lowering of the blood pressure up to 20–25% in initial few hours with the aim of normalising the mean arterial pressure [20]. As the name suggests, PRES is a benign and reversible condition, but long-term functional impairment and death can occur if not diagnosed early or treated properly [21]. Specifically, pazopanib-induced PRES can be associated with intracerebral haemorrhage, which may lead to permanent neurologic deficits or even death.