Kidney Cancer and Chronic Kidney Disease

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1		Pedro Caetano Pinto	+ 3430 word(s)	3430	2021-11-29 09:45:51

This entry is adapted from the peer-reviewed paper 10.3390/biomedicines9121761

Kidney cancer and chronic kidney disease are two renal pathologies with very different clinical management strategies and therapeutical options. Nonetheless, the cellular and molecular mechanisms underlying both conditions are closely related. Renal physiology is adapted to operate with a limited oxygen supply, making the kidney remarkably equipped to respond to hypoxia. This tightly regulated response mechanism is at the heart of kidney cancer, leading to the onset of malignant cellular phenotypes. Although elusive, the role of hypoxia in chronic kidney diseases is emerging as related to fibrosis, a pivotal factor in decaying renal function.

chronic kidney disease kidney cancer hypoxia new drug modalities biomarkers

1. Introduction

In healthy adults, both kidneys receive about 20–25% of the cardiac output. When considering their relatively small volume and weight, in comparison to other systems, the kidneys are the most perfused organs, receiving a substantially high flow of oxygenated blood ^[1]. Despite this fact, there is a paradoxical discrepancy between the oxygen levels perfused through the kidney and its actual tissue disposition and consumption. It is estimated that roughly only 10% of the oxygen reaching the kidney is consumed in cellular processes ^[2]. Arterial oxygen tension (pO₂) is approximately 100 mmHg (including in the renal artery, leading blood into the kidney) and systemic venous pO₂ is approximately 30 mmHg. In blood exiting the kidney, via the renal vein, pO₂ is approximately 70 mmHg. The reason behind this physiological attribute is the peculiar architecture of the renal vasculature ^[2]. The renal artery and vein branch-out in a parallel pattern, where arterioles and veins are arranged side-by-side, in close proximity ^[3]. This system allows oxygen to diffuse from the arterioles into the veins with little transit through the capillary network, therefore limiting the concentration of oxygen in the surrounding tissue. The nephrons—the functional units responsible for renal secretion—are exposed to variable levels of pO_2. In the renal cortex (outer-region) the glomerulus and convoluted tubules experience a higher pO₂ than the renal medulla (inner-region), approximately 30 and 10 mmHg, respectively. Arguably, the evolution of renal vasculature benefited the secretory functions of the kidneys at the expense of oxygen distribution to the tissue ^[4].

The kidneys are metabolically demanding organs that require a significant energy output to fulfil their blood filtering and reabsorption roles. Post-glomerular filtration processes depend on an array of membrane-bound transporter proteins, expressed in both the proximal and distal convoluted tubules, responsible for the removal of metabolic bi-products and xenobiotics as well as the reabsorption of solutes, water, glucose, amino-acids, and micro-nutrients ^[5]. In particular, the renal proximal tubules can concentrate a variety of compounds against steep concentration gradients ^[6]. Highly specialized renal proximal tubule epithelial cells (RPTEC) remove drugs and toxins from the blood while recovering large concentrations of glucose and sodium from the filtrate back into systemic circulation. RPTEC are rich in mitochondria, responsible for generating the adenosine triphosphate (ATP) necessary to power their active-transport machinery. With a high rate of aerobic respiration and a limited oxygen supply, renal cells constantly operate under potentially precarious pO₂ conditions ^[7]. Accordingly, the kidneys are often referred to as hypoxic organs due to their low pO₂. Hypoxia ensues when O₂ consumption exceeds supply, and renal cells have developed remarkable adaptations to function with borderline oxygen levels. An intricate regulatory mechanism maintains a fine balance between energy consumption and oxygen supply, preventing the kidneys from falling into an actual hypoxic state, where normal physiological processes can no longer be assured.

2. Regulating the Oxygen Supply to the Kidneys

The central mechanism in the cellular response to fluctuating O₂ levels is the activity of the Prolyl hydroxylases—Hypoxia-Inducible Factors (PHD-HIF) axis. This interaction functions as a cellular O₂ sensor, as PHD consume intracellular O₂ to catalyze the hydroxylation of HIFs, the nuclear transcription factors that regulate gene expression. HIFs activity is kept in check by continuous PHD-mediated hydroxylation ^[8]. When physiological O₂ levels are maintained (normoxia), hydroxylated HIFs are targeted for proteolytic degradation, which limits their expression. When O₂ levels drop, PHD activity is inhibited and HIFs expression is upregulated, prompting a response to counter the effects of reduced O₂. Several HIFs and PHD isoforms are differentially expressed across renal cells, promoting differential hypoxic responses ^[9]. A hallmark in renal hypoxic response is the increase of systemic erythropoietin (EPO). This hormone is produced in the fibroblasts of the peritubular interstitium that express PHD2 and stimulates the production of red blood cells, with the objective of increasing the concentration of O₂ delivered to the kidneys. Glomerular cells respond to hypoxia by releasing vascular endothelial growth factor (VEGF). This growth factor mediates microvasculature growth and repair by stimulating the proliferation of endothelial cells, leading to facilitated blood flow. While these responses are seemingly aimed at restoring renal pO₂ levels by augmenting supply ^[8], cells also manage hypoxic events by limiting O₂ consumption. The activity of adenosine triphosphate (ATP) dependent membrane carriers is reduced and the expression of glycolytic enzymes is enhanced in a push to preclude oxidative phosphorylation in the mitochondria in favor of non-O₂ mediated anaerobic metabolism ensuring ATP production. These mechanisms, among others, and the fact that they can be readily reversed when physiological O₂ levels are restored, illustrates the plasticity of renal cells in their hypoxic responses. Beyond the direct role of the PHD-HIF axis in sensing O₂ levels, this mechanism has a far-reaching impact in cellular regulation. PHD1 and PHD2 suppresses the activity of the nuclear factor-kappa B (NF-kB) pathway, which is involved in cell proliferation and inflammatory responses. PHD3 directly interacts with pyruvate kinase to inhibit glycolytic activity, in a way, by-passing HIF activity. Conversely, HIF activity is also induced independently of O₂ levels. Post-transcriptional regulation (e.g., phosphorylation) also plays an important role in recruiting the activity of these factors to meet different physiological needs under normoxic conditions. HIF is reported to control the expression of well over 500 genes involved in cell growth, energy production, mobility, angiogenesis, cell cycle, and even gene expression itself (chromatin remodeling) ^[10]. These pathways are critical to maintain cellular and tissue homeostasis, hence their importance in the hypoxic response.

3. Hypoxia Response and Renal Pathophysiology

The PHD-HIF axis plays a prominent role in renal pathophysiology. Kidney cancer and chronic kidney disease (CKD) are two diametrically opposed pathologies; however, at their core is the regulation of PHD-HIF and associated pathways. Both pathologies share the main, non-hereditary risk factors, including age, high-blood pressure, obesity, diabetes and smoking. Kidney cancer is also a risk factor for renal insufficiency and vice-versa ^[11]. Renal physiology with its low pO₂ is susceptible to hypoxic damage, in particular from conditions that compromise blood supply to the kidneys such as vasoconstriction and vascular damage. The resilient nature of kidney cells enables them to adapt and extensively recover from injury events and resume their physiological functions. In particular, the RPTEC, considering their high energy demand, are able to steer their physiology through hypoxic conditions. Mounting evidence underlines the fact that faults in their stress-response machinery are a major contribution to the onset of these renal pathologies (Figure 1).

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Figure 1. Cellular response to oxygen levels. (A): Under normal conditions, PHD have access to sufficient oxygen levels to promote the hydroxylation of HIF and maintain a stable expression of these transcription factors. Excess HIF is a target for proteolytic degradation mediated by VHL. (B): When cellular oxygen levels drop below the levels required to ensure PDH activity, HIF expression is destabilized. VHL is precluded from recognizing HIF and a lack of degradation leads to the activation of a myriad of genes with diverse functionalities. HIF activity will ensure cell survival and facilitate the restoration of physiological oxygen levels. Unchecked HIF activity can result in the sustained expression of inflammatory factors. (C): In RCC, the loss of VHL activity leads to the constitutive activation of HIF and a predominantly inflammatory and unbalanced cellular activity. (D): The differential activity of HIF in low oxygen conditions or in the absence of VHL leads to upregulation of several interconnected cellular pathways.

The most common type of kidney cancer is Renal Cell Carcinoma (RCC). RCC originate from RPTEC that differentiate and acquire a malignant phenotype. Depending on their aggressiveness, RCC can be fast-growing and invasive tumors. This carcinomas are characterized by the loss of function of the von Hippel-Lindau (VHL) protein ^[12]. This inactivation can result from hereditary factors, sporadic mutations or epigenetic modifications (e.g., DNA methylation), and its end-result is the constitutive activation of HIFs. VHL recognizes hydroxylated-HIF and facilities the activity of the E3 ubiquitin ligase complex, which then mediates HIF proteolytic degradation via ubiquitination. By removing VHL from this mechanism, HIF expression is stable and no longer kept in check leading to the deregulation of its target genes ^[13]. The balancing act between VHL suppressing and HIF activity is a major determinant in RCC onset, progression and outcome. Two HIF variants, -1α and -2α, are recognized by VHL and are of particular relevance in clear cell RCC (ccRCC), the most common RCC subtype. In the kidneys, HIF-1α is predominantly expressed in tubular cells, while HIF-2α is present in glomerular cells, fibroblasts and endothelial cells. In RPTEC, HIF-1α is key to the regulation of baseline glycolysis and the cell cycle, acting in this way as a tumor suppressing gene. With the onset of the malignant phenotype, cells acquire HIF-2α expression, a factor otherwise absent. HIF-2α is crucial for tumorigenic activity, and it upregulates proliferation, angiogenesis, and mediates inflammatory responses ^[14]. As cancer cells differentiate further, HIF-1α expression can be completely lost, with HIF-2α assuming its regulatory activity. RCC are highly glycolytic and angiogenic tumors that overexpress glucose membrane transporters and VEGF to meet the needs of their anaerobic metabolism ^[15].

Epidemiological studies show an interdependent link between CKD and the development of urogenital cancers, both direct and indirect. Early stages of renal insufficiency are not correlated with cancer onset, however late stage CKD patients have a 10–20-fold higher cancer incidence. This is understood to be derived from the systemic accumulation of toxic metabolites and, eventually, pharmaceuticals after diminished renal function, a factor that leads to both cellular toxicity and an impaired immune response ^[16]. On the other hand, several chemotherapeutical agents can induce kidney damage, given their cytotoxic nature and renal excretion. The latest generation of anti-cancer drugs (e.g., tyrosine kinase inhibitors, biopharmaceuticals) dramatically reduced nephrotoxic effects, overcoming chemical-induced renal damage associated with drugs of preceding generations, cisplatin being the classical example. Partial nephrectomy, the surgical procedure to remove an RCC tumor, frequently requires clamping of the renal vessels, effectively interrupting blood flow. This iatrogenic ischemia can also result in hypoxic damage to the kidney. There is a positive association between RCC diagnosis and CKD, however any underlying mechanisms connecting both pathologies are still largely unknown ^[11].

While the role of the PDH-VHL-HIF axis is well-characterized in RCC, its impact and the role played by hypoxia in CKD is far more elusive. CKD is characterized by the loss of overall kidney function and is a complex, multifactorial and insidious disease. It often leads to renal failure over time without appropriate clinical management ^[17]. Contrary to RCC, this pathology virtually affects all cell types in the nephron and not exclusively RPTEC. The effects of hypoxia in CKD are traditionally assumed to follow detrimental damage to the renal capillary network ^[18]. A restricted blood flow leads to a chain reaction where O₂ deprived renal cells promote scaring of the peritubular space and irreparable damage to nephrons and the vasculature. This damage is derived from renal fibrosis, one of the most prominent factors contributing to CKD pathophysiology, characterized by the deposition of extracellular matrix (ECM) proteins in the peritubular space. In an O₂ deficient environment, the turn-over of RPTEC is compromised, and aging epithelial cells result in the loss of tubules and degrading renal function ^[19]. The understanding of the impact of hypoxia in CDK is challenged by the contradictory activities of HIF-1α, described across a multitude of comprehensive studies. On one hand, HIF-1α activity facilitates the recovery of damaged tubular cells by controlling their de-differentiation and growth, suppresses inflammation, fibrosis and improves renal function. On the other, HIF-1α seemingly promotes the opposite, increasing fibrosis and accelerating tubular and glomerular damage. Interestingly, most detrimental effects were observed in studies involving the overexpression or knock-out of HIF-1α, while most positive effects were observed in studies using pharmacological interventions. This evidence is detailed by Faivre et al. ^[20], and arguably the experimental models used may be an important factor in the HIF-1α activity reported. Nonetheless, these dual effects suggest that HIF-1α post-transcriptional regulation, rather than its expression, dictate its physiological impact. Dedifferentiating renal epithelial cells can acquire a proto-fibrotic phenotype and drive tubulointerstitial inflammation ^[8]. HIF-1α appears to drive both regeneration and epithelial to mesenchymal transition (EMT) prompting the proliferation of differentiating RPTEC that did not fully recover their epithelial phenotype. These proto-fibrotic cells deposit extracellular matrix and can acerbate functional losses by promoting tissue fibrosis ^[21]. In a similar fashion, interstitial fibroblasts, in the peritubular space, can proliferate and deposit ECM when pushed towards a predominantly anaerobic metabolism. This process is mediated hypoxia-independently, with the transforming growth factor beta (TGF-β), a cytokine that controls cellular proliferation, inhibiting the activity of PHD2 resulting in unbalanced HIF expression ^[22]. The role of inflammation as another hypoxia-independent activator of HIF in pathophysiological conditions is now emerging, with different regulatory pathways interacting with HIF. The tumor necrosis factor alpha (TNF-α) is a cytokine released by macrophages in response to cellular stress, and can indirectly stabilize the cellular levels of HIF-1α via the transcriptional activity of the NF-kB.

4. Common Traits in RCC and CKD

Contrary to RCC, no evidence suggests that VHL expression and activity is compromised throughout the onset and progression of CKD. This supports the fact that a key difference between both pathologies is that HIF activity does not go completely unchecked during CKD. RCC, particularly in advanced stages, are highly inflammatory tumors. RCC release an array of cytokines believed to contribute to the maintenance of its microenvironment and the self-regulation of its cancer phenotype. Interleukin-6 (IL-6) and TNF-α play major roles in cancer proliferation by regulating cell growth and metabolism. Recently, systemic inflammation has been proposed as a marker for RCC progression ^[23]. The secretion of cancer-specific cytokines and chemokines enables advanced RCC to sequester the activity of immune cells to facilitate a metastatic cascade, leading to the spread and engraftment of cancer cells outside of the primary tumor ^[24]. The inflammatory nature of RCC can be considered as a mechanism responsible for cancer survival and proliferation, with tangible effects in systemic inflammation. Intra-tumor fibrosis (ITF), is the result of a complex interaction between cancer and infiltrating cells that results in dense ECM deposits populating primary tumors and plays an important role in maintaining the cancer microenvironment and as a repository of immune cells ^[25]. Circumstantial evidence shows an association between ITF and the progression of RCC into invasive tumors with poor clinical prognosis; however, to date little is known about the role that ITF plays in RCC pathophysiology ^[26]. The same mechanisms involved in renal fibrosis (e.g., TGF-β, EMT) are present in ITF tissue, and a better understanding of how prominent fibrosis is on RCC onset could shed light on the common causes of both diseases before they evolve and develop their intrinsic phenotypes. Moreover, the impact that both inflammation and ITF have on normal renal physiology is uncertain.

5. Available Therapies for RCC and CKD

Clinically, both pathologies present diverse outcomes. When detected at an early stage, RCC treatments offer a good prognosis. Tumor resection is the front-line treatment for localized RCC, enabling the removal of the tumor with limited impact on kidney function. Advanced RCC are associated with a poorer prognosis and about a third of RCC patients are estimated to be diagnosed with metastatic tumors. CKD is a progressive disease with very limited treatment options. About one in ten adults globally is estimated to experience some form of CKD. Managing lifestyle by controlling diet and blood-pressure -as well as maintaining physically active remain the best options to minimize the effects and slow the decay of renal function. Nonetheless, CKD often leads to renal failure, requiring renal replacement therapy, begins with dialysis and eventually leads to kidney transplant. RCC is stealthy and challenging to diagnose given its lack of symptoms during initial stages. This pathology does not seem to interfere with normal kidney function, even in a mid to advanced stage, rendering common markers to evaluate renal function, such as glomerular filtration rate (GFR), anemia and decreased systemic sodium, ineffective for its detection. Most RCC cases are detected by chance, when patients undergo diagnostic imaging (e.g., ultrasound, tomography scan) for unrelated reasons. Frequently, tumors are detected in patients in a risk group for renal insufficiency (e.g., high blood pressure, diabetes) that are tested for renal damage. Over the past two decades the treatment of RCC, namely in its advanced stages, saw a dramatic improvement. Patients with previously poor clinical prognosis have benefited from the introduction of, mainly, two novel drug classes, immune check-point inhibitors (ICI) and multi tyrosine kinase inhibitors (TKI). ICI are large biological immune-therapy molecules, either whole antibodies or antigen-binding fragments (Fab), that block the binding of check-point receptors in T-cells to their respective membrane ligands. Check-point receptors regulate immune responses and, under normal physiological conditions, help T-cells to discriminate between autologous, healthy and foreign cells, preventing disproportionate immune cascades. RCC cells shield themselves from the immune system by presenting specific check-point ligands in their membrane. ICI facilitate the activation of T-cells by exposing RCC as disease tissue, inducing cellular death pathways in tumor cells. TKI are small-molecule drugs that target the activity of specific tyrosine kinase proteins that regulate key cellular processes. TKIs effective in the treatment of RCC mainly target different subtypes of VEGF receptors and block their angiogenic activity. These drugs prevent endothelial cells in the vasculature from responding to VEGF secreted by RCC, compromising the tumor’s angiogenic activity and blood supply and therefore hindering cancer proliferation. Additionally, inhibitors of the mammalian target of rapamycin (mTOR) are also used to treat RCC ^[27]. The mTOR pathway is an upstream regulator of VEGF synthesis and plays a central role in cell proliferation and differentiation ^[28]. Its inhibition blocks VEGF release and hampers the proliferation of cancer cells, hence the benefits of mTOR inhibitors in RCC. Current front-line pharmacological interventions to treat RCC, depending on disease severity and risk factors at the time of diagnosis, consist of therapies combining ICI and TKI or different ICI molecules (Nivolumab and Ipilimumab) ^[29]. As of 2021, there are about 15 molecules approved for the treatment of RCC as single agents or within combinations by the European Medicines Agency (EMA) and the Federal Drug Administration (FDA) ^[30]^[31].

Contrasting with this scenario, the first molecule to treat the progression of CKD was FDA, which was approved in 2021. Dapagliflozin is a sodium glucose transport protein 2 (SLGT2) inhibitor, developed (and approved) to treat type 2 diabetes (T2D). It lowers blood sugar levels by preventing the RPTEC in the kidney from reabsorbing filtered glucose. This drug was repurposed to treat CKD after it substantially reduced the risk of renal failure and the onset of end-stage renal disease in patients with or without T2D ^[32]. In addition to blocking glucose uptake, SLGT2 inhibition in RPTEC reduces sodium uptake, which in turn reduces the workload of the Sodium-Potassium-ATPase (Na/K-ATPase) efflux pump. Na/K-ATPase are highly expressed in RPTEC and central to their physiology (e.g., maintaining electrochemical gradients, concerted activity with SLGT2, osmotic balance) and it is estimated that these pumps consume over a third of the cellular ATP production ^[33]. The downregulation of Na/K-ATPase activity is seemingly beneficial to renal physiology since it minimizes energy demand and incidentally reduces O₂ cellular consumption. With diminished pressure on their O₂ supply, HIF physiological regulation is restored and cells become more resilient to hypoxic events. Additionally, lower secretion of sodium into the renal medulla alleviates vasoconstriction. This reduces the stress in endothelial cells, improves their function and minimizes vascular damage, while restoring renal O₂ supply ^[34]. Dapagliflozin represents a direct pharmacological intervention to counter the progression of CKD; nonetheless, other therapies destined to manage other conditions can additionally help to prevent renal damage and the onset of CKD. Anti-hypertension drugs may exert a long-term protective effect in the kidneys by minimizing the effects of high blood pressure and facilitating vasodilation ^[35]. Moreover, evidence also shows that SLGT2 inhibitors have a cardioprotective role, given their anti-inflammatory and anti-fibrotic effects in cardiomyocytes derived from lower intracellular sodium levels ^[36]. Allegedly, one of the reasons behind the very limited therapeutic options for CKD is our limited understanding of its pathophysiology. This is compounded by the fact that kidney function decays with age, affecting the pharmacodynamics of several therapeutical agents and therefore precluding their potential use in the treatment of CKD ^[37].

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