Abstract

Epidemiological studies have shown a strong correlation between acute or chronic kidney injury and renal tumors. However, it is unclear whether these associations are causal and in which direction. Data accumulated from basic and clinical studies now shed light on this question and prompt us to propose a new pathophysiological concept that is intrinsically relevant to the management of patients with kidney disease and renal tumors. As a central paradigm, this paper proposes a mechanism of renal injury and repair, active in acute kidney injury and also in the persistent injury of chronic kidney disease, as a trigger of DNA damage that promotes the expansion of (pre)malignant cell clones. As renal progenitor cells have been identified by different studies as the cells of origin of several benign and malignant renal tumors, we discuss how different types of renal tumors are associated with germline or somatic mutations in renal progenitor cells at specific injury sites as well as in different signaling pathways. We explain how known risk factors for kidney cancer represent risk factors for kidney injury as an upstream cause of cancer. Finally, we propose a new role for nephrologists in kidney cancer (i.e., primary and secondary prevention and treatment of kidney injury to reduce the incidence, prevalence, and recurrence of kidney cancer).

Keywords

kidney injury;kidney cancer; Cistanche extract

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Introduction

Carcinogenesis is a complex process involving germline and/or somatic mutations that result in an uncontrolled expansion of mutant cells. Typically, this occurs in a series of steps in which a large combination of mutations only gradually passes the threshold of unrestricted cell growth Tissue damage is a known trigger for carcinogenesis for two reasons: (i) it may induce DNA damage and somatic mutations, particularly in tissue-resident long-lived stem cells; and (ii) it promotes the expansion of such mutant cells during tissue repair Potentially, these two mechanisms contribute, for example, to colorectal cancer associated with inflammatory bowel disease, lung cancer associated with exposure to toxic fumes and dust particles, gastric cancer associated with atrophic gastritis, and hepatocellular carcinoma associated with cirrhosis.

Many epidemiological studies have reported an association between chronic kidney disease (CKD) and kidney cancer. Although both preferably occur in the second half of life, it is unclear if and how these associations are linked through causality. For example, etiology may be one way because oncologic treatments, including surgery, anti-angiogenic drugs, or mechanistic targets of rapamycin (mTOR) and immune checkpoint inhibitors involve an increased risk of acute kidney injury (AKI) and CKD. Again, whether kidney injury leads to kidney cancer is unclear, although some studies suggest that kidney cancer occurs after an episode of AKI or years after CKD in the renal failure phase.

In this review, we discuss the role of kidney injury as a driver of kidney cancer. Starting from epidemiological and genetic evidence, we discuss the evolving experimental support for renal injury as a trigger for DNA damage and clonal proliferation of mutant renal cells in different renal compartments, identifying tumor tissue types. We discuss recent insights on the putative cellular origins of benign and malignant renal tumors and explain how injury-mediated alterations activated by different signaling pathways lead to different tissue types of renal tumors. We further explore how the mechanisms underlying renal repair, which play a role transiently in AKI episodes and persistently in CKD, promote tumor growth and tumor recurrence. Finally, we suggest that prevention of AKI and CKD is the best way to stop the development of renal cell carcinoma (RCC) and avoid its consequences. This concept of a bidirectional causal relationship between kidney disease and kidney tumors requires that nephrologists play a central role in the prevention and treatment of patients with kidney cancer.

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The risk factors for kidney cancer are risk factors for kidney disease

Epidemiologic studies have identified correlations but not causality, and such correlations often give rise to misleading interpretations. For example, in the search for unknown causes of kidney cancer, epidemiologic studies have identified several "risk factors" whose direct causal relationship with cancer is not always apparent. Obesity, diabetes, hypertension, smoking, nephrotoxic drugs, and heavy metals all contribute to kidney injury, including AKI or CKD, and may be indirectly associated with the incidence of injury-related kidney cancer. Indeed, nephrotoxic drugs and heavy metals can induce episodes of toxic AKI associated with necroinflammation and oxidative stress Obesity, diabetes, and smoking are recognized risk factors for glomerular filtration through glomerulosclerosis-related CKD, leading to renal unit loss and substantial adaptive cellular changes in residual renal units to adapt to metabolic needs Finally, hypertension is usually a consequence of kidney disease and a sensitive indicator of early CKD, and rather than an etiology.

Site-specific kidney injuries cause unique subtypes of kidney cancer

There is increasing evidence that different subtypes of renal tumors originate from cells located at the site of the initial injury. In addition, the prevalence of different renal cancer histotypes correlates with the prevalence of specific triggers of renal injury.

Most common: Clear cell carcinoma arising from a metabolic overload of the proximal tubule of the residual renal unit in CKD

Prospective studies have shown that CKD directly contributes to kidney cancer, particularly the clear cell RCC (ccRCC) histotype, which accounts for 70 - 80% of kidney cancers. A follow-up study of 33,346 subjects, aged 26 - 61 years at baseline with a median follow-up of 28 years, showed that moderate CKD at baseline increased the risk of subsequent kidney cancer Promoting CKD obesity and diabetes also drive the development of RCC. The link between these two conditions is demonstrated by the metabolic overload of proximal tubular cells in the residual nephron, with a significant increase in single nephron hyperfiltration (and high tubular reabsorption) This leads to chronic cortical damage and CKD in obese and diabetic patients, which may subsequently develop into ccRCC, usually originating from cells in the proximal tubule of the cortex (S1/S2 segment).

Still frequent: papillary carcinoma triggered by ischemic necrosis of proximal tubules

Data from Italian and Danish cohort studies suggest that patients with a history of AKI are at increased risk of developing papillary RCC (pRCC) Further multicenter analysis showed that patients who underwent pRCC tumor resection and experienced postoperative AKI episodes had a higher risk of tumor recurrence compared to patients who did not experience postoperative AKI, suggesting that ischemic injury promotes tumor growth This association was further confirmed in AKI was further confirmed in an experimental model where the authors observed that post-ischemic AKI promotes long-term development of papillary tumors in mice by activating tumor growth-promoting pathways Direct evidence for a causal link between ischemic AKI and renal cancer comes from experiments showing the appearance of papillary adenomas 3 - 6 months after ischemia and, in some cases, the later transformation of these adenoma-carcinoma sequences into pRCC papillary Adenomas and carcinomas are mostly located in the outer strips of the outer medulla, and ischemic necrosis affects cells in the S3 segment of the proximal tubule.

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Rare but specific: lithium is toxic to collecting ducts and causes collecting duct cell-derived tumors

Lithium-ion therapy is associated with collecting duct toxicity, leading to nephrogenic urinary incontinence in up to 40% of patients Studies have shown that lithium causes loss of the molecular water channel aquaporin-2. Lithium also alters the Notch pathway, which is involved in many aspects of cancer biology and plays an important role in regulating the maintenance of the mature renal epithelial cell state Long-term lithium exposure can lead to tubulointerstitial nephritis and renal cysts originating in the distal tubules and collecting ducts Although long-term lithium use is not associated with an increased cumulative risk of kidney cancer, example lithium-treated patients exhibit the development of pheochromocytoma/phobic RCC (caused by common progenitor cell lesions, similar in histology and morphology) and a high risk of collecting duct cancer. All of these tumors originate from the collecting ducts and are reported to be rare.

However, the European Medicines Agency's Drug Alert Risk Assessment Committee has agreed that there is sufficient evidence to conclude that long-term lithium use may induce micro cysticercosis, pheochromocytoma, and collecting duct renal carcinoma. Similarly, animals treated with lithium exhibited increased proliferation of principal cells, as well as increased numbers of intercalated cells, which may be due to the proliferation and differentiation of progenitor cells or conversion of principal cells to intercalated cells Thus, lithium treatment-associated pheochromocytomas and collecting duct carcinomas represent another example of site-specific carcinogenesis in the kidney injury.

Rare but specific: sickle cell anemia induces ischemic medulla injury and medullary carcinoma

Sickle cell anemia (SCA) is a monogenic hemoglobin disorder associated with recurrent episodes of organ hypoperfusion, tissue ischemia, and necrosis Sickle cell nephropathy is a serious complication of SCA that may progress to CKD and renal failure.66,67 In cross-sectional studies of children with SCA, elevated blood pressure and ischemia during episodes of CKD sickle cell disease were seen in 16.7% and 8.3% of patients, respectively can cause irreversible damage to the vascular structures of the renal medulla, sometimes leading to the development of medullary carcinoma, an aggressive form of kidney cancer almost exclusively associated with SCA. Indeed, extreme hypoxic and hyperosmotic conditions in the renal medulla, together with local ischemia caused by erythrocytic sickle disease, activate DNA repair mechanisms to drive the deletion and translocation of switch/sucrose non-fermentation-related, matrix-associated, chromatin subfamily b member 1 (SMARCB1), a tumor suppressor gene localized to a vulnerable region of chromosome 2268.

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This association suggests a causal relationship between injury to cancer because cancer cannot cause SCA, hemoglobin mutations cannot directly cause medullary carcinoma, and SCA-associated medullary carcinoma does not occur in the absence of renal injury.52,53 Thus, SCA-associated renal carcinoma provides a strong clue to the role of injury in renal carcinoma compared with single-gene forms of renal cancer that directly involve mutations in renal cells. because of the lack of causative genes within renal cells and the use of renal injury only as an upstream event in renal carcinogenesis. Furthermore, the role of analgesics and other potential third factors is unlikely in this setting because the medullary location of injury and cancer subtype does not support a toxic trigger, but supports a pathogenic role for SCA-mediated ischemic injury at this location. Thus, SCA-associated nephrocalcinosis provides another piece of evidence for the concept that renal injury may be a causative agent of renal cancer.

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