The Nephrologist's Tumor: Basic Biology and Management of Renal Cell Carcinoma

Abstract

Kidney cancer, or renal cell carcinoma (RCC), is a disease of increasing incidence that is commonly seen in the general practice of nephrology. However, RCC is under-recognized by the nephrology community, such that its presence in curricula and research by this group is lacking. In the most common form of RCC, clear cell renal cell carcinoma (ccRCC), inactivation of the von Hippel-Lindau tumor suppressor is nearly universal; thus, the biology of ccRCC is characterized by activation of hypoxia-relevant pathways that lead to the associated paraneoplastic syndromes. Therefore, RCC is labeled the internist's tumor. In light of this characterization and multiple other metabolic abnormalities recently associated with ccRCC, it can now be viewed as a metabolic disease. In this review, we discuss the basic biology, pathology, and approaches for treatment of RCC. It is important to distinguish between kidney confinement and distant spread of RCC, because this difference affects diagnostic and therapeutic approaches and patient survival, and it is important to recognize the key interplay between RCC, RCC therapy, and CKD. Better understanding of all aspects of this disease will lead to optimal patient care and more recognition of an increasingly prevalent nephrologic disease, which we now appropriately label the nephrologist's tumor.

Keywords: cancer; chronic renal disease; renal carcinoma.

Figure 1.

New therapeutic targets arise from metabolic reprogramming in RCC. Novel targets for therapeutic intervention on the basis of published work^, are shown in bold. Kidney cancer cells exhibit increased glucose uptake, glycolysis, and lactate production, with an associated decrease in pyruvate entering the tricarboxylic acid (TCA) cycle. These pathways can be targeted by inhibiting glucose uptake or the enzymes hexokinase, pyruvate kinase, and lactate dehydrogenase. Kidney cancer cells also exhibit alterations in glutamine metabolism to generate glutathione and reduce reactive oxygen species (ROS). This pathway can be targeted by inhibiting glutamine uptake, glutaminase, or enzymes involved in glutathione synthesis (γ-glutamylcysteine synthetase and glutathione synthetase). Kidney cancer cells also exhibit increased tryptophan metabolism, which results in increased levels of kynurenine, an immunosuppressive metabolite. The production of kynurenine can be inhibited by targeting indoleamine 2,3-diaxygenase (IDO). Reprinted from ref. with permission.

Figure 2.

Renal characteristics determine the need for nephrology referral in RCC patients. Several clinical parameters can be used to determine the need for nephrology evaluation before nephrectomy. This flowchart will assure that patients with high risk of postnephrectomy decline in renal function are evaluated by a nephrologist before nephrectomy is performed. Albumin is in mg/24 h; eGFR is in ml/min per 1.73m².

Figure 3.

New-onset CKD or progression of CKD and ESRD may develop after nephrectomy because of nephron loss in patients with underlying risk factors. Nephrectomy performed for RCC is associated with nephron loss caused by tissue removal as well as ischemic and vascular injuries. This loss of nephrons is associated with either new-onset CKD or progression of CKD in patients who have various risk factors as noted. GS, glomerulosclerosis; HTN, hypertension; IF, interstitial fibrosis; VS, vascular sclerosis.