Onconephrology

Although immune checkpoint inhibitors can prolong survival in people with clear-cell renal-cell carcinoma, disease progression is frequent. Here, the authors explore potential mechanisms that might drive intrinsic or acquired resistance to immune checkpoint inhibitors in clear-cell renal-cell carcinoma, including malignant cell-intrinsic and immune-cell factors.

Renal cell carcinoma is a metabolic disease linked to a variety of alterations in genes that regulate cellular metabolism. Here, the authors examine cell-intrinsic metabolic alterations in hereditary and sporadic renal cell carcinoma, and how they can be exploited to develop novel therapeutic interventions.

Renal cell carcinoma is sensitive to immune checkpoint blockade despite having a moderate traditional tumour mutational burden profile. Here, the authors discuss how the high prevalence of frameshift insertion or deletions in renal cell carcinoma, as well as the reactivation of endogenous retroviral gene expression, might provide alternative neoantigens that potentiate responses to immunotherapy.

Immune checkpoint inhibitors are increasingly used as anti-cancer treatments; however, their use can be associated with the development of immune-related adverse events, including acute kidney injury. This Review describes the symptoms, biochemical signs and possible underlying mechanisms of immune checkpoint inhibitor-associated acute kidney injury, and proposes an approach to its diagnosis and management.

Here, the authors review the mechanisms that underlie cisplatin-induced acute kidney injury and chronic kidney disease. They also discuss the challenges of developing renoprotective approaches for patients receiving cisplatin-based chemotherapy and potential targets for renoprotection.

Patients with haematological cancer are at risk of kidney injury, whether as a direct consequence of the malignancy or because of treatment-related effects. Here, the authors review the most common causes of kidney injury in these patients and discuss their pathophysiology, presentation and management.

The molecular features that define the initiation and progression of clear cell renal cell carcinoma (ccRCC) are being increasingly defined. This Review summarizes common genomic and chromosomal copy number abnormalities in ccRCC, providing a mechanistic framework with which to organize these features into initiating events, drivers of progression and factors that confer lethality.

Here, the authors describe the effector cell populations and immunosuppressive networks that are present in renal cell carcinoma (RCC) tumours. They also discuss the use of immune checkpoint inhibitors and novel approaches such as adoptive cell therapy in patients with RCC.

Genomic profiling of renal cell carcinoma has demonstrated the clinical relevance of several genetic alterations in different disease subtypes. Pal and colleagues discuss the prognostic and predictive value of these alterations, and how they might help to improve treatment selection and patient outcomes.

Oncometabolites — conventional metabolites that, when aberrantly accumulated, have pro-oncogenic capabilities — have been implicated in renal cell carcinoma (RCC). Here, the authors review the role of oncometabolites in RCC, their origins and downstream effects and their potential applications as novel therapeutic targets and biomarkers.

Effective adjuvant therapies are needed to reduce the risk of recurrence of kidney cancer. Here, the authors discuss the results of adjuvant therapy trials, the potential of immune checkpoint inhibitors as adjuvant therapies and the need for multidisciplinary management of patients with resected kidney cancer.

Wilms tumour is the most common renal malignancy of childhood. Here, the authors review the genetic landscape of Wilms tumour and discuss how precision medicine guided by genomic information might lead to new therapeutic approaches and improve patient survival.

Here, Lam and colleagues review advances in understanding the pathogenesis of tuberous sclerosis complex (TSC). Although rapalogues are effective cytostatic treatments for TSC, the unique metabolic vulnerabilities of cells lacking hamartin and/or tuberin might represent opportunities for developing cytocidal treatments.

Immune checkpoint inhibitors (ICIs) have led to a paradigm shift in cancer therapy; however, these agents can induce immune-related adverse events (irAEs) in off-target organs. This Review describes the mechanism of action of ICI therapies and how these agents induce irAEs in the kidney and heart.

Kidney transplant recipients have an increased risk of developing de novo or recurrent cancer compared with age-matched and gender-matched individuals from the general population. Here, Au et al. describe the epidemiology and outcomes of cancers in transplant recipients and discuss approaches to reduce cancer prevalence as well as post-transplantation cancer management, including approaches for modulating immunosuppression.

This Review provides an overview of the molecular determinants of renal cell carcinoma, how understanding the underlying mechanisms of disease has fuelled the development of targeted therapies, and tools to assess the value of these agents.

Clear cell renal cell carcinoma is associated with reprogramming of metabolic pathways including glucose and fatty acid metabolism and the tricarboxylic acid cycle. Here, the authors discuss these reprogrammed pathways and the opportunities they provide for new therapies, imaging modalities and biomarkers.

New data suggests that, in addition to mutations in tumour-suppressor genes, renal cancer is associated with epigenetic aberrations. Here, the authors discuss the mechanisms by which epigenetically silenced genes and mutations in genes that are involved in histone modification or chromatin remodelling dysregulate crucial cellular pathways in renal cancer.

Epigenetic machinery and chromatin remodelling complexes are disrupted in >80% of clear cell renal cell carcinoma tumours. Here, the authors discuss the impact of genomics in identifying genes that affect susceptibility to renal cell carcinoma as well as the opportunities for a precision medicine approach to diagnosis and treatment.

A recent clinical trial reports promising efficacy and safety data for belzutifan in patients with von Hippel–Lindau (VHL) disease–associated renal cell carcinoma. On the basis of these results, belzutifan became the first therapeutic agent to be approved for the systemic treatment of cancer associated with VHL disease.

Paradoxically, elevated BMI is a recognized positive prognostic factor in renal cell carcinoma (RCC). A recent investigation of the transcriptomic signatures of RCC tumours and peritumoural tissues suggests potential biological mechanisms underlying this effect. However, the clinical utility of BMI in the context of RCC remains uncertain.

In recent years, the molecular view of clear cell renal cell carcinoma (ccRCC) has been based primarily on gene transcription data with limited information on protein features. A new study led by the Clinical Proteomic Tumor Analysis Consortium now offers a comprehensive view of the ccRCC proteome.

New data from the JAVELIN Renal 101 and KEYNOTE-426 trials provide evidence that immune-based combination therapy has superior efficacy to sunitinib monotherapy in patients with advanced renal cell carcinoma. The new findings raise important questions regarding the optimum choice of combination therapy for these patients.

Cytoreductive nephrectomy is the current treatment paradigm for metastatic renal cell carcinoma (RCC). However, the introduction of targeted therapies has dramatically changed the treatment landscape and may limit the role of nephrectomy in this disease. The recent CARMENA trial supports initial medical treatment of patients with RCC and synchronous metastases.

Three reports from the TRACERx Renal study delineate the precise origin and evolution of clear cell renal cell carcinoma in minute detail. The insights gained from these studies might provide improved disease prognostics and identify novel therapeutic targets.

The cellular origins of angiomyolipoma and other tuberous sclerosis complex-associated neoplasms are unknown. Now, two studies show that these neoplasms derive from cancer stem cells that originate from multipotent renal epithelial cells. The new findings provide a link between stemness and tumorigenesis in the kidney.

Renal cell carcinoma (RCC) is the most common malignancy seen in the nephrology clinic, yet most nephrologists have inadequate knowledge of current treatment options. Here we discuss RCC presentation and therapies, including potential renal adverse effects, and highlight the need for involvement of nephrologists in the multidisciplinary management of this disease.