Cabozantinib for the Management of Metastatic Clear Cell Renal Cell Carcinoma

Cabozantinib is a multi-tyrosine kinase inhibitor used for the treatment of various solid-organ tumours. It was recently approved as a first- and second-line therapeutic for the management of advanced/metastatic renal cell carcinoma based on the results of two randomised controlled trials. The phase III METEOR trial compared cabozantinib against everolimus as a second- or greater line therapy and found benefits in progression-free and overall survival, and the phase II CABOSUN trial compared cabozantinib against sunitinib as a first-line therapeutic and found benefits in terms of progression-free survival. This review briefly summarises how cabozantinib fits into current treatment paradigms for the management of advanced renal cell carcinoma

Kidney cancer biobanking: considerations for a single institutional biorepository

The Princess Alexandra Hospital Kidney Cancer Biobank, housed at the Translational Research Institute in Brisbane, is an Australian biorepository which contains fixed and fresh-frozen cancer and non-cancer kidney tissue, perinephric fat, urine and peripheral blood. The patient samples are linked to de-identified clinical information via a secure database. Participants undergoing nephrectomy for suspected renal malignancy are recruited prospectively. Recruitment began in 2013 and the biobank currently contains biofluids, tissue and clinical information for more than 330 participants. This biobank contains linked de-identified clinical data, which provide comprehensive information about biospecimens, and information about clinical outcomes

Multifocal primary neoplasms in kidney allografts: evaluation of two cases

Renal cell carcinoma (RCC) is the fifth most common malignancy in kidney transplant recipients, with increased risk arising due to immunosuppression. De novo RCC occurrence in kidney allografts is much less common when compared with the native kidneys. Multifocal RCC in allograft kidneys is rarely described. In this report, we discuss two cases of de novo multifocal renal neoplasms in allograft kidneys. Case 1 had three distinct neoplastic lesions of >5 mm, and case 2 had four. Using the World Health Organization 2016 classification of adult renal tumours, case 1 had one clear-cell (cc) RCC (grade 3) and two papillary adenomas; all confined to the kidney. Case 2 had a nodular lesion classified as ccRCC (grade 4) with focal rhabdoid differentiation and some infiltration of renal sinus fat; a cc tubulopapillary RCC; a multilocular cystic renal neoplasm of low malignant potential; and a mucinous tubular and spindle cell carcinoma; the last three all confined to the kidney. This is the first report of mucinous tubular and spindle cell carcinoma in a kidney allograft. When considering multifocal RCC with discordant histology, it is likely that these represent independent tumourigenic events

Kidney cancer subtypes, identified by two dimensional MR spectroscopy, may eventually allow treatment Of clinically distinct diseases

Small renal masses, such as non-clear cell renal carcinoma (non-ccRCC), can be monitored rather than resected as morbidity is unlikely. The distinction between malignant clear cell RCC (ccRCC) from indolent RCC subtypes and benign renal tumour is not possible by imaging thus some patients undergo unnecessary surgery1. Using 2D COrrelated SpectroscopY we report that normal renal tissue, non-ccRCC and ccRCC each has different chemical profile. ccRCC differs from normal tissue with cholesterol and lipid increased by 572% and 481% (P=0.001); decreased alanine 51% (P=0.001); valine 57% (P=0.003) and lysine 46% (P=0.005). When comparing ccRCC to the non-ccRCC there are increases in valine 48% (P=0.004) and lysine 40% (P=0.04)

Association between preoperative hydration status and acute kidney injury in patients managed surgically for kidney tumours

The purpose of this study was to investigate whether preoperative dehydration and intraoperative hypotension were associated with postoperative acute kidney injury in patients managed surgically for kidney tumours.A retrospective analysis of 184 patients who underwent nephrectomy at a single centre was performed, investigating associations between acute kidney injury after nephrectomy, and both intraoperative hypotension and preoperative hydration/volume status. Intraoperative hypotension was defined as mean arterial pressure 20 mS/cm). Multivariable logistic regression was used to evaluate associations between exposures and the primary outcome, with adjustment made for potential confounders.Patients who were dehydrated and mildly dehydrated had an increased risk of acute kidney injury (adjusted odds ratio [aOR] 4.1, 95% CI 1.3-13.5; and aOR 2.4, 95% CI 1.1-5.3, respectively) compared with euhydrated patients (p = 0.009). Surgical approach appeared to modify this effect, where dehydrated patients undergoing laparoscopic surgery were most likely to develop acute kidney injury, compared with patients managed using an open approach. Intraoperative hypotension was not associated with acute kidney injury.Preoperative dehydration may be associated with postoperative acute kidney injury. Avoiding dehydration in the preoperative period may be advisable, and adherence to international evidence-based guidelines on preoperative fasting is recommended

Outcome measures used to report kidney function in studies investigating surgical management of kidney tumours: a systematic review

Most practice decisions relevant to preserving kidney function in patients managed surgically for kidney tumours are driven by observational studies. A wide range of outcome measures are used in these studies, which reduces comparability and increases the risk of reporting bias.To comprehensively and succinctly describe the outcomes used to evaluate kidney function in studies evaluating surgical management of kidney tumours.Electronic search of the PubMed database was conducted to identify studies with at least one measure of kidney function in patients managed surgically for kidney tumours, published between January 2000 and September 2017. Abstracts were initially screened for eligibility. Full texts of articles were then evaluated in more detail for inclusion. A narrative synthesis of the evidence was conducted.A total of 312 studies, involving 127905 participants, were included in this review. Most were retrospective (n=274) studies and conducted in a single centre (n=264). Overall, 78 unique outcome measures were identified, which were grouped into six outcome categories. Absolute postoperative kidney function (n=187), relative kidney function (n=181), and postoperative chronic kidney disease (n=131) were most frequently reported. Kidney function was predominantly quantified using estimated glomerular filtration rate or creatinine clearance (n=255), most using the modification of diet in renal disease equation (n=182). Only 70 studies provided rationale for specific outcome measures used.There is significant variability in the reporting and quantification of kidney function in studies evaluating patients managed surgically for kidney tumours. A standardised approach to measuring and reporting kidney function will increase the effectiveness of outcomes reported and improve relevance of research findings within a clinical context.Although we know that the removal of a kidney can reduce kidney function, clinical significance of various approaches is a matter of debate. This article demonstrates significant variability in the way kidney function was reported across all studies of patients with kidney cancer undergoing surgery, indicating a need for standardisation

GRP78 expression in tumor and perinephric adipose tissue is not an optimal risk stratification marker for clear cell renal cell carcinoma

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer, which is difficult to treat and lacks a reliable prognostic marker. A previous study showed that the endoplasmic reticulum stress marker, glucose-regulated-protein-78 (GRP78), is a potential prognostic marker for ccRCC. The present study aimed to: (1) examine whether GRP78 was upregulated in ccRCC compared with matched non-neoplastic renal tissue; and (2) investigate whether GRP78 expression in ccRCC tissue or perinephric adipose tissue has any association with ccRCC aggressiveness.A retrospective cross-sectional study of 267 patients who underwent nephrectomy for renal tumors between June 2013 and October 2017 was conducted at Princess Alexandra Hospital, Brisbane, Australia. Software-assisted quantification of average grey value of staining intensity (staining intensity method) and proportion of positive pixels (positive pixel method) was applied to measure expression of GRP78 in archived specimens of renal tumor tissues (n = 114), adjacent non-neoplastic renal tissues (n = 68), and perinephric adipose tissues (n = 60) in participants diagnosed with ccRCC.GRP78 was not upregulated in renal tumor tissue compared with paired normal renal tissue. In tumor tissue, GRP78 expression did not show any association with ccRCC aggressiveness using either quantification method. In adipose tissue, downregulation of GRP78 demonstrated poor correlation with increased probability of metastasis, with one unit increase in average grey value of GRP78 staining weakly correlating with a 17% increase in the odds ratio of metastasis (95% confidence interval: 0.99 to 1.38, p = 0.07).GRP78 is not valuable as a risk stratification marker for ccRCC

Isovalerylglycine and α-Ketobutyrate are novel biomarkers that discriminate clear cell renal cell carcinoma in biopsy specimens using two-dimensional magnetic resonance spectroscopy

Tumor heterogeneity and lack of pre-operative diagnostic biomarkers are key topics in the field of renal cell carcinoma (RCC) identification. Clear cell RCC (ccRCC) is an aggressive cancer subtype which accounts for most RCC related deaths. The capacity to monitor changes at a molecular or biochemical level using two-dimensional (2D) correlated magnetic resonance spectroscopy of human kidney cancer biopsies, offers an insight into how ccRCC differs from other kidney cancer subtypes (termed here, non-ccRCC). Using this technology, two new spectral assignments, isovalerylglycine and α-ketobutyrate, were elevated in the potentially aggressive ccRCC cancer subtype. The crosspeak at F2: 0.95 ppm, F1: 2.05 ppm was assigned to isovalerylglycine and the diagonal resonance at 2.77 ppm to α-ketobutyrate. Isovalerylglycine, an amino acid leucine catabolite, was 55% higher (p = 0.004) and α-ketobutyrate 108% higher (p < 0.001) in ccRCC compared with non-ccRCC tissue biopsies. They were also elevated compared with non-cancer kidney. The increase in α-ketobutyrate in ccRCC compared with non-ccRCC also provides further insight into the role of homocysteine metabolism in kidney cancer. These biomarkers provide metabolic insight that could have future diagnostic or clinical value. They may help develop a spectral signature that, preoperatively, improves distinction between life-threatening ccRCC, non-ccRCC and non-cancer kidney

End-stage kidney disease following surgical management of kidney cancer

We investigated the incidence of ESKD after surgical management of kidney cancer in the Australian state of Queensland, and described patterns in the initiation of kidney replacement therapy resulting from kidney cancer across Australia.All newly diagnosed cases of kidney cancer in the Australian state of Queensland between January of 2009 and December of 2014 were ascertained through the Queensland Cancer Registry. There were 2739 patients included in our analysis. Patients who developed ESKD were identified using international classification of disease-10-coded hospital administrative data. Incidence rate and 3-year cumulative incidence were calculated, and multivariable Cox proportional hazards models were used to identify factors associated with ESKD. Additional descriptive analysis was undertaken of Australian population data.The incidence rate of ESKD in all patients was 4.9 (95% confidence interval [95% CI], 3.9 to 6.2) per 1000 patient-years. The 3-year cumulative incidence was 1.7%, 1.9%, and 1.0% for all patients, and patients managed with radical or partial nephrectomy, respectively. Apart from preoperative kidney disease, exposures associated with increased ESKD risk were age≥65 years (adjusted hazard ratio [aHR], 2.0; 95% CI, 1.2 to 3.2), male sex (aHR, 2.3; 95% CI, 1.3 to 4.3), preoperative diabetes (aHR, 1.8; 95% CI, 1.0 to 3.3), American Society of Anesthesiologists classification ≥3 (aHR, 4.0; 95% CI, 2.2 to 7.4), socioeconomic disadvantage (aHR, 1.6; 95% CI, 0.9 to 2.7), and postoperative length of hospitalization ≥6 days (aHR, 2.1; 95% CI, 1.4 to 3.0). Australia-wide trends indicate that the rate of kidney replacement therapy after oncologic nephrectomy doubled between 1995 and 2015, from 0.3 to 0.6 per 100,000 per year.In Queensland between 2009 and 2014, one in 53 patients managed with radical nephrectomy and one in 100 patients managed with partial nephrectomy developed ESKD within 3 years of surgery.This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018_09_28_CJASNPodcast_18_1_.mp3