Laura Cosmai

Use of tyrosine kinase inhibitors in patients with metastatic kidney cancer receiving haemodialysis: a retrospective Italian survey

Study Type – Therapy (case series)

Glomerular diseases and cancer: evaluation of underlying malignancy

Onconephrology is an emerging medical subspecialty focused on the numerous interconnections between cancer and kidney diseases. Patient with malignancies commonly experience kidney problems including acute kidney injury, tumor lysis syndrome, fluid and electrolyte disorders and chronic kidney disease, often as a consequence of the anti-cancer treatment. Conversely, a number of glomerulopathies, tubulopathies and vascular renal diseases can early signal the presence of an underlying cancer. Furthermore, the administration of immunosuppressive drugs, especially cytotoxic drugs and calcineurin inhibitors, may strongly impair the immune response increasing the risk of cancer. The objective of this review article is to: (i) discuss paraneoplastic glomerular disease, (ii) review cancer as an adverse effect of immunosuppressive agents used to treat glomerulopathies, and (iii) in the absence of international approved guidelines, propose a screening program based on expert opinion aimed at guiding nephrologists to early detect malignancies during their clinical practice.

Renal toxicity of anticancer agents targeting HER2 and EGFR

EGFR and HER2 are found overexpressed and/or activated in many different human malignancies (e.g. breast and colon cancer), and a number of drugs specifically targeting these two tyrosine kinases have been developed over the years as anticancer agents. In the present review, the renal safety profile of presently available agents targeting either HER2 or EGFR will be discussed, together with the peculiarities related to their clinical use in patients with impaired renal function, or even in dialysis. Indeed, even though renal toxicity is not so common with these agents, it may nevertheless happen, especially when these agents are combined with traditional chemotherapeutic agents. As a whole, kidney impairment or dialysis should not be regarded per se as reasons not to administer or to stop an active anti-HER or anti-EGFR anticancer treatment, especially given the possibility of significantly improving the life expectancy of many cancer patients with the use of these agents.

Severe Symptomatic Hyponatremia During Sibutramine Therapy: A Case Report

Sibutramine, a serotonin reuptake inhibitor, currently is used in treatment of obesity. The known side effects of sibutramine, ie, hypertension and tachycardia, depend on its adrenergic and serotoninergic effects. We describe a case of life-threatening hyponatremia associated with sibutramine use in an obese woman. We hypothesize that sibutramine, through its effect on neurotransmitters, may induce antidiuretic hormone secretion and lead to a syndrome of inappropriate antidiuretic hormone secretion. We advise careful monitoring of water-electrolytic balance during sibutramine therapy.

Renal toxicity of anticancer agents targeting vascular endothelial growth factor (VEGF) and its receptors (VEGFRs)

Since angiogenesis plays a key role in tumor growth, progression and metastasization, anti-vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) agents have been developed over the years as anticancer agents, and have changed, for the better, the natural history of a number of cancer types. In the present review, the renal safety profile of presently available agents targeting either VEGF or VEGFRs will be discussed, together with the peculiarities related to their clinical use in patients with impaired renal function, or even in dialysis. Indeed, renal toxicity (especially, but not exclusively, hypertension and proteinuria) are quite commonly observed with these agents, and may be increased by the concomitant use of cytoxic chemotherapeutics. Despite all the above, kidney impairment or dialysis must not be regarded di per se as reasons not to administer or to stop an active anticancer treatment, especially considering the possibility of a significant survival improvement in many cancer patients treated with these agents.

Introduction to the Journal of Onco-Nephrology:

Renal insufficiency is highly prevalent among cancer patients, which negatively impacts on their survival. Furthermore, many oncological treatments may severely impair kidney function or exasperate preexisting renal diseases. Thus, the relationship between cancer and the kidney could be regarded as “circular” and warrants specific competencies and expertise for its management. This is why onco-nephrology, as a subspecialty of both oncology and nephrology, has begun to gain importance over the past few years. The complex issues of the management of cancer patients in dialysis, of candidates for kidney transplantation who have had a previous malignancy, and of transplant recipients who subsequently develop a malignancy, also fall into the field of onco-nephrology.

Harmonization of Renal Function Assessment Is Needed Throughout the Whole Process of Anticancer Drug Development

TO THE EDITOR: The article by Beumer et al addressed the effect of renal impairment on the toxicity of anticancer compounds tested in phase I trials over three decades, and the accompanying editorial by Rudek et al called for harmonization of kidney function assessment during early clinical development of anticancer agents. Although the authors should be congratulated for their interesting and clinically relevant work, we strongly believe that, with this work, Beumer et al have opened a Pandora’s box. Indeed, despite the fact that the Renal Insufficiency and Cancer Medications study demonstrated that more than half of patients affected with an active cancer concomitantly show an estimated glomerular filtration rate , 90 mL/min/1.73 m and that the prevalence of stage 3 to 5 chronic kidney disease (CKD) accounts for approximately 12% of patients with cancer, patients affected with CKD are often denied entry not only into early-phase studies, but also into registrative, randomized, controlled, phase III trials, which introduces a significant selection bias. It appears that many phase III trial designs are all too often written using a cut-and-paste function, without adequate knowledge of the pharmacokinetic properties of a given drug. For example, because large molecular weight monoclonal antibodies are not metabolized or excreted by the kidneys, it is not sensible to limit their clinical use to patients with normal or near-normal kidney function. Furthermore, it is often difficult, if not impossible, to evaluate the true nature and incidence of adverse renal events from phase III trials. Indeed, it is common to find definitions such as creatinine increase in tables summarizing adverse events. This vague descriptor has little meaning for the clinician and has no clinical value. This approach leads to a dramatic lack of uniformity in the definition of CKD between oncologic trials, drug summaries of product characteristics, and nephrologic classifications of adverse renal events. Although it is clear that pharmacokinetic studies in patients with impaired renal function are sorely needed, as suggested by a recent European Medicine Agency guideline, it is also clear that harmonization of kidney function assessment is mandatory, not only in early clinical trials, but also—because of a larger practical impact—within registrative trials of novel anticancer agents. Excluding patients with CKD and end-stage renal disease from these trials, especially from those that generate specific pharmacokinetic data, makes the results obtained in these studies highly biased and not transferrable to a significant number of patients with cancer with underlying kidney disease. For these reasons, nephrologists should be involved in the design of the next generation of oncologic trials, especially (but not exclusively) when renal toxicity is expected to be an issue. Furthermore, the respective scientific societies should work together to accomplish this goal. Indeed, the development of onconephrology as a new subspecialty is badly needed because a number of key questions in the field remain not only unaswered, but also never asked.

Retrospective analysis on safety and efficacy of everolimus in treatment of metastatic renal cancer patients receiving dialysis

AIMS This retrospective study aimed to investigate safety and efficacy of everolimus in patients with metastatic renal cell carcinoma (mRCC) and end-stage renal disease requiring dialysis. PATIENTS & METHODS From November 2009 to December 2012, 11 mRCC patients undergoing dialysis were treated with everolimus after failure of anti-VEGF therapy at six Italian institutions. Patient characteristics, safety and outcomes were collected. RESULTS Progression-free survival and overall survival were determined using the Kaplan-Meier method. Median progression-free survival and overall survival were 9.01 and 15.7 months, respectively. No unexpected adverse events were reported. CONCLUSION Everolimus appears to be safe in mRCC patients with renal impairment or end-stage renal disease requiring dialysis. Larger prospective studies are required to confirm these findings.

Acute Kidney Injury in Oncology and Tumor Lysis Syndrome

Abstract The epidemiology and causes of acute renal injury (AKI) in cancer patients as well as the pathophysiologic mechanisms of AKI (which depend on different drugs and cancers) are addressed. We have checked all the available literature on AKI and tumor lysis syndrome in hematologic and solid malignancies, including management strategies and suggestions. AKI appears to be common in cancer patients and leads to a number of negative consequences, including length of hospitalization, denial of active cancer treatment, worsening of overall prognosis, and increase in costs. Most concerning is the increased mortality noted in cancer patients with a preexisting chronic kidney disease who have developed AKI, as compared with those without kidney disease. The relationship between kidney disease and cancer already has been defined as “circular”; indeed, AKI may disturb the bioavailability and/or safety profile of many oncologic drugs, potentially leading to suboptimal treatments, or enhance risk for drug-induced toxicities (not only to the kidney). Some very effective anticancer agents may be avoided as a potential option in cancer patients with AKI just because of the lack of specific information on their pharmacokinetic properties in this setting.

Should CARMENA Really Change our Attitude Towards Cytoreductive Nephrectomy in Metastatic Renal Cell Carcinoma? A Systematic Review and Meta-Analysis Evaluating Cytoreductive Nephrectomy in the Era of Targeted Therapy

BackgroundCytoreductive nephrectomy in metastatic renal cell carcinoma (mRCC) patients has been common clinical practice due to evidence that resection of the primary tumor results in a survival benefit regardless of systemic treatment. Recently, the first large phase III randomized, non-inferiority prospective clinical trial evaluating this surgical approach demonstrated that systemic treatment alone was not inferior to primary surgery plus systemic treatment.ObjectiveOur aim was to evaluate if cytoreductive nephrectomy results in a survival benefit over systemic treatment alone in patients with mRCC and in specific subgroups, including patients with brain metastases, poor performance status, poor prognosis according to IMDC or MSKCC criteria, and clear cell and non-clear cell histologies.Patients and MethodsWe identified 16 published studies providing complete data for the comparison between cytoreductive nephrectomy + systemic treatment versus systemic treatment alone, and selected 9 for subgroup analysis. The inverse variance technique was applied for the meta-analysis of hazard ratios (HR), and, due to the intrinsic heterogeneity of the data, we adopted a random effects model. Risk of bias among the studies was estimated by the Newcastle-Ottawa Scale (NOS).ResultsOur analysis suggested a survival benefit for patients receiving cytoreductive nephrectomy (pooled HR of 0.48, 95% confidence interval of 0.42–0.56) in the overall population. Survival advantages were also observed in patients with clear cell and non-clear renal cell carcinoma, while no benefit was evident in patients with brain metastasis, poor performance status, and poor risk.ConclusionCytoreductive nephrectomy seems to result in a survival benefit in both clear cell and non-clear cell histology, while no survival advantage was found in patients with specific clinical features. Despite a high level of heterogeneity, our results highlight the importance of a good selection of patients to whom a primary surgical approach could be proposed.