Evaluation of Cisplatin-Induced Acute Kidney Injury in Patients Co-Prescribed Serotonin Receptor Antagonists: A Retrospective Analysis.

BACKGROUND: Cisplatin is an effective first line therapy for a variety of cancers. Cisplatin is highly emetogenic and resulting volume depletion can contribute to acute kidney injury (AKI). Anti-emetic drugs such as 5-hydroxytryptamine type 3 receptor antagonists (5-HT3RAs) are commonly prescribed to prevent this complication. Preclinical studies suggest first generation 5-HT3RAs may alter the renal clearance and increase cisplatin toxicity. This retrospective study evaluated whether different 5-HT3RAs modify the risk of AKI in patients receiving cisplatin. METHODS: Patients with cancer who received cisplatin between January 1, 2010 and December 31, 2016 were included. Patients over 18 years old with available data for baseline and post-treatment serum creatinine, cisplatin cumulative dose, and administration of 5-HT3RAs including first generation (ondansetron, granisetron, and ramosetron) and second generation (palonosetron) were analyzed. AKI defined as 1.5x increase in serum creatinine. Fisher's exact and Wilcoxon rank-sum tests were used to assess univariable associations between baseline covariates and AKI, and logistic regression for multivariable associations with AKI. RESULTS: Of 8703 patients identified with cisplatin exposure, 6889 were included. A total of 3881 (56.3%) patients received at least one 5-HT3RA, including palonosetron (3750, 54.4%), ondansetron (1399, 20.3%) and granisetron (11, 0.2%). AKI developed in 1666 (24.2%) patients following cisplatin. Patients who received any 5-HT3RAs were less likely to experience AKI as compared to patients that did not (22.6% vs 26.2%, p=0.001). Older age, male gender, African ethnicity, and cumulative cisplatin dose were univariately associated with higher risk for AKI (P<0.001). After adjusting for these variables, use of any of these antiemetic drugs was protective for AKI (OR 0.84, 95% CI: 0.75, 0.94; P= 0.003) with no difference detected between type of 5-HT3RA. CONCLUSION: Nephrotoxicity continues to be a concern following cisplatin therapy. Given its emetogenic nature, use of antiemetic drugs such as 5-HT3RAs can lessen emesis and lower risk of kidney injury. This retrospective analysis supports use of any 5-HT3RAs to lower risk of AKI.

Rescue Therapies for AKI in Onconephrology: Rasburicase and Glucarpidase.

Tumor lysis syndrome (TLS) and high-dose methotrexate (HD MTX) toxicity can present with potentially severe complications, including acute kidney injury, in patients with malignancy. Guidelines for using rasburicase and glucarpidase as rescue therapies for TLS and HD MTX toxicity, respectively, are widely used by clinicians intending to mitigate organ toxicity and decrease morbidity and mortality as a consequence of cancer therapy. This review discusses the pathogenesis of TLS and HD MTX-associated toxicity, to understand the mechanism of action of these therapeutic agents and to review the currently available evidence supporting their use.

Initiation and termination of dialysis in older patients with advanced cancer: providing guidance in a complicated situation.

Cancer and chronic kidney disease prevalence both increase with age. As a consequence, physicians are more frequently encountering older people with cancer who need dialysis, or patients on dialysis diagnosed with cancer. Decisions in this context are particularly complex and multifaceted. In this Review, we aim to provide an overview of the key points to address when making a treatment strategy in these patients. We provide information on what happens if dialysis is not started or is stopped, and how physicians should deal with such patients. Informed decisions about dialysis require a personalised care plan that considers the prognosis and treatment options for each condition while also respecting patient preferences. The concept of prognosis should include quality-of-life considerations, functional status, and burden of care. Close collaboration between oncologists, nephrologists, and geriatricians is crucial to making optimal treatment decisions, and several tools are available for estimating cancer prognosis, prognosis of renal disease, and general age-related prognosis. Emerging evidence shows that these geriatric assessment tools, which measure degrees of frailty, are useful in patients with chronic kidney disease. In this Review, we try to hand tools to practising physicians, to guide decision making regarding the initiation and termination of dialysis in patients with advanced cancer.

Cancer Screening in End-Stage Kidney Disease.

The incidence of cancer is higher in patients with end-stage kidney disease (ESKD) than among the general population. Despite this, screening for cancer is generally not cost-effective and may worsen quality of life in these patients. This is due to high mortality rates (patients are not living long enough to reap the benefits of screening), the inaccuracy of cancer screening tests, and the increased risks associated with therapy in patients with ESKD. Specific groups of patients with ESKD who have a longer-than-expected life expectancy or higher-than-expected cancer risk may benefit from screening. These groups include patients on peritoneal dialysis, patients on home hemodialysis, Black and Asian-American patients, transplant-eligible patients, and those at higher risk of cancer including patients with acquired cystic kidney disease, those who have been previously exposed to cytotoxic agents or aristolochic acid, and patients with a genetic predisposition to cancer. In this narrative review, we will examine the prevalence of and risk factors for cancer in patients with ESKD and the effectiveness of cancer screening, and discuss specific situations in which cancer screening may be effective.

Perspectives From an Onconephrology Interest Group: Conference Report.

INTRODUCTION AND OBJECTIVE: Onconephrology is a new and evolving field that deals with kidney complications in patients with cancer as well as the management of cancer in patients with preexisting kidney disease. With increasing numbers of patients with cancer with kidney-related complications, the field has garnered increased attention. Thus, an annual Greater Toronto Area Onconephrology Interest Group symposium was held in May 2019. The objective of the meeting was to demonstrate the junctures between oncology and nephrology by highlighting recent data regarding (1) kidney impairment in solid organ malignancies, (2) management and treatment of kidney cancer, (3) kidney impairment in hematologic malignancies, (4) malignancy and kidney transplantation, and (5) hyponatremia in patients with cancer. METHODS AND SOURCES OF INFORMATION: Through a structured presentation, the group explored key topics discussed at a Kidney Disease Improving Global Outcomes (KDIGO) Controversies Conference on Onconephrology. Expert opinions, clinical trial findings, and publication summaries were used to illustrate patient and treatment-related considerations in onconephrology. KEY FINDINGS: Kidney complications in patients with cancer are a central theme in onconephrology. An estimated 12% to 25% of patients with solid organ malignancies have chronic kidney disease (CKD), although in certain cancers, the prevalence of CKD is higher. Kidney impairment is also a common complication of some hematologic malignancies. The incidence of renal failure in patients with multiple myeloma is estimated at 18% to 56% and light chain cast nephropathy is seen in approximately 30% of these patients. In addition, there appears to be a bidirectional relationship between kidney cancer and CKD, with some data sets suggesting the risk increases as kidney function declines. Cancer is also of concern in patients with preexisting kidney disease. Kidney transplant recipients have a greater risk of cancer and a higher risk of cancer-related mortality. Kidney complications have also been associated with novel cancer therapies, such as immune checkpoint inhibitors and chimeric antigen receptor (CAR) T-cell therapy. An estimated 2% to 4% of patients initiating an immune checkpoint inhibitor may develop nephrotoxicity, whereas up to 40% of patients on CAR T-cell therapy experience cytokine release syndrome (CRS). Tumor lysis syndrome and electrolyte abnormalities, such as hyponatremia, have also been reported with CAR T-cell therapy. While the incidence and prevalence of hyponatremia vary depending on the cancer type and serum sodium cutoff point, hyponatremia may be seen in up to 46% of patients hospitalized in cancer centers. CONCLUSIONS: Onconephrology is a developing field and the themes arising from this meeting indicate a need for greater collaboration between oncologists and nephrologists. Educational symposia and onconephrology fellowship programs may allow for improved cancer care for patients with kidney disease.

CONTEXTE ET OBJECTIFS: L'onconéphrologie est une discipline nouvelle et évolutive qui traite les complications néphrologiques chez les patients atteints d'un cancer et assure également la prise en charge des patients soignés en oncologie et présentant une néphropathie préexistante. En mai 2019, le symposium du Greater Toronto Area Onconephrology Interest Group a eu pour objectif de démontrer les points de jonction entre l'oncologie et la néphrologie en mettant en évidence les données récentes concernant : 1) l'insuffisance rénale en présence de tumeurs malignes touchant les organes solides; 2) la prise en charge et le traitement des cancers rénaux; 3) l'insuffisance rénale en présence de tumeurs malignes hématologiques; 4) la malignité et la transplantation rénale; et 5) l'hyponatrémie chez les patients atteints d'un cancer. SOURCES ET MÉTHODOLOGIE: Par le biais d'une présentation structurée, le groupe s'est penché sur les thèmes clés discutés lors d'une conférence du KDIGO portant sur les controverses entourant l'onconéphrologie. Des avis d'experts, des résultats d'essais cliniques et des résumés de publications ont été utilisés pour illustrer les considérations relatives aux patients et aux traitements en onconéphrologie. PRINCIPAUX RÉSULTATS: Les complications rénales chez les patients atteints d'un cancer sont un thème central en onconéphrologie. On estime qu'environ 12 à 25 % des patients présentant une tumeur maligne touchant les organes solides sont atteints d'insuffisance rénale chronique (IRC), bien que la prévalence soit plus élevée pour certains cancers. L'insuffisance rénale s'avère également une complication fréquente de certaines tumeurs malignes hématologiques. L'incidence d'IRC chez les patients atteints d'un myélome multiple est estimée entre 18 et 56 %, et une néphropathie à chaînes légères est observée chez environ 30 % de ces patients. En outre, on soupçonne l'existence d'une relation bidirectionnelle entre le cancer du rein et l'IRC; certains ensembles de données suggérant que le risque de cancer augmenterait avec le déclin de la fonction rénale. Le cancer est également préoccupant chez les patients ayant une néphropathie préexistante. Enfin, les receveurs d'une greffe rénale présentent un risque accru de cancer et de mortalité liée au cancer. Les complications rénales ont également été associées aux nouveaux traitements contre le cancer, comme les inhibiteurs du point de contrôle immunitaire et les thérapies par cellules CAR T. Environ 2 à 4 % des patients amorçant un traitement par les inhibiteurs de point de contrôle immunitaire pourraient développer une néphrotoxicité, alors que jusqu'à 40 % des patients traités par cellules CAR T présentent un syndrome de relargage de cytokines. Le syndrome de lyse tumorale et des anomalies électrolytiques, comme l'hyponatrémie, ont également été observés chez les patients traités par cellules CAR T. Bien que l'incidence et la prévalence de l'hyponatrémie varient en fonction du type de cancer et du seuil de natrémie, jusqu'à 46 % des patients hospitalisés dans les centres de cancérologie présentent cette anomalie. CONCLUSION: L'onconéphrologie est une discipline en évolution et les thèmes issus de ce colloque soulignent le besoin d'accroître la collaboration entre les oncologues et les néphrologues. Les symposiums à caractère éducatif et les programmes de bourses d'études et de recherche en onconéphrologie pourraient améliorer les soins oncologiques prodigués aux patients atteints de néphropathies.

How to determine kidney function in cancer patients?

A precise and efficient method for estimating kidney function in cancer patients is important to determine their eligibility for clinical trials and surgery and to allow for appropriate dose adjustment of anti-cancer drugs, especially toxic drugs with a narrow therapeutic index. Since direct measurement of glomerular filtration rate (GFR) is cumbersome, several formulae have been developed to estimate kidney function. Most of these are based on serum creatinine concentration. Though the CKD-EPI formula is recognised as being the most accurate, there is an ongoing debate on which is the optimal formula for cancer patients. In this review, we provide an overview of different GFR estimating equations for kidney function and the advantages and disadvantages of each method and compare their performance in cancer patients. We discuss the importance of body surface area-indexing and propose a framework for evaluating kidney function in cancer patients.

"Please Keep Mom Alive One More Day"-Clashing Directives of a Dying Patient and Her Surrogate.

All medical care providers are legally and ethically bound to respect their patients' wishes. However, as patients lose decision-making capacity and approach end of life, their families or surrogates, who are confronted with grief, fear, self-doubt, and/or uncertainty, may ask physicians to provide treatment that contradicts the patients' previously stated wishes. Our work discusses the legal and ethical issues surrounding such requests and provides guidance for clinicians to ethically and compassionately respond-without compromising their professional and moral obligations to their patients.

Correlation of IL-6 secretion and hyponatremia with the use of CD19+ chimeric antigen receptor T-cells
.

BACKGROUND: Various studies have demonstrated that interleukin-6 (IL-6) activates the central magnocellular arginine vasopressin (AVP)-secreting neurons in the brain to produce non-osmotic, non-volume-mediated increases in AVP. The most common toxicity of CD19+ chimeric antigen receptor (CAR) T-cells is cytokine release syndrome, which is related to increased levels of IL-6. This study will evaluate the correlation of IL-6 levels with hyponatremia in patients receiving CD19+ CAR T-cells. MATERIALS AND METHODS: This is a single-center retrospective analysis of adult patients who received CD19+ CAR T-cells for the treatment of relapsed/refractory acute lymphoblastic leukemia (ALL). RESULTS: Hyponatremia, defined as a serum sodium (Na) ≤ 135 mEq/L, occurred in 31 (61%) patients. A change in Na > 7 mEq occurred in 32 (63%) patients, and the median lowest Na was 133 mEq/L (interquartile range (IQR): 131 - 136)). There was an inverse linear relationship between IL-6 levels and lowest Na (p = 0.001). Overall, per 10-fold increase in IL-6, Na decreased by an average of 2.68 mEq/L. CONCLUSION: Hyponatremia is common in patients who received CD19+ CAR T-cells. There is an inverse linear relationship between IL-6 levels and nadir Na (p = 0.001). Further studies will be needed to confirm a causative relationship between IL-6 levels and hyponatremia following CD19+ CAR T-cell infusion.

Anemia management in cancer patients with chronic kidney disease.

Cancer and kidney disease are linked by causality and comorbidities. Observational data show an increased risk of malignancy as renal function declines. Erythropoietin stimulating agents (ESAs), which are the cornerstone therapy for anemia patients with chronic kidney disease and cancer, are associated with increased risks for cancer, cancer-related mortality, progression of disease, and thromboembolic events. This article examines the recently published guidelines for ESA use in cancer patients from the American Society of Clinical Oncology and American Society of Hematology and attempts to contextualize them to the care of patients with coexistent CKD, cancer, and anemia.

Decision making for the initiation and termination of dialysis in patients with advanced cancer.

Age is a risk factor for both cancer and end-stage renal disease (ESRD). Newer cancer treatments are allowing patients to live longer with their cancer, the renal toxicity from the cancer itself or from the therapies that was used to treat the malignancy. Consequently, nephrologists will increasingly be asked to evaluate and counsel patients with ESRD and advanced cancer regarding the initiation of dialysis. Data on morbidity, mortality, and quality of life (QOL) outcomes in this population are sparse. Expectations regarding what dialysis can reasonably accomplish in this cohort can be unrealistically high among patients, their family members and the rest of the health care team. This article will discuss some results from the available studies on mortality and QOL outcomes in this cohort and advise the nephrologist about how to approach these challenging discussions.

Rate and risk factors for AKI after CT scans in a cancer cohort
.

AIMS: The proinflammatory milieu in cancer patients may expose them to increased risk for acute kidney injury (AKI) after IV contrast (CON). The aims of this study were to determine: (1) the rates of AKI after CON and noncontrast (NC) CT scans in cancer inpatients, (2) if rates differed among cancer subtypes, and (3) whether recent chemotherapy, comorbid conditions, or nephrotoxins increase AKI after CON. MATERIALS AND METHODS: Retrospective data was collected on adults who had received a CON or NC CT from January 1, 2012 to December 30, 2014. AKI was defined as a > 1.5 increased baseline creatinine. Data was analyzed using Rao-Scott χ<2-test, propensity score matching, and logistic regressions. RESULTS: A total of 7,512 CT scans were performed in 4,456 patients (4,958 NC, 2,554 CON). The rate for AKI with CON was 7.3% and 11.4% (p <0.001) with NC imaging. The risk of AKI increased with lower baseline eGFR: for eGFR ≤ 29 mL/min/1.73m2, OR = 1.83 (p = 0.0002); for eGFR 30 - 59 mL/min/1.73m2, OR = 1.5 compared to eGFR ≥ 60 mL/min/1.73m2 (p < 0.0001). AKI rates were higher when any chemotherapy was given within 60 days of CT (OR = 1.22, p < 0.02), with congestive heart failure (OR 1.51, p = 0.0006), and history of AKI (OR 3.89, p < 0.0001). In 1:1 propensity score matched samples, the OR for AKI after CON was 0.87 (p = 0.23) compared to NC. CONCLUSION: In cancer patients, eGFR below 59mL/min/1.73m2 were associated with increased rate of AKI, independent of contrast exposure. Congestive heart failure and prior AKI were also associated with increased rates of AKI.
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Management of Small Renal Masses: American Society of Clinical Oncology Clinical Practice Guideline.

Purpose To provide recommendations for the management options for patients with small renal masses (SRMs). Methods By using a literature search and prospectively defined study selection, we sought systematic reviews, meta-analyses, randomized clinical trials, prospective comparative observational studies, and retrospective studies published from 2000 through 2015. Outcomes included recurrence-free survival, disease-specific survival, and overall survival. Results Eighty-three studies, including 20 systematic reviews and 63 primary studies, met the eligibility criteria and form the evidentiary basis for the guideline recommendations. Recommendations On the basis of tumor-specific findings and competing risks of mortality, all patients with an SRM should be considered for a biopsy when the results may alter management. Active surveillance should be an initial management option for patients who have significant comorbidities and limited life expectancy. Partial nephrectomy (PN) for SRMs is the standard treatment that should be offered to all patients for whom an intervention is indicated and who possess a tumor that is amenable to this approach. Percutaneous thermal ablation should be considered an option if complete ablation can reliably be achieved. Radical nephrectomy for SRMs should only be reserved for patients who possess a tumor of significant complexity that is not amenable to PN or for whom PN may result in unacceptable morbidity even when performed at centers with expertise. Referral to a nephrologist should be considered if chronic kidney disease (estimated glomerular filtration rate < 45 mL/min/1.73 m2) or progressive chronic kidney disease occurs after treatment, especially if associated with proteinuria.

Long-Term Renal Outcomes after Cisplatin Treatment.

BACKGROUND AND OBJECTIVES: Nephrotoxicity remains the dose-limiting side effect of cisplatin, an effective chemotherapeutic agent with applications across diverse tumor types. This study presents data on renal outcomes across multiple tumor types in 821 adults. We report on incidence of AKI, initial and long-term changes in eGFR after cisplatin, and relationships between cumulative dose, initial eGFR, age, sex, and long-term renal function. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a retrospective study of adult patients treated with cisplatin from January 1, 2000 to September 21, 2011 who had survived ≥5 years after initial dose. The Modification of Diet in Renal Disease equation was used to calculate eGFR. AKI was defined as an increase from the baseline creatinine of >25% within 30 days after the first cycle of cisplatin. Chi-squared tests were done to evaluate the relationships between categorical or ordinal variables; ANOVAs or t tests were used to evaluate continuous or categorical variables. Changes in eGFR over time were evaluated in a growth curve model. RESULTS: Mean follow-up was 6 years (25th and 75th percentiles, 4 and 9 years). AKI occurred in 31.5% of patients, with a median initial decline in eGFR of 10 ml/min per 1.73 m(2) (25th and 75th percentiles, -41.5 and -23.3 ml/min per 1.73 m(2)). At any time point after the first cycle of cisplatin, <3% of patients progressed to eGFR<29 ml/min per 1.73 m(2), and none were known to be on dialysis. Age was associated with a higher risk for AKI after cisplatin. Compared with age <25 years old, the odds ratios for AKI versus no AKI are 1.22 for >26-44 years old (95% confidence interval [95% CI], 0.60 to 2.4), 1.54 for >45-65 years old (95% CI, 0.78 to 3), and 2.96 for >66 years old (95% CI, 1.4 to 6.1). The lowest dose categories of cisplatin (≤100 and 101-250 mg/m(2)) are associated with increases in eGFR (P=0.06 and P=0.02, respectively) compared with the highest dose category (>701 mg/m(2)). CONCLUSIONS: This is the largest study of adult patients with cancer who received cisplatin for treatment across multiple tumor types. Most patients experience small but permanent declines in eGFR, but none progressed to ESRD requiring hemodialysis.

Long term renal toxicity of ifosfamide in adult patients--5 year data.

Ifosfamide is indicated as first line treatment in a variety of solid tumours in adults. It is known to be nephrotoxic and is often used following therapy with, or as concomitant therapy with other potent nephrotoxins. To date, there are sparse case reports on the incidence of acute kidney injury (AKI) or chronic kidney disease (CKD) in adults exposed to ifosfamide. The available data on the long term renal complications for patients exposed to ifosfamide are thus based entirely on the paediatric population. The aim of this study was to assess the long term effects of ifosfamide exposure on renal function in an adult population and to determine if there are any treatment or patient specific factors that contribute to long term nephrotoxicity. The mean decline in estimated glomerular filtration rate (eGFR) following the first cycle of ifosfamide was 15 ml/min/1.73 m(2). Thereafter, there was a slower but steady decline in eGFR. No patient progressed to end stage renal disease (ESRD). Patient age and concomitant exposure to carboplatin were the only two factors which significantly affected eGFR. This represents the only long term study on the nephrotoxicity of ifosfamide in adults.

A retrospective observational study on the use of capecitabine in patients with severe renal impairment (GFR <30 mL/min) and end stage renal disease on hemodialysis.

Capecitabine (Xeloda) is an orally administered precursor of 5'deoxy-5-fluorouridine, which is a preferentially activated to 5-fluorouracil in tumors. It is used in the treatment of colorectal, gastric, and breast cancers. Based on a single Phase II trial, which included a total of 4 patients with severe renal impairment (GFR <30 mL/min), the manufacturer issued a 'Dear Doctor' letter contraindicating the use of capecitabine in these patients since a high rate of grade 3 and 4 adverse events were observed and because these patients tolerated shorter treatment durations.(1) We retrospectively studied 12 patients with a GFR <30 mL/min, including 2 patients with end stage renal disease on hemodialysis, who received capecitabine for mean duration of 7.1 months (1-26 months). The mean serum creatinine at the time of initiation of the drug was 2.63 mg/dL (1.8-6.4 mg/dL) and mean GFR was 20.9 mL/min (8-29 mL/min). Two patients remained on capecitabine after they progressed to end stage renal disease (ESRD) requiring hemodialysis (HD) for an additional 17 and 6 months, respectively. Most patients reported grade 1 and 2 adverse effects (AE), 2 patients reported grade 3 diarrhea and one patient died while on treatment with capecitabine. The starting dose ranged from 250 to 1000 mg/m(2), given twice daily at variable intervals. Dose modifications, with reductions of up to 50% of the starting dose, were made following reports of AEs. Serum tumor marker levels and/or follow up imaging studies were available on 9 patients. Response to capecitabine was documented in 4 patients, stable disease in 2, and disease progression in 3. We conclude that, with close monitoring of their clinical and chemical data, and with dose modification based on reported AEs, capecitabine can be safely administered to patients with severe renal impairment, including patients on hemodialysis.

Effect of hemodialysis on the plasma levels of clofarabine.

Clofarabine, a nucleoside analogue for treatment of relapsed leukemia, is 50-60% excreted in urine. Clofarabine has not been studied in patients on hemodialysis. We measured levels in one patient in acute renal failure. Prior to dialysis, 43 hr after a 40 mg/m(2) infusion, plasma concentration was 139 ng/ml. One hour after beginning hemodialysis, a 20 mg/m(2) infusion began. Plasma concentrations were 84.2, 81.1, and 88.0 ng/ml while the dialysis and clofarabine infusion occurred simultaneously. Post-dialysis, while the clofarabine was still infusing, the level was 95.8 ng/ml. Hemodialysis does decrease clofarabine levels, but given its large volume distribution, hemodialysis may not be effective for clofarabine overdose.