Programme

C-KIN Annual Conference 2015

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Legend

Plenary Session
General Session
Parallel Session
Tuesday, 14 April 2015
07:30 Registrations open
10:00 ─ 10:30 Opening Ceremony
10:30 ─ 12:00

Plenary Session 1
Cancer & the Kidney: Theory to Practice

Moderators:
Vincent Launay-Vacher, CHU Pitié-Salpêtrière, France
Eric Cohen, Medical College of Wisconsin, USA

How to Evaluate the Renal Function in Cancer Patients
Vincent Launay-Vacher, CHU Pitié-Salpêtrière, France

Carboplatin Dosing in Chronic Renal Failure
Martin Fehr, Kantonsspital St. Gallen, Switzerland

Cisplatin Renal Toxicity Prevention.
Giuliano Ciarimboli, Universitätsklinikum Münster, Germany

12:00 ─ 13:30 Lunch Break and Poster Viewing
13:30 ─ 15:00

Plenary Session 2
Targeted Therapies & the Kidney

Moderators:
Norbert Lameire, University of Gent, Belgium
Vincent Launay-Vacher, CHU Pitié-Salpêtrière, France

Comparative Renal Safety Profiles of New and Ancient Cancer Therapies
Norbert Lameire, University of Gent, Belgium

BRAF in the Kidney: Does the Target Make the Damage?
Kenar Jhaveri, North Shore University Hospital, USA

Renovascular Safety of Antiangiogenics: Update from the C-KIN Working Group
Gilbert Deray, CHU Pitié-Salpêtrière, France

15:00 ─ 15:30 Coffee, Networking Break and Poster Viewing
15:30 ─ 17:00

Oral Communications Session 1
Clinical Research

Moderator: Gilberto de Castro, Jr, Clinical Oncology, Instituto do Câncer do Estado de Sao Paulo, Brazil

Outcomes of Late Relapse Metastatic Renal Cell Carcinoma Patients Treated with Targeted Therapies
Kamal Mandalapu, Ochsner Medical Center, USA

Everolimus-Associated Acute Kidney Injury in Cancer Patients with Impaired Kidney Function
Jung Eun Lee, Samsung Medical Center, Korea

Management of Cancer PTS with (or at risk of) CKD. Experience of an Ambulatory of Onco-Nephrology
Laura Cosmai, Nephrology and Dialysis, Istituti Ospitalieri, Italy

New Insights in Renal Toxicity of BRAF Inhibitor Vemurafenib in Patients with Metastatic Melanoma
Cécile Teuma, Centre Hospitalier Lyon Sud, France

eGFR Equations as Predictors of Outcomes after Cisplatin Chemotherapy in Cancer Patients
Gilberto de Castro, Jr, Clinical Oncology - Instituto do Câncer do Estado de Sao Paulo Brazil

17:15 ─ 17:45

Cancer & the Kidney: 2014 News Review
Speaker: Nicolas Janus, CHU Pitié-Salpêtrière, France

17:45 ─ 18:30 C-KIN General Assembly
Vincent Launay-Vacher, PharmD

Dr Vincent Launay-Vacher is Clinical Pharmacologist in the Department of Nephrology at Pitie-Salpetriere Hospital in Paris, France. Since 1999, he is Director of Service ICAR, a national medical advisory service and clinical research unit on drug management in patients with renal failure (renal tolerance, dosage adjustment, etc.) dedicated to French physicians, with a focus on oncology

He received his Doctorate of Pharmacy (PharmD) from the Université René Descartes Paris V and graduated with honours in 2000. He specialized in biodynamics and biopharmacy (pharmacokinetics).

Dr Launay-Vacher is the author of a number of publications mainly in indexed international journals (150), on drug pharmacokinetics and renal effects, and prevalence of kidney disease in cancer. His clinical research activities have focused on the study of drugs’ pharmacokinetics and dosage adjustment in patients with renal insufficiency. He coordinated several National studies, among which the “IRMA” studies (1 and 2) (Renal Insufficiency and Anticancer Medications) on the prevalence of renal insufficiency in French cancer patients, dosage adjustment of anticancer drugs, and impact on survival

Eric Cohen

Eric Cohen is a Nephrologist whose research is in Radiation Biology. His clinical interests extend to the clinical frontier of Oncology and Nephrology, which overlaps precisely with the mission of C-KIN. His book, Cancer and the Kidney, is the text of reference in this field.

He has developed the concept of mitigation of normal tissue radiation injuries, specifically with regard to late lung and kidney injury after hematopoietic stem cell transplantation. He is on the Faculty at the Medical College of Wisconsin, and also holds an appointment at the Zablocki VA Medical Center, both in Milwaukee, Wisconsin, USA. His research is funded by the US Department of Veterans Affairs

Guiliano

Dr. Giuliano Ciarimboli is Associate Professor at the Faculty of Medicine of the Münster University, Germany. He studied Biology at the Pisa University, Italy. He was awarded a scholarship from the Italian Research Council in Pisa from 1988 to 1994. From 1995 to 1999 Dr. Ciarimboli was graduate student at the Hannover Medical School (Germany). In 1999 he received a PhD in natural sciences at the Hannover University. From 2001 to 2005 he was Assistant Professor at the Münster University Clinic, Experimental Nephrology, Germany. Since 2006 is Associate Professor for Physiology. Research interests have included regulation of organic cation transporters and their interaction with drugs. In particular, Dr. Ciarimboli has studied the cellular processing of organic cation transporter 2 and its role in mediating the uptake of cisplatin and its toxicity in renal proximal tubular cells and in hair cells of the cochlea.

Nicolas Janus

Dr. Nicolas Janus was graduated as a PharmD in 2005 and was recruited by Service ICAR at Pitié-Salpêtrière Hospital in Paris, France.

Service ICAR is a medical advisory service on "drugs and the kidney" ie:

  1. drug dosage adjustment in patients with renal disease
  2. drug-drug interactions with immunosuppressive
  3. drugs renal effects.

Service ICAR is dedicated to physicians and pharmacists in order to give them advices on how to manage drugs in their renal failure/transplanted patients according to published data in the international medical and scientific literature. Furthermore, Service ICAR is running SiteGPR® (www.sitegpr.com). SiteGPR® is a website providing guidelines on how to use drugs in patients with kidney disease. Dr Janus was also graduated in clinical research management and biostatistics

Norbert Lameire

Prof. Norbert Lameire is graduated from the University of Ghent. He subsequently received his training in internal medicine and nephrology at the same faculty. He performed a research training in the Renal Division of the Texas Medical School in San Antonio, USA, from 1975–1976.

After his appointment to full professor of Medicine 1991 at the Medical Faculty of Ghent he became Chief of the Renal Division and was Chairman of the Department of Medicine from 1999–2004. He is Emeritus Professor of Medicine from October 2005 at the Medical Faculty of the Ghent University.

He has been involved in the Renal Sister Program of the ISN and of the Renal Disaster Relief Task Force. He was a member of the ISN Executive from 2002-2005. From 2006 he is responsible for the worldwide CME programs of ISN Global Outreach of the ISN, ending his term in June 2013.

Kenar D. Jhaveri

Kenar D. Jhaveri, MD, is an Associate Professor of Medicine in the Division of Kidney Diseases and Hypertension at the Hofstra North Shore Long Island Jewish School of Medicine in New York. He is core faculty member of the medical school and the Department of Internal Medicine.

Dr. Jhaveri's clinical interests are in taking care of patients with renal complications following bone marrow transplantation and chemotherapy (Onco-Nephrology). He is one of the founding members of ASN's workgroup on Onco-Nephrology. He is a columnist for the ASN Kidney News for the section called "Detective Nephron". His interest in nephrology education is vested in using creative ways of teaching nephrology to the medical students, residents and fellows.

He has published on onco-nephrology, using social media, and other innovative tools (games, concept maps, role playing, and creative writing) to make nephrology a fun and exciting field. He has conducted numerous faculty development seminars locally to teach these techniques. He has an active role in the newly found medical school Hofstra NSLIJ School of Medicine. He serves as the internal medicine clerkship director for the medical students for the department of Internal Medicine.

He continues to have interest in novel ways of sharing information that can make an impact on all fronts: physicians, allied health staff and the patients. He is a fellow of American Society of Nephrology, American College of Physicians and National Kidney Foundation. He has a teaching oriented blog called NephronPower and is the Web editor for the official blog of the American Journal of Kidney Diseases (AJKD).

Martin Fehr

Martin Fehr graduated from Medical School of the University of Innsbruck, Austria.

He has trained as a general physician and a medical oncologist in Switzerland and England at the Cantonal Hospital Grisons, University Hospital Basel and Southampton University Hospital.

Since 2012 he is working as a consultant oncologist at the Cantonal Hospital of St. Gallen, Switzerland with a focus on gastrointestinal and haematological malignancies. Current research projects and interests include measurement and estimation of the glomerular filtration rate with a view to Carboplatin dosing as well the integration of FDG-PET-CT in colorectal cancer patients.

Cisplatin renal toxicity prevention
Cisplatin is an effective but highly nephrotoxic and ototoxic antineoplastic agent. In this work, we studied the role of organic cation transporters (OCT) in mediating the uptake of cisplatin and its toxicity in vitro and in vivo. Interaction of cisplatin with the transport of the fluorescent cation 4-(4-(dimethyl-amino)styril)-methylpyridinium (ASP+) was investigated in HEK293 cells stably transfected with hOCT1 or hOCT2 and in tissues physiologically expressing these transporters, human hepatocyte and human proximal tubules.

Cisplatin (100 µM) inhibited ASP+ transport via hOCT2, but not via hOCT1. 15 h incubation with cisplatin induced apoptosis in hOCT2 cells, which was completely suppressed by contemporaneous incubation with the hOCT2 substrate cimetidine (100 µM). In vivo, the effects of cisplatin treatment (15 mg/kg) on kidney (24 hr excretion of glucose, water, and protein and apoptosis) and hearing (auditory brainstem response, ABR) were studied in wild type (WT) and OCT1/2 double knock-out (KO) mice. While in WT cisplatin led to reduced ABR and increased renal glucose, water, and protein excretion and apoptosis, no sign of ototoxicity and only mild nephrotoxicity was observed after cisplatin treatment of KO mice.

Co-medication of WT mice with cisplatin and the organic cation cimetidine protected from ototoxicity and partly from nephrotoxicity. We also showed that OCT2 is expressed on hair cells of the cochlea and that it plays a critical role in cisplatin-induced ototoxicity. Furthermore, cisplatin sensitive cell lines from pediatric tumors showed no expression of mRNA for OCT, indicating the feasibility of a therapeutical approach aimed to reduce cisplatin toxicities by competing OCT2-mediated cisplatin uptake in renal proximal tubular and cochlear hair cells with another organic cation. These findings are very important to establish chemotherapeutical protocols aimed to maximize the antineoplastic effect of cisplatin, while reducing the risk of toxicities. Supported by the IZKF Münster, Grant Cia2/013/13

Carboplatin dosing in chronic renal failure Impaired renal function is frequent in cancer patients and Carboplatin is amongst the most frequently prescribed chemotherapeutic drugs. Renal clearance and toxicity of Carboplatin is closely related to the glomerular filtration rate (GFR).

“Calvert’s formula” - Carboplatin Dose (mg) = AUC x (GFR + 25) - is the most commonly used equation to calculate the Carboplatin dose. It was developed using 51Cr-EDTA as the reference method for GFR measurement. However, in clinical practice equations to calculate an estimated GFR (eGFR) based on serum creatinine (SCr) are often applied as this offers the advantage of being a cheaper, easier, faster and readily available alternative to the radioisotope measurements. Several studies have evaluated the performance of various eGFR equations in different cohorts of cancer patients. The conclusion that all available formulae have limitations is shared by several authors. As radioisotope measurements of GFR are not available in all centres or countries, alternative methods for GFR measurement or estimation and the level of inaccuracy, which could be regarded as acceptable without detrimental impact on clinical outcomes, remain key issues.

Plenary Session 1: Carboplatin dosing in chronic renal failure
The care of cancer patients is often complicated by renal issues, mainly represented by the high prevalence of renal insufficiency, often undiagnosed, which has been reported in several studies during the past 10 years. The second major issue regarding the kidney in cancer patients’ care is the question of anticancer drugs renal safety, and especially platinum salts.

In this session, speakers will present recent data on how to screen for renal dysfunction in cancer patients, how to handle carboplatin in patients with renal insufficiency, and how to prevent the kidney from cisplatin renal toxicity, in clinical practice.

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Plenary Session 2: Targeted therapies and the Kidney
Recent targeted therapies, although initially thought as better tolerated compared with chemotherapies and cytotoxic drugs, present a number of toxicities through different mechanisms as compared to older drugs, among which renal toxicities. A recent communication given at the last European Society of Medical Oncology congress reported that around 20% of patients treated with targeted therapies may present renal adverse events.

In this session, experts will review the toxicity profile of recent targeted therapies, as compared to ancient chemotherapies, and consequences on patient care. The specific question of BRAF inhibitors renal toxicity will also be developed, and advices on how to monitor and treat antiangiogenics’ renovascular effects will also be presented.

Carboplatin dosing in chronic renal failure
Short Summary

Impaired renal function is frequent in cancer patients and Carboplatin is amongst the most frequently prescribed chemotherapeutic drugs. Renal clearance and toxicity of Carboplatin is closely related to the glomerular filtration rate (GFR).

“Calvert’s formula” - Carboplatin Dose (mg) = AUC x (GFR  25) - is the most commonly used equation to calculate the Carboplatin dose. It was developed using 51Cr-EDTA as the reference method for GFR measurement. However, in clinical practice equations to calculate an estimat-ed GFR (eGFR) based on serum creatinine (SCr) are often applied as this offers the advantage of being a cheaper, easier, faster and readily available alternative to the radioisotope meas-urements. Several studies have evaluated the performance of various eGFR equations in dif-ferent cohorts of cancer patients. The conclusion that all available formulae have limitations is shared by several authors. As radioisotope measurements of GFR are not available in all centres or countries, alternative methods for GFR measurement or estimation and the level of inaccuracy, which could be regarded as acceptable without detrimental impact on clinical out-comes, remain key issues.

Gilberto de Castro Jr.

Gilberto de Castro Jr. received his MD degree from the University of Sao Paulo Medical School, Brazil, in 1995, and completed his training in Internal Medicine and Clinical Oncology in 2000 at Hospital das Clínicas, University of Sao Paulo Medical School, where he also received his PhD degree in 2009. He is an ex-fellow of the Medical Oncology Clinic at the Institut Jules Bordet, Brussels, Belgium. His current position is Chief at the Unit of Head and Neck and Thoracic Tumors of the Clinical Oncology Service of the Instituto do Cancer do Estado de Sao Paulo, Brazil – the largest cancer center in the South America. His areas of interest are the medical management of head and neck cancer and thoracic malignancies, focusing on the development of molecular targeted therapies, predictive factors of response to chemotherapy, supportive care and quality of life studies.

Dr. Gilbert Deray
Gilbert Deray, MD, is Professor of Nephrology and Assistant Physician in the Department of Nephrology at the Pitié-Salpêtrière Faculty of Medicine in Paris, France. In addition, he is Head of the Department of Nephrology at Pitié-Salpêtrière Hospital.

Dr. Deray earned his MD at the Paris Faculty of Medicine. After graduating, he completed his residency in medicine at Paris Hospital and his residency in nephrology at Pitié-Salpêtrière Hospital, where he was designated Chief Resident. His fellowship in clinical pharmacology was conducted at Vanderbilt University in Nashville, Tennessee.

His clinical and basic science interests are viral infections and kidney diseases, anaemia in patients with renal insufficiency and renal tolerance of drugs

He is a member of the Society of Nephrology, the French Society of nephrology, the European Dialysis and Transplantation Association/European Renal Association, the International Society of Nephrology, the American Society of Nephrology, and the American Society of Hypertension.

Background: Approximately 20-30 % of patients with renal cell carcinoma (RCC) develop recurrence after treatment of localized disease. Of these patients, the great majority recur within the first few years following surgery. Rarely, late recurrences are seen after 5 years of disease free survival. The outcome of metastatic Renal Cell Carcinoma has improved markedly with targeted therapies (TT). Little data is available about outcomes of patients with metastatic Renal Cell Carcinoma from late recurrences who are treated with TT.

Methods: We retrospectively reviewed records of consecutive patients with metastatic Renal Cell Carcinoma who had late recurrence > 5 years and were treated with TT between 11/1/2006 and 11/1/2013. All the patients had prior nephrectomies. Outcomes were tabulated using basic statistical techniques. Adverse Events (AEs) were graded using CTCAE v4.0

Results: 25 patients (100% clear-cell, all with prior nephrectomies) met inclusion criteria with late recurrence > 5 years. 76% of patients had favourable risk and 24 % had intermediate risk on MSKCC criteria.11 pts died. Estimated median overall survival time for all patients was 60.5 months. The 3-year overall survival rate was 71.78%. The median number of sequential TT received was 2 (range 1-4). Median time on first line TT was 20.7 months. 41% of pts received pazopanib in the frontline setting, 26% received sunitnib, and 26% received sorafenib, and 7% received other TT. 68% received TT in the second-line and subsequent settings. Common adverse events of TT included fatigue (52%), diarrhea (36%), hypertension (36%), anorexia (28%), hair and skin changes (24%), increased liver function tests (20%), nausea/vomiting (16%), and 95% of adverse events were grade 1/2 .

Conclusions: In this retrospective study, patients who were diagnosed with metastatic disease from RCC after disease free interval >5yrs have prolonged survival when treated with TT. Overall survival and 3-year survival rates were better than historical controls. Adverse events were mild/moderate and manageable.

Authors: T Poosarla, M Matrana, Ochsner Medical Center, New Orleans, Louisiana

Références: Survival Outcome and Treatment Response of Patients with Late Relapse from Renal Cell Carcinoma in the Era of Targeted Therapy , Kroeger N et al, Eur Urol. 2013 Jul 30

Background: Everolimus was recently introduced as a second-line treatment for renal cell carcinoma (RCC) and many other cancers. Several prospective studies have shown that serum creatinine levels are increased in a significant proportion of patients receiving everolimus. However, data on the occurrence of acute kidney injury (AKI) during everolimus treatment in clinical practice are sparse. Here, we report the incidence, risk factors, and clinical significance of AKI associated with everolimus treatment in patients with cancer.

Methods: We analyzed patients who received everolimus for more than 4 weeks as an anticancer therapy. AKI was defined as increase in creatinine levels from baseline levels greater than 1.5-fold.

Results: The majority of the 110 patients enrolled in this analysis had RCC (N = 93, 84.5%). AKI developed in 21 (23%) RCC patients; none of the patients (N = 17) with other cancers had AKI. Fourteen of 21 cases were considered to be everolimus-associated AKI, in which there were no other nephrotoxic insults other than everolimus at the onset of AKI. The incidence of AKI increased progressively as baseline estimated glomerular filtration rate (eGFR) decreased (10% in subjects with eGFR >90 mL/min/1.73 m2, 17% in subjects with eGFR 60–90 mL/min/1.73 m2, 28% in subjects with eGFR 30–60 mL/min/1.73 m2, and 100% in subjects with eGFR 15–30 mL/min/1.73 m2; P = 0.029 for trend). Baseline eGFR was an independent risk factor for the development of everolimus-associated AKI (hazard ratio per 10 mL/min/1.73 m2 increase, 0.70; 95% confidential interval, 049–1.00; P = 0.047). Nine of 14 patients with everolimus-associated AKI continued receiving the drug at a reduced dose or after a short-term off period. Administration of the drug was discontinued in four of 14 patients because of progression of an underlying malignancy. Only one patient stopped taking the drug because of AKI.

Conclusions: Our study suggests that AKI is a common adverse effect of everolimus treatment, especially in subjects with impaired renal function. However, the occurrence of AKI did not require the discontinuation of the drug, and the treatment decision should be made via a multidisciplinary approach, including the assessment of the oncological benefits of everolimus and other therapeutic options.

Authors: Ji Hyeon Park, Hye Ryoun Jang, Wooseong Huh, Yoon-Goo Kim, Dae Joong Kim, Ha Young Oh, Jung Eun Lee

Background: Onco-Nephrology is a novel subspecialty dealing with 1) renal toxicity from chemotherapy (CT), targeted agents (TA) or contrast medium (CM), 2) active cancer treatment (aTx)-related electrolyte disturbances, alterations of the calcium/phosphorus metabolism and hypertension, 3) management of pts nephrectomized for a malignancy. Here we report the preliminary results of 3 years’ experience of a dedicated ambulatory of Onco-Nephrology.

Patients: This ambulatory, run by a Nephrologist, takes place once a week within an Oncology outpatient ward, in order to allow closer interaction between specialists and easier access to pts’ data.

Results: Until now, we have followed 349 cancer pts with CKD on aTx, and 92 untreated cancer pts with CKD; 127 pts were nephrectomized for a localized or metastatic renal cell carcinoma (RCC); beyond RCC, patients had also lung (48 cases), gastric (50), prostate (34), bladder (38), or other cancers (52). Among 47 pts nephrectomized for metastatic RCC under aTx, we had only 4 aTx interruptions, while among the 80 previously nephrectomized pts for a localized RCC (not on aTx), at a median follow-up of 12 months, we did not observe any CKD progression (vs an expected percentage of 63% at 3 years). Only one patient (out of 15) treated with cisplatin had to discontinue CT because of renal toxicity. Only 10 pts have developed an episode of acute kidney injury (AKI), but all were able to resume aTx; 6 pts with advanced CKD began dialysis while on aTx. Furthermore, no cases of AKI from CM were observed (vs an expected rate of 50% in high-risk pts, and of 5% in low-risk pts), thanks to the implementation of specific protocols of CM nephropathy prevention. Finally, previously some cases of previously unreported renal toxicities were observed.

Conclusions: Our experience shows that an Onco-Nephrological assessment may improve pts’ outcome. Further development of Onco-Nephrology (e.g. dedicated ambulatories and specific trials) is warranted.

Authors: Laura Cosmai1,5, Camillo Porta2,5, Wanda Liguigli3, Marina Foramitti1, Fabio Malberti1, Maurizio Gallieni4, 1Nephrology and 3Medical Oncology, Istituti Ospitalieri Cremona; 2Medical Oncology, IRCCS San Matteo University Hospital Foundation, Pavia; 4Nephrology, San Carlo Borromeo Hospital, Milan; 5Joint AIOM/SIN Working Group on Nephro-Oncology, Italy.

Introduction: Vemurafenib is a selective B-RAF inhibitor used in treatment of BRAF-V600-mutant metastatic melanoma. It improves patients’ survival as compared to the standard chemotherapy. Side effects that are more common are cutaneous and hepatic, leading regularly to discontinuation or diminution of the treatment. Acute kidney injury (AKI) has recently been reported, but his incidence, mechanism and impact in daily practice are unknown.

Material and methods: We conducted a retrospective study including 74 patients with metastatic melanoma treated by vemurafenib in a single institution. Serum creatinine was collected before treatment, monthly during targeted therapy and one month after treatment disruption. AKI was defined as an increase of at least 25% of creatinine from baseline value according to RIFLE criteria. Patients were defined in two groups with or without AKI (defined as AKI+ and AKI – respectively). Kidney biopsies were performed on three patients with AKI.

Results: The mean duration of treatment was 10 months (from 2 months to 39 months). 78% of patients (n=58) experimented AKI. The AKI occurred mainly during the first trimester of treatment (51 patients; 69%): 39 patients (53%) during the first month; 8 (11 %) during the second and 4 (5%) during the third month. The median time of onset was at 2.2 months.

In the AKI+ group, the severity of the renal failure was variable: an increase of 25 to 50% of the baseline creatinine was observed in 67% of AKI+ patients (n=39), between 50 and 75% in 24% (n=14) and above 75% in 9% (n=5). When compared AKI + to the AKI- group (n=16; 21.6%), no difference was shown in blood pressure, diabetes, cardiovascular diseases, history of nephropathy or nephrotoxic treatment. In contrast, men were more exposed to AKI that women (39/45 men (87%) vs 19/29 women (66%); p= 0.031). The two groups were similar by age (61 and 60 years old). 9% of patients had Chronic Kidney Disease (CKD) before Vemurafenib. There was no more AKI in CKD population (5/7 (71%) vs 53/67 normal renal function (79 %); p=0.64). Kidney biopsies showed tubular toxicity and interstitial fibrosis. One biopsy showed focal, non-inflammatory and discrete lesions of interstitial fibrosis seven month after the first observation of AKI. The two others performed less than three months after AKI showed marked a specific chronic tubular and interstitial lesions in the one hand, and acute and focal lesions of epithelial damage, compatible with acute tubular necrosis in the other hand. We collected creatinine evolution after treatment discontinuation for 27 patients in AKI + group. Every patient returned to creatinine basal rate with margin of 25%.

Conclusion: Our study, which includes so far the largest cohort on this topic in the literature, found frequent renal toxicity of Braf inhibition by vemurafenib, highlighting the necessity of monitoring renal function, with particular attention during the first trimester. Histological evidence has been made for the first time with three biopsy showing consistent tubular and interstitial lesions. AKI is most of the time moderate and do not justify the discontinuation of treatment. Creatinine elevation is also tolerated, especially because response to vemurafenib is might increase the overall survival of the patients, allowing temporarily stabilization or regression of metastatic lesions. We show for the first time that AKI is secondary to tubular injury, suggesting the possibility of renal recovery. Moreover, when vemurafenib is stopped for any reason, creatinine level usually returns to baseline value.

Authors: Cécile Teuma, Marie Perier-Muzet, Solenne Pelletier, Mathilde Nouvier, Mona Amini-Adl, Frédérique Dijoud, Gérard Duru, Luc Thomas, Stéphane Dalle, Maurice Laville.

Références:
  • Davies H and al. Mutations of the BRAF gene in human cancer. Nature.2002 Jun 27;417(6892):949-54. PubMed PMID:23397951.
  • Chapman PB and al, Improved survival with vemurafenib in melanoma with BRAF V600E mutation, N. England J Med 2011, 364:2507-16. PubMed PMID: 21639808.
  • Sosman J and al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N.England J Med 2012; 366:707-14. PubMed PMID:22356324.
  • E. Regnier-Rosencher and al. Acute kidney injury in patients with severe rash on vemurafenib treatment for metastatic melanomas. Br J Dermatol. 2013 Oct;169(4):934-8. PubMed PMID:23909652.
  • Launey-Vacher and al. Acute renal failure associated with the new BRAF inhibitor Vemurafenib. Cancer. 2014 Jul 15;120(14):2158-63 PubMed PMID:24737576.

Background: Estimation of renal function is essential in patients (pts) treated with cisplatin (DDP). We aimed to compare the estimated glomerular filtration rate (eGFR) according to Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), Modification of Diet in Renal Disease (MDRD) and Cockcroft-Gault (CG) equations to investigate if a decrease in eGFR using these equations could predict negative outcomes, as death, need of dialysis or acute renal failure (ARF).

Methods: Uniinstitutional, retrospective and exploratory study. All pts were >18y, diagnosed with head & neck (H&N) or thoracic cancers and had been treated with DDP, for at least for one cycle. DDP was administered in NS 500mL in 60 min, following NS 1000 mL, KCl 25 mEq, MgSO4 100 mg and manitol 20 g. Baseline eGFR was calculated using CKD-EPI, MDRD and CG equations and ARF was defined as an elevation of serum creatinine ≥ 0.3 md/dL or more than 50% in comparison to baseline. We defined treatment-related deaths if they occurred in the first 28 days after DDP dose. Results: 157 pts were included: median age 58y (26–78), 68% male. Lung (61%), larynx (13%), oral cavity (8%) and oropharynx (8%) were the most common primary sites. First DDP cycle was administered to all 157 pts, the second to 154 pts, the third to 127 pts and 91 pts received the fourth one. Median DDP dose was 80mg/m2 for all cycles. Median baseline pre-DDP serum creatinine was 0.75mg/dL (0.46–1.76) and it increased to 0.78 (0.40–1.51, p=0.044, t-test), 0.80 (0.42–1.68; p=0.005) and 0.77 (0.41–1.69, p=0.075) after each DDP dose. At baseline, median eGFR (ml/min/1.73 m2) was 86 (34–175) (CG), 107 (44–226) (MDRD) and 100 (45–145) (CKD-EPI). Considering normal eGFR as >90 (CG), >125 (MDRD) and >100 (CKD-EPI), according to ROC analysis, the agreement between MDRD and CG was fair (k=0.291) and between MDRD and CKD-EPI was moderate (k=0.553). Bland-Altman analysis revealed that CG underestimates eGFR in comparison to MDRD (-19) and to CKD-EPI (-7). Furthermore, MDRD overestimated eGFR in comparsion to CKD-EPI (+11). After first DDP dose, according to ROC analysis, cutoff values of eGFR reductions were calculated as follows (ml/min/1.73m2): 10 (CG; sensitivity 78%, specificity 72%, AUC 0.816, 95%CI 0.74–0.88, p=0.0001), 8 (CKD-EPI; 72%, 76%, 0.75, 0.67–0.82, 0.0003) and 20 (MDRD; 78%, 89%, 0.83, 0.76– 0.90, 0.0001). Decreased renal function estimated by any equations was able to predict negative outcomes, with OR 9.0 (CG, 95%CI 2.8–29.2, p<0.0001), OR 33.0 (MDRD, 95%CI 9.3–116.3, p<0.0001) and OR 8.5 (CKD-EPI, 95%CI 2.8–25.6, p<0.0001). Overall, four treatment-related deaths were observed and the incidence of ARF was low: 9 pts (6%), 11 pts (8%) and 1 pt (1%) after first, second and third DDP cycles, respectively.

Conclusions: Decrease in renal function estimated by all three equations seemed to predict negative outcomes (ARF, dialysis and 28-day mortality) after one cycle of DDP-based chemotherapy in patients with H&N and thoracic cancers. The agreement between these equations is not good and CG should be used with caution as the reference eGFR in these pts.

Authors: Tiago Biachi de Castria, Rafael Caparica Bitton, Alan Alves do Amaral, José Guilherme Lollo Correa, Veronica Torres da Costa e Silva, Emmanuel de Almeida Burdmann

Kamal Mandalapu

Kamal Mandalapu, is currently a second year medical oncology fellow in training ar Ochsner Medical Center, New Orleans, LA, USA. He has special interest in kidney cancers and has done numerous projects with my mentor Dr Matrana. His focus area is targeted therapies in metastatic renal cell carcinoma. Kamal is planning on joing an acadamic facility with good oppourtunities for kidney cancer.

Laura Cosmai is responsible of the first Nephro-Oncological outpatient ambulatory in Italy and member of the joint Italian Association of Medical Oncology (AIOM)/ Italian Society of Nephrology (SIN) Working Group on Nephro-Oncology.

It is the beginning of Cecile's third year of nephrological medicine study. After stages in department of nephrology (clinical nephrology, dialysis and graft) she is now in department of intensive care unit for six months.After writing of a case report last year, this is her first major work within a collaborative medical team.

BRAF in the Kidney: Does the Target Make the Damage?

The prognosis of metastatic melanoma has recently changed substantially thanks to the approval of kinase inhibitors vemurafenib, dabrafenib, and trametinib, and the immune checkpoint inhibitor ipilimumab. BRAF is a human gene that makes a protein called B-Raf. Mutations of BRAF have been identified especially in melanoma. Vemurafenib and dabrafenib are selective inhibitors of BRAF V600, a mutation carried by almost half of melanomas, and are approved by the US Food and Drug Administration (FDA) and European Medicines Agency for the treatment of unresectable or metastatic melanoma with mutant BRAF V600. Phase III trials of both agents has achieved superior median progression free survival rates. The safety profile did not include any renal manifestations at that time. Since the advent of these agents, a case series of renal toxic effects of vemurafenib has been published. Scattered additional case reports also signal renal injury. The talk will focus on the role of BRAF inhibitors on the kidney and the type of toxicities that have been reported. Renal function monitoring and early detection of renal failure might be crucial in preventing CKD in these patients.

Dr Jung Eun Lee

Dr Jung Eun Lee is Associate Professor in the Division of Nephrology at Samsung Medical Center, Seoul, Korea. Prior to her appointment, she has worked as Research Associate at the Joslin Diabetes Center, Harvard Medical School, Boston, MA. Jung has obtained an MD from the Seoul National University College of Medicine and an MS in Internal Medicine and PhD in Immunology from the Seoul National University Graduate School of Medicine.

Wednesday, 15 April 2015
09:00 ─ 10:30

Plenary Session 3
Supportive Care & the Kidney

Joint session with ASCO

Moderators:
Matti Aapro, Multidisciplinary Oncology Institute, Switzerland
Florian Scotte, George Pompidou European Hospital, France

Anemia in Cancer Patients with CKD
Matti Aapro, Multidisciplinary Oncology Institute, Switzerland

The Specific Role of Antiemetics in Kidney Protection
Florian Scotte, George Pompidou European Hospital, France

Venous Thromboembolism, Cancer, and CKD
Ismail Elalamy, Hématologie Biologique, Hôpital Tenon, France

10:30 ─ 11:00 Coffee, Networking Break and Poster Viewing
11:00 ─ 12:00

The Elderly and the Ageing Kidney: Which Specificities?

Joint session with SIOG

Moderators:
Hans Wildiers, UZ Leuven, Belgium
Marije Hamaker, Diakonessenhuis Hospital, Utrecht-Zeist-Doorn, the Netherlands

Renal Dysfunction and Cancer in the Elderly Patient
Marije Hamaker, Diakonessenhuis Hospital, Utrecht-Zeist-Doorn, the Netherlands

SIOG Guidelines on Dose Reduction of Chemotherapy in Renal Dysfunction
Hans Wildiers, UZ Leuven, Belgium

12:00 ─ 13:00

Parallel Session 1
Clinical Pharmacy and Clinical Pharmacists Roles

Joint session with EAHP

Moderator:
Jean-Baptiste Rey, Institut Jean Godinot – Reims Regional Cancer Treatment Centre, France

Speaker:
Clinical Pharmacy and Clinical Pharmacists Roles
Jean-Baptiste Rey, Institut Jean Godinot – Reims Regional Cancer Treatment Centre, France

Cancer and Renal Failure, a Challenge for the Hospital Pharmacist​
Sophie Renet, Hopital Antoine Béclère, AP-HP, France

Parallel Session 2
Practice and Research on Cancer & the Kidney

Joint session with the EORTC

Moderators:
Eric Cohen, Medical College of Wisconsin, USA
Vincent Launay-Vacher, CHU Pitié-Salpêtrière, France

Speaker:
New Guidelines and Regulations Regarding Drugs and CKD
Vincent Launay-Vacher, CHU Pitié-Salpêtrière, France

Evaluation of the Renal Function in Patients with Solid Tumors Receiving Targeted Therapies. An EORTC-Led Project.
Laurence Collette, EORTC, Belgium

13:00 ─ 14:00 Lunch Break & Poster Viewing Tours
14:00 ─ 15:30

Oral Communications Session 2
Sharing and Discussing Clinical Case Reports


Moderator: Michael Dooley, Alfred Health, Australia

A Case of Acute Kidney Injury from Crystal Nephropathy Secondary to Pomalidomide Use
Sam Leung, Hofstra North Shore-LIJ SOM, USA

An Unusual Case of Renal Carcinomatous Embolus with Rapid Renal Failure During Axitinib Treatment
Didier Mayeur, Hôpital Mignot, France

Thrombotic Microangiopathy Associated with the Use of Bortezomib in a Patient with Multiple Myeloma
Jan van Keer, UZ Leuven, Belgium

Cancer and Dialysis: Practical Issues in the Daily Practice
Damien Parent, Institut Jean Godinot - Département de Pharmacie, France

Tumor-Induced Osteomalacia (TIO) with Elevated FGF23 Causing Hypophosphatemia in Ovarian Malignancy
Lauren Paster, North Shore-LIJ Health System, USA

A Biopsy-Confirmed Case of Native Kidney-BK Nephropathy in Patient Receiving Ibrutinib or CLL
Jason Prosek, Ohio State University Wexner Medical Center, USA

15:30 ─ 16:00 Closing Ceremony
Matti Aapro

Matti Aapro is presently Dean of the Multidisciplinary Oncology Institute, Genolier, Switzerland. He coordinates the SPCC programme of the European School of Oncology (ESO) and serves the International Society for Geriatric Oncology (SIOG) as Executive Board member. He has been member of the Board of EORTC and ESMO. He is past-President of the Multinational Association for Supportive Care in Cancer (MASCC), is now on its Board of Directors for 2014-2016, and is appointed Co-Chair of MASCC’s Antiemetic Study Group, effective June 2014

He is Editor-in-Chief of Critical Reviews in Oncology/Hematology, associate editor for the geriatric section of the Oncologist and founding editor of the Journal of Geriatric Oncology (JGO). He is past Associate Editor for Annals of Oncology. He directs the qualityoflife.elsevierresource.com website. He has authored more than 250 publications and his major interests are new drug development, breast cancer, supportive care, and cancer in the elderly. Dr Aapro has received the 2012 ASCO B.J. Kennedy prize.

Florian Scotté

Dr Florian Scotté is Medical Oncologist in the Department of Medical Oncology at George Pompidou European Hospital in Paris, France. Dr Scotté founded and is Head of the Oncology Supportive Care Unit, and responsible for the outpatient clinic. He received his PhD on Medical Ethics at Université RenéDescartes Paris V.

Actively involved in teaching in several courses, he created the first inter-universities diploma in Supoprtive Care in Oncology in France. He is coordinator and co-investigator in a number of clinical trials in oncology supportive care, among which the first which demonstrated the interest of frozen protections against nail and skin toxicity of docetaxel.

Dr Scotté holds the positions of Secretary and chairman of the education and training committe of the French-Speaking Association for Supportive Care in Cancer (AFSOS: Association Francophone pour les Soins Oncologiques de Support). He is the founder and director of Transatlantiques en Oncologie, an annual international congress that gathers oncologists from Europe and the US, from both sides of the Atlantic.

Florian Scotté

Hans Wildiers is a medical oncologist dedicated to breast cancer research and geriatric oncology. He is staff member at the department of medical oncology in the University Hospital Gasthuisberg Leuven, Belgium since 2004. He has been coordinator of several academic studies in the field of breast cancer and geriatric oncology, and author of more than 120 peer reviewed papers in 10 years. He is Belgian national representative and has been board member of SIOG, the international society of geriatric oncology. He is also board member of the Belgian Society of Medical Oncology (BSMO), the Belgian Journal of Medical Oncology (BJMO) since 2007, and of the Journal of Geriatric Oncology. Since 2009, he is chairmen of the elderly task force cancer of the elderly of the European Organization of Research and Treatment of Cancer (EORTC). Stuart Lichtman, Memorial Hospital for Cancer and Allied Diseases, USA (TBC)

Florian Scotté

Titles and Diplomas

  • Lecturer “Clinical harmacy”: University of Reims – Champagne-Ardenne
  • Hospital Pharmacist, Head of the Pharmacy Department: Institut Jean Godinot – Reims Regional Cancer Treatment Centre
  • PhD: Faculty of Pharmacy, University of Reims – Champagne-Ardenne
  • Pharm D: Faculty of Pharmaceutical and Biological Sciences, University Paris V
  • M Sc Pharm: Faculty of Pharmaceutical and Biological Sciences, University Paris V
  • B Sc Pharm: Faculty of Pharmaceutical and Biological Sciences, University Paris V Scientific work
  • 15 publications indexed in the Medline database
  • 40 publications not indexed in the Medline database
  • 8 chapters of medical books Lessons
  • Lecturer “Clinical Pharmacy” (90 hours of lectures + 55 hours of tutorials/year)
  • Lecturer in several University Diplomas, InterUniversity Degrees.
  • Supervision of 18 theses(17 Pharm D and 1 PhD)
  • Teaching at the Institute of Nursing Training
  • Supervision of pharmacy students and pharmacy residents at Institut Jean Godinot
Vincent Launay-Vacher, PharmD

Eric Cohen is a Nephrologist whose research is in Radiation Biology. His clinical interests extend to the clinical frontier of Oncology and Nephrology, which overlaps precisely with the mission of C-KIN. His book, Cancer and the Kidney, is the text of reference in this field.

He has developed the concept of mitigation of normal tissue radiation injuries, specifically with regard to late lung and kidney injury after hematopoietic stem cell transplantation. He is on the Faculty at the Medical College of Wisconsin, and also holds an appointment at the Zablocki VA Medical Center, both in Milwaukee, Wisconsin, USA. His research is funded by the US Department of Veterans Affairs

Vincent Launay-Vacher, PharmD

Dr Vincent Launay-Vacher is Clinical Pharmacologist in the Department of Nephrology at Pitie-Salpetriere Hospital in Paris, France. Since 1999, he is Director of Service ICAR, a national medical advisory service and clinical research unit on drug management in patients with renal failure (renal tolerance, dosage adjustment, etc.) dedicated to French physicians, with a focus on oncology

He received his Doctorate of Pharmacy (PharmD) from the Université René Descartes Paris V and graduated with honours in 2000. He specialized in biodynamics and biopharmacy (pharmacokinetics).

Dr Launay-Vacher is the author of a number of publications mainly in indexed international journals (150), on drug pharmacokinetics and renal effects, and prevalence of kidney disease in cancer. His clinical research activities have focused on the study of drugs’ pharmacokinetics and dosage adjustment in patients with renal insufficiency. He coordinated several National studies, among which the “IRMA” studies (1 and 2) (Renal Insufficiency and Anticancer Medications) on the prevalence of renal insufficiency in French cancer patients, dosage adjustment of anticancer drugs, and impact on survival

Marije Hamaker

Marije Hamaker has been working as a clinical geriatrician working at the Diakonessenhuis in Utrecht, the Netherlands since 2010. In 2012, she defended her PhD thesis on “Decision making in geriatric oncology”. She has remained active in geriatric oncology research, and additionally has set up a project regarding geriatric nephrology in 2014.

Clinical Pharmacy and Clinical Pharmacists Roles
The C-KIN / EAHP joint session, mainly (but not only) dedicated to hospital and clinical pharmacists, has several learning objectives:

  • Be able to recognize that renal impairment is frequent in cancer
  • Be able to name specific and validate information regarding drug dosage adjustment in patients with cancer and renal failure
  • Be able to identify the possible roles the pharmacist can have in this particular field of “cancer and renal failure” 1) at the pharmacy; 2) in the oncology unit; 3) with the patient and his/her relatives
  • Be able to illustrate why clinical pharmacy is possible in routine practice through the examples of several experiences that are transposable from an institution to another.

The medication use process for cancer requires the development of a collaborative practice between all the stakeholders (oncologist, physician, nephrologist, pharmacist, nurse, etc). This parallel session aims to having exchanges with the attendees on models of collaborative care, to share local practices, experience and knowledge. The new partnership ‘Patient-healthcare providers’ will also be introduced.

Practice and Research on Cancer & the Kidney
This session is jointly organized with the European Organization for the Research and Treatment of Cancer (EORTC). EORTC will present the rationale and future organization of the C-KIN/EORTC Task Force, which will aim at developing clinical trials in cancer patients with renal dysfunction. The recently released “Guideline on the evaluation of the pharmacokinetics of medicinal products in patients with decreased renal function” by the European Medicines Agency and its importance in cancer drugs development will be presented.

Renal dysfunction and cancer in the elderly patient
Both renal dysfunction and cancer are common in these patients, and it can be expected that the number of elderly suffering from the combination of these two conditions will also increase as Western societies continue to age. Older patients require personalized care, which is tailored to their specific needs and issues. This presentation will focus on ageing-related issues in patients with renal dysfunction and cancer.

The elderly and the ageing kidney: Which specificities
This session is jointly organized with the International Society of Geriatric Oncology (SIOG) and will address issues in the care of elderly cancer patients, who often present decreased renal function. The SIOG clinical practice recommendations will be presented in detail.

Plenary Session 3: Supportive care & the Kidney
The specific care of cancer patients with concomitant renal disease may be consideredas falling into the field of supportive cancer care. This session will address three important questions regarding supportive care in cancer patients with kidney disease. Firstly, we will analyse the question of anemia, which may be chemotherapy-induced or cancer-related anemia, complicated with renal anemia, and the potential consequences on diagnosis and treatment. Secondly, we will discuss on the prevention of chemotherapy-induced nausea and vomiting which may have a positive impact on the renal toxicity of some chemotherapies, and especially cisplatin renal nephrotoxicity. Preventing vomiting may prevent from dehydration, which is a known risk factor. Preventing nausea may help patients hydrate themselves orally, and prevent from cisplatin renal toxicity. Consequently, we will debate on the very specific, and somehow complicated, question of thrombosis, cancer and renal insufficiency, with a focus on how to treat these patients.

Damien Parent Pharm. D.

Damien Parent Pharm. D. is currently hospital pharmacist at the Institut Jean Godinot, a regional cancer treatment centre in Reims (France). He is specialized in oncological clinical pharmacy which led him to work on chemotherapy complications (e.g. : renal complications, infections, thrombosis, ...). He coordinates the development of a therapeutic education program for patients with breast cancer treated by hormone therapy. He formerly participated in training programs on oncology for pharmacists.

Jan Van Keer

Jan Van Keer qualified as MD at the Catholic University of Leuven (KUL) in 2012. He started his training in Internal Medicine at the Regional Hospital of Turnhout. He is currently working as a third-year resident at the Nephrology Department of the University Hospitals Leuven. His main interests are heart failure and cardio-renal dilemma.

MICHAEL DOOLEY

PROFESSOR MICHAEL DOOLEY
BPharm Grad Dip Hosp Pharm PhD FSHPA FISOPP FAAQHC
Director of Pharmacy
Alfred Health, Melbourne Australia

Professor of Clinical Pharmacy
Centre for Medicine Use and Safety
Faculty of Pharmacy and Pharmaceutical Sciences
Monash University, Victoria, Australia

Michael holds a joint appointment as Director of Pharmacy at Alfred Health and Professor of Clinical Pharmacy, Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences of Monash University in Melbourne Australia.

His career has focused in the acute healthcare sector and has spanned special clinical roles in oncology through to senior leadership positions within health services. He was previously the Director of Pharmacy at the Peter MacCallum Cancer Centre. He contributes to many national and local professional committees and working parties related to improving the delivery of quality heath care services. He has been actively involved in a range of research activities from practice based undergraduate projects through to competitively funded NHMRC and ARC collaborative initiatives and post graduate programs. He has extensive clinical experience in oncology and has presented and published locally and internationally on practice and research endeavours.

His contribution to pharmacy and improvements in medication use have been recognized by receiving the Australia Council of Health Standard (ACHS) 2005 Gold Medal and the Society of Hospital Pharmacists of Australia Clinical Pharmacy Award and the 2003 Medal of Merit.

He currently leads the pharmacy services at The Alfred, Caulfield and also the Sandringham Hospitals were the service is one of the nine clinical programs at Alfred Health. The program include comprehensive unit based clinical services as well as a range of educational and research initiatives and is recognized as one of Australia’s most eminent pharmacy services.

Background: Pomalidomide is an analogue of thalidomide indicated for treatment of refractory Multiple Myeloma. The reported incidence of renal failure is less than 5%. We report a case suggesting crystal nephropathy as the mechanism for acute kidney injury (AKI) in pomalidomide use.

Case presentation: A 76 year-old female with a history of refractory IgG Kappa multiple myeloma presented with a two-day history of fevers, productive cough and weakness. Prior to admission, she had taken four days of a planned 21-day course of pomalidomide. Upon admission, she was noted to have a fever of 102.2 degrees Fahrenheit and a white cell count of 2.6 K/ul with absolute neutrophil count of 1.6 K/ul and 17% bands. Respiratory viral panel was positive for respiratory syncytial virus. In the setting of neutropenic fever, she was started on vancomycin, piperacillin/tazobactam and levofloxacin for multifocal pneumonia, seen on computed tomography of the chest without contrast. Additionally, pamolidomide was held. On hospital day 2, her creatinine was noted to increase to 1.65 mg/dl from 1.10mg/dl on admission. Her creatinine continued to trend upwards despite adequate hydration and avoidance of nephrotoxins. Urinalysis was significant for pH of 5, and protein of 25 mg/dl with no granular casts. Microscopic analysis of urine sediment collected on second day of admission was significant for long, spindle shaped crystals. A diagnosis of pomalidomide induced crystal associated tubular necrosis was made. Levofloxacin was discontinued on day 2 and the other antibiotics were continued. Vancomycin levels ranged between 10-27 µg/ml. Urine culture grew out 30,000 CFU E. coli, but blood cultures were negative. Over the following 3 weeks, her serum creatinine peaked at 3.99mg/dl, but returned to a baseline of 0.9mg/dl after three months. Due to thrombocytopenia, a kidney biopsy could not be performed.

Conclusions: This patient’s urine microscopy showed long, spindle-shaped crystals, which strongly supports a diagnosis of drug induced crystal nephropathy. Given the time course of chemotherapy, urine microscopy findings and lack of use of other medications that are known to cause crystal nephropathy, pomalidomide is the most likely cause of her crystal nephropathy in an acidic urine environment. This rare case of acute kidney injury due to crystal nephropathy after treatment with pomalidamide illustrates an unreported and potentially serious side effect of pomalidamide.

Authors: Sam Leung, Phylicia Baird, Olawumi Babalola, Craig Devoe, Rimda Wanchoo and Kenar D. Jhaveri

Références:

  • Girona L, Mendy D, Ito T et al. Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide. Leukemia 2012: 26(11):2326–2335.
  • Pomalidomide package insert last accessed Jan 7, 2014.
  • Hoffmann M, Kasserra C, Reyes J et al. Absorption, metabolism and excretion of [14C]pomalidomide in humans following oral administration. Cancer Chemother Pharmacol. 2013 Feb;71(2):489-501.
  • Lacy M, Gertz MA, Hayman SR, et al. Activity of pomalidomide plus dexamethasone (pom/dex) in dual lenalidomide/bortezomib refractory multiple myeloma (MM). 46th Annual Meeting of the American Society of Clinical Oncology; June 4-8, 2010; Chicago, IL. J Clin Oncol; 2010
  • Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney Inter Suppl 2012 Mar;2(1):1-138 PDF KDIGO Appendices 2012 Mar PDF, KDIGO Supplementary Tables 2012 Mar PDF
  • Yarlagadda S, Perazella M .Drug-induced crystal nephropathy: an update Expert Opin. Drug Saf 2008: 7(2):147-158
  • Ball P. Ciprofloxacin: an overview of adverse experiences. J Antimicrob Chemother 1986; 18 Suppl D:187
  • Sedlacek M, Suriawinata AA, Schoolwerth A, Remillard BD. Ciprofloxacin crystal nephropathy--a 'new' cause of acute renal failure. Nephrol Dial Transplant 2006; 21:2339.
  • Stratta P, Lazzarich E, Canavese C, et al. Ciprofloxacin crystal nephropathy. Am J Kidney Dis 2007; 50:330.

Introduction: Anti-angiogenic treatment with Anti-VEGF orRTKI in metastatic cancer is expected to prolong PFS, even if often not increasing overall survival. Renal complications of these treatments are common, blood hypertension, proteinuria, de novo renal failure or progression of a known chronic renal failure, which do not lead, most often, to document the renal underlying process by a renal biopsy. Renal biopsy may be indicated in case of a rapidly progressive renal failure, and if information afforded may have an impact on treatment. Our observation shows that, in such cases, renal biopsy may not always reveal thrombotic microangiopathy as the main cause of renal failure, but sometimes complex lesions, and unexpected findings, here carcinomatous embolus.

Case report: A 64-years-old man, type 2 diabetes since ten years, treated by Metformin and Vildagliptin, without retinopathy, without microalbuminuria, and with normal renal function (eGFR 76 ml/mn), presents with lumbar pain and anorexia. Diagnosis of left kidney tumour, with locoregional metastatic lymph nodes is made. The patient undergoes an extended nephrectomy in May 2013. Pathological examination shows clear cell renal carcinoma with a component of eosinophilic cells, Führman 3 to 4, with lymphatic and vascular embolus, two metastatic lymph nodes and classified pT3apN1. Treatment with SUNITINIB has then started. Toxicity is moderate: nausea grade 2, asthenia grade 2, leukopenia and thrombocytopenia grade 2; eGFR (MDRD) is 39,7 ml/mn/1,73m² at the beginning of SUNITINIB treatment and 37 ml/mn/1,73m² when SUNITINIB is stopped on October 2013, due to lymph node progression. Second line AXITINIB has started on mid-November 2013. Blood pressure increased, but was controlled by introduction of AMLODIPIN. In the following three weeks, eGFR decreased to 25 ml/mn/1,73m² and 18 ml/mn/1,73m² on mid-December, proteinuria was 0,7 g/24 H, Haptoglobin and LDH were normal, schistocytosis was less than 1%. The patient had unfortunately taken NSAID. Diagnostic discussion was AKI secondary to NSAID and/or thrombotic microangiopathy. Oncologists faced a dilemma: should one stop AXITINIB and deprive the patient of any chance to stop progression, or take opportunity to exonerate AXITINIB of any renal toxicity and pursue the treatment. Transjugular renal biopsy was performed. The main picture was acute tubular necrosis, with glomerular ischemia. Mesangial matrix was slightly increased, and there were several images of double contour, but no intra-capillary thrombi. Surprisingly, there were two distinct pictures of intra-vascular carcinoma embolus. There was soon after a progression of disease, leading to stop AXITINIB, and palliative care was provided to the patient who died two months later.

Discussion and conclusion: The underlying process behind a renal failure in a context of treatment with RTKI might be complex, as illustrates our observation, cumulating toxicity of NSAID, microangiopathy, and here, a very unusual carcinomatous embolus, of undefined significance. Carcinomatous embolus of the pulmonary vessels is a well-known clinical entity, even if rare, with a dramatic evolution in some weeks and a frequent post-mortem diagnosis. To our knowledge, carcinomatous embolus of the renal vessels has not been described, but in our observation, seems to share the same catastrophic prognosis as its pulmonary counterpart.

Authors: FOURNIER P., SIMONAGGIO A., ROUVIER P.

Background: Bortezomib is a first generation proteasome inhibitor that is extensively used in the treatment of patients with multiple myeloma (MM). Several reports have linked bortezomib exposure with the development of thrombotic microangiopathy (TMA). Here we report a case of biopsy-proven renal TMA associated with the use of bortezomib in a patient with MM, in whom re-exposure to bortezomib 18 months later was associated with recurrence of TMA.

Case presentation: A 51-year-old Caucasian male is treated with bortezomib - thalidomide - dexamethasone (VTD) after diagnosis of IgG lambda MM. 9 years earlier he was diagnosed with severe MGUS related acral ulcers, for which he had received treatment with rituximab (7 doses) and therapeutic plasma exchange prior to diagnosis of MM. Therapeutic plasma exchange was continued afterwards on an approximately bi-weekly basis throughout the course of his illness.
After completion of the first cycle of VTD therapy, the patient developed acute kidney failure (creatinine elevation from 1.3 mg/dL at baseline to 2.7 mg/dL), dysmorphic hematuria, subnephrotic range proteinuria and peripheral blood schistocytosis. Kidney biopsy findings were consistent with TMA. Creatinine slowly returned to a new baseline value of 2,1 mg/dL. Therapy was subsequently changed to VCD (cyclophosphamide instead of thalidomide) and lenalidomide - dexamethasone, mainly because of worsening acral ulcers. 18 months later he was rechallenged with bortezomib and dexamethasone because of disease progression under lenalidomide. After completion of the first cycle he developed acute on chronic kidney failure with nephrotic range proteinuria, macroscopic hematuria, high peripheral blood schistocytes and end stage renal failure (creatinine 7,5 mg/dL) necessitating hemodialysis.

Conclusion: We describe a case of TMA associated with exposure to bortezomib in MM. To our knowledge, this is the first biopsy-proven case to be reported. The recurrence of TMA after rechallenge supports a causal role of bortezomib. The exact mechanisms remain to be elucidated.

Authors: Jan Van Keer, Michel Delforge, Evelyne Lerut, Ben Sprangers Daan Dierickx, MD, PhD and Kathelijne Peerlinck, MD, PhD

Références

  • Morita R, Hashino S, Shirai S, Fujita N, Onozawa M, Kahata K, Kondo T, Imamura M, Asaka M: Thrombotic microangiopathy after treatment with bortezomib and dexamethasone in a patient with multiple myeloma. Int J Hematol 2008, 88(2):248–250.
  • Moore H, Romeril K: Multiple myeloma presenting with a fever of unknown origin and development of thrombotic thrombocytopenic purpura post-bortezomib. Intern Med J 2011, 41(4):348–350.
  • Salmenniemi U, Remes K: Thrombotic microangiopathy associated with bortezomib treatment in a patient with relapsed multiple myeloma. Hematol Rep 2012, 4(2):e13.
  • Mehta N, Saxena A, Niesvizky R: Bortezomib-induced thrombotic thrombocytopaenic purpura. BMJ Case Rep 2012.

Introduction: Kidney failure is most often an exclusion criterion in the clinical studies. Few data are available in dialysis patients receiving cancer drugs. A response to two situations that may be encountered is proposed here.

Patients and methods: Patient A: a 79 years old with a history of colon adenocarcinoma, acute renal failure in peri-prosthetic inflammation requiring 3 weekly dialysis sessions. Discovery of an urothelial carcinoma to be treated with chemotherapy according to the following regimen: gemcitabine 1000 mg / m2 on day 1 and carboplatin AUC 4 on day 1. Patient B: 55 years old presenting with a history of squamous cell carcinoma of the mandible treated with surgery and adjuvant radiation therapy, chronic renal failure dialyzed 3 weekly sessions. He is taken in charge for a metastatic esophageal adenocarcinoma. The following chemotherapy regimen is prescribed: 5-FU = 1000 mg / m² D1 to D5 continuously and carboplatin AUC 5 at D1. A literature search was conducted as well as a request for information from the ICAR- Service (Pitié-Salpêtrière, Paris).

Results:

  • Carboplatin is mainly eliminated by the kidney (95%) in the form of platinum and derivatives. It is significantly dialyzed during a hemodialysis session.
  • Fluorouracil is mainly metabolized by the liver in 3 metabolites: DHFU, FUPA, and BET. Urinary excretion is the main elimination mode: 10% unchanged, 60 to 90% as metabolites, mainly BET (pharmacologically active in animal and in vitro). It is dialyzable.
  • The pharmacokinetics of gemcitabine is not altered in patients with renal failure. It is not necessary to adjust the dose in these patients. An increase by a factor of 5 to 10 of the elimination half-life and of the AUC of an inactive metabolite of gemcitabine (dFdU) is observed.


Discussion – Conclusion: Based on pharmacokinetic data, the following dosing regimens can be recommended:
  • Carboplatin and 5FU (both dialyzable) should be administered after the session, the days of hemodialysis. Carboplatin dosage is adapted to the patient considering a glomerular filtration rate of 0 mL / min. The prescribed dose is thus 25 x AUC
  • The lack of data on the clearance of gemcitabine leads to advise the administration after the session, the days of hemodialysis.

The patient A’s chemotherapy regiment is administered after hemodialysis.
Patient B to receive chemotherapy during hemodialysis session, dose adjusted carboplatin should be administered after the session. 5FU, usually diluted in a 1L bag of NaCl 0.9%, should be prepared pure in a cassette to limit fluid intake. Moreover, the use of pump will allow stopping the administration during dialysis sessions and then resuming later. These cases illustrate the difficulties encountered in the medical management of kidney failure patients due to the lack of available information. The physician-pharmacist dialogue is essential. This kind of clinical situation demonstrates the importance of studying the “kidney failure - drugs” relationship on significant cohorts of patients.

Authors: Damien PARENT, Jean-Baptiste REY

Introduction: Tumour-induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by elevated phosphatonins (FGF 23), renal phosphate wasting and abnormal Vitamin D metabolism. It has been reported in benign mesenchymal tumors and head and neck cancers. Serum or plasma FGF23 concentrations are known to be elevated in patients with advanced-stage epithelial ovarian cancer, however reductions in serum phosphate concentrations are not commonly seen. We report a case of resistant hypophosphatemia secondary to elevated FGF23 in the setting of ovarian malignancy.

Case report: A 63-year-old female was diagnosed with ovarian cancer (unknown type) with lung and liver metastases after presenting with abdominal distention and decreased appetite. She had persistent severe hypophosphatemia that was difficult to replete, for which a nephrology consultation was requested. Laboratory findings revealed an inappropriately elevated urine phosphorous (Fe Phos of 35.7%), a low serum 1,25-OH vitamin D3 with a moderately low serum 25-OH vitamin D3, normal PTHrP, low normal intact PTH and eventually a strikingly elevated FGF23 level (238 RU/mL, normal < 180). Given her significant phosphaturia with elevated FGF23 levels, a diagnosis of paraneoplastic FGF 23 production from ovarian cancer was made. Imaging findings confirmed metastatic ovarian malignancy with CDX2 positive pulmonary metastases. No additional pathology was available as the patient subsequently elected for hospice care. Despite repletion with high doses of intravenous and oral phosphate, intravenous and oral vitamin D, normalizing her phosphate continued to be challenging as her underlying malignancy was progressive and untreated.

Conclusion: Serum or plasma FGF23 concentrations are elevated in patients with advanced-stage epithelial ovarian cancer without reductions in serum phosphate concentrations. Our patient was unique in that there was significant reduction in the serum phosphorous level. We could find only one case similar to ours in the literature. TIO and ovarian neoplasm (if not already diagnosed) should be considered in patients presenting with weakness, bone pain, hypophosphatemia and fractures.

Authors: Lauren Paster, Fiore Mastroianni, Daniel Ross, Rimda Wanchoo and Kenar D. Jhaveri Nephrology, Hofstra NSLIJ School of Medicine, Great Neck, NY

Références

  • Lin HA, Shih SR, Tseng YT, et al. Ovarian Cancer-related hyophosphatemic osteomalacia – A Case Report. J Clin Endocrinol Metab. 2014 Sept 2; jc20142120
  • Radiadeh AR, Jardat D, Abu-Kalaf MM, et al. Resolution of severe oncogenic hypophosphatemic osteomalacia after resection of a deeply located soft-tissue tumour. Curr Oncol. 2009 Sept;16(5): 87–90.
  • Tebben PJ, Kalli KR, Cliby WA, et al. Elevated fibroblast growth factor 23 in women with malignant ovarian tumors. Mayo Clin Proc. 2005 Jun;80(6):745-51.

Introduction: BK polyoma virus nephropathy (PVN) is a well-described cause of renal allograft dysfunction; however, its occurrence in native kidneys is rare. We report a case of BK PVN involving the native kidneys in a patient receiving ibrutinib for chronic lymphocytic leukemia (CLL).

Case description: A 48-year-old male was diagnosed with complex karyotype CLL two years prior to presentation with poor responses to multiple standards of care regimens (FCR, RICE, ofatumumab, steroids). There were no documented episodes of acute kidney injury (AKI) for the duration of these treatments. He was referred to our institution for consideration for a clinical trial, and at that time his serum creatinine was 1.28 mg/dL. He was enrolled in a trial to receive ibrutinib, a novel inhibitor of Bruton’s tyrosine kinase. The patient achieved a sustained response to this single agent at 420 mg daily. However, serum creatinine rose to 1.6 mg/dl approximately after 7 months of therapy, which was accompanied by microscopic hematuria and subnephrotic proteinuria of 600 mg per day. The patient’s renal function continued to decline and he was referred to nephrology for further evaluation. After fourteen months of ibrutinib treatment, the patient underwent kidney biopsy for evaluation of progressive acute kidney injury of unknown etiology. Creatinine was 2.1 mg/dl at the time of biopsy. Light microscopy revealed zonal renal cortical scarring with an associated interstitial inflammatory infiltrate comprised primarily of small, mature lymphocytes. The cortical scarring involved approximately 25% of the renal cortex overall. Immunohistochemical staining was negative for kidney involvement by CLL; however, a BK polyoma virus immunostain was positive in a few tubular epithelial cells in the scarred areas, consistent with BK PVN. Plasma and urine BK viral loads were 2.9x105 c/ml and 6.8x109 c/ml, respectively. Given the decline in renal function, ibrutinib was stopped for one month, during which time the plasma BK viral load decreased to 1.7x105 c/ml. Unfortunately, his CLL progressed and ibrutinib was resumed in combination with leflunomide with the intention of reducing BK viremia. Despite leflunomide, serum creatinine has since continued to rise and is most recently 2.2 mg/dl.

Discussion: BK PVN is a well described cause of kidney allograft dysfunction as a consequence of longterm immunosuppression. However, BK PVN is becoming more appreciated in native kidneys in the setting of an immunocompromised state. In a recent case series 1, BK PVN in native kidneys was seen in hematologic malignancies, all of which were either bone marrow transplant recipients on immunosuppression or on immunosuppressive agents as treatment for the underlying malignancy. This case series also noted BK PVN in native kidneys of immunosuppressed non-kidney solid-organ recipients. Our patient had stable renal function while suffering from refractory CLL and then developed BK PVN while clinically improving with ibrutinib. While this does not imply a direct causal relationship between BK PVN and ibrutinib, it does suggest that the immunosuppression resulting from ibrutinib is related to BK PVN as opposed to the immunosuppression associated with advanced CLL. Ibrutinib has shown considerable promise in relapsed and refractory CLL as well as other B cell malignancies 2, 3. Thus, we suggest including BK PVN in the differential diagnosis for patients who develop unexplained AKI while receiving ibrutinib, especially when the underlying B cell malignancy is clinically responding to treatment.

Authors: Jason Prosek-MD, Jessica Hemminger-MD, Samir Parikh-MD

Références

  • Sharma SG, Nickeleit V, Herlitz LC, de Gonzalez AK, et al. BK polyoma virus nephropathy in the native kidney. Nephrol Dial Transplant. 2013 Mar;28(3):620-31. PubMed PMID: 23249622
  • Byrd JC, Furman RR, Coutre SE, Flinn IW, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013 Jul4;369(1):32-42. PubMed PMID: 23782158
  • Aalipur A, Advani RH. Bruton’s tyrosine kinase inhibitors and their clinical potential in the treatment of B-cell malignancies: focus on ibrutinib. Ther Adv Hematol. 2014 Aug;5(4):121-33. PubMed PMID: 25360238
Sam Leung

Sam Leung is currently a second year nephrology fellow in North Shore-LIJ Health System. He graduated from St. George's University Medical School, and completed internal medicine residency at Stony Brook University Hospital.

Didier Mayeur

Didier Mayeur, MD, is a medical oncologist at the Hematology-Oncology Department of Mignot Hospital, which is the hospital of Versailles. He is now Head of a Supportive Care Department at Hospital Mignot while continuing his job of medical oncologist.

Resident of internal medicine at the University Hospitals Leuven

Lauren Paster

Lauren Paster, MD MS is a nephrology fellow at North Shore-LIJ Health System in Manhasset, NY. She completed her internal medicine residency training at North Shore-LIJ as well. She completed medical school at New York Medical College in Valhalla, NY and an MS in Physiology and Biophysics at Georgetown University in Washington, DC. She completed undergraduate training at the University of Pennsylvania, Philadelphia, PA.

Jason Prosek

Jason Prosek, MD is an academic nephrologist at the Ohio State University Wexner Medical Center (OSUWMC) in Columbus, Ohio. His background in chemical engineering attracted him to renal physiology and the principles of renal replacement therapies. Now with the expansion of the James Cancer Hospital at the OSUWMC and introduction of targeted therapies for malignancies (tyrosine kinase inhibitors for example) there became a need for sub-specialization. Dr. Prosek has developed an onconephrology clinic where the kidney, electrolyte and hypertension issues of cancer patients are managed.

MICHAEL DOOLEY

Dr. Laurence Collette PhD, MSc received her Master of Science in Biostatistics, Hasselt University, Diepenbeek, Belgium in 1994. She defended her PhD thesis: “Design of phase III clinical trials in prostate cancer: prognostic and predictive factors and surrogate endpoints.” at the Erasmus Medical Center, Rotterdam University, The Netherlands in 2006. Since 1995, Dr. L Collette is working at the EORTC Headquarters Statistics Dept. She is currently Associate Head of the Statistics Dept. and is responsible for trials conducted by the EORTC Genito-Urinary Cancer Group and the EORTC Radiation Oncology Group. Her research interests concern the use of biomarkers as surrogate endpoints or in the design of phase II and phase III trials, and methods for selecting patients with prostate cancer for more/less intensive treatment strategies based on their risk factors. As associated head of the department, Dr. L Collette also oversees the work of several EORTC statisticians and statistical fellows. She also is member of the Independent Data Monitoring Committee (IDMC) for several non-EORTC studies. Since March 2012, Dr. L. Collette coordinates the activities of the central EORTC IDMC. She is responsible for maintaining EORTC policies related to data sharing, publication, and IDMC and she is a member of the EORTC Quality Assurance Committee. Dr. L Collette is external statistical reviewer for a number of peer review journals, including The Journal of Urology, European Journal of Cancer and Journal of Clinical Oncology. She is a member of the Editorial board of European Urology since 2006

Research studies conducted in patients treated with classical chemotherapies showed that impairment of renal function - both acute and chronic - is common in patients with cancer and cancer survivors. Emerging evidence suggests that in this patient population kidney dysfunction is associated with increased morbidity and mortality. In collaboration with individual specialized research centers, EORTC is conducting phased research project aiming ultimately to recommend a minimal renal monitoring pan to implement in future studies. In the first phase, the project will evaluate the renal function in patients with solid tumors and treated with classical chemotherapies and targeted therapies, both at inclusion (baseline), during treatment and during follow-up, using data from its existing large database of clinical trials, It will determine how baseline kidney function and nephrotoxicity affects the treatment of patients and ultimately patients’ outcome. This new information will then be used to inform the eventual recommendations for monitoring in studies. In the last phase of this project, the recommended monitoring plan will be prospectively tested in new studies which will in turn, allow for more detailed assessment of the incidence of CKD and AKI, and its impact on outcomes.We will report on the initiation phase and first results of this large EORTC research initiative.

Sophie Renet

Sophie Renet has a position of Hospital Pharmacist in a teaching hospital. Her project target is to reinforce the Pharmacist status as a health professional partner of patients and others healthcare providers. She supervises several projects about medication reconciliation, therapeutic patient education and patient counseling in cardiology and oncology, and optimizes clinical pharmacy services. She also worked in the Oncology Care Network of Paris Region, where she supervised research protocols to improve the seamless care of the Outpatients hospital treated by oral chemotherapy.

The programme is subject to change