MANAGEMENT OF AKI AND CKD IN MALIGNANCY KDIGO ANITHA VIJAYAN MD PROFESSOR OF MEDICINE DIVISION OF NEPHROLOGY DISCLOSURES NxStage – Speaker, Scienfic Advisory Board Sanofi - Speaker KDIGO DEFINITION CANCER RELATED AKI TLS ACUTE KIDNEY INJURY CAST NEPHROPATHY MANAGEMENT KDIGO Definion of AKI (KDIGO guidelines) An abrupt (within 48 hours) reducon in kidney funcon – Ørise in serum creanine (SCr) by ≥ 0.3mg/dL Øa percentage increase in SCr of ≥ 50% from baseline over the past 7 days Øor documented oliguria of less than 0.5ml/kg/hour for more than 6 hours KDIGO Kidney Intl 2: 8-12, 2012 Classificaon/Staging System for AKI Stage Serum Creanine Criteria Urine Output Criteria Rise in SCr ≥ 0.3mg/dL or ≥ 150-200% from < 0.5 ml/kg/hr for > 6 hr 1 baseline Rise in SCr > 200-300% from baseline < 0.5ml/kg/hr for > 12 hr 2 KDIGO Rise in SCr > 300% from baseline, or SCr > 4mg/ < 0.3 ml/kg/hr for > 24hr dL with an acute increase of at least 0.5mg/dL or anuria > 12 hr 3 Kidney Intl 2: 8-12, 2012 ICU acquired AKI Overall incidence is about 20% 60% CAUSES OF AKI AMONG ALL PATIENTS 50% Paents with malignancy: 40% Most common cause of AKI is sepsis Incidence 12 – 50% 30% Requiring RRT – 9-30% KDIGO20% Mortality in those needing RRT:70–85% 10% 0% Sepsis Ischemia Nephrotoxins Rhabdo Obstrucon Bouchard et al, CJASN 2015; Campbell et al ACKD 2014 Rocha et al, NDT, Jan 2009 AKI IN SETTING OF OTHER CO- MORBIDITIES KDIGO Zeng et al, CJASN 2014 AKI Increases The Risk Of Progression To ESRD KDIGO Hsu et al, CJASN 2009 Cost of AKI ALL AKI PATIENTS AKI-D PATIENTS KDIGO Silver et al, J Hosp Med 2017 DIRECTLY RELATED BY DIRECT EFFECTS OF MALIGNANCY CHEMOTHERAPY ACUTE KIDNEY INJURY COMPLICATIONS OF TREATMENT KDIGO OTHER FACTORS OF MALIGNANCY Directly caused by malignancy Obstrucon ◦Prostate cancer ◦Urothelial malignancy ◦Ovarian/Uterine malignancy ◦Extrinsic compression from metastases, lymphadenopathy Infiltraon ◦Lymphoma/leukemia KDIGO Intrinsic damage ◦Mulple myeloma with cast nephropathy/light chain deposion disease Hypercalcemia Direct toxicity from chemotherapy agents Glomerular injury/TMA ◦Checkpoint inhibitors ◦VEGF inhibitors ◦Gemcitabine Intersal Nephris ◦Checkpoint inhibitors Tubular injury ◦Planum compounds KDIGO ◦Methotrexate ◦Trabecdin (rhabdomyolysis) ◦Pemetrexed Complicaons of treatment Pre-renal AKI (especially if concomitantly on NSAIDs, RAAS blockers) ◦severe diarrhea with irinotecan ◦nausea/voming with other chemotherapy agents Intrinsic renal injury ◦Tumor lysis syndrome KDIGO Obstrucon ◦Urothelial strictures (previous surgery/radiaon) Other factors Sepsis AKI post hematopoiec stem cell transplant Contrast induced AKI Nephrotoxins ◦ Bisphosphonates ◦ NSAIDs ◦ ACEI ◦ ARB ◦ Aminoglycosides KDIGO ◦ Vancomycin ◦ Amphotericin ◦ IV Acyclovir MANAGEMENT OF AKI KDIGO KDIGO RECOMMENDATIONS FOR MANAGEMENT OF AKI High Risk AKI Stage 1 AKI Stage 2 AKI Stage 3 Disconnue nephrotoxic agents Ensure adequate volume status and perfusion pressure Consider funconal hemodynamic monitoring Monitor serum creanine and urine output Avoid hyperglycemia Consider alternaves to radiocontrast procedures Non-invasive diagnosc work up Consider invasive diagnosc work-up KDIGO Check for changes in drug dosing Consider RRT ICU admission Assess for RRT Avoid subclavian catheters Kidney Internaonal Supplements (2012) Tumor lysis syndrome KDIGO Uric acid CELL LYSIS TUMOR CELLS crystallizaon Hyperphosphatemia Ca-P nephropathy Hyperkalemia Elevated Uric acid Spontaneous AKI Aer chemotherapy Trigger inflammatory KDIGO Renal vasoconstricon mediators Inflammaon Purine catabolism Hypoxanthine Xanthine oxidase Xanthine Xanthine oxidase Urate oxidase KDIGO ALLANTOIN Uric acid EXCRETION Excretion CAIRO-BISHOP CLASSIFICATION FOR TLS LABORATORY CRITERIA CLINICAL CRITERIA ØSerum K > 6.0 mEq/L or increase by 25% from ØAKI: increase in SCr 1.5 x ULN baseline ØSerum Ca < 7 mg/dL or decrease by 25% from ØCardiac arrhythmia baseline KDIGOØSeizures ØSerum P > 4.5 mg/dL or increase by 25% from baseline CAVEATS: ØSerum UA > 8.0 mg/dL or increase by 25% 3 days before or within 7 days aer chemotherapy from baseline In same In same 24 hour period May be delayed for solid tumors RISK FACTORS FOR TLS Tumor characteriscs Paent characteriscs Chemotherapy factors • Hematological malignancies • Underlying CKD • Specific targeted with high tumor burden • Concomitant treatments • WBC >50,000 nephrotoxins • Venetoclax (BCL-2 • Elevated LDH • Concomitant CHF/Liver inhibitor) • Burkis’s lymphoma disease • Obinutuzumab (CD-20 • DLBCL • Volume depleon monoclonal Ab) • Lymphoblasc leukemia KDIGO • Lymphac/leukemic • Ibrunib (BTK infiltraon of the kidney inhibitor) • Solid tumors with very large tumor burden* • Hyperuricemia at • Dinaciclib (CDK baseline inhibitor) TLS AFTER TREATMENT OF CLL WITH VENETOCLAX 20.0% 18.0% 16.0% 14.0% 12.0% 10.0% 8.0% 6.0% KDIGO % PATIENTS WITH TLS 4.0% 2.0% 0.0% Total TLS Lab TLS Clinical TLS Roberts et al NEJM 2016 RISK STRATIFICATION TUMOR CHARACTERISTICS PATIENT CHARACTERISTICS TYPE OF CHEMOTHERAPY IV FLUIDS – NS or Isotonic fluid AVOID NEPHROTOXINS MODERATE/HIGH IV FLUIDS – NS or Isotonic fluid LOW RISK ALLOPURINOL OR FEBUXOSTAT RISK AVOID NEPHROTOXINS CONSIDER PROPHYLACTIC RASBURICASE IF VERY HIGH RISK URINARY ALKALINATION NOT RECOMMENDED INITIATION OF CHEMOTHERAPY MONITOR FOR TLS – Renal Panel, Uric KDIGOAcid every 12-24 hours IF TLS OCCURS Rasburicase/ Iniaon of RRT Randomized trials of rasburicase KDIGO Wilson and Berns CJASN 2012 CAST NEPHROPATHY KDIGO CAST NEPHROPATHY Mulple myeloma ◦represents approximately 1% of all malignancies ◦Approximately 15% of all hematological malignancies Approximately 20-30% of MM paents have cast nephropathy Most common cause of AKI in MM Is cast nephropathy AKI associated with reduced survival KDIGO KDIGO K Basnayake et al, Kidney Internaonal (2011) 79, 1289–1301; KDIGO DIFFERENCE IN SIEVING COEFFICIENT BETWEEN HIGH- FLUX and HCO DIALYZERS KDIGO Gondouin B and Hutchison CA, Adv CKD 2011 KDIGO Hutchison CA et al, CJASN 2009 P <0.001 KDIGO Hutchison CA et al, CJASN 2009 MYRE STUDY High flux 33.3% 35.4% dialyzer 98 Dialysis independence Dialysis independence paents KDIGOat 3 mo at 6 mo High cutoff 41.3% 56.5% dialyzer P = 0.42 P = 0.04 Bridoux et al, JAMA 2017 KDIGO Finkel and Fabbrini_J OncoNeph 2017 RRT IN AKI KDIGO CONSIDERATIONS REGARDING RRT IN PATIENTS WITH MALIGNANCY AND AKI SHOULD RRT BE INITIATED? ◦Ethical concerns in terminal malignancy ◦If current illness felt to be reversible, then RRT should be considered TIMING OF RRT MODALITY KDIGO DOSE OF RRT Mortality in crically ill paents with hematological malignancies and AKI KDIGO Darmon et al, NDT 2015 Differences between CRRT and IHD CRRT IHD Hemodynamic stability + - Fluid balance achievement + - Superior metabolic control + - Connuous removal of toxins + - Stable intracranial pressure + - Unlimited nutrion + - Need for intensive care nursing supportKDIGO + - Simple to perform ± - Rapid removal of poisons - + Limited anCoagulaon - + Need for hemodialysis nursing support ± + Paent mobility - + OUTCOMES: HD VS CRRT No difference in mortality between paents iniated on CRRT vs IHD No difference in renal recovery No difference in ICU/hospital LOS KDIGO KDIGO Recommenda@ons for RRT in AKI Use connuous and intermient RRT as complementary therapies in AKI paents (Not graded) We suggest using CRRT, rather than standard intermient RRT, for hemodynamically unstable paents (Grade 2b) We suggest using CRRT, rather than intermient RRT, for AKI paents with acute KDIGO brain injury or other causes of increased intracranial pressure or generalized brain edema (Grade 2b) Kidney Internaonal 2:(1) 2012 COMPARISON OF DIFFERENT MODALITIES KDIGO Edrees, Li, Vijayan, ACKD 2016 DOSING OF RRT IN IHD AND CRRT IHD ◦Goal is sp Kt/Vurea of 1.3/treatment, 3 mes/week CRRT KDIGO ◦Effluent volume of 20-25ml/kg/hour MANAGEMENT OF CKD IN MALIGNANCY KDIGO Toxicity from other drugs Chemotherapy toxicity Chronic Kidney Disease Loss of nephron mass KDIGOMechanical issues CAUSES OF CKD IN CANCER PATIENTS Chemotherapy Other Mechanical Nephron loss OTHER toxicity nephrotoxins issues VEGF inhibitors Intrinsic DM Bisphosphonates obstrucon of Paral Tyrosine kinase ureter inhibitors nephrectomy Planum based drugs Extrinsic HTN NSAIDs compression of Gemcitabine KDIGO ureter Checkpoint Unilateral inhibitors nephrectomy Infiltraon of the IV contrast GN Pemetrexed kidney Management of CKD in paents with malignancy BP control Management of proteinuria Use of ACEI/ARB Management of anemia of CKD Other CKD related issues ◦ Bone and mineral metabolism ◦ Metabolic acidosis KDIGO Chemotherapy associated complicaons Glomerulonephris associated with malignancy KDIGO Perazella and Izzedine, Kidney Internaonal (2015) 87, 909–917 Hypertension and Proteinuria with VEGF inhibion Hypertension ◦ Dose dependent ◦ Range from 20 – 40% ◦ Treatment – standard anHTN medicaons ◦ Chemotherapy should not be interrupted for hypertension Proteinuria ◦ Endotheliosis, focal foot process effacement, GBM damage – double contouring, mesangiolysis. ◦ In severe cases – TMA noted (fibrin deposion and red blood cell entrapment) ◦ Dose dependent KDIGO ◦ *Incidence range from 5-10% with bevacizumab, depending on dose, type of tumor and concomitant tx ◦ Treatment: Judicious use of RAAS blockers. ◦ Connue chemotherapy unless rapid worsening of renal funcon or heavy proteinuria ◦ Proteinuria correlates with regression of malignancy *Wu et al, J Am Soc Nephrol. 2010 Aug; 21(8): 1381–1389 Membranous GN Malignancy may be seen in 5 – 20% of paents with membranous GN Most common – Solid tumors (lung,